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Recent developments in enantioselective scandium–catalyzed transformations
Accepted Manuscript Title: nRecent developments in enantioselective scandium-catalyzed transformations Author: H´el`ene Pellissier PII: DOI: Reference:
S0010-8545(15)30092-8 http://dx.doi.org/doi:10.1016/j.ccr.2016.01.005 CCR 112186
To appear in:
Coordination Chemistry Reviews
Received date: Revised date: Accepted date:
19-11-2015 18-1-2016 20-1-2016
Please cite this article as: H. Pellissier, nRecent developments in enantioselective scandium-catalyzed transformations, Coordination Chemistry Reviews (2016), http://dx.doi.org/10.1016/j.ccr.2016.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent developments in enantioselective
an
Hélène Pellissier*
us
scandium-catalyzed transformations
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313,
Ac ce p
1. Introduction
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Contents
d
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13397, Marseille, France
2. Enantioselective scandium-catalyzed domino reactions 3. Enantioselective scandium-catalyzed Michael additions 4. Enantioselective scandium-catalyzed cycloaddition reactions 5. Enantioselective scandium-catalyzed ring-opening reactions 6. Enantioselective scandium-catalyzed α-functionalizations of 3-substituted oxindoles 7. Enantioselective scandium-catalyzed aldol reactions 8. Enantioselective scandium-catalyzed oxidations 8.1. Epoxidations 8.2. Baeyer−Villiger reactions 9. Enantioselective scandium-catalyzed reductions
1 Page 1 of 135
10. Enantioselective scandium-catalyzed Friedel−Crafts reactions 11. Miscellaneous enantioselective scandium-catalyzed reactions 12. Conclusions
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References
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Keywords: Scandium
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Asymmetric catalysis
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Enantioselectivity Chirality
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Enantioselective transformations
Ac ce p
1. Introduction
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d
*Tel.: +33 4 91 28 27 65. E-mail: [email protected]
The synthesis of chiral compounds is an important and challenging area of contemporary synthetic organic chemistry [1]. Although asymmetric synthesis is sometimes viewed as a subdiscipline of organic chemistry, actually this topical field transcends any narrow classification and pervades essentially all chemistry [2]. The broad utility of synthetic chiral molecules in medicines and materials has made asymmetric catalysis a prominent area of investigation. Indeed, of the methods available for preparing chiral compounds, catalytic asymmetric synthesis has attracted most attention. In particular, asymmetric metal catalysis has emerged as a powerful tool to perform reactions in a highly enantioselective fashion over the past few decades in spite of the common drawbacks of metals, such as moisture 2 Page 2 of 135
sensitivity, recoverability, and toxicity, particularly for heavy metals. [2,3]. On the other hand, because rare earth metal triflates, such as Sc(OTf)3, are water-compatible and recoverable Lewis acids, they have been regarded as new types of Lewis acids. The application of
ip t
scandium complexes in organic chemistry has been scarce for a long time probably due to the less reserve and difficulties in separation until Sc(OTf)3 was first introduced as a promising
cr
reusable Lewis acid in Diels−Alder reaction by Kobayashi in 1993 [4]. Afterwards, the unique characteristics of Sc(OTf)3 which feature advantages as stability, recovery, and
us
reusability have drawn intense attentions in catalytic organic chemistry. In particular, over the past two decades, scandium asymmetric chemistry has become an important component of
an
asymmetric organic synthesis. Scandium complexes derived from Sc(OTf)3 constitute a special type of Lewis acids with a unique and extraordinary high catalytic activity in many
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organic reactions which may be attributed to the small ionic radii of scandium compared with other rare earth metal complexes. The combination of the electronic properties of scandium
d
with chiral ligands results in a myriad of novel asymmetric organic transformations often
te
performed in remarkable enantioselectivities and under convenient experimental conditions.
Ac ce p
Scandium is expected to have the strongest Lewis acidity among rare earth metals, is compatible with water and Lewis bases, and is regarded as one of the standard and, more importantly, environmentally benign Lewis acids. All these advantages have ensured that enantioselective scandium-catalyzed reactions have received continuous ever-growing attention during the two last decades leading to exciting and fruitful research. This interest was initiated by the early success of enantioselective Diels−Alder reactions catalyzed by the first chiral scandium catalyst reported by Kobayashi in 1994 [5]. Ever since, many types of chiral ligands, such as bipyridines, bisoxazolines, bis(oxazolinyl)pyridines, and N,N’-dioxides etc., have been successfully applied in the presence of scandium triflate to catalyze almost all types of asymmetric organic reactions. Among important recent results, remarkable enantioselectivities have been reported by several groups for a range of unprecedented
3 Page 3 of 135
fascinating scandium-catalyzed domino reactions including multicomponent ones. For example, the group of Feng reported very high enantioselectivities of up to 99% ee for various types of completely novel domino reactions. Remarkable results were also achieved by other
ip t
groups, such as those of Davies, Ding, Kingsbury, Kesavan, Chi, Shi, Franz, and Cai. In addition, a number of important advances have been independently developed by the groups
cr
of Vaccaro, Kobayashi, Wang, and Feng, in the area of asymmetric scandium-catalyzed Michael additions of a range of substrates, providing various types of functionalized chiral
us
products in generally remarkable enantioselectivities of up to 99% ee. Furthermore, important advances in scandium-catalyzed asymmetric chemistry have been reported by several groups
an
in the field of Mannich reactions, [4+2] and [2+2] cycloaddition reactions, ring-opening of epoxides, allylation reactions, α-functionalizations of oxindoles, Baeyer−Villiger reactions,
M
epoxidation of alkenes, reductions of ketones, aldol reactions, Friedel−Crafts reactions, hydroamination and amination reactions, Povarov reactions, as well as addition reactions. The
d
goal of this review is to collect the major developments in all types of enantioselective
te
scandium-catalyzed transformations published since the beginning of 2011, since this field
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was most recently reviewed by Feng and Liu in a book chapter published in 2011, covering the literature up to 2010 [6]. More generally, the field of reactions catalyzed by (racemic) scandium catalysts among other rare earth complexes has been reviewed by several authors up to 2010 [7]. For the reader’s convenience, the review has been divided into ten parts, dealing successively with enantioselective scandium-catalyzed domino reactions, enantioselective scandium-catalyzed Michael additions, enantioselective scandium-catalyzed cycloaddition reactions, enantioselective scandium-catalyzed ring-opening reactions, enantioselective scandium-catalyzed
α-functionalizations
scandium-catalyzed
aldol
enantioselective
reactions,
scandium-catalyzed
of
3-substituted
enantioselective reductions,
oxindoles,
enantioselective
scandium-catalyzed
enantioselective
oxidations,
scandium-catalyzed
Friedel−Crafts reactions, and miscellaneous enantioselective scandium-catalyzed reactions. 4 Page 4 of 135
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2. Enantioselective scandium-catalyzed domino reactions
Tietze has defined a domino reaction as a process involving two or more bond-forming
cr
transformations, taking place under the same reaction conditions, without adding additional reagents, catalysts, and additives, in which the subsequent reactions result as a consequence of
us
the functionality formed by bond formation or fragmentation in the previous step [8]. The use of these fascinating reactions in organic synthesis is increasing constantly [9], allowing the
an
synthesis of a wide range of complex molecules, including natural products and biologically active compounds, through an economically favourable way by using one-pot processes that
M
avoid the use of costly and time-consuming protection-deprotection processes, as well as purification procedures of intermediates [10]. The economical interest in combinations of
d
asymmetric metal catalytic processes with the concept of domino reactions is obvious, and
te
has allowed reaching easily high molecular complexity with often excellent levels of
Ac ce p
stereocontrol with simple operational one-pot procedures, and advantages of savings in solvent, time, energy, and costs. In the last decade, an increasing number of enantioselective domino processes catalyzed by metals have been developed [10k]. The wide variety of these novel highly efficient domino processes well reflects that of metals employed to induce them. Indeed, an increasing number of different metals such as magnesium, titanium, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, aluminum, as well as tin were effective catalysts. In recent years, chiral scandium catalysts have been successfully applied to various asymmetric domino reactions including multicomponent ones, such as three-component Mannich-type reactions [11], three-component aza-Diels-Alder reactions [12], and three-component allylation reactions [13] among others. A more recent example reported by Kingsbury et al. involved the use of a combination of scandium triflate 5 Page 5 of 135
with a chiral trisoxazoline ligand 1 to promote an enantioselective domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones 2a-d (Scheme 1) [14]. Actually, despite their highly versatile coordination chemistry, the use of oxazoline-containing ligands
ip t
tends to be polarized towards late transition metals; indeed their use with early transition metals and the f-elements is significantly less developed [15]. This type of ligands was first
cr
employed in molecular lanthanide catalysis as early as 1997 [16], yet there is still a significant void in the literature in this respect. In the domino reaction depicted in Scheme 1, a series of
us
chiral arylated medium ring carbocycles 3a-k were rapidly accessed through scandium-
an
catalyzed domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones 2a-d with aryldiazoalkanes 4a-g in both high yields and enantioselectivities of up to > 98% and
M
97% ee, respectively. The transformation took place by 1,2-rearrangement in Sc-complexed diazonium betaine intermediate 5, cleanly affording the corresponding α-tertiary 2-
d
arylcycloalkanone 3a-k in one step with dinitrogen as the only byproduct. As shown in
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Scheme 1, the highest levels of enantioselectivity were reached with cycloheptanones (n = 4)
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compared to the other ring sizes evaluated.
6 Page 6 of 135
O
O N
1 (5.5-11 mol%)
X +
( )n
O
Sc(OTf)3 (5-10 mol%)
Y
N2
toluene, -78 °C
( )n
Z
2a-d
Z
Y
cr
O
N O
ip t
N
4a-g
X 3a-k
d
M
an
us
3a: n = 1, X = Y = Z = H: > 98% yield, 71% ee 3b: n = 3, X = Y = Z = H: 94% yield, 90% ee 3c: n = 3, X = Y = H, Z = Me: 96% yield, 88% ee 3d: n = 3, X = Z = H, Y = Br: > 98% yield, 89% ee 3e: n = 4, X = Y = Z = H: 94% yield, 94% ee 3f: n = 4, X = Y = H, Z = CF 3: 78% yield, 96% ee 3g: n = 4, X = Z = H, Y = OMe: > 98% yield, 94% ee 3h: n = 4, X = Me, Y = Z = H: 97% yield, 87% ee 3i: n = 4, X = Y = H, Z = Me: > 98% yield, 97% ee 3j: n = 4, X,Y = (CH=CH)2, Z = H: 94% yield, 94% ee 3k: n = 5, X = Y = Z = H: > 98% yield, 86% ee
X Y
te
proposed mechanism:
O
Sc(OTf)3/1
X Y
+ N2
Ac ce p
N2 +
( )n
Z
4
2
1,2-rearrangement
addition of diazoalkane
Z
O [Sc]-
( )n 5
Z
O
Y ( )n
X 3
Scheme 1. Domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones [14].
In recent years, the group of Feng has explored a new type of C2-symmetric ligands, namely chiral N,N’-dioxides synthesized from cheap optically pure amino acids [17]. These particular ligands have two alkyl amine oxide-amide subunits separated by a straight-chain alkyl spacer. 7 Page 7 of 135
They are full of conformationally flexible subunits that challenge the notion of the rigid feature of succesfull ligands. Interestingly, N,N’-dioxides provide an intriguing arsenal of chiral metal complexes for asymmetric catalysis upon coordination with a variety of metal
ip t
precursors. In particular, excellent results have been reported by using these ligands in combination with scandium triflate in a wide range of enantioselective transformations
cr
including domino reactions [11-13]. As a recent example, enantioselective domino
us
diazoalkane addition/1,2-rearrangement reaction of isatins 6a-j with α-alkyl-α-diazoesters 7aw was developed by this group, affording the corresponding highly functionalized C4-
an
quaternary 2-quinolone chiral derivatives 8a-af in remarkable yields and enantioselectivities of up to 94% and 99% ee, respectively (Scheme 2) [18]. This asymmetric ring-expansion
M
reaction performed well in the presence of chiral N,N’-dioxide ligand 9 used at a catalyst loading as low as 0.05 mol% in combination with Sc(OTf)3. The study of the scope of the
d
domino reaction showed that varying the ester group of the α-diazoester (R1) had no adverse
te
effect on yield and enantioselectivity (8a-d). The rate and enantioselectivity of the reactions of a series of substituted α-benzyl diazoacetates were uniformly high (94-99% ee for products
Ac ce p
8e-n). The electronic properties, bulkiness, or positions of the substituents on the benzyl group of diazoacetates had very little effect on the reaction outcome. Moreover, 2naphthylmethyl-substituted α-diazoester was also tolerated in the process, providing the corresponding product 8o in 94% yield and 99% ee. The reactions of diazoesters containing an alkyl substituent at the α-position were relatively fast to give the corresponding products 8p-r in 93-97% ee. In these reactions, the catalyst loading could be reduced to 0.05 mol%. Moreover, diazoesters containing substituents bearing functional groups, such as cinnamyl and allyl moieties, also led to the corresponding α-cinnamyl and α-allylic ketone derivatives 8s-t in excellent enantioselectivities (98-99% ee). Furthermore, other α-alkyl diazoesters bearing a terminal substituent, such as an ester, a nitrile, and a silyl ether group also gave very 8 Page 8 of 135
high enantioselectivities of 93-97% ee for the corresponding products 8u-w. The investigation of the scope of the reaction with respect to the isatin substrate showed that the position and electronic nature of the substituents of the isatin (R3) had significant effects on both
ip t
enantioselectivity and reactivity (8x-af). Isatins 8x-aa, which have substituents at the C5 position, gave lower levels of enantioselectivity (80-93% ee) and were less reactive (76-88%
cr
yield) than isatins with substituents at the C6 and C7 positions (8ab-af). This work
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represented the first catalytic asymmetric ring-expansion reaction of isatins with α-alkyl-α-
Ac ce p
te
d
M
an
diazoesters.
9 Page 9 of 135
N+
N
O
+
-
O-
O
O
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (0.05-0.2 mol%)
O R2
N2
R3
N Bn 8a-af
CH2Cl2, 30 °C
7a-w [Sc]
addition of diazoalkane
R2 O
R3
N2+ CO2R1 O
1,2-rearrangement
an
N Bn
O
us
N Bn 6a-j
CO2R1 Sc(OTf)3 (0.05-0.2 mol%)
CO2R1 O
cr
O +
R3
R2
ip t
N H
Ac ce p
te
d
M
8a: R1 = Et, R2 = Bn, R3 = H: 91% yield, 99% ee 8b: R1 = Me, R2 = Bn, R3 = H: 89% yield, 99% ee 8c: R1 = i-Pr, R2 = Bn, R3 = H: 90% yield, 99% ee 8d: R1 = t-Bu, R2 = Bn, R3 = H: 91% yield, 97% ee 8e: R1 = Et, R2 = CH2(o-FC6H4), R3 = H: 94% yield, 94% ee 8f: R1 = Et, R2 = CH2(m-Tol), R3 = H: 91% yield, 97% ee 8g: R1 = Et, R2 = CH2(m-FC6H4), R3 = H: 92% yield, 99% ee 8h: R1 = Et, R2 = CH2(m-MeOC6H4), R3 = H: 93% yield, 99% ee 8i: R1 = Et, R2 = CH2(m-PhOC6H4), R3 = H: 91% yield, 99% ee 8j: R1 = Et, R2 = CH2(p-FC6H4), R3 = H: 90% yield, 99% ee 8k: R1 = Et, R2 = CH2(p-ClC6H4), R3 = H: 94% yield, 99% ee 8l: R1 = Et, R2 = CH2(p-BrC6H4), R3 = H: 91% yield, 95% ee 8m: R1 = Et, R2 = CH2(p-PhC6H4), R3 = H: 90% yield, 99% ee 8n: R1 = Et, R2 = CH2(3,4-Cl2C6H3), R3 = H: 94% yield, 99% ee 8o: R1 = Et, R2 = CH2(2-Naph), R3 = H: 94% yield, 99% ee 8p: R1 = Et, R2 = CH2Bn, R3 = H: 71% yield, 97% ee 8q: R1 = Et, R2 = n-Pr, R3 = H: 65% yield, 94% ee 8r: R1 = Et, R2 = n-Bu, R3 = H: 63% yield, 93% ee 8s: R1 = Et, R2 = CH2(E)-CH=CHPh, R3 = H: 83% yield, 99% ee 8t: R1 = Et, R2 = allyl, R3 = H: 84% yield, 98% ee 8u: R1 = Et, R2 = CH2CO2Et, R3 = H: 77% yield, 97% ee 8v: R1 = Et, R2 = (CH2)3CN, R3 = H: 54% yield, 93% ee 8w: R1 = Et, R2 = (CH2)3OTBS, R3 = H: 67% yield, 96% ee 8x: R1 = Et, R2 = Bn, R3 = 5-F: 88% yield, 93% ee 8y: R1 = Et, R2 = Bn, R3 = 5-Cl: 84% yield, 90% ee 8z: R1 = Et, R2 = Bn, R3 = 5-Br: 84% yield, 87% ee 8aa: R1 = Et, R2 = Bn, R3 = 5-I: 76% yield, 80% ee 8ab: R1 = Et, R2 = Bn, R3 = 6-F: 90% yield, 99% ee 8ac: R1 = Et, R2 = Bn, R3 = 6-Br: 89% yield, 98% ee 8ad: R1 = Et, R2 = Bn, R3 = 6-F: 90% yield, 99% ee 8ae: R1 = Et, R2 = Bn, R3 = 7-F: 80% yield, 98% ee 8af: R1 = Et, R2 = Bn, R3 = 7-Me: 82% yield, 96% ee
10 Page 10 of 135
Scheme 2. Domino diazoalkane addition/1,2-rearrangement reaction of isatins [18].
Later in 2015, these authors applied the same catalyst system to promote related
ip t
enantioselective domino intramolecular diazoalkane addition/1,2-rearrangement reaction of ketones [19]. As shown in Scheme 3, the intramolecular reaction of a series of simple ketones
cr
bearing an α-diazoester 10a-s afforded, through diazoalkane addition followed by 1,2-
us
rearrangement reaction, the corresponding cyclic β-ketoesters 11a-s in good to excellent yields (63-96%) and enantioselectivities of up to 96% ee. The reactions were generally
an
performed with 0.5 mol% of catalyst loading and were not affected by moisture and oxygen. Varying the ester group of the 2-diazo-6-ketoalkanoate 10 affected the enantioselectivity
M
slightly. Meanwhile, the methyl ester gave better yield than the ethyl and tert-butyl esters (11a-c), thus indicating that enhancing the steric hindrance on the ester group hampered the
d
yield. The influence of position and electronic nature of substituents on the phenyl group (R2
te
= aryl) was investigated, showing that almost all substrates with a substituent on the meta- or
Ac ce p
para-position of this phenyl group provided the corresponding β-ketoesters 11d-l in excellent enantioselectivities (91-96% ee) and good yields (80-96%). Notably, condensed-ring and heteroaromatic ketone substrates were tolerated under the current system, producing the corresponding products 11n-p with high yields (87-95%) and enantioselectivities (80-95% ee). In addition, the scope of the process was extended to aliphatic ketones 10q-s which required only 0.05 mol% of catalyst loading to afford the corresponding domino products 11q-s in good yields (80-94%) albeit lower enantioselectivities of 66-86% ee (Scheme 3). Notably, these results constituted the first intramolecular homologation of simple ketones with α-diazoesters which provided a novel and efficient method for the construction of αalkyl/alkyl-substituted 2-oxocyclopentanecarboxylates with a chiral all-carbon quaternary center. 11 Page 11 of 135
+ N
N+ O-
O
O-
O
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (0.05-0.5 mol%) N2
R2
O
Sc(OTf)3 (0.05-0.5 mol%) CO2R1
2
OR1
R
us
CH2Cl2, 20 or 30 °C 10a-s
O
cr
O
ip t
N H
11a-s
R2
O-
CO2R1
1,2-rearrangement
an
addition of diazoalkane
N2+
Ac ce p
te
d
M
11a: R1 = Et, R2 = Ph: 81% yield, 93% ee 11b: R1 = Me, R2 = Ph: 86% yield, 95% ee 11c: R1 = t-Bu, R2 = Ph: 63% yield, 92% ee 11d: R1 = Me, R2 = m-Tol: 84% yield, 96% ee 11e : R1 = Me, R2 = m-MeOC6H4: 88% yield, 96% ee 11f: R1 = Me, R2 = m-(CH2=CH)C6H4: 82% yield, 95% ee 11g: R1 = Me, R2 = p-Tol: 86% yield, 92% ee 11h: R1 = Me, R2 = p-(t-Bu)C6H4: 88% yield, 94% ee 11i: R1 = Me, R2 = p-MeOC6H4: 96% yield, 92% ee 11j: R1 = Me, R2 = p-FC6H4: 85% yield, 91% ee 11k: R1 = Me, R2 = p-ClC6H4: 85% yield, 93% ee 11l: R1 = Me, R2 = p-BrC6H4: 80% yield, 93% ee 11m: R1 = Me, R2 = 3,5-Me 2C6H3: 65% yield, 92% ee 11n: R1 = Me, R2 = 2-Naph: 87% yield, 95% ee 11o: R1 = Me, R2 = 2-furyl: 95% yield, 84% ee 11p: R1 = Me, R2 = 2-thienyl: 93% yield, 80% ee 11q: R1 = R2 = Me: 80% yield, 66% ee 11r: R1 = Me, R2 = n-Bu: 94% yield, 86% ee 11s : R1 = Me, R2 = n-Hex: 89% yield, 85% ee
Scheme 3. Domino intramolecular diazoalkane addition/1,2-rearrangement reaction of ketones [19].
12 Page 12 of 135
In the last few years, an explosive number of multiple-catalyst systems for various organic transformations have been developed [20]. This novel methodology is particularly adapted to enantioselective domino reactions, allowing a rapid and economic construction of highly
ip t
functionalized chiral molecules from simple and readily available starting materials in onepot. Moreover, a reaction catalyzed by two different catalysts at the same time can allow a
cr
reactivity and a selectivity to be achieved otherwise not possible by using a single catalyst alone. The main problem, however, lies in finding the proper catalyst which should not only
us
be compatible with the other catalysts but also tolerates reagents, solvent and intermediates
an
generated during the course of the reaction. In particular, the development of multimetallic catalytic systems and their application to asymmetric catalysis has become an emerging area
M
in modern organic synthesis [21]. In this context, an asymmetric domino reaction involving diazoesters was developed by Davies et al., in 2011 [22]. It evolved through successive formation, and
ene
reaction
rearrangement, of
allylic
alcohols
oxy-Cope 12a-h
with
te
rearrangement/tautomerization,
[2,3]-sigmatropic
d
oxygen-ylide
vinyldiazoacetates 13a-e to give a series of chiral highly functionalized cyclopentanes 14a-l
Ac ce p
bearing four stereogenic centers in moderate to good yields (48-95%) along with enantioselectivities of 64-92% ee (Scheme 4). This remarkable process employed a combination of Rh2(S-DOSP)4 and Sc(OTf)3 as catalyst system which worked through relay catalysis. Therefore, the chiral rhodium catalyst induced the oxygen-ylide formation of 15, which was converted into 16 through [2,3]-sigmatropic rearrangement (Scheme 4). The latter was then submitted to oxy-Cope rearrangement to give intermediate 17 which tautomerized to afford 18. Finally, under scandium catalysis, ketoester 18 underwent an ene reaction to produce the final cyclopentane 14. The steric tolerance of the process was probed through substrates with various linear as well as branched alkyl chains (products 14a-d). All aliphatic substituents proved efficient substrates for the reaction even those bearing function groups,
13 Page 13 of 135
such as olefin, silyl ether, and phenyl (products 14e-h). Moreover, the reaction conditions tolerated aliphatic as well as aromatic vinyldiazoacetates which allowed the introduction of different functionality at the C4-position of the final cyclopentane to be achieved.
ip t
Remarkably, in all cases of substrates studied, the diastereoselectivity of the one-pot reaction
Ac ce p
te
d
M
an
us
cr
was > 90% de.
14 Page 14 of 135
C12H25
Rh2(S-DOSP)4 (1 mol%)
R1
+
R2
MeO2C
Sc(OTf)3 (20 mol%)
N2
OH
CO2Me
R2
13a-e
12a-h
OH
R1
cr
heptane, 0 to 80 °C
ip t
O S H O Rh O N O Rh
14a-l
> 90% de
te
d
M
an
us
14a: R1 = Me, R2 = Ph: 95% yield, 82% ee 14b: R1 = i-Pr, R2 = Ph: 67% yield, 80% ee 14c: R1 = i-Bu, R2 = Ph: 73% yield, 80% ee 14d: R1 = n-Hex, R2 = Ph: 80% yield, 78% ee 14e: R1 = CH2CH=CH2, R2 = Ph: 86% yield, 76% ee 14f: R1 = CH2OTBS, R2 = Ph: 65% yield, 78% ee 14g: R1 = CH2OTMS, R2 = Ph: 59% yield, 84% ee 14h: R1 = Bn, R2 = Ph: 42% yield, 87% ee 14i: R1 = Me, R2 = p-CF3C6H4: 63% yield, 78% ee 14j: R1 = Me, R2 = p-MeOC6H4: 94% yield, 87% ee 14k: R1 = Me, R2 = p-BrC6H4: 48% yield, 92% ee 14l: R1 = Me, R2 = Et: 63% yield, 64% ee proposed mechanism:
Ac ce p
OH
R1
+
R2
12
[2,3]-sigmatropic rearrangement
MeCO2
oxygen-ylide formation
N2
Rh +H O
2
R
CO2Me
R1
Rh2(S-DOSP)4
13
15
MeCO2
oxy-Cope rearrangement
OH
MeCO2
R2
OH
R2
R1
17
16 tautomerization
MeCO2
R1
O
R2 18
ene reaction R1
Sc(OTf)3
MeO2C
R2
OH
R1 14
15 Page 15 of 135
Scheme 4. Rh- and Sc-catalyzed domino oxygen-ylide formation/[2,3]-sigmatropic rearrangement/oxy-Cope rearrangement/tautomerization/ene reaction of allylic alcohols with
ip t
vinyldiazoacetates [22].
4-Aminobenzopyrans and related compounds are one of the common subunits of natural
cr
products, which can also be used as drugs. Therefore, considerable attention has been devoted
Feng
et
al.
have
developed
novel
us
to develop highly efficient methods for constructing this fused cyclic structure. In this context, enantioselective
scandium-catalyzed
domino
an
addition/ketalization reaction of salicylaldimines 19a-q with 2,3-dihydro-2H-furan 20 to afford the corresponding chiral cis-aminobenzopyrans 21a-q with excellent yields (up to
M
98%), diastereoselectivities (> 90% de), and enantioselectivities of up 99% ee [23]. Various salicylaldimines 19a-h (R1 = H) substituted at the N-aryl ring reacted with furan 20 in the
d
presence of N,N’-dioxide ligand 22 to give the corresponding cis-4-aminobenzopyrans 21a-h
te
in excellent outcomes (Scheme 5). The position of the substituent on the N-aryl ring of salicylaldimines (R2) had an evident effect on the enantioselectivities. Indeed, substrates with
Ac ce p
the substituent on the para-position afforded better results than those with the substituent on the ortho- or meta-position (21b-d). On the other hand, the electronic effect of the substituent on the N-aryl ring of salicylaldimines had no evident influence on the stereoselectivities (21dh). However, a dramatic decrease in enantioselectivities was observed for the salicylaldimines derived from substituted salicylaldehydes (R1 ≠ H) except for substrate 19i (R1 = 4-OMe, R2 = H) which provided 91% ee. To explain these results, the authors proposed a steric hindrance between the substrates and chiral ligand 22, and reasoned that chiral ligands with relative small steric hindrance could be suitable for these substrates. Investigating a series of chiral N,N’-dioxide ligands with different amide subunits, ligand 23, derived from L-pipecolic acid and (S)-2-phenylethanamine, was suitable for subtrates substituted (R1 ≠ H) on the
16 Page 16 of 135
salicyladehyde moiety (19j-q). As shown in Scheme 5, enantioselectivities of 90-93% ee were
( )n N+ N H R3
+ ( )n
O-
O
H N R3
cr
O-
O
N
ip t
achieved for a range of variously substituted chiral cis-aminobenzopyrans 21j-q.
22 (R3 = Ph2 CH, n = 1) or 23 (R3 = (S)-2-phenylethyl, n = 2)
R2
(5 mol%)
us
N
Sc(OTf )3 (5.5 mol%)
R1
+ OH
O
N
R1
+
O
te
OH
M
R2
d
[Sc]
20
an
19a-q
5 Å M.S.
CHCl3 , -20 °C
HN
R2 H
R1 O H 21a-q
O
Ac ce p
> 90% de with ligand 22: 21a: R 1 = R 2 = H: 97% yield, 97% ee 21b: R 1 = H, R 2 = 2-Cl: 97% yield, 82% ee 21c: R 1 = H, R 2 = 3-Cl: 85% yield, 85% ee 21d: R 1 = H, R 2 = 4-Cl: 83% yield, 97% ee 21e: R 1 = H, R 2 = 4-F: 87% yield, 97% ee 21f: R1 = H, R2 = 4-CF 3: 87% yield, 91% ee 21g: R 1 = H, R 2 = 4-Me: 98% yield, 95% ee 21h: R 1 = H, R 2 = 4-MeO: 94% yield, 99% ee 21i: R1 = 4-MeO, R2 = H: 85% yield, 91% ee with ligand 23: 21j: R1 = 5-Cl, R 2 = H: 83% yield, 92% ee 21k: R 1 = 5-Me, R 2 = H: 92% yield, 90% ee 21l: R1 = 5-MeO, R2 = H: 84% yield, 92% ee 21m: R1 = 5-Cl, R2 = 4-MeO: 86% yield, 92% ee 21n: R 1 = 5-Br, R2 = 4-MeO: 95% yield, 93% ee 21o: R 1 = 5-Me, R2 = 4-MeO: 97% yield, 91% ee 21p: R 1 = 5-Cl, R2 = 4-F: 96% yield, 92% ee 21q: R 1 = 5-Me, R2 = 4-F: 87% yield, 90% ee
17 Page 17 of 135
Scheme 5. Domino addition/ketalization reaction of salicylaldimines with 2,3-dihydro-2Hfuran [23].
ip t
2,3-Dihydroquinazolinone constitutes a privileged scaffold because of its extensive pharmacological activities. In 2012, Prakash and Kesavan reported a highly enantioselective
cr
synthesis of 2,3-dihydroquinazolinones 24a-n based on a scandium-catalyzed domino imine
us
formation/intramolecular amidation reaction of 2-aminobenzamides 25a-b with aldehydes 26a-m performed in the presence of pybox ligand 27 [24]. As shown in Scheme 6, a range of
an
chiral 2,3-dihydroquinazolinones 24a-n were generated in general excellent yields and enantioselectivities of up to 96% and 98% ee by using 2.5 mol% of ligand 27 in combination
M
with 1 mol% of Sc(OTf)3 at ambient temperature. Variously substituted aromatic aldehydes provided similar excellent results at room temperature while aliphatic aldehydes required
d
lowering the reaction temperature to -20 °C to achieve the corresponding products 24m-n in
te
good enantioselectivities (86-92% ee). This process represented the first metal-catalyzed highly enantioselective synthesis of 2,3-dihydroquinazolinones through intramolecular
Ac ce p
amidation of imines in very good yields.
18 Page 18 of 135
O
O
N
N
NH2 NH2 25a-b
27 (2.5 mol%) Sc(OTf)3 (1 mol%)
+ O
4 Å M.S.
O
O X
X N
NH
us
NH2
cr
CH2Cl2, r.t. or -20 °C
R H 26a-m
ip t
X
O
N
N H
R
R
an
24a-n
Ac ce p
te
d
M
at r.t.: 24a: R = Ph, X = H: 94% yield, 98% ee 24b: R = 2-Naph, X = H: 92% yield, 98% ee 24c: R = m-FC6H4, X = H: 91% yield, 98% ee 24d: R = m-BrC6H4, X = H: 94% yield, 80% ee 24e : R = p-FC6H4, X = H: 92% yield, 90% ee 24f: R = p-BrC6H4, X = H: 90% yield, 94% ee 24g: R = p-CNC6H4, X = H: 88% yield, 90% ee 24h: R = p-PhC6H4, X = H: 95% yield, 96% ee 24i: R = p-PhC6H4, X = Cl: 96% yield, 97% ee 24j: R = p-(CF3CO)C6H4, X = Cl: 94% yield, 95% ee 24k : R = 3,4-(MeO)2C6H3, X = H: 90% yield, 95% ee 24l: R = p-EtC6H4, X = H: 91% yield, 86% ee at -20 °C: 24m: R = n-Hex, X = H: 86% yield, 92% ee 24n: R = n-Pr, X = H: 80% yield, 86% ee
Scheme 6. Domino imine formation/intramolecular amidation reaction of 2-aminobenzamides with aldehydes in the presence of a pybox ligand [24].
Later in 2015, this process was reinvestigated by Cai et al. by using fluorous chiral bisoxazoline ligand 28 at 5 mol% of catalyst loading in combination with 1 mol% of Sc(OTf)3 [25]. Bisoxazoline 28 was selected as optimal ligand among a variety of chiral bisoxazoline derivatives. As shown in Scheme 7, the reaction of 2-aminobenzamide 25a with a variety of
19 Page 19 of 135
aldehydes 26a-o afforded the corresponding chiral 2,3-dihydroquinazolinones 24a-o in high yields (76-94%) along with enantioselectivities of 87-98% ee. Substituted benzaldehydes bearing either electronically poor, neutral, or rich group had remarkable differences in
ip t
enantioselectivities of this reaction although the corresponding products 24a-k were obtained in generally high yields and good to high enantioselectivities (76-94% yield, 87-98% ee). The
cr
scope of the methodology was extended to an heteroaromatic aldehyde, a α,β-unsaturated
us
aldehyde, and an aliphatic aldehyde to give the corresponding products 24l, 24n, and 24o in good enantioselectivities of 87, 94, and 89% ee, respectively. One advantage of using
Ac ce p
te
d
M
without significant loss of enantioselectivity.
an
fluorinated ligand 28 is that it could be easily recovered and reused at least three times
20 Page 20 of 135
C 8F17 O
O
O NH2
N
N
NH 2
Ph
25a
28 (5 mol%)
O
ip t
Sc(OTf )3 (1 mol%)
+
4 Å M.S. CH 2Cl2, r.t.
H O
26a-o
NH R
us
24a-o N H
cr
R
Ph
Ac ce p
te
d
M
an
24a : R = Ph: 84% yield, 97% ee 24b: R = p-ClC6 H4 : 89% yield, 98% ee 24c : R = p-CF3C6H4 : 94% yield, 97% ee 24d: R = p-NO2 C6H4: 92% yield, 98% ee 24e : R = p-MeOC 6H 4: 86% yield, 92% ee 24f: R = p-Me2NC 6H4 : 83% yield, 93% ee 24g: R = p-Tol: 86% yield, 95% ee 24h: R = m-BrC 6H 4: 84% yield, 88% ee 24i: R = o-BrC 6H 4: 91% yield, 89% ee 24j: R = m-NO2C6H 4: 81% yield, 91% ee 24k : R = o-NO2C 6H 4: 90% yield, 92% ee 24l: R = 2-pyridinyl: 82% yield, 87% ee 24m: R = 1-Naph: 79% yield, 92% ee 24n: R = (E)-PhCH=CH: 76% yield, 94% ee 24o: R = Cy: 90% yield, 89% ee
Scheme 7. Domino imine formation/intramolecular amidation reaction of 2-aminobenzamide with aldehydes in the presence of a fluorinated bisoxazoline ligand [25].
In another context, Franz et al. recently reported the first catalytic asymmetric [3+2] annulation of unsaturated carbonyl compounds with allylsilanes [26]. This evolved through enantioselective scandium-catalyzed domino Michael/1,2-silyl shift/cyclization reaction of a variety of alkylidene oxindoles 29a-k with allyltriisopropylsilane 30 to give the corresponding highly functionalized chiral spirocyclopentanes 31a-k bearing three stereogenic centers in high yields, diastereo-, and enantioselectivities of up to 97%, 98% de , 21 Page 21 of 135
and 99% ee, respectively (Scheme 8). The reaction was catalyzed by 10 mol% of Sc(OTf)3 and pybox ligand 27 in the presence of NaBArF as additive. It began with the Michael addition of allyltriisopropylsilane 30 to alkylidene oxindole 29 to give intermediate 32, which
ip t
was subsequently submitted to a 1,2-silyl shift followed by cyclization reaction to finally provide spirocyclopentane 31. The role of NaBArF was attributed to the formation of a
cr
cationic scandium complex. Very good results were achieved with various ester and nitrile substrates 29a-f and 29h-k while phenyl-substituted alkylidene 29g required a higher catalyst
us
loading (20 mol% instead of 10 mol%) and extended reaction times (4 days), to afford the corresponding spirocyclopentane 31g in moderate enantioselectivity of 68% ee. In addition to
afforded
the
corresponding
products
31h-i
in
both
excellent
yields
and
M
also
an
N-acetylated alkylidene oxindoles 29a-g, chelating oxindoles containing urea and Cbz groups
enantioselectivities of 80-83% and 92-96% ee, respectively. The NH spirooxindoles 31j-k
d
could be accessed by simple deprotection of the corresponding N-acyl oxindoles with KHCO3
Ac ce p
te
and H2O2 in high yields (80-88%) and enantioselectivities of 92-98% ee.
22 Page 22 of 135
R
O
X
O
N N
N
O N Z Y 29a-k +
ip t
27 (10 mol%) Sc(OTf) 3 (10 mol%) 4 Å M.S., NaBArF
Si(i-Pr)3
CH 2Cl2, r.t.
cr
30 Si(i-Pr) 3 R O
Y
N Z
an
Y
N Z
X
Si(i-Pr)3 O [Sc]
us
R X
32
31a-k
Ac ce p
te
d
M
31a: R = CO2Et, X = H, Y = F, Z = Ac: 82% yield, 94% de, 92% ee 31b: R = CO 2Et, X = Y = H, Z = Ac: 92% yield, 90% de, 96% ee 31c: R = CO2Et, X = OMe, Y = H, Z = Ac: 75% yield, 96% de, 96% ee 31d: R = CO 2t -Bu, X = F, Y = H, Z = Ac: 80% yield, 70% de, 99% ee 31e: R = CO2Me, X = F, Y = H, Z = Ac: 95% yield, 80% de, 96% ee 31f: R = CN, X = F, Y = H, Z = Ac: 92% yield, 90% de, 96% ee 31g: R = Ph, X = Y = H, Z = Ac: 72% yield, 84% de, 68% ee (with 20 mol% of catalyst and reaction run of 4 days) 31h: R = CO 2Et, X = F, Y = H, Z = CONHPh: 97% yield, 88% de, 98% ee 31i: R = CO2 Et, X = F, Y = H, Z = Cbz: 83% yield, 98% de, 96% ee 31j: R = CO2 Bn, X = F, Y = Z = H: 80% yield, 94% de, 92% ee 31k: R = CO2Et, X = F, Y = Z = H: 88% yield, 90% de, 98% ee
Scheme 8. Domino Michael/1,2-silyl shift/cyclization reaction of alkylidene oxindoles with allyltriisopropylsilane [26].
The chiral spirocyclic-3,3’-oxindole unit is encountered in a large variety of natural products and pharmaceutical candidates with a wide spectrum of biological activities [27]. To access even more complex and functionalized chiral products of this type, Feng et al. very recently described a novel enantioselective scandium-catalyzed domino 1,5-hydride shift/ring closure reaction of alkylidene oxindoles 33a-m which allowed a wide range of chiral spirooxindole tetrahydroquinolines 34a-m bearing contiguous quaternary or tertiary carbon 23 Page 23 of 135
stereocenters to be achieved in good to excellent yields (73-97%) and good to high enantioselectivities (85-94% ee) (Scheme 9) [28]. In the presence of N,N’-dioxide ligand 9 (10 mol%) in combination with Sc(OTf)3 (10 mol%), alkylidene oxindole 33 underwent a 1,5-
ip t
hydride shift to give intermediate 35 which was subsequently submitted to ring closure reaction to provide final product 34. Remarkably, in all cases of substrates, the
cr
diastereoselectivity of the reaction was > 90% de. Oxindole derivatives with N-Me, N-Boc, and N-Bn protecting groups were tolerated with no influence on the diastereo- and
Ac ce p
te
d
M
an
us
enantioselectivity.
24 Page 24 of 135
+ N
N+ O-
O
O-
O
N H
R3 R4
H
R1
H
Sc(OTf)3 (10 mol%)
X
X
O Z
O
DCE, 35 °C
N R2
R4
Y
R1
Z
33a-m
N R2
35
N R3 H O R4
Y Z
N R2
34a-m > 90% de
an
X
us
Y
R3 N
ip t
( )n N
cr
R1
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (10 mol%)
Ac ce p
te
d
M
34a: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH=CH)2: 97% yield, 91% ee 34b: R1 = X = Y = Z = H, R2 = Boc, R3,R4 = (CH=CH)2: 93% yield, 91% ee 34c: R1 = X = Y = Z = H, R2 = Bn, R3,R4 = (CH=CH)2: 89% yield, 90% ee 34d: R1 = X = Z = H, Y = Cl, R2 = Me, R3,R4 = (CH=CH)2: 80% yield, 85% ee 34e: R1 = X = Z = H, Y = Br, R2 = Me, R3,R4 = (CH=CH)2: 84% yield, 88% ee 34f: R1 = X = Y = H, Z = F, R2 = Me, R3,R4 = (CH=CH)2: 87% yield, 87% ee 34g: R1 = Y = Z = H, X = R2 = Me, R3,R4 = (CH=CH)2: 83% yield, 90% ee 34h: R1 = Y = Z = H, X = MeO, R2 = Me, R3,R4 = (CH=CH)2: 73% yield, 89% ee 34i: R1 = Y = Z = H, X = F, R2 = Me, R3,R4 = (CH=CH)2: 92% yield, 87% ee 34j: R1 = Br, X = Y = Z = H, R2 = Me, R3,R4 = (CH=CH)2: 92% yield, 90% ee 34k: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH=C(OMe))2: 93% yield, 94% ee 34l: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH2)3: 83% yield, 92% ee 34m: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH2)4: 78% yield, 91% ee
Scheme 9. Domino 1,5-hydride shift/ring closure reaction of alkylidene oxindoles [28].
Chiral dihydropyrrole frameworks are a privileged structural unit in a number of natural compounds with important biological activities and also a key building block in the synthesis of complex molecules [29]. In 2015, Feng et al. reported a novel asymmetric approach to this type
of
products
based
on
enantioselective
scandium-catalyzed
domino
ring-
opening/cyclization/dehydration reaction of cyclopropyl ketones 36a-p with primary amines
25 Page 25 of 135
37a-h [30]. As shown in Scheme 10, the process employed a catalyst system composed by 10 mol% of Sc(OTf)3 and 10 mol% of N,N’-dioxide ligand 38 which was used in the presence of LiCl as an additive. The reaction began with the ring-opening of cyclopropyl ketone 36 with
ip t
primary amine 37 to give intermediate 39 which further underwent cyclization reaction followed by dehydration to give the final 2,4,5-trisubstituted 2,3-dihydropyrrole 40. As shown
cr
in Scheme 10, a series of cyclopropyl ketones 36a-p reacted smoothly with phenylamine 37a 3 (R = Ph), providing the corresponding chiral products 40a-p in good to excellent
1
us
enantioselectivities (66-96% ee) and poor to excellent yields (16-98%). Both electron-rich and
an
electron-deficient aryl groups at the 2-position (R ) of cyclopropyl ketones had a small effect on the enantioselectivity (40b-k). The reaction tolerated naphthyl-substituted cyclopropyl
M
ketones which gave the corresponding products 40l-m in high enantioselectivities (94-96% ee) and excellent yields (97-98%). On the other hand, a lower enantioselectivity of 66% ee
d
1 was obtained in the reaction of methyl-substituted cyclopropyl ketone (R = Me) 36p. In
te
addition to phenyl amine, various other aromatic primary amines provided high enantioselectivities of 90-97% ee (40q-v) while cyclopropyl amine 37h led to the
Ac ce p
corresponding product 40w in lower enantioselectivity (87% ee). Other aliphatic amines, including cyclopentanamine, 2-methylpropan-2-amine, and phenylmethanamine, did not provide the desired dihydropyrrole products. Importantly, this methodology also constituted an effective procedure for the kinetic resolution of 2-substituted cyclopropyl ketones which were recovered in enantioselectivities of up to 95% ee.
26 Page 26 of 135
N+
COR2 36a-p
OO H N Ar Ar Ar = 2,4,6-i-Pr3C6H2
+ R3NH2 37a-h
R3 N
38 (10 mol%) Sc(OTf)3 (10 mol%) LiCl (1 equiv) CHCl2CHCl2, 35 °C
R3H2N
R2
R1
O
R1
R2
ip t
R1
ON H
COR2
40a-w
cr
COR2
+
us
O
N
COR2
an
39
Ac ce p
te
d
M
40a: R1 = R2 = R3 = Ph: 82% yield, 91% ee 40b : R1 = p-Tol, R2 = R3 = Ph: 95% yield, 91% ee 40c: R1 = p-MeOC6H4, R2 = R3 = Ph: 96% yield, 92% ee 40d : R1 = p-FC6H4, R2 = R3 = Ph: 94% yield, 95% ee 40e: R1 = p-BrC6H4, R2 = R3 = Ph: 88% yield, 95% ee 40f: R1 = m-Tol, R2 = R3 = Ph: 96% yield, 92% ee 40g: R1 = m-MeOC6H4, R2 = R3 = Ph: 81% yield, 94% ee 40h: R1 = o-Tol, R2 = R3 = Ph: 92% yield, 94% ee 40i: R1 = o-MeOC6H4, R2 = R3 = Ph: 95% yield, 92% ee 40j: R1 = 3,4-Cl2C6H3, R2 = R3 = Ph: 66% yield, 96% ee 40k: R1 = 3,4-(MeO)2C6H3, R2 = R3 = Ph: 98% yield, 92% ee 40l: R1 = 1-Naph, R2 = R3 = Ph: 98% yield, 96% ee 40m: R1 = 2-Naph, R2 = R3 = Ph: 97% yield, 94% ee 40n : R1 = R3 = Ph, R2 = p-Tol: 63% yield, 96% ee 40o: R1 = R3 = Ph, R2 = Me: 59% yield, 73% ee 40p : R1 = Me, R2 = R3 = Ph: 16% yield, 66% ee 40q: R1 = R2 = Ph, R3 = p-Tol: 86% yield, 92% ee 40r: R1 = R2 = Ph, R3 = p-FC6H4: 95% yield, 90% ee 40s : R1 = R2 = Ph, R3 = p-BrC6H4: 85% yield, 96% ee 40t: R1 = R2 = Ph, R3 = p-NO2C6H4: 96% yield, 95% ee 40u: R1 = R2 = Ph, R3 = m-ClC6H4: 96% yield, 96% ee 40v: R1 = R2 = Ph, R3 = o-ClC6H4: 46% yield, 97% ee 40w: R1 = R2 = Ph, R3 = Cy: 41% yield, 87% ee
Scheme 10. Domino ring-opening/cyclization/dehydration reaction of cyclopropyl ketones with primary amines [30].
27 Page 27 of 135
In 2012, Franz et al. reported a nice synthesis of chiral biologically interesting spirooxindoles on the basis of a catalytic asymmetric [3+2] annulation of allylsilanes 41a-d with isatins 6a-h [31]. The reaction was promoted by a combination of ScCl2(SbF6) with
ip t
chiral pybox ligand 27 in the presence of TMSCl as additive. The domino process between allylsilanes and isatins began with allylation which afforded intermediates 42 which were
cr
further submitted to 1,2-silyl migration to provide intermediates 43. The latter then underwent cyclization to afford the final chiral spirooxindoles 44a-k in moderate to good yields,
us
remarkable enantioselectivities of 97-99% ee, along with complete diastereoselectivity in
an
almost all cases of substrates (Scheme 11). The best yields were reached in the case of using
Ac ce p
te
d
M
allyltriisopropylsilane.
28 Page 28 of 135
O O
(R4)2R3Si
O N R1 6a-h
27 (10 mol%) ScCl2(SbF6) (10 mol%)
O R2
4 Å M.S. TMSCl (3 equiv)
SiR3(R4)2
CH2Cl2, r.t.
41a-d
O
N R1 44a-k
cr
+
N
N
ip t
R2
O
N
proposed mechanism:
2
O
R
6
+
(R4)2R3Si
allylation
Ac ce p
N R1
te
O
d
M
an
us
44a: R1 = Me, R2 = 5-Br, R3 = R4 = i-Pr: 71% yield, 99% ee, > 99% de 44b: R1 = Me, R2 = 5-Cl, R3 = R4 = i-Pr: 74% yield, 99% ee, > 99% de 44c: R1 = Me, R2 = 4-Cl, R3 = R4 = i-Pr: 62% yield, 99% ee, 42% de 44d: R1 = Me, R2 = 5-F, R3 = R4 = i-Pr: 67% yield, 99% ee, > 99% de 44e: R1 = Bn, R2 = 5-OCF3, R3 = R4 = i-Pr: 82% yield, 99% ee, > 99% de 44f: R1 = PMB, R2 = 5-F, R3 = R4 = i-Pr: 55% yield, 99% ee, > 99% de 44g: R1 = Me, R2 = H, R3 = R4 = i-Pr: 47% yield, 99% ee, > 99% de 44h: R1 = Ph, R2 = H, R3 = R4 = i-Pr: 81% yield, 97% ee, > 99% de 44i: R1 = Me, R2 = 5-Br, R3 = p-MeOC6H4, R4 = i-Pr: 20% yield, 99% ee, > 90% de 44j: R1 = Me, R2 = 5-Br, R3 = CHPh2, R4 = Me: 34% yield, 99% ee, > 90% de 44k: R1 = Me, R2 = 5-Br, R3 = o-MeOC6H4, R4 = Me: 13% yield, 99% ee, > 90% de
O
2
R
O N R1
SiR3(R4)2
42
41
SiR3(R4)2 SiR3(R4)2
1,2-silyl migration
R2
cyclization
O R2
O
O N R1
O N R1
44
43
Scheme 11. Domino allylation/1,2-silyl migration/cyclization reaction of allylsilanes with isatins [31].
29 Page 29 of 135
Enantioselective organocatalytic processes have reached maturity in recent years with an impressive and steadily increasing number of studies [32]. The ability of organocatalysts to promote a wide range of reactions by different activation modes makes organocatalysis ideal
ip t
for its application in domino reactions. First introduced by Krische et al. in 2003 [33], the combination of catalysts from different disciplines, such as organocatalysis, and metal
cr
catalysis, has attracted increasing attention in the synthetic community in the past several years, allowing enable unprecedented transformations not currently possible by use of any
us
catalysis alone, and making current synthetic methods more economical and practical [20]. Although the combination of transition metal catalysis with organocatalysis has allowed a
an
range of novel and useful reactions to be achieved, the development of domino reactions induced by a combination of two types of catalysts still remains a challenge. While the
M
organocatalysis is dominated by Lewis base catalysts, such as amines, carbenes, and tertiary phosphines, a metal catalyst usually has an empty coordination site to interact and activate a
d
substrate. The challenge in combining an organocatalyst and a metal catalyst is in part to
te
avoid the deactivation of catalyst by Lewis acid/base interaction. In this area, Chi et al.
Ac ce p
recently reported the first use of scandium in cooperative N-heterocyclic carbene (NHC) catalysis [34]. As shown in Scheme 12, the combination of Sc(OTf)3 and Mg(OTf)2 with chiral NHC catalyst 45 allowed a novel enantioselective domino γ-addition/cyclization reaction of enals 46a-k with trifluoromethyl ketones 47a-h to be achieved in good to high yields and enantioselectivities of up to 82% and 94% ee, respectively. The reaction afforded a wide range of chiral unsaturated δ-lactones 48a-r through the first oxidative generation of vinyl enolates for γ-functionalization of enals under NHC catalysis. A postulated reaction pathway is illustrated in Scheme 12 to explain the results. The vinyl enolate intermediate 51 likely arose from γ-deprotonation of the oxidatively generated unsaturated intermediate 50, although direct oxidation of the enal γ-carbon of the homoenolate intermediate 49 leading to
30 Page 30 of 135
51 could not be completely ruled out. Vinyl enolate 51 then underwent nucleophilic addition to ketone 47, affording product 48. The Sc(III) Lewis acid, which is known to have good affinities for carbonyl oxygens and carboxylates, likely was involved in multisite coordination
ip t
to bring the ketone electrophile into close proximity with intermediate 51 and the chiral NHC catalyst, as illustrated by 52. This coordination amplified the otherwise weak chiral induction
Ac ce p
te
d
M
an
us
cr
by the chiral NHC catalyst.
31 Page 31 of 135
O N N
N
BF4 Mes
45 (20 mol%)
O
O O R2
F3C
+
t-Bu
O
R1 46a-k
O
t-Bu THF, 0 °C or r.t.
K2CO3 (50 mol%)
O
cr
H
ip t
Sc(OTf)3 (10 mol%) Mg(OTf)2 (10 mol%) t-Bu t-Bu
CF3
R1
R2 48a-r
us
47a-h
Ac ce p
te
d
M
an
48a: R1 = R2 = Ph: 81% yield, 94% ee 48b: R1 = p-Tol, R2 = Ph: 76% yield, 91% ee 48c: R1 = p-MeOC6H4, R2 = Ph: 82% yield, 90% ee 48d: R1 = p-BrC6H4, R2 = Ph: 76% yield, 88% ee 48e: R1 = p-ClC6H4, R2 = Ph: 74% yield, 90% ee 48f: R1 = 2-Naph, R2 = Ph: 67% yield, 90% ee 48g: R1 = 1-thienyl, R2 = Ph: 76% yield, 84% ee 48h: R1 = 1-furyl, R2 = Ph: 78% yield, 84% ee 48i: R1 = 1-pyridinyl, R2 = Ph: 81% yield, 86% ee 48j: R1 = (E)-PhCH=CH, R2 = Ph: 65% yield, 79% ee 48k: R1 = (E)-(p-Tol)CH=CH, R2 = Ph: 71% yield, 77% ee 48l: R1 = Ph, R2 = p-Tol: 61% yield, 93% ee 48m: R1 = Ph, R2 = p-BrC6H4: 74% yield, 91% ee 48n: R1 = Ph, R2 = p-ClC6H4: 76% yield, 91% ee 48o: R1 = Ph, R2 = 1-thienyl: 75% yield, 90% ee 48p: R1 = Ph, R2 = Me: 52% yield, 80% ee 48q: R1 = Ph, R2 = CO2Et: 64% yield, 60% ee 48r: R1 = Ph, R2 = 1-thienyl: 75% yield, 90% ee
proposed mechanism:
O
2
Mes
R
O
CF 3
N N N
O
O
H
O Mes
O CF3
R1 48
N N
46
R2
R1
N
1 OH R
O
1
R
45 49
53
[O] Mes N N N O
Mes
H
O
R1
N N O
R1 [Sc] O
CF3 R
F3C 52
N
Mes
O
N N
2
O Sc(OTf)3
R2 47
50 N O
1
R
O 51
K2CO3
32 Page 32 of 135
Scheme 12. Multicatalyzed domino γ-addition/cyclization reaction of enals with trifluoromethyl ketones [34].
ip t
Inspired by these pioneering results, Wang et al. employed a closely related chiral NHC catalyst 54 in combination with Sc(OTf)3 to promote asymmetric domino γ-
cr
addition/cyclization reaction of enals 46a-l with β-bromo-α-ketoesters 55a-m to provide the
us
corresponding chiral unsaturated δ-lactones 56a-w (Scheme 13) [35]. When the reaction was performed in the presence of CsOAc as a base, a wide range of these highly functionalized
an
products were achieved at room temperature in good yields (67-88%), general excellent diastereoselectivity of > 90% de, and high enantioselectivities of 85-98% ee when starting from enals bearing various aromatic or heteroaromatic substituents (R ). Replacement of a β-
M
1
(hetero)aryl group by a vinyl substituent gave the corresponding product 56v in 83% yield, >
d
90% de, and 89% ee while the use of a methyl group resulted in a slow conversion (< 10% at
te
r.t., 67% yield at 50°C) and a moderate enantioselectivity of 40% ee for product 56w but with 2
Ac ce p
always an excellent diastereoselectivity of > 90% de. The nature of the substituent (R ) at the γ-position of β-bromo-α-ketoesters 55a-m had no influence on the results since they were homogeneous for (hetero)aromatic and aliphatic groups. This process constituted the first intermolecular dynamic kinetic resolution of α-ketoesters through cooperative catalysis by an NHC catalyst with a Lewis acid.
33 Page 33 of 135
O N
BF4 Ar
O
R2
O
O
O
O +
H
R1
O
O
toluene, r.t.
O
O
cr
t-Bu t-Bu CsOAc (50 mol%)
55a-m
ip t
54 (20 mol%) Ar = 2,6-Et2C6H3 Sc(OTf)3 (10 mol%) t-Bu t-Bu
O
Br
N N
Br
2
us
R
46a-l
56a-w
R1
an
> 90% de
1
2
Ac ce p
te
d
M
56a: R = Ph, R = p-Tol: 81% yield, 92% ee 56b: R1 = Ph, R2 = p-MeOC6H4: 80% yield, 85% ee 56c: R1 = Ph, R2 = p-FC6H4: 79% yield, 90% ee 56d: R1 = Ph, R2 = p-CF3C6H4: 86% yield, 93% ee 56e: R1 = Ph, R2 = m-ClC6H4: 82% yield, 90% ee 56f: R1 = Ph, R2 = o-FC6H4: 80% yield, 92% ee 56g: R1 = Ph, R2 = 2-Naph: 83% yield, 90% ee 56h: R1 = Ph, R2 = 2-thienyl: 83% yield, 86% ee 56i: R1 = Ph, R2 = CH=CH2: 70% yield, 87% ee 56j: R1 = Ph, R2 = Cy: 85% yield, 91% ee 56k: R1 = Ph, R2 = Et: 76% yield, 90% ee 56l: R1 = Ph, R2 = H: 77% yield, 91% ee 56m: R1 = p-Tol, R2 = Ph: 79% yield, 92% ee 56n: R1 = p-MeOC6H4, R2 = Ph: 70% yield, 94% ee 56o: R1 = p-FC6H4, R2 = Ph: 80% yield, 91% ee 56p: R1 = p-ClC6H4, R2 = Ph: 81% yield, 85% ee 56q: R1 = p-BrC6H4, R2 = Ph: 84% yield, 90% ee 56r: R1 = p-NO2C6H4, R2 = Ph: 85% yield, 96% ee 56s: R1 = 2-Naph, R2 = Ph: 80% yield, 93% ee 56t: R1 = 3-pyridyl, R2 = Ph: 88% yield, 98% ee 56u: R1 = 2-thienyl, R2 = Ph: 75% yield, 90% ee 56v: R1 = allyl, R2 = Ph: 83% yield, 89% ee 56w: R1 = Me, R2 = Ph: 67% yield, 40% ee (50 °C)
Scheme 13. Multicatalyzed domino γ-addition/cyclization reaction of enals with β-bromo-αketoesters [35].
34 Page 34 of 135
Even though the history of multicomponent reactions dates back to the second half of 19
th
century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in the last decades with the work of Ugi that the concept of multicomponent reaction has emerged as a powerful
ip t
tool in synthetic chemistry [36]. Multicomponent reactions are defined as domino reactions involving at least three substrates and, consequently, constitute a subgroup of domino
cr
reactions [9b,37]. In spite of the recent emergence of organocatalysis, enantioselective metalcatalyzed multicomponent reactions represent the majority of catalytic enantioselective
us
multicomponent reactions. A range of various metal catalysts, such as copper, rhodium, gold, platinum, palladium, cobalt, ruthenium, scandium, magnesium, titanium, zinc, aluminum,
an
nickel, silver, iridium, as well as tin have been demonstrated to induce a wide number of types of these powerful one-pot reactions. In the last few years, chiral scandium catalysts have also
M
been successfully applied to induce various types of enantioselective multicomponent reactions, such as asymmetric three-component chloroamination reaction of α,β-unsaturated
d
γ-ketoesters 57a-m [38]. As shown in Scheme 14, these substrates reacted with TsNCl2 and
te
TsNH2 in the presence of a combination of Sc(OTf)3 with N,N’-dioxide ligand 58 as catalyst
Ac ce p
system to give the corresponding chiral chloroaminated products 59a-m generally in high yields (up to 98%) and enantioselectivities (92-99% ee) along with moderate to high diastereoselectivities (66-98% de). The lowest yield (65%) was observed in the case of substrate 57d bearing a bulky tert-butyl group. The diastereoselectivity was influenced by the electronic property of the substituents at the aromatic group (Ar). Indeed, generally the substrates with an electron-donating group gave the desired products (59f-g) with a high diastereoselectivity (96% de), while electron-withdrawing substituents on the phenyl group reduced the stability of the chloronium intermediate 60 (Scheme 14) which resulted in a relatively lower diastereoselectivity (66-86% de for 59h-k). Notably, this process employed a remarkably low catalyst loading of only 0.05 mol%.
35 Page 35 of 135
+ N O-
N+
O Ar
ON H
O
H N R'
R' R' = 1-adamantyl 58 (0.05 mol%) Sc(OTf)3 (0.05 mol%)
CO2R 57a-m + TsNCl2
4 Å M.S. + TsNH2
O Ar
cr
CH2Cl2, 35 °C O Ar
+ CO2R Cl
an
60
TsNH2
us
TsNCl2
NHTs * * CO R 2 Cl 59a-m
ip t
O
Ac ce p
te
d
M
59a: Ar = R = Ph: 93% yield, 92% ee, 97% de 59b: Ar = Ph, R = Et: 98% yield, 97% ee, 92% de 59c: Ar = Ph, R = Me: 98% yield, 96% ee, 90% de 59d: Ar = Ph, R = t-Bu: 65% yield, 96% ee, 94% de 59e: Ar = Ph, R = Bn: 98% yield, 95% ee, 92% de 59f: Ar = p-MeOC6H4, R = Et: 97% yield, 99% ee, 96% de 59g: Ar = p-Tol, R = Et: 99% yield, 97% ee, 96% de 59h: Ar = p-ClC6H4, R = Et: 96% yield, 98% ee, 86% de 59i: Ar = p-BrC6H4, R = Et: 95% yield, 93% ee, 74% de 59j: Ar = p-NO2C6H4, R = Et: 95% yield, 93% ee, 66% de 59k: Ar = m-NO2C6H4, R = Et: 93% yield, 94% ee, 86% de 59l: Ar = 2-Naph, R = Et: 96% yield, 97% ee, 90% de 59m: Ar = 2-furyl, R = Et: 95% yield, 98% ee, 98% de
Scheme 14. Three-component chloroamination reaction of α,β-unsaturated γ-ketoesters [38].
The scope of this nice methodology was extended to a range of α,β-unsaturated ketones 61a-q which provided under the same reaction conditions the corresponding α-chloro-βamino-ketone derivatives 62a-q as almost single anti-diastereomers (up to > 98% de) in nearly quantitative yields and remarkable enantioselectivities of up to 99% ee (Scheme 15) [38]. To explain the anti-configuration of the products, the formation of bridged chloronium ion intermediate 63 can be proposed (Scheme 15). Thus, a possible mechanism was that the highly reactive species TsNHCl was generated from TsNH2 and TsNCl2 upon the promotion 36 Page 36 of 135
of molecular sieves initially. Then, a N,N’-dioxide-Sc(III) complex mediated the formation of the chiral chloronium ion intermediate 63, which was followed by nucleophilic attack of
Ac ce p
te
d
M
an
us
cr
ip t
nitrogen to deliver final product 62 (Scheme 15).
37 Page 37 of 135
N+
O Ar 61a-q
ON H
OO H N R' R' R' = 1-adamantyl 58 (0.05 mol%) Sc(OTf)3 (0.05 mol%)
NHTsO R
+ TsNCl2
Ar
4 Å M.S. CH2Cl2, 35 °C
+ TsNH2
Cl 62a-q
cr
R
+
ip t
O
N
Ac ce p
te
d
M
an
us
62a: R = Ar = Ph: 99% yield, 98% ee, > 98% de 62b: R = Ph, Ar = p-Tol: 99% yield, 98% ee, > 98% de 62c: R = Ph, Ar = m-Tol: 99% yield, 96% ee, > 98% de 62d: R = Ph, Ar = p-FC6H4: 99% yield, 97% ee, > 98% de 62e: R = Ph, Ar = p-ClC6H4: 96% yield, 98% ee, > 98% de 62f: R = Ph, Ar = p-MeOC6H4: 92% yield, 98% ee, > 98% de 62g: R = Ph, Ar = p-NO2C6H4: 91% yield, 97% ee, 90% de 62h: R = Ph, Ar = m-NO2C6H4: 96% yield, 95% ee, > 98% de 62i: R = Ph, Ar = 2-Naph: 99% yield, 98% ee, > 98% de 62j: R = Ph, Ar = 2-furyl: 99% yield, 99% ee, > 98% de 62k: R = m-Tol, Ar = Ph: 99% yield, 97% ee, 94% de 62l: R = p-Tol, Ar = Ph: 97% yield, 97% ee, 96% de 62m: R = p-FC6H4, Ar = Ph: 99% yield, 98% ee, > 98% de 62n: R = m-MeOC6H4, Ar = Ph: 99% yield, 96% ee, > 98% de 62o: R = p-PhC6H4, Ar = Ph: 88% yield, 97% ee, > 98% de 62p: R = 2-Naph, Ar = Ph: 96% yield, 98% ee, > 98% de 62q: R = (E)-PhCH=CH, Ar = Ph: 95% yield, 98% ee, 94% de
possible mechanism: TsNCl2
+ TsNH2
4 Å M.S.
TsNHCl +
O
p-Tol O S O NH
[Sc]
Sc(OTf)3/58
O R
Ar Ar
61
R Cl 63
O
NHTs
Ar
R Cl 62
38 Page 38 of 135
Scheme 15. Three-component chloroamination reaction of α,β-unsaturated ketones [38].
In 2011, the same authors also developed highly efficient enantioselective iodoamination
ip t
reactions of α,β-unsaturated ketones 64a-o with N-iodosuccinimide (NIS) and TsNH2 in the presence of 0.5 mol% of a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral
cr
N,N’-dioxide ligand 65 [39]. As shown in Scheme 16, the three-component process allowed a
us
range of trans-α-iodo-β-amino products 66a-o to be achieved most of the time as single diastereomers (> 98% de) in very good yields of up to 97% and remarkable
an
enantioselectivities of up to 98% ee. Interestingly, these excellent results were obtained regardless of the electronic nature or position of the substituents on the phenyl rings (66b-g
M
and 66j-l). Moreover, naphthyl-, cinnamyl-, and furyl-substituted chalcones were also suitable substrates for the reaction, providing the corresponding products 66n, 66o, and 66m in 98%
d
ee. TsNHI species, generated from the reaction between NIS and TsNH2 in the presence of
te
molecular sieves, was confirmed by the authors as the active species in the iodoamination
Ac ce p
process involved in the formation of the key iodonium ion intermediates.
39 Page 39 of 135
ON H
O
O
H N R3 R3 3 R = BnCH2 65 (0.5 mol%) Sc(OTf)3 (0.5 mol%)
R2 64a-o + NIS + TsNH2
TsNH
O
R1
R2
4 Å M.S., dark
I
CH2Cl2, 23 °C
66a-o
cr
O R1
+ N O-
ip t
N+
te
d
M
an
us
66a: R1 = R2 = Ph: 96%, 96% ee, > 98% de 66b: R1 = o-Tol, R2 = Ph: 95%, 98% ee, > 98% de 66c: R1 = m-Tol, R2 = Ph: 96%, 98% ee, > 98% de 66d: R1 = p-Tol, R2 = Ph: 86%, 98% ee, > 98% de 66e: R1 = p-FC6H4, R2 = Ph: 85%, 97% ee, > 98% de 66f: R1 = p-ClC6H4, R2 = Ph: 95%, 98% ee, > 98% de 66g: R1 = p-MeOC6H4, R2 = Ph: 90%, 95% ee, > 90% de 66h: R1 = Me, R2 = Ph: 86%, 94% ee, > 98% de 66i: R1 = H, R2 = Ph: 90%, 90% ee 66j: R1 = Ph, R2 = p-Tol: 93%, 97% ee, > 98% de 66k: R1 = Ph, R2 = p-FC6H4: 97%, 97% ee, > 98% de 66l: R1 = Ph, R2 = p-MeOC6H4: 91%, 98% ee, > 98% de 66m: R1 = Ph, R2 = 2-furyl: 90%, 98% ee, > 98% de 66n: R1 = Ph, R2 = 2-Naph: 92%, 98% ee, > 98% de 66o: R1 = Ph, R2 = (E)-PhCH=CH: 93%, 98% ee, > 98% de
Ac ce p
Scheme 16. Three-component iodoamination reaction of α,β-unsaturated ketones [39].
The same reaction conditions were applied to the asymmetric iodoamination of a variety of α,β-unsaturated γ-ketoesters 57a-k which afforded the corresponding chiral β-iodo-α-amino acid derivatives 67a-k as almost single trans-diastereomers (> 90% de) in excellent enantioselectivities of 95-98% ee and very high yields except in the cases of substrates with bulky groups on the ester moiety (75-83% yields for products 67c-d) [39]. On the other hand, both the steric hindrance of ester moieties and the electronic properties of the substituents on the aromatic ring had little influence on the diastereoselectivities always > 90% de (Scheme 17).
40 Page 40 of 135
+ N
N+ O-
O
O-
O
Ar
OR O
65 (0.5 mol%)
57a-k
O
Sc(OTf)3 (0.5 mol%) Ar
+ NIS 4 Å M.S., dark + TsNH2
CH2Cl2, 23 °C
NHTs OR * * I O
cr
R'
O
H N R' R' = BnCH2
ip t
N H
us
67a-k
M
an
67a: Ar = Ph, R = Me: 96%, 96% ee, 96% de 67b: Ar = Ph, R = Et: 96%, 98% ee, 98% de 67c: Ar = Ph, R = i-Pr: 83%, 96% ee, 98% de 67d: Ar = Ph, R = t-Bu: 75%, 97% ee, > 98% de 67e: Ar = R = Ph: 90%, 97% ee, > 90% de 67f: Ar = Ph, R = Bn: 94%, 97% ee, 96% de 67g: Ar = p-MeOC6H4, R = Et: 92%, 95% ee, 94% de 67h: Ar = p-Tol, R = Et: 89%, 96% ee, 96% de 67i: Ar = p-FC6H4, R = Et: 97%, 97% ee, 96% de 67j: Ar = p-BrC6H4, R = Et: 88%, 97% ee, 96% de 67k: Ar = m-MeOC6H4, R = Et: 90%, 98% ee, > 90% de
te
d
Scheme 17. Three-component iodoamination reaction of α,β-unsaturated γ-ketoesters [39].
Ac ce p
In another context, a three-component asymmetric Mannich reaction of silyl ketene imines 68a-f was reported by these authors by using a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 69 [40]. As shown in Scheme 18, substrates 71a-f reacted with imines in situ generated from aldehydes 26a-m and aminophenol 70 to give the corresponding chiral β-amino nitriles 71a-r bearing vicinal tertiary and quaternary stereogenic centers in high yields of up to 96%, high enantioselectivities of up to 97% ee, and moderate to excellent diastereoselectivities of 60-98% de. Indeed, a wide range of aldehydes were suitable substrates for the reaction of α-methyl-α-aryl silyl ketene imines derived from electron-rich as well as electron-deficient aromatic aldehydes. The diastereoselectivity was slightly influenced by the position of the substituents on the aromatic ring of the aldehydes. 41 Page 41 of 135
Generally, ortho-substituted aromatic aldehydes gave the desired products 71b and 71h-i with better diastereoselectivity (90-94% de) than the meta-substituted ones (78-80% de for products 71c and 71e). Both excellent diastereo- and enantioselectivities were also achieved
ip t
(96% ee, 94-96% de) for products 71j-k derived from fused-ring aromatic aldehydes while 3furyl and cyclohexyl aldehydes provided the corresponding products 71l-m in lower
cr
stereoselectivities (77% ee and 60% de for 71l, 89% ee and 80% de for 71m). On the other hand, linear aliphatic aldehydes were unreactive. Concerning the scope of the aryl group of
us
the silyl ketene imines, electron-rich as well as electron-poor silyl ketene imines provided the
an
corresponding β-amino nitriles 71n-r in good yields (80-95%) and high diastereo- and
Ac ce p
te
d
M
enantioselectivities of 82-98% de, and 90-93% ee, respectively.
42 Page 42 of 135
+ N
N+ O-
O
O-
O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2
O + H2N Ar +
OH
69 (10 mol%) Sc(OTf)3 (10 mol%)
OH 70
i-PrNH2 (20 mol%)
TBS
EtOAc, -20 °C
NH R
C N
cr
R H 26a-m
ip t
N H
Ar
C N
71a-r
us
68a-f
Ac ce p
te
d
M
an
71a: R = Ar = Ph: 92% yield, 95% ee, 84% de 71b: R = o-Tol, Ar = Ph: 77% yield, 95% ee, 94% de 71c: R = m-Tol, Ar = Ph: 85% yield, 94% ee, 80% de 71d: R = p-Tol, Ar = Ph: 94% yield, 93% ee, 88% de 71e: R = m-MeOC6H4, Ar = Ph: 94% yield, 89% ee, 78% de 71f: R = p-MeOC6H4, Ar = Ph: 79% yield, 97% ee, 90% de 71g: R = p-ClC6H4, Ar = Ph: 95% yield, 94% ee, 80% de 71h: R = o-ClC6H4, Ar = Ph: 95% yield, 94% ee, 90% de 71i: R = o-BrC6H4, Ar = Ph: 96% yield, 93% ee, 90% de 71j: R = 1-Naph, Ar = Ph: 91% yield, 96% ee, 96% de 71k: R = 2-Naph, Ar = Ph: 88% yield, 96% ee, 94% de 71l: R = 3-furyl, Ar = Ph: 87% yield, 77% ee, 60% de 71m: R = Cy, Ar = Ph: 65% yield, 89% ee, 80% de 71n: R = Ph, Ar = m-Tol: 88% yield, 92% ee, 82% de 71o: R = Ph, Ar = p-MeOC6H4: 80% yield, 90% ee, 88% de 71p: R = Ph, Ar = p-ClC6H4: 95% yield, 92% ee, 96% de 71q: R = Ph, Ar = o-BrC6H4: 87% yield, 93% ee, 98% de 71r: R = Ph, Ar = p-BrC6H4: 88% yield, 92% ee, 88% de
Scheme 18. Three-component Mannich reaction of silyl ketene imines [40].
Intramolecular
versions
of
asymmetric
scandium-catalyzed
two-component
halogenoaminations have been recently reported by Shi et al. For example, these authors have described an efficient enantioselective domino bromination/aminocyclization reaction of allyl N-tosylcarbamates 72a-o with N-bromosuccinimide (NBS) as bromine source to afford the corresponding chiral functionalized oxazolidinones 73a-o [41]. In all cases, the reactions proceeded regioselectively to give the 5-exo products as single diastereomers. The process, catalyzed by a combination of Sc(OTf)3 and Trost ligand 74, allowed a variety of these 43 Page 43 of 135
products to be achieved in generally good yields of up to 90% and high enantioselectivities of up to 97% ee (Scheme 19). The substituents (R1) on the olefin could be linear (products 73ad) or branched alkyl groups (products 73e-f). Moreover, various functional groups, such as
ip t
OBn, OAc, OTs, CN, Cl, and NHBoc, could be present in the side chains (products 73g-l). Other chiral ligands were investigated thus demonstrating that the phosphine group and its
cr
position were crucial for maintaining good yield and enantioselectivity of the reaction.
an
H N
us
Furthermore, it was assumed that the phosphine could be involved in the activation of NBS.
PPh2
O O
O
R1
72a-o NBS
Ac ce p
+
NHTs
Sc(OTf)3 (2-5 mol%)
te
O
74 (2-5 mol%)
d
R2
PPh2
M
N H
toluene/CH2Cl2, -50 °C
O O
NTs R1 R2
Br
73a-o > 99% de
73a: R1 = Et, R2 = H: 88% yield, 96% ee 73b: R1 = n-Bu, R2 = H: 80% yield, 96% ee 73c: R1 = n-Hex, R2 = H: 90% yield, 96% ee 73d: R1 = CH2Bn, R2 = H: 83% yield, 93% ee 73e: R1 = CH2Cp, R2 = H: 77% yield, 96% ee 73f: R1 = Cy, R2 = H: 71% yield, 96% ee 73g: R1 = CH2OBn, R2 = H: 80% yield, 94% ee 73h: R1 = (CH2)3OAc, R2 = H: 80% yield, 97% ee 73i: R1 = (CH2)3OTs, R2 = H: 75% yield, 97% ee 73j: R1 = (CH2)3CN, R2 = H: 75% yield, 96% ee 73k: R1 = (CH2)3Cl, R2 = H: 87% yield, 96% ee 73l: R1 = (CH2)3NHBoc, R2 = H: 50% yield, 92% ee 73m: R1 = R2 = Me: 81% yield, 83% ee 73n: R1 = n-Bu, R2 = Me: 83% yield, 91% ee 73o: R1 = i-Bu, R2 = Me: 87% yield, 88% ee
Scheme 19. Domino bromination/aminocyclization reaction of allyl N-tosylcarbamates [41]. 44 Page 44 of 135
In 2015, a related methodology was reported by the same group, dealing with asymmetric domino bromination/aminocyclization reaction of homoallylic N-tosylcarbamates 75a-i [42].
ip t
In this case, the bromine source was N-bromoacetamide and the optimal catalyst was derived from a novel chiral monophosphine 76 and Sc(OTf)3. In these conditions, a wide variety of
cr
chiral oxazinanones 77a-i were produced through highly enantioselective 6-exobromoaminocyclization in moderate yields albeit remarkable enantioselectivities of up to >
us
99% ee (Scheme 20). The substrates could bear various functional groups, including OBn, Cl,
M
an
and N3 among others, in the side chains (75e-g).
H N
PPh2
O O
te
d
N H
O
NHTs
O
Ac ce p
R
75a-i
+ MeCONHBr
NO2 76 (10 mol%)
Sc(OTf)3 (10 mol%)
O O
NTs R
CH2Cl2, -15 °C
Br 77a-i
77a: R = Me: 58% yield, 99% ee 77b: R = Et: 57% yield, > 99% ee 77c: R = n-Pent: 57% yield, > 99% ee 77d: R = CH2Cy: 54% yield, 99% ee 77e: R = (CH2)2OBn: 48% yield, 97% ee 77f: R = (CH2)2Cl: 45% yield, 99% ee 77g: R = (CH2)2N3: 48% yield, 98% ee 77h: R = allyl: 59% yield, 98% ee 77i: R = H: 72% yield, 64% ee
Scheme
20.
Domino
bromination/aminocyclization
reaction
of
homoallylic
N-
tosylcarbamates [42].
45 Page 45 of 135
In addition, these authors recently developed an efficient regio- and enantioselective 6-endo bromoaminocyclization of 2,4-dienyl N-tosylcarbamates 78a-n using 1,3-dibromo-5,5-
ip t
dimethylhydantoin (DBDMH) as the bromine source and a chiral phosphine oxide/Sc(OTf)3 complex as catalyst employed at 5 mol% of catalyst loading [43]. As shown in Scheme 21,
cr
the domino process afforded a range of chiral 5-bromo-1,3-oxazinan-2-ones 79a-n bearing various functional groups, such as OMe, OAc, and N3, in good yields (up to 91%) and general
us
excellent enantioselectivities of 92-99% ee. The substituents on the diene could be linear
an
(78b-d) or branched alkyl groups (78e). Moreover, aryl-substituted (78i-k) and trisubstituted dienes (78l-n) were also effective substrates for the reaction. While much lower yield (28%)
M
and enantioselectivity (84% ee) were obtained for product 79a when using chiral diphosphine ligand 74, the use of the corresponding phosphine oxide ligand 80 allowed these excellent
Ac ce p
te
d
results to be achieved. An additive, such as NaCl, was crucial for the reaction.
46 Page 46 of 135
H N OO O O O O
NHTs
78a-n
Sc(OTf)3 (5 mol%)
NTs R2
O
2
R
Br
N
cr
+
R1
NaCl (1.2 equiv)
O
CHCl3, -50 °C
N Br
Br
3
R
79a-n
us
R
O
80 (5 mol%)
R3 1
PPh2
ip t
N H
PPh2
an
O DBDMH
Ac ce p
te
d
M
79a: R1 = Me, R2 = R3 = H: 91% yield, 97% ee 79b: R1 = Et, R2 = R3 = H: 83% yield, 96% ee 79c: R1 = n-Pr, R2 = R3 = H: 87% yield, 95% ee 79d: R1 = n-Bu, R2 = R3 = H: 79% yield, 93% ee 79e: R1 = i-Pr, R2 = R3 = H: 84% yield, 95% ee 79f: R1 = CH2OMe, R2 = R3 = H: 77% yield, 97% ee 79g: R1 = CH2OAc, R2 = R3 = H: 71% yield, 95% ee 79h: R1 = CH2N3, R2 = R3 = H: 65% yield, 95% ee 79i: R1 = Ph, R2 = R3 = H: 61% yield, 95% ee 79j: R1 = p-ClC6H4, R2 = R3 = H: 71% yield, 95% ee 79k : R1 = p-FC6H4, R2 = R3 = H: 68% yield, 97% ee 79l: R1 = R2 = Me, R3 = H: 79% yield, 92% ee 79m: R1 = R3 = Me, R2 = H: 81% yield, 98% ee 79n: R1,R3 = (CH2)4, R2 = H: 64% yield, 99% ee
Scheme 21. Domino bromination/aminocyclization reaction of 2,4-dienyl N-tosylcarbamates [43].
Closely related conditions were also applied by these authors to the asymmetric domino bromination/aminocyclization reaction of 2-benzofuranylmethyl N-tosylcarbamates 81a-n with DBDMH [44]. As shown in Scheme 22, the process afforded a novel class of chiral spiro benzofuran oxazolidinones 82a-n in good to excellent yields of 62-97% and remarkable enantioselectivities of 91-97% ee when using Na2CO3 as an additive. Homogeneous results 47 Page 47 of 135
were achieved for a range of 2-benzofuranylmethyl N-tosylcarbamates 81a-n containing various electron-rich or electron-deficient substituents at the C4, C5, and C6 positions. The utility of the process was shown by the transformation of some products into other
OO O O N H
1
R
PPh2 PPh2
NHTs
2
R
Sc(OTf)3 (5 mol%)
81a-n
Na2CO3 (1.2 equiv)
M
+
80 (5 mol%)
O
O
R3
an
O
O
us
H N
cr
ip t
functionalized chiral spiro benzofuran oxazolidinones without loss of optical purity.
O N Ts
R3
O
82a-n
te
O DBDMH
O
d
Br
N
Br
R2
CHCl3, -60 °C
N Br
R1
Ac ce p
82a: R1 = R2 = R3 = H: 90% yield, 94% ee 82b : R1 = F, R2 = R3 = H: 80% yield, 94% ee 82c: R1 = Br, R2 = R3 = H: 87% yield, 96% ee 82d : R1 = R3 = H, R2 = Me: 89% yield, 94% ee 82e: R1 = R3 = H, R2 = t-Bu: 90% yield, 97% ee 82f: R1 = R3 = H, R2 = F: 97% yield, 94% ee 82g: R1 = R3 = H, R2 = Cl: 93% yield, 92% ee 82h: R1 = R3 = H, R2 = Br: 82% yield, 93% ee 82i: R1 = R3 = H, R2 = I: 62% yield, 91% ee 82j: R1 = R2 = H, R3 = F: 83% yield, 93% ee 82k: R1 = R2 = H, R3 = Cl: 91% yield, 91% ee 82l: R1 = R2 = H, R3 = Br: 91% yield, 93% ee 82m: R1 = H, R2 = R3 = F: 95% yield, 91% ee 82n : R1 = R3 = Me, R2 = Cl: 88% yield, 96% ee
Scheme 22. Domino bromination/aminocyclization reaction of 2-benzofuranylmethyl Ntosylcarbamates [44].
3. Enantioselective scandium-catalyzed Michael additions 48 Page 48 of 135
Although firstly reported by Komnenos in 1883 [45], the nucleophilic 1,4-addition of stabilized carbon nucleophiles to electron-poor olefins, generally α,β-unsaturated carbonyl
ip t
compounds, is known as the Michael addition. More generally, Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereocontrolled formation of
cr
carbon−carbon and carbon−heteroatom bonds [46], as has been demonstrated by the huge
us
number of examples in which it has been applied as a key strategic transformation in total synthesis. Although base catalysis is commonly known as a very efficient and high-yielding
an
process in Michael reactions, the strongly basic conditions are often a limiting factor since they can lead to a number of side- and subsequent reactions generating by-products. In order
M
to circumvent these drawbacks, catalysis by metals which work formally under neutral conditions, has attracted the attention of the chemists in this area as a mild and efficient
d
alternative to base catalysis [46b,f,k,l,]. Actually, the catalysis of the Michael reaction by transition metals was first reported in 1972 by Saegusa et al. who treated malonates and
te
diketones with various α,β-unsaturated carbonyl compounds and derivatives using achiral
Ac ce p
copper complexes [47]. The first asymmetric Michael addition catalyzed by a chiral scandium complex was described in 1997 by Katsuki and Kitajima [48]. It involved the addition of 2(trimethylsilyloxy)furans to give the corresponding chiral butenolides achieved by using Sc(OTf)3 and 3,3’-bis(diethylaminomethyl)-1,1’-bi-2-naphthol as catalyst system. Ever since, various other ligands have been investigated in a range of scandium-catalyzed Michael additions of β-ketoesters, malonates, hydroxylamines, or thiols to α,β-unsaturated carbonyl compounds, among which N,N’-dioxides [49], pybox derivatives [50], and BNP ligands [51]. A recent example was reported by Vaccaro et al. dealing with enantioselective scandiumcatalyzed addition of thiols 83a-e to α,β-unsaturated ketones 64a-f [52]. As shown in Scheme 23, this process was performed in water with a catalyst system composed of 1 mol% of
49 Page 49 of 135
Sc(OTf)3 and 2 mol% of chiral bipyridine ligand 84. It provided the corresponding chiral βketo sulfides (R)-85a-m in satisfactory yields of up to 93% and good to high enantioselectivities of up to 97% ee (Scheme 23). Other Lewis acids derived from the same
ip t
ligand, including Yb(OTf)3, In(OTf)3, and Bi(NO3)3, all resulted in lower yields and enantioselectivities. The substrate scope showed that in contrast to all aliphatic thiols which
cr
provided very good results in general, thiophenol 83d led to a moderate enantioselectivity of
us
52% ee. Highly enantioenriched products were obtained with both aryl- and alkyl-substituted enones (Scheme 23). An advantage of this methodology was that the catalyst system could be
an
recovered and recycled with no loss in enantioselectivity. Notably, this work represented the
M
first Lewis acid-catalyzed enantioselective sulfa-Michael addition performed in water.
d
N
N
O
te
t-Bu
3
R1 + R SH
Ac ce p
R2
64a-f
83a-e
t-Bu
OH HO 84 (2 mol%) SR3 O
Sc(OTf) 3 (1 mol%) H2O, 30 °C
R2
R1 85a-m
85a: R1 = Me, R2 = Ph, R3 = n-Bu: 93% yield, 94% ee 85b: R1 = Me, R2 = Ph, R3 = t-Bu: 93% yield, 97% ee 85c: R1 = Me, R2 = Ph, R3 = c-Pent: 83% yield, 97% ee 85d: R1 = Me, R2 = R3 = Ph: 81% yield, 52% ee 85e: R1 = Me, R2 = p-ClC6H4, R3 = Bn: 87% yield, 90% ee 85f: R1 = Me, R2 = p-NO2C6H4, R3 = Bn: 88% yield, 89% ee 85g: R1 = Me, R2 = n-Pent, R3 = Bn: 82% yield, 94% ee 85h: R1 = R2 = Ph, R3 = Bn: 73% yield, 92% ee 85i: R1 = Me, R2 = p-ClC6H4, R3 = t-Bu: 79% yield, 97% ee 85j: R1 = R2 = Ph, R3 = t-Bu: 60% yield, 97% ee 85k: R1 = Me, R2 = p-ClC6H4, R3 = c-Pent: 75% yield, 95% ee 85l: R1 = Me, R2 = n-Pr, R3 = c-Pent: 71% yield, 76% ee 85m: R1 = R2 = Ph, R3 = c-Pent: 84% yield, 96% ee
Scheme 23. Michael reaction of thiols with α,β-unsaturated ketones [52]. 50 Page 50 of 135
These reactions were also independently investigated by Kobayashi et al. at room temperature by using a combination of Sc(OTf)3 with an even lower catalyst loading (1.2
ip t
mol%) of the enantiomer of ligand 84 (ent-84) in water [53]. Using 10 mol% of pyridine as an additive allowed better yields of up to 92% and enantioselectivities of up to 97% ee to be
cr
achieved for a range of β-keto sulfides (S)-85a-j arising from Michael reactions of the
us
corresponding thiols 83a-e with α,β-unsaturated ketones 64a-f. As in the preceding work (Scheme 21), a much lower enantioselectivity (44% ee) was obtained in the case of reaction
an
of thiophenol to give product (S)-85g while general high enantioselectivities were observed
d
M
from aliphatic thiols.
N
N
Ac ce p
O
te
t-Bu
3 R1 + R SH
R2
64a-f
83a-e
OH
t-Bu HO
ent-84 (1.2 mol%) SR3 O
Sc(OTf)3 (1 mol%) pyridine (10 mol%) H2O, r.t.
R2
R1 85a-j
85a: R1 = Me, R2 = Ph, R3 = Bn: 92% yield, 93% ee 85b: R1 = R2 = Ph, R3 = Bn: 83% yield, 94% ee 85c : R1 = Me, R2 = n-Pent, R3 = Bn: 65% yield, 85% ee 85d: R1 = Et, R2 = Me, R3 = Bn: 84% yield, 84% ee 85e : R1 = Ph, R2 = Me, R3 = Bn: 88% yield, 90% ee 85f: R1 = Me, R2 = p-ClC6H4, R3 = Bn: 82% yield, 92% ee 85g: R1 = R2 = R3 = Ph: 92% yield, 44% ee 85h: R1 = R2 = Ph, R3 = Et: 80% yield, 97% ee 85i: R1 = R2 = Ph, R3 = i-Pr: 81% yield, 86% ee 85j: R1 = R2 = Ph, R3 = c-Pent: 91% yield, 93% ee
Scheme 24. Michael reaction of thiols with α,β-unsaturated ketones [53].
51 Page 51 of 135
Closely related reaction conditions were later applied by these authors to the Michael addition of benzylmercaptan 83a to indanone- and tetralone-derived enones 86a-g [54]. As shown in Scheme 25, a range of chiral functionalized indanone- and tetralone products 87a-g
ip t
were achieved in moderate to good yields of up to 90%, generally high enantioselectivities of up to 98% ee, along with moderate to high syn-diastereoselectivities of up to 94% de by using
cr
6 mol% of chiral ligand ent-84 in combination with 5 mol% of Sc(OTf)3. General high syn/anti ratios were obtained in the case of using tetralone-derived enones as substrates 86a-d
us
and 86f-g while indanone-derived enone 86e provided only 36% de (Scheme 25). Lower
an
yields (26-37%) were obtained in the case of tetrasubstituted tetralone products 87f-g. Higher yields and selectivities were reached performing the reactions in water than in organic
d
M
solvents.
te
N
N
t-Bu
R3
Ac ce p
O
R2 + BnSH
R1
( )n
86a-g
t-Bu
OH HO ent-84 (6 mol%)
83a
O
SBn R2
Sc(OTf)3 (5 mol%)
3
R pyridine (20 mol%) H2O, r.t.
R1
( )n 87a-g
87a : R1 = R3 = H, R2 = Ph, n = 1: 90% yield, 80% de, 96% ee 87b: R1 = R3 = H, R2 = p-MeOC6H4, n = 1: 75% yield, 90% de, 97% ee 87c : R1 = R3 = H, R2 = p-ClC6H4, n = 1: 56% yield, 88% de, 97% ee 87d: R1 = OMe, R2 = Ph, R3 = H, n = 1: 83% yield, 94% de, 98% ee 87e : R1 = R3 = H, R2 = Ph, n = 0: 75% yield, 36% de, 97% ee 87f: R1 = H, R2 = R3 = Me, n = 1: 37% yield, 92% ee 87g: R1 = MeO, R2 = R3 = Me, n = 1: 26% yield, 94% ee
Scheme 25. Michael reaction of benzylmercaptan with tetralone- and indanone-derived enones [54].
52 Page 52 of 135
Earlier in 2011, Feng et al. described enantioselective scandium-catalyzed Michael additions of 4-substituted pyrazolones 88a-e to 4-oxo-4-arylbutenoates 57a-i to give the
ip t
corresponding 4-disubstituted pyrazolones 89a-m [55]. As shown in Scheme 26, these Michael products bearing a quaternary stereogenic center were produced in generally high
cr
yields and enantioselectivities of up to 97% and 95% ee, respectively, in combination with
us
moderate to high diastereoselectivities (64-90% de) in the presence of a scandium catalyst derived from chiral N,N’-dioxide ligand 90 and Sc(OTf)3. The more sterically hindered
an
isopropyl 4-oxo-4-arylbutenoate exhibited better diastereo- and enantioselectivities than ethyl 4-oxo-4-arylbutenoate (products 89a-b), and the reaction proceeded well for many differently
M
substituted 4-oxo-4-arylbutenoates and 4-substituted pyrazolones, independently of the electron-donating or electron-withdrawing character of the substituents. Moreover,
Ac ce p
te
products 89h-i with good results.
d
heteroaromatic and fused-ring substrates were also applicable, giving the corresponding
53 Page 53 of 135
R1
O
ON H
O
+ N O-
O
H N Ar'
Ar' Ar' = 2,4,6-Me3C6H2 90 (5.5 mol%) Sc(OTf)3 (5 mol%)
Ph N N 88a-e +
O Ar
O
CO2R2 R1 O
EtOH, 30 °C N 89a-m
N
Ph
cr
CO2R2
Ar
ip t
N+
57a-i
te
d
M
an
us
89a: R1 = Bn, Ar = Ph, R2 = Et: 95%, 86% ee, 64% de 89b: R1 = Bn, Ar = Ph, R2 = i-Pr: 83%, 90% ee, 80% de 89c: R1 = Bn, Ar = p-Tol, R2 = i-Pr: 91%, 92% ee, 74% de 89d: R1 = Bn, Ar = p-FC6H4, R2 = i-Pr: 85%, 94% ee, 72% de 89e: R1 = Bn, Ar = p-ClC6H4, R2 = i-Pr: 95%, 93% ee, 76% de 89f : R1 = Bn, Ar = p-MeOC6H4, R2 = i-Pr: 85%, 92% ee, 70% de 89g: R1 = Bn, Ar = m-ClC6H4, R2 = i-Pr: 83%, 92% ee, 86% de 89h: R1 = Bn, Ar = 2-thienyl, R2 = i-Pr: 95%, 90% ee, 60% de 89i: R1 = Bn, Ar = 2-Naph, R2 = i-Pr: 97%, 91% ee, 78% de 89j: R1 = p-Tol, Ar = Ph, R2 = i-Pr: 91%, 95% ee, 80% de 89k: R1 = 2-furanylmethyl, Ar = Ph, R2 = i-Pr: 95%, 95% ee, 90% de 89l: R1 = Et, Ar = Ph, R2 = i-Pr: 97%, 93% ee, 90% de 89m: R1 = Me, Ar = Ph, R2 = i-Pr: 92%, 86% ee, 86% de
Ac ce p
Scheme 26. Michael reaction of 4-substituted pyrazolones with 4-oxo-4-arylbutenoates [55].
Over the past decade, tremendous progress has been achieved in the catalytic asymmetric aza-Michael reaction, since the resulting chiral β-amino carbonyl compounds are both biologically and synthetically of great importance [56]. As a result, numerous attractive nitrogen nucleophiles were attempted. In this context, benzoyl hydrazine has been added to α,β-unsaturated ketones 92a-t by Feng et al. in the presence of Sc(OTf)3 and another N,N’dioxide chiral ligand 91 [57]. The interest in using hydrazine is not only due to its derivatives having pharmacological activities, but also to the challenging issue of regioselectivity between two competitive amines. Thus, this process afforded the corresponding aza-Michael products 93a-t through regioselective addition of the nonactivated amine moiety of the 54 Page 54 of 135
hydrazine in moderate to high yields of up to 87% and good to high enantioselectivities (8497% ee). As shown in Scheme 27, the electron-withdrawing as well as electron-donating substituents at the aromatic R were tolerated under these mild reaction conditions with
ip t
excellent enantioselectivity and yield (93b-g). In contrast, the corresponding aryl (Ar)substituted analogs furnished the desired products 93k-p with moderate yields and unequal
cr
enantioselectivities, due to the electronic effect of functional groups. The process tolerated fused-ring, styryl or multi-substituted and heteroaromatic-substituted substrates, providing the
us
corresponding Michael products 93h-j and 93q-t in moderate yields with up to 97% ee. The
an
absolute configuration was determined to be S in the case of product 93k through X-ray analysis. This work constituted the first catalytic asymmetric aza-Michael reaction through
M
the nonactivated amine moiety of benzoyl hydrazine toward chalcones achieved highly
Ac ce p
te
d
enantio- and regioselectively.
55 Page 55 of 135
N+ O
O-
N
+
O-
O H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 Ph O 91 (6 mol%) HN NH O Sc(OTf)3 (5 mol%)
Ar
R + Ph
N H
NH2
4 Å M.S.
92a-t
CH2Cl2, 25 °C
Ar
*
R
93a-t
cr
O
O
ip t
N H
Ac ce p
te
d
M
an
us
93a: Ar = R = Ph: 78% yield, 93% ee 93b: Ar = Ph, R = p-FC6H4: 81% yield, 95% ee 93c: Ar = Ph, R = p-ClC6H4: 77% yield, 96% ee 93d: Ar = Ph, R = m-FC6H4: 75% yield, 89% ee 93e : Ar = Ph, R = p-MeOC6H4: 74% yield, 94% ee 93f: Ar = Ph, R = p-Tol: 71% yield, 94% ee 93g: Ar = Ph, R = m-Tol: 70% yield, 94% ee 93h: Ar = Ph, R = 2-thienyl: 75% yield, 90% ee 93i: Ar = Ph, R = 2-Naph: 68% yield, 90% ee 93j: Ar = Ph, R = (E)-PhCH=CH: 87% yield, 86% ee 93k: Ar = p-ClC6H4, R = Ph: 69% yield, 84% ee (S) 93l: Ar = p-Tol, R = Ph: 62% yield, 91% ee 93m: Ar = m-Tol, R = Ph: 71% yield, 91% ee 93n: Ar = o-Tol, R = Ph: 67% yield, 94% ee 93o: Ar = p-MeOC6H4, R = Ph: 64% yield, 97% ee 93p: Ar = p-PhC6H4, R = Ph: 51% yield, 94% ee 93q: Ar = 3-thienyl, R = Ph: 42% yield, 88% ee 93r: Ar = 1-Naph, R = Ph: 75% yield, 97% ee 93s: Ar = 2-Naph, R = Ph: 64% yield, 91% ee 93t: Ar = 2,3-Cl2C6H3, R = Ph: 60% yield, 85% ee
Scheme 27. Aza-Michael reaction of benzoyl hydrazine with α,β-unsaturated ketones [56].
Catalytic asymmetric addition of azoles to electron-deficient olefins provided a protocol for the introduction of optically active azole moieties that can be found in many drugs. However, only a few examples of this type of methodology exist. Among them, enantioselective scandium-catalyzed aza-Michael addition of 1H-benzotriazole 94 to α,β-unsaturated ketones 61a-v reported by Feng et al., which afforded the corresponding N-1 products 95a-v in both excellent yields of up to 99% and enantioselectivities of up to 99% ee (Scheme 28) [58]. 56 Page 56 of 135
These results were achieved by using chiral N,N’-dioxide ligand 96 which was selected among a variety of other N,N’-dioxides. The electronic nature and the position of the substituents at the aromatic ring of R or Ar had little influence on the enantioselectivity (95b-
ip t
m and 95p-r). The electronic and stereochemical effects of the β-aromatic substituents were greater than those of the aromatic substituents of the carbonyl moiety. Notably, when the β-
cr
substituent R was an unsaturated cinnamyl group or an aliphatic cyclohexyl group, the
us
corresponding Michael products 95n-o were obtained in moderate yields (45-60%) with 82 and 88% ee, respectively. Good to high enantioselectivities (80-95% ee) were also achieved
Ac ce p
te
d
M
an
with substrates bearing heteroaromatic substituents (61t-v).
57 Page 57 of 135
N+ O-
O
+ N O-
O
O R
N Ar +
N H
5 Å M.S. CHCl3, -20 °C
94
N
N R *
O
Ar
95a-v
us
61a-v
Sc(OTf)3 (2.5 mol%)
N
N
cr
H N Ar' Ar' Ar' = p-ClC6H4 96 (2.5 mol%)
ip t
N H
Ac ce p
te
d
M
an
95a: R = Ar = Ph: 99% yield, 96% ee 95b: R = o-ClC6H4, Ar = Ph: 65% yield, 88% ee 95c: R = m-ClC6H4, Ar = Ph: 99% yield, 97% ee 95d: R = p-ClC6H4, Ar = Ph: 99% yield, 97% ee 95e: R = p-FC6H4, Ar = Ph: 88% yield, 97% ee 95f: R = p-BrC6H4, Ar = Ph: 98% yield, 96% ee 95g: R = m-NO2C6H4, Ar = Ph: 87% yield, 98% ee 95h: R = p-NO2C6H4, Ar = Ph: 80% yield, 99% ee 95i: R = p-CNC6H4, Ar = Ph: 60% yield, 98% ee 95j: R = m-Tol, Ar = Ph: 99% yield, 95% ee 95k: R = p-Tol, Ar = Ph: 98% yield, 93% ee 95l: R = p-MeOC6H4, Ar = Ph: 90% yield, 85% ee 95m: R = 2-Naph, Ar = Ph: 65% yield, 96% ee 95n: R = (E)-PhCH=CH, Ar = Ph: 45% yield, 82% ee 95o: R = Cy, Ar = Ph: 60% yield, 88% ee 95p: R = Ph, Ar = p-ClC6H4: 99% yield, 97% ee 95q: R = Ph, Ar = p-NO2C6H4: 99% yield, 95% ee 95r: R = Ph, Ar = p-MeOC6H4: 99% yield, 95% ee 95s: R = Ph, Ar = 2-Naph: 96% yield, 96% ee 95t: R = 2-thienyl, Ar = Ph: 50% yield, 80% ee 95u: R = Ph, Ar = 2-thienyl: 35% yield, 95% ee 95v: R = Ph, Ar = 2-furyl: 98% yield, 92% ee
Scheme 28. Aza-Michael reaction of 1-H-benzotriazole with α,β-unsaturated ketones [58].
More recently, a chiral scandium catalyst in situ generated from ScCl3•6H2O and chiral N,N’-dioxide ligand 97 was applied to develop enantioselective aza-Michael reactions of pyrazole 99 with α-substituted vinyl ketones 98a-n to provide in excellent yields the corresponding optically active pyrazole derivatives 100a-n [59]. As shown in Scheme 29, 58 Page 58 of 135
general high enantioselectivities of 89-94% ee were achieved for vinyl ketones 98a-m bearing an aromatic α-substituent (R ) while substrate 98n having a methyl group (R = Me) gave a 2
2
R2 R1
O2N
R1
H
R2
N N
NO2
CHCl3, 2N HCl, 30 °C
100a-n
100a: R1 = H, R2 = Ph: 99%, 93% ee 100b: R1 = 4-F, R2 = Ph: 87%, 94% ee 100c: R1 = 4-Cl, R2 = Ph: 86%, 94% ee 100d: R1 = 4-Br, R2 = Ph: 98%, 94% ee 100e: R1 = 4-Me, R2 = Ph: 91%, 92% ee 100f: R1 = 4-MeO, R2 = Ph: 97%, 90% ee 100g: R1 = H, R2 = o-ClC6H4: 99%, 94% ee 100h: R1 = H, R2 = p-ClC6H4: 98%, 91% ee 100i: R1 = H, R2 = o-BrC6H4: 99%, 93% ee 100j: R1 = H, R2 = m-BrC6H4: 99%, 93% ee 100k: R1 = H, R2 = m-BrC6H4: 99%, 90% ee 100l: R1 = 4-Me, R2 = p-FC6H4: 99%, 90% ee 100m: R1 = 4-OMe, R2 = 2-Naph: 93%, 89% ee 100n: R1 = H, R2 = Me: 93%, 60% ee
Ac ce p
te
d
99
N
ScCl3(6H2O) (10 mol%)
O
an
H N
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3 97 (10 mol%)
M
98a-n
cr
O
+
ON H
O
us
+ N O-
N+
ip t
lower enantioselectivity of 60% ee. The use of HCl(aq.) as additive accelerated the process.
Scheme 29. Aza-Michael reaction of a pyrazole with α-substituted vinyl ketones [59].
The butenolide skeleton ranks among one of the most ubiquitous structural motifs found in naturally occurring products and biologically active compounds [60]. In 2011, Feng et al. developed a very efficient synthesis of chiral γ-substituted butenolides 101a-u based on
59 Page 59 of 135
enantio- and regioselective scandium-catalyzed Michael reaction of 2-silyloxyfuran 102 with chalcones 103a-u [61]. A broad range of these fuctionalized products were achieved as single anti-diastereomers with complete γ-regioselectivity, almost quantitative yields in general, and
ip t
good to high enantioselectivities of 82-94% ee (Scheme 30). The process was catalyzed by a combination of 5 mol% of Sc(OTf)3 and the same quantity of chiral N,N’-dioxide ligand 104
cr
in a mixture of ethyl propionate and tert-butanol as solvent. It is notable that this catalyst system exhibited a remarkably broad substrate scope under exclusive diastereocontrol without
us
any side product from α-addition. Regardless of the electronic properties or steric hindrance
an
of the substituent (Ar1) at the β-phenyl group of the chalcones, excellent enantioselectivities were observed (101b-m). The catalyst was also applicable to heterocyclic systems, which
Ac ce p
te
d
M
delivered the corresponding Michael products 104n-o with 90-92% ee.
60 Page 60 of 135
N+ O-
O
+ N O-
O
N H
O Ar1
Ar2
TBSO +
O
O O
Sc(OTf)3 (5 mol%)
O
t-BuOH/ethyl propionate, 0 °C 102
Ar1
Ar2
101a-u
cr
103a-u
ip t
H N Ar3 Ar3 3 Ar = 2,6-Et2C6H3 104 (5 mol%)
Ac ce p
te
d
M
an
us
> 98% de 101a: Ar1 = Ar2 = Ph: 99% yield, 90% ee 101b: Ar1 = p-Tol, Ar2 = Ph: 99% yield, 87% ee 101c: Ar1 = m-Tol, Ar2 = Ph: 97% yield, 90% ee 101d: Ar1 = o-Tol, Ar2 = Ph: 99% yield, 90% ee 101e: Ar1 = p-MeOC6H4, Ar2 = Ph: 98% yield, 90% ee 101f: Ar1 = m-MeOC6H4, Ar2 = Ph: 99% yield, 91% ee 101g: Ar1 = p-FC6H4, Ar2 = Ph: 98% yield, 90% ee 101h: Ar1 = p-ClC6H4, Ar2 = Ph: 92% yield, 90% ee 101i: Ar1 = m-ClC6H4, Ar2 = Ph: 95% yield, 92% ee 101j: Ar1 = p-BrC6H4, Ar2 = Ph: 99% yield, 91% ee 101k: Ar1 = m-BrC6H4, Ar2 = Ph: 96% yield, 92% ee 101l: Ar1 = p-CNC6H4, Ar2 = Ph: 99% yield, 92% ee 101m: Ar1 = m-CF3C6H4, Ar2 = Ph: 98% yield, 94% ee 101n: Ar1 = 2-thienyl, Ar2 = Ph: 99% yield, 92% ee 101o: Ar1 = 3-thienyl, Ar2 = Ph: 99% yield, 90% ee 101p: Ar1 = Ph, Ar2 = p-Tol: 99% yield, 88% ee 101q: Ar1 = Ph, Ar2 = m-Tol: 96% yield, 84% ee 101r: Ar1 = Ar2 = p-MeOC6H4: 92% yield, 82% ee 101s: Ar1 = p-BrC6H4, Ar2 = p-Tol: 92% yield, 88% ee 101t: Ar1 = m-BrC6H4, Ar2 = p-Tol: 99% yield, 91% ee 101u: Ar1 = m-CF 3C6H4, Ar2 = p-Tol: 99% yield, 89% ee
Scheme 30. Michael reaction of a 2-silyloxyfuran with chalcones [61].
In addition, chiral γ,γ-disubstituted butenolides 105a-o were highly efficiently synthesized through enantioselective Michael addition of β,γ-unsaturated butenolides 106a-c to α,βunsaturated γ-ketoesters 107a-m upon catalysis with a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand 108 [62]. These highly functionalized products were achieved in
61 Page 61 of 135
moderate to good yields of up to 93%, good to high diastereoselectivities of up to > 90% de, and high to excellent enantioselectivities of up to 97% ee (Scheme 31). Ligand 108 was selected among a variety of N,N’-dioxides, as well as Sc(OTf)3 as most efficient Lewis acid
ip t
among a series of other precatalysts including Ni(OTf)2, Cu(OTf)2, La(OTf)3, and Y(OTf)3 which gave either no products or poor enantioselectivities (< 27% ee). Under the optimized
cr
reaction conditions, the ester group (R2) of substrate 107 exhibited an influence on both diastereo- and enantioselectivities (products 105a-c). The bulkier alkyl group (t-butyl) gave
us
slightly better diastereo- and enantioselectivities than methyl and ethyl groups. The stereocontrol of the reaction was sensitive to neither the electronic property nor the steric
an
hindrance of substituents on the phenyl ring (R1) of aromatic α,β-unsaturated γ-ketoesters
M
107, however, generally the meta-substituted substrates gave lower yields than the ortho- and para-substituted ones (Scheme 31). The substrate scope could be extended to fused-ring and
d
heteroaromatic substrates 107j-l with good diastereo- and enantioselectivities of up to 88% de
te
and 95% ee, respectively. Notably, good results (86% de, 90% ee) were also reached with aliphatic α,β-unsaturated γ-ketoester 107m. The steric hindrance of the alkyl group from
Ac ce p
methyl to ethyl and n-C10H21 was investigated, showing that the diastereo- and enantioselectivity of the process increased (92% ee and 86% de for product 105a, 97% ee and > 90% de for product 105n, and 96% ee and > 90% de for product 105o, respectively).
62 Page 62 of 135
ON H
O Ar R
Ar = 2,6-Me2-4-(t-Bu)C6H2 108 (5 mol%) O Sc(OTf)3 (5 mol%)
O 106a-c
+
OO *
MeOAc, 4 Å M.S., 0 °C R1
O R1
O
H N Ar
CO2R2
R3
2 * CO2R
105a-o
cr
O
3
+ N O-
ip t
N+
107a-m
Ac ce p
te
d
M
an
us
105a: R1 = Ph, R2 = t-Bu, R3 = Me: 85%, 92% ee, 86% de 105b: R1 = Ph, R2 = R3 = Me: 88%, 89% ee, 74% de 105c: R1 = Ph, R2 = Et, R3 = Me: 83%, 86% ee, 75% de 105d: R1 = o-Tol, R2 = t-Bu, R3 = Me: 92%, 89% ee, > 90% de 105e: R1 = m-Tol, R2 = t-Bu, R3 = Me: 59%, 89% ee, 82% de 105f: R1 = p-Tol, R2 = t-Bu, R3 = Me: 64%, 96% ee, 86% de 105g: R1 = o-MeOC6H4, R2 = t-Bu, R3 = Me: 84%, 90% ee, > 90% de 105h: R1 = p-MeOC6H4, R2 = t-Bu, R3 = Me: 86%, 95% ee, 90% de 105i: R1 = m-MeOC6H4, R2 = t-Bu, R3 = Me: 68%, 87% ee, 78% de 105j: R1 = 1-Naph, R2 = t-Bu, R3 = Me: 69%, 82% ee, 88% de 105k: R1 = 2-Naph, R2 = t-Bu, R3 = Me: 72%, 95% ee, 82% de 105l: R1 = 2-thienyl, R2 = t-Bu, R3 = Me: 93%, 83% ee, 82% de 105m: R1 = Cy, R2 = t-Bu, R3 = Me: 57%, 90% ee, 86% de 105n: R1 = Ph, R2 = t-Bu, R3 = Et: 50%, 97% ee, > 90% de 105o: R1 = Ph, R2 = t-Bu, R3 = n-C10H21: 63%, 96% ee, > 90% de
Scheme 31. Michael reaction of β,γ-unsaturated butenolides with α,β-unsaturated γ-ketoesters [62].
The catalytic asymmetric conjugate addition of carbon nucleophiles to alkynyl carbonyl compounds is an efficient way to construct versatile and useful building blocks because the newly formed C=C bond can be further functionalized. In contrast to extensive and fruitful studies on enantioselective 1,4-addition reactions of electron-deficient alkenes, investigations of conjugate additions of electron-deficient alkynes are still limited. The difficulty in controlling both E/Z selectivity and enantioselectivity is probably the reason for this limited
63 Page 63 of 135
amount of studies. Generally, the predominant product of these reactions is the thermodynamically stable E isomer. In 2012, Feng et al. reported enantioselective scandiumcatalyzed Michael reactions of alkynones 109a-l with a 4-substituted pyrazolone 88a which
ip t
afforded highly stereoselectively the corresponding thermodynamically unstable Z products 110a-l bearing a quaternary stereogenic center in high enantiomeric and geometric control
cr
[63]. As shown in Scheme 32, these highly Z-selective additions were catalyzed by a combination of Sc(OTf)3 (5 mol%) and 6 mol% of chiral N,N’-dioxide ligand 111, providing
us
a series of functionalized optically active 4-alkenyl-pyrazol-5-ones 110a-l in high yields of up to 95%, high diastereoselectivities of up to > 90% de, and excellent enantioselectivities of up
an
to 99% ee. This catalyst system showed a remarkably broad substrate scope, since a wide range of aromatic, aliphatic, and heterocyclic alkynone derivatives 109a-l provided
Ac ce p
te
d
M
homogeneous excellent results.
64 Page 64 of 135
N+ O-
O
+ N O-
R 109a-l
Sc(OTf)3 (5 mol%)
+ Bn
R
O O
CHCl3, 0 or 25 °C Ph N N
Ph
Bn N N
cr
110a-l
ip t
H N Ar Ar Ar = 1-adamantyl 111 (6 mol%)
O
O
O
N H
88a
d
M
an
us
110a: R = o-Tol: 95% yield, Z/ E = 91:9, 99% ee 110b: R = m-Tol: 93% yield, Z/ E = 93:7, 97% ee 110c: R = p-Tol: 90% yield, Z/ E = 95:5, 98% ee 110d: R = o-FC6H4: 93% yield, Z/ E = 91:9, 96% ee 110e: R = p-FC6H4: 93% yield, Z/ E = 89:11, 96% ee 110f: R = p-ClC6H4: 92% yield, Z/E = 94:6, 96% ee 110g: R = o-MeOC6H4: 93% yield, Z/ E > 95:5, 98% ee 110h: R = 4-F-3-OPhC6H3: 92% yield, Z/E = 88:2, 91% ee 110i: R = 2-Naph: 91% yield, Z/ E > 95:5, 98% ee 110j: R = 2-thienyl: 92% yield, Z/E = 89:11, 96% ee 110k: R = Cy: 90% yield, Z/ E = 88:12, 97% ee 110l: R = n-Pent: 85% yield, Z/E = 92:8, 98% ee
Ac ce p
te
Scheme 32. Michael reaction of alkynones with a 4-substituted pyrazolone [63].
In the same area, these authors also developed enantioselective Michael reactions of alkynones 109a-i with 3-substituted oxindoles 112a-h through catalysis with a scandium complex derived from Sc(OTf)3 and another chiral N,N’-dioxide ligand 113 [64]. As shown in Scheme 33, the reactions were again highly Z-stereoselective since the corresponding enone derivatives 114a-p with a vinyl-substituted quaternary stereogenic center were achieved in very high Z/E ratios of 89:11 to > 95:5. Remarkable yields of up to 99% along with enantioselectivities of 93-99% ee were obtained for a range of substrates, such as 3aryloxindoles bearing electron-donating as well as electron-withdrawing aryl groups and oxindoles bearing 3-thienyl or 3-condensed ring substituent (products 114f-g). Furthermore,
65 Page 65 of 135
the process tolerated a series of alkynones with aromatic as well as aliphatic substituents.
+ N
N+ -
O-
O
O
ip t
Notably, the catalyst loading could be reduced to 0.5 mol%.
R3 109a-i +
Sc(OTf)3 (0.5-5 mol%)
R2
O
R3 R2
R1 O
THF, 30 °C
N H 112a-h
O
N H 114a-p
an
4 Å M.S.
R1
cr
O
us
H N Ar Ar Ar = 2,6-Et2-4-MeC6H2 113 (0.6-6 mol%)
O
N H
Ac ce p
te
d
M
114a: R1 = 5-Me, R2 = R3 = Ph: 96% yield, Z/E > 95:5, 94% ee 114b: R1 = 5-Cl, R2 = R3 = Ph: 98% yield, Z/ E > 95:5, 99% ee 114c: R1 = H, R2 = p-FC6H4, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114d: R1 = H, R2 = p-ClC6H4, R3 = Ph: 99% yield, Z/ E = 94:6, 99% ee 114e: R1 = H, R2 = m-Tol, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114f: R1 = H, R2 = 2-thienyl, R3 = Ph: 93% yield, Z/ E > 95:5, 99% ee 114g: R1 = H, R2 = 2-Naph, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114h: R1 = H, R2 = Bn, R3 = Ph: 94% yield, Z/ E = 95:5, 96% ee 114i: R1 = 5-Me, R2 = Ph, R3 = p-Tol: 98% yield, Z/ E > 95:5, 98% ee 114j: R1 = 5-Me, R2 = Ph, R3 = p-FC6H4: 97% yield, Z/ E > 95:5, 99% ee 114k: R1 = 5-Me, R2 = Ph, R3 = p-BrC6H4: 97% yield, Z/ E > 95:5, 99% ee 114l: R1 = 5-Me, R2 = Ph, R3 = p-CF3C6H4: 97% yield, Z/ E > 95:5, 94% ee 114m: R1 = 5-Me, R2 = Ph, R3 = 2-Naph: 96% yield, Z/ E > 95:5, 98% ee 114n: R1 = 5-Me, R2 = Ph, R3 = 2-thienyl: 98% yield, Z/ E = 89:11, 93% ee 114o: R1 = 5-Me, R2 = Ph, R3 = Cy: 90% yield, Z/ E = 90:10, 98% ee 114p: R1 = 5-Me, R2 = Ph, R3 = n-Pent: 90% yield, Z/E > 95:5, 96% ee
Scheme 33. Michael reaction of alkynones with 3-substituted oxindoles [64].
In 2015, a series of 3-substituted oxindoles 112a-m were reacted with linear dienyl ketones 115a-c in the presence of a catalytic amount of Sc(OTf)3 and chiral N,N’-dioxide ligand 9 to give regioselectively the corresponding chiral oxindoles 116a-u with quaternary stereocenters 66 Page 66 of 135
through 1,6-addition [65]. In the case of 1,6-addition of δ-unsubstituted dienyl ketones 115a-b (R3 = H), the corresponding Michael products 116a-n were achieved in moderate to good yields of 63-89% along with high enantioselectivities of 92-99% ee. As shown in Scheme 34,
ip t
the electronic properties of the substituents on the aromatic ring (Ar) had only little effect on the enantioselectivity of the reaction. Similarly, both the electronic nature and the position of
cr
the substituents R2 at the aromatic ring of oxindole substrates had a limited influence on the enantioselectivity (116b-h). Substrates bearing a condensed-ring or heteroaromatic-ring
us
substituent as R2 were also applicable, affording the corresponding products 116i-k with 96-
an
99% ee. The scope of this methodology was also successfully applied to the 1,6-addition of 3substituted oxindoles 112o-u to δ-methyl-substituted dienyl ketone 115c (R3 = Me) by simply
M
changing the solvent from chloroform to THF, providing the corresponding enantiopure Michael adducts 116o-u with a very high general diastereoselectivity of up to > 90% de, and
d
good yields of up to 87% (Scheme 34). Again, both the electronic properties and the steric
te
hindrance of the substituent R2 of the oxindole substrate had no obvious effect on the
Ac ce p
enantioselectivity and diastereoselectivity of the process.
67 Page 67 of 135
+ N O-
R2
R1
O O
N H 112a-m +
ON H
O
H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 9 (6 mol%) Sc(OTf)3 (5 mol%)
R1
R2
Ar
Ar
O
N H
4 Å M. S. CHCl3 or THF, 30 °C
O
cr
R3
*
*
O
R3
ip t
N+
116a-u
us
115a-b
Ac ce p
te
d
M
an
116a: R1 = R3 = H, R2 = Bn, Ar = p-MeOC6H4: 67% yield, 97% ee 116b: R1 = R3 = H, R2 = m-BrC6H4, Ar = Ph: 72% yield, 96% ee 116c: R1 = R3 = H, R2 = m-BrC6H4, Ar = p-MeOC6H4: 72% yield, 96% ee 116d: R1 = R3 = H, R2 = m-NO2C6H4, Ar = p-MeOC6H4: 79% yield, 96% ee 116e: R1 = R3 = H, R2 = m-Tol, Ar = p-MeOC6H4: 63% yield, 97% ee 116f: R1 = R3 = H, R2 = p-BrC6H4, Ar = p-MeOC6H4: 79% yield, 96% ee 116g: R1 = R3 = H, R2 = p-CNC6H4, Ar = p-MeOC6H4: 81% yield, 96% ee 116h: R1 = R3 = H, R2 = Ar = p-MeOC6H4: 68% yield, 98% ee 116i: R1 = R3 = H, R2 = 2-naphthylmethyl, Ar = p-MeOC6H4: 85% yield, 96% ee 116j: R1 = R3 = H, R2 = 2-thienylmethyl, Ar = p-MeOC6H4: 80% yield, 99% ee 116k: R1 = R3 = H, R2 = 2-furanylmethyl, Ar = p-MeOC6H4: 84% yield, 98% ee 116l: R1 = R3 = H, R2 = Me, Ar = p-MeOC6H4: 80% yield, 92% ee 116m: R1 = R3 = H, R2 = Ph, Ar = p-MeOC6H4: 89% yield, 94% ee (S) 116n: R1 = R3 = H, R2 = 2-Naph, Ar = p-MeOC6H4: 80% yield, 93% ee 116o: R1 = H, R2 = Bn, R3 = Me, Ar = p-MeOC6H4: 83% yield, > 99% ee, > 90% de 116p: R1 = H, R2 = m-Tol, R3 = Me, Ar = p-MeOC6H4: 74% yield, > 99% ee, > 90% de 116q: R1 = H, R2 = m-BrC6H4, R3 = Me, Ar = p-MeOC6H4: 80% yield, 99% ee, 90% de 116r: R1 = H, R2 = Ar = p-MeOC6H4, R3 = Me: 78% yield, > 99% ee, > 90% de 116s: R1 = H, R2 = 2-naphthylmethyl, R3 = Me, Ar = p-MeOC6H4: 87% yield, > 99% ee, > 90% de 116t: R1 = H, R2 = 2-thienylmethyl, R3 = Me, Ar = p-MeOC6H4: 80% yield, > 99% ee, > 90% de 116u: R1 = H, R2 = R3 = Me, Ar = p-MeOC6H4: 72% yield, > 99% ee, 80% de
Scheme 34. Michael reaction of dienyl ketones with 3-substituted oxindoles [65].
In 2015, the same authors reported enantioselective Michael addition of 3-substituted oxindoles 112a-m to N-(2-t-butylphenyl)maleimide 117 in the presence of a scandium catalyst in situ generated from chiral N,N’-dioxide ligand 69 and Sc(OTf)3 [66]. As shown in
68 Page 68 of 135
Scheme 35, when the reaction was performed in the presence of K2HPO4, a range of chiral atropoisomeric succinimides 118a-m bearing adjacent quaternary and tertiary centers were afforded in remarkable yields of up to 99%, enantio- and diastereoselectivities of up to 99%
ip t
ee and > 90% de, respectively. Excellent results were reached for various 3-substituted benzyl oxindoles 112a-h as well as for oxindoles 112i-k substituted by heteroaromatic or fused-ring.
cr
Lower diastereo- and enantioselectivities of 50-80% de and 88-89% ee, respectively, were
N+ R R2
+
O t-Bu
Ac ce p
N O 117
O
K2HPO4 (3 equiv) CH2Cl2, 30 °C
H N R2 1
R
Sc(OTf)3 (10 mol%)
te
N H 112a-m
O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 69 (10 mol%)
d
O
ON H
+ N O-
M
O
1
an
us
obtained in the case of reactions of 3-phenyl oxindole 112l and 3-methyl oxindole 112m.
O
N
O t-Bu
118a-m
118a: R1 = Bn, R2 = H: 99% yield, 97% ee, > 90% de 118b: R1 = o-BrC6H4CH2, R2 = H: 99% yield, 96% ee, > 90% de 118c: R1 = m-BrC6H4CH2, R2 = H: 98% yield, 98% ee, > 90% de 118d: R1 = p-BrC6H4CH2, R2 = H: 94% yield, 96% ee, > 90% de 118e: R1 = p-ClC6H4CH2, R2 = H: 87% yield, 95% ee, > 90% de 118f: R1 = m-NO2C6H4CH2, R2 = H: 99% yield, 97% ee, > 90% de 118g: R1 = p-MeOC6H4CH2, R2 = H: 99% yield, 97% ee, > 90% de 118h: R1 = p-TolCH2, R2 = H: 99% yield, 97% ee, > 90% de 118i: R1 = 2-furanylmethyl, R2 = H: 93% yield, 94% ee, > 90% de 118j: R1 = 2-thienylmethyl, R2 = H: 93% yield, 95% ee, > 90% de 118k: R1 = 2-naphthylmethyl, R2 = H: 99% yield, 97% ee, > 90% de 118l: R1 = Ph, R2 = H: 96% yield, 89% ee, 80% de 118m: R1 = Me, R2 = H: 91% yield, 88% ee, 50% de
69 Page 69 of 135
Scheme 35. Michael reaction of N-(2-t-butylphenyl)maleimide with 3-substituted oxindoles
ip t
[66].
Although impressive progress in the metal-catalyzed asymmetric Michael additions has
cr
been made in the past decades, there remains a great challenge in the diastereoselectivity issue of these reactions, especially those involving nitroalkanes with α,β-unsaturated ketones. In
us
this context, Wang et al. have employed an in situ generated scandium catalyst from Sc(OTf)3 and novel chiral C2-symmetric tridentate Schiff base ligand 119 to promote the first
an
enantioselective Michael reaction of nitroalkanes 120a-b with 2-enoyl-pyridine N-oxides 121a-n [67]. This novel process allowed a range of chiral Michael products 122a-o to be
M
achieved in good yields of up to 89%, moderate to good anti-diastereoselectivities of 50-92% de, and high enantioselectivities of 91-95% ee (Scheme 36). 2-Enoyl-pyridine N-oxides 121a-
d
m and 121o with (hetero)aromatic substituents as well as substrates such as 121n bearing an
te
aliphatic substituent were tolerated. To illustrate the synthetic utility of this process, one of
Ac ce p
the products was converted into a biologically active analogue of nicotine. It is important to note that the level of diastereoselectivity reached in these reactions was unprecedented in the asymmetric 1,4-addition of nitroalkanes to α,β-unsaturated ketones.
70 Page 70 of 135
CF3 F3C OH HO N
Bn NH
R2
HN
O
O 119 (15 mol%)
121a-n
Sc(OTf)3 (15 mol%)
+ R1
O N
O
R2
R1
NO2
Cs2CO3 (15 mol%)
NO2
ip t
O
cr
O N
N
Bn
THF, r.t.
122a-o
us
120a-b
Ac ce p
te
d
M
an
122a: R1 = Me, R2 = Ph: 87% yield, 93% ee, 84% de 122b: R1 = Me, R2 = p-FC6H4: 86% yield, 93% ee, 80% de 122c: R1 = Me, R2 = p-ClC6H4: 76% yield, 92% ee, 82% de 122d: R1 = Me, R2 = p-BrC6H4: 72% yield, 95% ee, 84% de 122e: R1 = Me, R2 = p-Tol: 84% yield, 92% ee, 82% de 122f: R1 = Me, R2 = p-MeOC6H4: 89% yield, 91% ee, 80% de 122g: R1 = Me, R2 = m-MeOC6H4: 86% yield, 95% ee, 78% de 122h: R1 = Me, R2 = m-NO2C6H4: 64% yield, 91% ee, 60% de 122i: R1 = Me, R2 = m-FC6H4: 81% yield, 91% ee, 66% de 122j: R1 = Me, R2 = o-FC6H4: 79% yield, 93% ee, 80% de 122k: R1 = Me, R2 = 2,4-(MeO)2C6H3: 89% yield, 92% ee, 84% de 122l: R1 = Me, R2 = 2-Naph: 84% yield, 95% ee, 78% de 122m: R1 = Me, R2 = 2-furyl: 76% yield, 92% ee, 50% de 122n: R1 = Me, R2 = n-Hex: 69% yield, 95% ee, 92% de 122o: R1 = Et, R2 = Ph: 72% yield, 93% ee, 80% de
Scheme 36. Michael reaction of nitroalkanes with 2-enoyl-pyridine N-oxides [67].
Recently, Yoon et al. reported the first highly enantioselective intermolecular reaction of αamino radicals achieved through cooperative photoredox and Lewis acid catalysis [68]. This process began with the in situ generation of these radicals from the corresponding αsilylamines 123a-g (Scheme 37) in the presence of Ru(bpy)3Cl2 under irradiation with fluorescent light. These radicals were then submitted to asymmetric conjugate addition to α,βunsaturated ketones 124a-j bearing a pyrazolidinone moiety. A range of chiral γaminocarbonyl products 125a-s were achieved in moderate to excellent yields (35-96%) and good to high enantioselectivities of 85-96% ee when using an in situ generated scandium catalyst from pybox ligand 126 and Sc(OTf)3. A variety of electron-withdrawing para 71 Page 71 of 135
substituents (R1 = F, Cl, Br) were easily accommodated on the N-aryl moiety of α-silylamines 123b-d (90-96% yields, 92-94% ee for products 125b-d) while modestly electron-donating substituents (R1 = Me) slowed the rate of the reaction (79% yield) without affecting the enantioselectivity (product 125e). High enantioselectivities (92-96% ee) were also reached with substrates having substituents in ortho and meta substituents (products 125f-g).
ip t
Generally, N-alkyl-N-aryl α-silylamines were employed but a good result was also achieved with a N,N-diaryl α-silylamine (R4 = Ph) giving the corresponding product 125h in 93% yield
cr
and 91% ee. Sterically bulky N-alkyl-N-aryl α-silylamines (R4 = Bn, i-Pr) reacted sluggishly in the reaction, providing the corresponding products 125i-j in 33-60% yields albeit with
us
excellent enantioselectivities (94-95% ee). Concerning the Michael acceptors, aliphatic as well as aromatic ones bearing both electron-poor and electron-rich substituents provided
an
comparable high enantioselectivities (91-96% ee). A marginally diminished enantioselectivity of 85% ee was obtained for ortho-substituted product 125r. To expand the utility of this methodology, an efficient removal of the pyrazolidinone auxiliary was achieved from some
Ac ce p
te
d
M
products without erosion of the enantioselectivity.
72 Page 72 of 135
O
R1
R3
O
N N
TMS
N
i-Bu
i-Bu 126 (20 mol%)
R4 N
Sc(OTf)3 (15 mol%)
R2 123a-g
Ru(bpy)3Cl2 (2 mol%)
+ O R5
O
R1
Bu4NCl (30 mol%)
R5
O N N
R3
Et
R2
MeCN, visible light
125a-s
cr
N N
O
ip t
R4 N
Et
us
124a-j
Ac ce p
te
d
M
an
125a: R1 = R2 = R3 = H, R4 = R5 = Me: 87% yield, 93% ee 125b: R1 = F, R2 = R3 = H, R4 = R5 = Me: 94% yield, 94% ee 125c: R1 = Cl, R2 = R3 = H, R4 = R5 = Me: 96% yield, 93% ee 125d: R1 = Br, R2 = R3 = H, R4 = R5 = Me: 90% yield, 92% ee 125e: R1 = Me, R2 = R3 = H, R4 = R5 = Me: 79% yield, 91% ee 125f: R1 = R3 = H, R2 = OMe, R4 = R5 = Me: 85% yield, 92% ee 125g: R1 = R2 = H, R3 = F, R4 = R5 = Me: 80% yield, 96% ee 125h: R1 = R2 = R3 = H, R4 = Ph, R5 = Me: 93% yield, 91% ee 125i: R1 = R2 = R3 = H, R4 = Bn, R5 = Me: 60% yield, 94% ee 125j: R1 = R2 = R3 = H, R4 = i-Pr, R5 = Me: 33% yield, 95% ee 125k: R1 = R2 = R3 = H, R4 = Me, R5 = n-Pr: 76% yield, 93% ee 125l: R1 = R2 = R3 = H, R4 = Me, R5 = i-Pr: 71% yield, 93% ee 125m: R1 = R2 = R3 = H, R4 = Me, R5 = CH2OBn: 75% yield, 91% ee 125n: R1 = R2 = R3 = H, R4 = Me, R5 = t-Bu: 35% yield, 96% ee 125o: R1 = R2 = R3 = H, R4 = Me, R5 = Ph: 74% yield, 93% ee 125p: R1 = R2 = R3 = H, R4 = Me, R5 = p-ClC6H4: 63% yield, 91% ee 125q: R1 = R2 = R3 = H, R4 = Me, R5 = p-MeOC6H4: 83% yield, 94% ee 125r: R1 = R2 = R3 = H, R4 = Me, R5 = o-MeOC6H4: 81% yield, 85% ee 125s: R1 = R2 = R3 = H, R4 = Me, R5 = 2-furyl: 83% yield, 91% ee
proposed mechanism: R4 N
R1
R3
O
TMS
R2 123a-g
R1 Ru(bpy)3Cl2
N N Et
R3 Michael
2
R
R4 N R1
R5
R4 N
photoredox activation
[Sc]* O
R5
O
O N N
R3
Et
2
R
125a-s
73 Page 73 of 135
Scheme 37. Michael reaction of α-amino radicals with α,β-unsaturated ketones [68].
ip t
4. Enantioselective scandium-catalyzed cycloaddition reactions
cr
Cycloaddition reactions which form multiple bonds, rings, and stereocenters are particularly
us
important tools for the efficient assembly of complex molecular structures [69]. Of the many families of reactions discovered over the past century, cycloaddition reactions hold a
an
prominent place in the arsenal of synthetic methods currently available to organic chemists and the research activity in this field shows no signs of abatement [70]. Among
M
cycloadditions, the 1,3-dipolar cycloaddition (Huisgen cycloaddition [71]) is a classic reaction in organic chemistry consisting of the reaction of a dipolarophile with a 1,3-dipolar compound
d
that allows the production of important 5-membered heterocycles. This reaction represents
te
one of the most productive fields of modern synthetic organic chemistry. Indeed, catalytic methods encompassing metal carbene intermediates constitute a vast array of transformations
Ac ce p
that offer the synthetic chemist great scope in the synthesis of many complex molecules [72]. Among the metals used to catalyze cycloadditions [73], scandium has been recently used by Zhang and Li in an enantioselective [3+2] cycloaddition of alkyne 127 with N-tosylaziridine 128 to give the corresponding chiral highly substituted 3-pyrroline 129 [74]. The latter was produced in 80% yield with a moderate enantioselectivity of 70% ee when using chiral pybox ligand 27 in combination with Sc(OTf)3 as catalyst system (Scheme 38).
74 Page 74 of 135
O
Ph 128
N
N
CO2Et 27 (5.5 mol%)
CO2Et
Ph
Ts N
Sc(OTf)3 (5 mol%)
CO2Et
+ p-MeOC6H4
MeO
CO2Et p-MeOC6H4
4 Å M.S.
OMe
CH2Cl2, r.t.
129
cr
127
ip t
Ts N
O
N
80% yield, 70% ee
an
us
Scheme 38. [3+2] Cycloaddition of an alkyne with an N-tosylaziridine [74].
The importance of optically active β-lactones as versatile chiral synthons underscores
M
current research efforts for developing novel catalytic enantioselective methods, among which the asymmetric [2+2] cycloaddition between ketenes and carbonyl compounds appears to be
d
the most elegant. In 2014, Feng et al. developed highly efficient [2+2] cycloadditions of
te
disubstituted ketenes 130a-l with substituted isatins 6a-i to give the corresponding chiral βlactones 131a-t [75]. This process was catalyzed by a chiral scandium complex in situ
Ac ce p
generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 9, and provided a range of chiral spiro cycloadducts bearing two contiguous quaternary stereogenic centers as almost single diastereomers (> 98% de) in high yields of up to 99%, and generally excellent enantioselectivities of up to 98% ee (Scheme 39). Remarkably, in most cases of substrates, the catalyst loading could be reduced as low as 0.2-0.5 mol%. Studying the substrate scope of the reaction, the authors demonstrated its generality and functional group tolerance. For example, the substituent on the aryl group (Ar1) of aryl alkyl ketenes had little or no effect on the stereoselectivity.
75 Page 75 of 135
O
+ O
H N Ar2 Ar2 2 Ar = 2,6-i-Pr2C6H3 9 (0.2-2 mol%)
O R2
ON H
N O-
O N Bn 6a-i
O O
Sc(OTf)3 (0.2-2 mol%)
+
R
N Bn
cr
CH2Cl2, 30 °C
C O
Ar1 O
2
3 Å M.S.
Ar1
R1
ip t
N+
131a-t
R1
> 98% de
us
130a-l
Ac ce p
te
d
M
an
131a: Ar1 = Ph, R1 = Et, R2 = H: 96% yield, 95% ee 131b: Ar1 = Ph, R1 = n-Pr, R2 = H: 95% yield, 88% ee 131c: Ar1 = Ph, R1 = n-Bu, R2 = H: 97% yield, 91% ee 131d: Ar1 = o-FC6H4, R1 = Et, R2 = H: 90% yield, 96% ee 131e: Ar1 = m-FC6H4, R1 = Et, R2 = H: 91% yield, 95% ee 131f: Ar1 = p-FC6H4, R1 = Et, R2 = H: 95% yield, 96% ee 131g: Ar1 = o-MeOC6H4, R1 = Et, R2 = H: 77% yield, 86% ee 131h: Ar1 = m-MeOC6H4, R1 = Et, R2 = H: 96% yield, 97% ee 131i: Ar1 = p-MeOC6H4, R1 = Et, R2 = H: 87% yield, 96% ee 131j: Ar1 = p-Tol, R1 = Et, R2 = H: 91% yield, 98% ee 131k: Ar1 = p-ClC6H4, R1 = Et, R2 = H: 99% yield, 96% ee 131l: Ar1 = 2-Naph, R1 = Et, R2 = H: 95% yield, 97% ee 131m: Ar1 = Ph, R1 = Et, R2 = 6-F: 80% yield, 96% ee 131n: Ar1 = Ph, R1 = Et, R2 = 5-F: 95% yield, 85% ee 131o: Ar1 = Ph, R1 = Et, R2 = 6-Br: 90% yield, 80% ee 131p: Ar1 = Ph, R1 = Et, R2 = 7-F: 90% yield, 98% ee 131q: Ar1 = Ph, R1 = Et, R2 = 7-Cl: 84% yield, 97% ee 131r: Ar1 = Ph, R1 = Et, R2 = 7-Br: 96% yield, 97% ee 131s: Ar1 = Ph, R1 = Et, R2 = 7-Me: 79% yield, 98% ee 131t: Ar1 = Ph, R1 = Et, R2 = 7-CF 3CO: 80% yield, 96% ee
Scheme 39. [2+2] Cycloaddition of ketenes with isatins [75].
The asymmetric hetero-Diels−Alder reaction is one of the most efficient synthetic methodologies for the regio- and stereoselective construction of chiral six-membered heterocycles [76]. In recent years, several examples of these reactions have used chiral scandium catalysts. For example, Desimoni et al. have developed enantioselective hetero-
76 Page 76 of 135
Diels−Alder cycloaddition of 4-aryl-2-oxo-3-butenoates 132a-b with 1-trialkylsiloxy-1cyclohexenes 133a-b catalyzed by a combination of Sc(OTf)3 and chiral pybox ligand 134 in the presence of HFIP as an additive [77]. The corresponding almost enantiopure cycloadducts
ip t
135a-d were obtained in moderate to good yields (53-73%) as major diastereomers bearing a
N N
Ph + O 132a-b
OSiRR'2 133a-b
Ph 134 (10 mol%) Sc(OTf)3 (10 mol%) 3 Å M.S. HFIP (1.7 equiv) CH2Cl2, -20 °C
M
MeO2C
N
H
an
Ar
O
us
O
cr
trans ring junction with moderate diastereoselectivities of 14-66% de (Scheme 40).
R'2RSiO
Ar
O
CO2Me
135a-d major
te
d
135a: Ar = Ph, R = R' = Me: 55% yield, 98% ee, 14% de 135b: Ar = p-BrC6H4, R = R' = Me: 62% yield, 99% ee, 56% de 135c: Ar = Ph, R = t-Bu, R' = Me: 73% yield, 99% ee, 66% de 135d: Ar = p-BrC6H4, R = t-Bu, R' = Me: 53% yield, 98% ee, 42% de
Ac ce p
Scheme 40. Hetero-Diels−Alder cycloaddition of 4-aryl-2-oxo-3-butenoates with 1trialkylsiloxy-1-cyclohexenes [77].
Chiral dihydrocoumarin derivatives have attracted much attention due to their pharmacological and physiological activities. Consequently, significant efforts have been devoted to the asymmetric synthesis of these fascinating molecules. Among them, enantioselective inverse-electron-demand hetero-Diels−Alder cycloadditions of o-quinones 136a-b with azlactones 137a-p were recently developed by Feng et al. by using a chiral scandium catalyst [78]. Among a series of N,N’-dioxides investigated, L-ramipril-derived ligand 138 was selected as optimal to achieve the corresponding chiral functionalized 3,4dihydrocoumarins 139a-p bearing nitrogen atom substituents as almost single diastereomers 77 Page 77 of 135
(> 90% de) in good yields of up to 94% and generally high enantioselectivities of up to 96% ee, as illustrated in Scheme 41. Under these mild reaction conditions, a wide range of azlactones with either electron-withdrawing or electron-donating substituents on the phenyl
ip t
ring in the R1 group were tolerated. Interestingly, only moderate enantioselectivities were reached by using other metals as precatalysts, such as Ni(OTf)2 or Yb(OTf)3 (19-24% ee vs
cr
74% ee with Sc(OTf)3 under similar conditions). This work constituted the first use of
an
us
azlactones in the inverse-electron-demand hetero-Diels−Alder reaction with o-quinones.
N+ ON H
Ar
136a-b +
O
R2
M
O
Sc(OTf)3 (10 mol%)
O
d
O
+
O H N Ar' Ar' Ar' = 2,6-Me2-4-t-BuC6H2 138 (10.5 mol%)
O O
N O-
O
N
O
Ac ce p
R1 137a-p
te
imidazole (15 mol%) THF, 35 °C
O
Ar
O R2 NHCOR1
139a-p > 90% de
139a: R1 = Ph, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139b: R1 = p-FC6H4, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139c: R1 = p-ClC6H4, R2 = Bn, Ar = p-MeOC6H4: 89% yield, 94% ee 139d: R1 = p-BrC6H4, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139e: R1 = p-NCC6H4, R2 = Bn, Ar = p-MeOC6H4: 64% yield, 92% ee 139f: R1 = p-CF3C6H4, R2 = Bn, Ar = p-MeOC6H4: 68% yield, 92% ee 139g: R1 = p-Tol, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 93% ee 139h: R1 = Ar = p-MeOC6H4, R2 = Bn: 85% yield, 90% ee 139i: R1 = p-NO2C6H4, R2 = Bn, Ar = p-MeOC6H4: 94% yield, 96% ee 139j: R1 = m-ClC6H4, R2 = Bn, Ar = p-MeOC6H4: 88% yield, 91% ee 139k: R1 = R2 = Bn, Ar = p-MeOC6H4: 63% yield, 94% ee 139l: R1 = Ph, R2 = p-FC6H4, Ar = p-MeOC6H4: 42% yield, 91% ee 139m: R1 = Ph, R2 = p-BrC6H4, Ar = p-EtOC6H4: 91% yield, 91% ee 139n: R1 = Ph, R2 = MeS(CH2)2, Ar = p-MeOC6H4: 75% yield, 82% ee 139o: R1 = Ph, R2 = Me, Ar = p-MeOC6H4: 71% yield, 77% ee 139p: R1 = Ph, R2 = H, Ar = p-MeOC6H4: 70% yield, 91% ee
78 Page 78 of 135
Scheme 41. Hetero-Diels−Alder cycloaddition of o-quinones with azlactones [78].
ip t
5. Enantioselective scandium-catalyzed ring-opening reactions
cr
The asymmetric nucleophilic addition of meso-epoxides is an efficient method to construct chiral 1,2-difunctional compounds, such as 1,2-diol monoethers, 1,2-amino alcohols, or 1,2-
us
thioalcohols. In the past decade, scandium complexes of chiral bipyridine ligands have been successfully applied to the reactions of alcohols, amines, including N-heterocycles and
an
indoles, as well as thiols with racemic epoxides [79]. In the last few years, another type of ligands, such as chiral N,N’-dioxides, have led to very good results in these reactions. For
M
example, ligand 140 was used by Feng et al. in enantioselective scandium-catalyzed ringopening of epoxides 141a-d with pyrazole derivatives 142a-f to give the corresponding chiral
d
β-pyrazole-substituted alcohols 143a-i as single diastereomers (98% de) in moderate to
te
quantitative yields and high enantioselectivities of 87-99% ee (Scheme 42) [80]. Meso-
Ac ce p
epoxides with electron-withdrawing or electron-donating substituents at the meta- and paraposition of the aryl group allowed the maintenance of the high enantioselectivity and complete syn-diastereoselectivity (143g-i). Moreover, a range of variously substituted pyrazole derivatives provided comparable excellent results (143b-f). The importance of this nice reaction is related to the fact that pyrazole is a motif found in a number of small molecules possessing diverse chemical, biological, and pharmaceutical activities [81].
79 Page 79 of 135
ON H
O Ar'
O
141a-d R1
R3 OH
N N
Ar
H N
3 Å M.S. CH2Cl2, 35 °C
N R2
O
H N Ar'
Ar' = 3,5-Me2C6H3 140 (5.25 mol%) Sc(OTf)3 (5 mol%)
Ar
+
+
Ar
R2
R1
cr
Ar
N O-
ip t
N+
143a-i
3
98% de
us
R 142a-f
d
M
an
143a: R1 = R2 = R3 = H, Ar = Ph: 99% yield, 87% ee 143b: R1 = R3 = Me, R2 = H, Ar = Ph: 96% yield, 95% ee 143c: R1 = R3 = H, R2 = NO2, Ar = Ph: 88% yield, 89% ee 143d: R1 = R3 = Et, R2 = NO2, Ar = Ph: 54% yield, 87% ee 143e: R1 = R3 = Me, R2 = Br, Ar = Ph: 95% yield, 95% ee 143f: R1,R2 = (CH=CH)2, R3 = H, Ar = Ph: 87% yield, 99% ee 143g: R1 = R3 = Me, R2 = Br, Ar = p-FC6H4: 99% yield, 95% ee 143h: R1 = R3 = Me, R2 = Br, Ar = m-MeOC6H4: 99% yield, 96% ee 143i: R1 = R3 = Me, R2 = H, Ar = m-MeOC6H4: 99% yield, 92% ee
Ac ce p
te
Scheme 42. Ring-opening of epoxides with pyrazole derivatives [80].
While tremendous advances have been made in asymmetric synthesis, the resolution of racemates is still the most important industrial approach to the synthesis of chiral compounds [82]. The use of enzymes for the kinetic resolution of racemic substrates to afford enantiopure compounds in high enantioselectivity and good yield has long been a popular strategy in synthesis. However, transition metal-mediated (and more recently organocatalyzed) kinetic resolutions have gained popularity within the synthetic community over the last two decades due to the progress made in the development of chiral catalysts for asymmetric reactions. Indeed, many catalytic nonenzymatic procedures have been developed providing high enantioselectivity and yield for both products and recovered starting materials [83]. A kinetic resolution of 2,3-epoxy 3-aryl ketones 144a-m was recently reported by Feng et al. through 80 Page 80 of 135
enantioselective scandium-catalyzed ring-opening with pyrazole derivatives 142a-e to give the corresponding chiral β-pyrazole-substituted alcohols 145a-q [84]. As shown in Scheme 43, the reaction was catalyzed by a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand
ip t
with a two-carbonic linkage 146, providing these opened products in moderate yields (3251%) and high enantioselectivities of up to 97% ee along with the recovered epoxides 144a-m
cr
in very high enantioselectivities of up to > 99% ee and yields of up to 65%. In this reaction, the molecular sieves were indispensable part of the catalytic system. Regardless of the 1
2
us
electronic nature or position of the substituents on the aryl rings of Ar and Ar of the racemic
an
epoxides 144a-m reacting with pyrazole derivative 142a (R1 = R3 = Me, R2 = NO2), the kinetic resolution process occurred smoothly with high yields and enantioselectivities. In all cases of
Ac ce p
te
d
M
reactions, single diastereomers were achieved in up to > 90% de.
81 Page 81 of 135
+ N
ON H
O
O-
O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2
O
R1
O Ar2
Ar1
H N N
+ R2
146 (10 mol%) Sc(OTf)3 (5 mol%) 3 Å M.S.
R3
R3
R1 Ar
CH2Cl2, 35 °C
N
N
O
1
Ar OH
142a-e
145a-q
O
+
2
O Ar2
Ar1
144a-m
cr
144a-m
R2
ip t
N+
> 90% de
te
d
M
an
us
Ar 1 = Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 47% yield (145a), 95% ee (145a), 49% yield (144a), 94% ee (144a) Ar 1 = p-ClC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145b), 94% ee (145b), 49% yield (144a), 95% ee (144a) Ar 1 = p-FC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2 : 48% yield (145c), 96% ee (145c ), 51% yield (144a), 91% ee (144a ) Ar 1 = p-Tol, Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145d), 91% ee (145d), 43% yield (144a), > 99% ee (144a) Ar 1 = p-PhOC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145e), 91% ee (145e), 46% yield (144a), > 99% ee (144a) Ar 1 = m-PhOC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 42% yield (145f), 93% ee (145f), 53% yield (144a), 83% ee (144a) Ar 1 = m-ClC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2 : 32% yield (145g), 97% ee (145g), 63% yield (144a), 54% ee (144a) Ar 1 = Ph, Ar2 = p-ClC6H4, R1 = R3 = Me, R2 = NO2: 50% yield (145h), 95% ee (145h), 49% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-FC6H4, R1 = R3 = Me, R2 = NO2 : 51% yield (145i), 95% ee (145i), 49% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-BrC6H4, R1 = R3 = Me, R2 = NO2 : 51% yield (145j), 96% ee (145j), 51% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = Me, R2 = NO2 : 50% yield (145k), 97% ee (145k), 49% yield (144a) > 99% ee (144a) Ar 1 = Ph, Ar2 = p-PhOC6H4, R1 = R3 = Me, R2 = NO2: 50% yield (145l), 91% ee (145l), 46% yield (144a ), > 99% ee (144a) Ar 1 = Ph, Ar2 = 2-thienyl, R1 = R3 = Me, R2 = NO2 : 35% yield (145m), 82% ee (145m), 65% yield (144a), 44% ee (144a) Ar 1 = Ar2 = Ph, R1 = R3 = Me, R2 = Br: 49% yield (145n), 90% ee (145n), 50% yield (144b), 91% ee (144b) Ar 1 = p-PhOC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = H: 40% yield (145o), 88% ee (145o), 49% yield (144c), 90% ee (144c) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = H, R2 = NO2 : 44% yield (145p), 95% ee (145p), 50% yield (144d), 90% ee (144d) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = R2 = H: 40% yield (145q), 57% ee (145q), 50% yield (144e), 84% ee (144e)
Ac ce p
Scheme 43. Ring-opening of 2,3-epoxy 3-aryl ketones with pyrazole derivatives [84].
Earlier, Bhanage et al. employed a chiral scandium catalyst, derived from (R)-BINOL, Sc(OTf)3, and N-methylmorpholine, to promote enantioselective ring-opening of mesoepoxide 141a with a series of aromatic amines such as anilines 147a-i to afford the corresponding chiral β-amino alcohols 148a-i [85]. The latter were obtained in good yields of up to 92% along with moderate to high enantioselectivities of 64-94% ee (Scheme 44). This novel catalytic system had competitive advantages, such as short reaction times (10-22 h), no additives, and no expensive chiral ligands requiring a multistep synthesis under harsh reaction conditions.
82 Page 82 of 135
(R)-BINOL (12 mol%)
NH2
Ph
Sc(OTf)3 (10 mol%)
+
Ph
N-methylmorpholine (24 mol%)
Ph
R Ph
CH2Cl2, 0 °C 141a
OH
R N H
ip t
O
148a-i
147a-i
an
us
cr
148a: R = H: 91% yield, 94% ee 148b: R = 2-Me: 86% yield, 76% ee 148c: R = 4-Me: 90% yield, 82% ee 148d: R = 2-OMe: 81% yield, 67% ee 148e: R = 4-OMe: 89% yield, 88% ee 148f: R = 3-F-4-OMe: 92% yield, 83% ee 148g: R = 4-Br: 87% yield, 68% ee 148h: R = 2,4,6-(Me)3: 78% yield, 64% ee 148i: R = 2,3-(CH=CH)2: 90% yield, 74% ee
M
Scheme 44. Ring-opening of epoxides with anilines [85].
d
In another context, cyclopropyl ketones have been successfully submitted to ring-opening
te
with various nucleophiles in the presence of a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 38, which provided a novel route to optically active
Ac ce p
γ-substituted carbonyl compounds [86]. For example, a range of aromatic as well as aliphatic thiols 83a-n were reacted with cyclopropyl ketones 150a-g in the presence of this catalyst system and LiCl in 1,1,2,2-tetrachloroethane at 60°C. The process afforded the corresponding chiral sulfides 149a-s in generally good to high yields and enantioselectivities of up to 98% and 95% ee, respectively (Scheme 45). This work represented the first example of one catalytic system working for the ring-opening reaction of donor-acceptor cyclopropanes.
83 Page 83 of 135
ON H
O
N O-
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 38 (11 mol%) Ar1
COAr2 150a-g
+
S
Sc(OTf)3 (10 mol%)
RSH
Ar1 *
LiCl (1 equiv) 83a-n
CHCl2CHCl2, 60 °C
R
COAr2
COAr2
149a-s
cr
COAr2
ip t
N+
Ac ce p
te
d
M
an
us
149a: Ar1 = Ar2 = R = Ph: 94% yield, 92% ee 149b: Ar1 = Ar2 = Ph, R = o-Tol: 95% yield, 92% ee 149c: Ar1 = Ar2 = Ph, R = p-Tol: 97% yield, 91% ee 149d: Ar1 = Ar2 = Ph, R = p-MeOC6H4: 95% yield, 89% ee 149e: Ar1 = Ar2 = Ph, R = p-FC6H4: 84% yield, 91% ee 149f: Ar1 = Ar2 = Ph, R = p-BrC6H4: 90% yield, 92% ee 149g: Ar1 = Ar2 = Ph, R = m-ClC6H4: 90% yield, 93% ee 149h: Ar1 = Ar2 = Ph, R = o-ClC6H4: 83% yield, 92% ee 149i: Ar1 = Ar2 = Ph, R = 1-Naph: 98% yield, 90% ee 149j: Ar1 = Ar2 = Ph, R = 2-Naph: 95% yield, 91% ee 149k: Ar1 = Ar2 = Ph, R = 1-thienyl: 74% yield, 90% ee 149l: Ar1 = Ar2 = Ph, R = Cy: 90% yield, 91% ee 149m: Ar1 = Ar2 = Ph, R = t-Bu: 55% yield, 86% ee 149n: Ar1 = p-Tol, Ar2 = Ph, R = p-ClC6H4: 83% yield, 91% ee 149o: Ar1 = m-Tol, Ar2 = Ph, R = p-ClC6H4: 94% yield, 93% ee 149p: Ar1 = p-FC6H4, Ar2 = Ph, R = p-ClC6H4: 88% yield, 93% ee 149q: Ar1 = m-ClC6H4, Ar2 = Ph, R = p-ClC6H4: 62% yield, 95% ee 149r: Ar1 = 2-Naph, Ar2 = Ph, R = p-ClC6H4: 92% yield, 88% ee 149s: Ar1 = Ph, Ar2 = p-FC6H4, R = p-ClC6H4: 85% yield, 95% ee
Scheme 45. Ring-opening of cyclopropyl ketones with thiols [86].
The scope of the preceding reaction was extended to other nucleophiles, such as alcohols 152a-h and carboxylic acids 152i-m (Scheme 46) [86]. By reaction with cyclopropyl ketone 151a, they led to the corresponding chiral alcohols 153a-h and esters 153i-m, respectively, in moderate to high yields (62-94%) along with enantioselectivities of 50-92% ee for the first ones, and high yields (90-99%) combined with moderate to good enantioselectivities of 6983% ee for the second ones.
84 Page 84 of 135
ON H
O
N O-
+ O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 38 (11 mol%)
Ph
+
RXH
COPh 152a-m
CHCl2CHCl2, 60 °C
COPh
COPh
153a-m
us
151a
Ph *
LiCl (1 equiv)
R
cr
COPh
X
Sc(OTf)3 (10 mol%)
ip t
N+
te
d
M
an
153a: X = O, R = Me: 69% yield, 91% ee 153b: X = O, R = Et: 78% yield, 92% ee 153c: X = O, R = n-Oct: 78% yield, 91% ee 153d: X = O, R = Bn: 60% yield, 90% ee 153e: X = O, R = c-Bu: 72% yield, 92% ee 153f: X = O, R = c-Pent: 94% yield, 92% ee 153g: X = O, R = Cy: 78% yield, 91% ee 153h: X = O, R = Ph: 62% yield, 50% ee 153i: X = COO, R = Me: 90% yield, 76% ee 153j: X = COO, R = n-Hept: 98% yield, 82% ee 153k: X = COO, R = Bn: 99% yield, 83% ee 153l: X = COO, R = Ph: 96% yield, 69% ee 153m: X = COO, R = Cy: 99% yield, 72% ee
Ac ce p
Scheme 46. Ring-opening of cyclopropyl ketones with alcohols and carboxylic acids [86].
6. Enantioselective scandium-catalyzed α-functionalizations of 3-substituted oxindoles
Oxindoles constitute an important structural motif in the library of natural products and biologically active drugs. The enantioselective construction of 3-functionalized oxindoles is among the most attractive and valuable synthetic targets due to the unique properties of such a structural motif [87]. In addition to enantioselective Michael additions of carbon nucleophiles to 3-substituted oxindoles described in Schemes 33-35 [64-66], other scandium-catalyzed asymmetric reactions have been recently reported to construct C-N, C-S, and C-C bonds at the
85 Page 85 of 135
C3 position of oxindoles. As an exemple, Feng et al. have developed enantioselective hydroxyamination reaction of 3-substituted oxindoles 112a-j with nitrosoarenes 154a-e performed in the presence of a chiral scandium catalyst in situ generated from Sc(OTf)3 and
ip t
chiral N,N’-dioxide ligand 97 [88]. While other rare earth metal sources, such as La(OTf)3, Lu(OTf)3, and Sm(OTf)3, only resulted in trace amounts of products, the use of Sc(OTf)3
cr
allowed a range of N-nitroso aldol products 155a-n to be achieved in generally very good yields and enantioselectivities of up to 98% and 98% ee, respectively (Scheme 47).
us
Remarkably, the reactions were complete in only 20 to 60 minutes. In all cases of substrates,
an
the yields were > 89% except for 2-methyl-nitrosobenzene for which the corresponding
M
product 155l was obtained in only 66% yield.
N+
O
ON H
+ N O-
O
2
R1
R
te
d
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (5 mol%) Sc(OTf)3 (3.3 mol%)
ArNO
Ac ce p
O
+
N H
112a-j
154a-e
R2
Ar R1 N OH O
MeCCl3, 30 °C
N H 155a-n
155a: Ar = Ph, R1 = Me, R2 = H: 92%, 95% ee 155b: Ar = Ph, R1 = Et, R2 = H: 91%, 92% ee 155c: Ar = Ph, R1 = n-Pr, R2 = H: 92%, 90% ee 155d: Ar = Ph, R1 = allyl, R2 = H: 98%, 94% ee 155e: Ar = Ph, R1 = Bn, R2 = H: 97%, 95% ee 155f: Ar = Ph, R1 = p-MeOC6H4, R2 = H: 94%, 97% ee 155g: Ar = Ph, R1 = p-PhOC6H4, R2 = H: 95%, 95% ee 155h: Ar = Ph, R1 = p-BrC6H4, R2 = H: 93%, 97% ee 155i: Ar = Ph, R1 = 2-naphthylmethyl, R2 = H: 95%, 98% ee 155j: Ar = Ph, R1 = 2-thienylmethyl, R2 = H: 89%, 92% ee 155k: Ar = m-ClC6H4, R1 = Me, R2 = H: 92%, 94% ee 155l: Ar = o-Tol, R1 = Me, R2 = H: 66%, 92% ee 155m: Ar = m-Tol, R1 = Me, R2 = H: 90%, 88% ee 155n: Ar = p-MeOC6H4, R1 = Me, R2 = H: 95%, 92% ee
86 Page 86 of 135
Scheme 47. Hydroxyamination of 3-substituted oxindoles [88].
The same authors also demonstrated that 3-substituted oxindoles 112a-u reacted with
ip t
readily available N-(phenylthio)phthalimide 156 as sulfur source to give a wide range of chiral 3-phenylthio-substituted oxindoles 157a-u under mild reaction conditions, as illustrated
cr
in Scheme 48 [89]. These products were generally produced in both high to excellent yields
us
and enantioselectivities of 85-98% and 87-> 99% ee, respectively, when the process was performed in the presence of Sc(OTf)3 as scandium source, chiral N,N’-dioxide ligand 97, and
an
a Brønsted base such as Na2CO3. The reaction did not occur in the absence of this base. They assumed that the reaction was initiated by the formation of an enolate anion formed via base-
M
promoted deprotonation of the 3-substituted oxindole. This enolate subsequently reacted with the sulfenylation reagent 156 to afford the final product. It is worth noting that this work
Ac ce p
te
d
constituted the first enantioselective synthesis of 3-thiooxindoles.
87 Page 87 of 135
N+ O
97 (3 or 5 mol%) Sc(OTf)3 (3 or 5 mol%)
2
R
O
N H
cr
Na2CO3, 4 Å M.S. CH2Cl2, 35 °C
O
R1 SPh
ip t
O N H 112a-u +
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3
R1
R2
ON H
+ N O-
157a-u
N SPh
us
O 156
Ac ce p
te
d
M
an
with 3 mol% of catalyst: 157a: R1 = p-MeOC6H4, R2 = H: 98%, 97% ee 157b: R1 = p-NO2C6H4, R2 = H: 95%, 92% ee 157c: R1 = 1-naphthylmethyl, R2 = H: 98%, 97% ee 157d: R1 = 2-naphthylmethyl, R2 = H: 95%, 97% ee 157e: R1 = 2-thienylmethyl, R2 = H: 85%, 94% ee 157f: R1 = Me, R2 = H: 83%, 87% ee 157g: R1 = n-Bu, R2 = H: 89%, 98% ee 157h: R1 = i-Bu, R2 = H: 91%, 98% ee 157i: R1 = allyl, R2 = H: 85%, 95% ee 157j: R1 = MeCO2CH2, R2 = H: 98%, 96% ee with 5 mol% of catalyst: 157k: R1 = Ph, R2 = H: 95%, 99% ee 157l: R1 = o-Tol, R2 = H: 92%, > 99% ee 157m: R1 = m-Tol, R2 = H: 93%, 99% ee 157n: R1 = p-Tol, R2 = H: 94%, 99% ee 157o: R1 = p-FC6H4, R2 = H: 97%, 98% ee 157p: R1 = p-ClC6H4, R2 = H: 91%, 97% ee 157q: R1 = 1-Naph, R2 = H: 91%, 99% ee 157r: R1 = Ph, R2 = 5-Me: 90%, 99% ee 157s: R1 = Ph, R2 = 5-OMe: 97%, 98% ee 157t: R1 = Ph, R2 = 5-F: 93%, 97% ee 157u: R1 = Ph, R2 = 7-F: 88%, 93% ee
Scheme 48. Sulfenylation of 3-substituted oxindoles [89].
In addition, excellent results were reported by these authors for enantioselective scandiumcatalyzed fluorination of 3-substituted oxindoles 112a-r with N-fluorobisbenzenesulfonimide (NFSI) as fluorination agent [90]. As shown in Scheme 49, the use of a catalyst system 88 Page 88 of 135
composed by Sc(OTf)3, chiral N,N’-dioxide ligand 97, and Na2CO3 allowed a series of chiral 3-aryl- and 3-alkyl-3-fluoro-2-oxindoles 158a-r to be achieved in good yields of up to 98% and general excellent enantioselectivities of up to 99% ee. The highest enantioselectivities
ON H
O
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3 97 (5 mol%)
R1
R
O + NFSI
an
2
us
+ N O-
N+
cr
substituted ones 112o-r provided enantioselectivities of 90-95% ee.
Sc(OTf)3 (5 mol%) Na2CO3
M
N H 112a-r
CHCl3, 0 °C
ip t
were generally reached for (hetero)aryl-substituted substrates 112b-l (94-99% ee) while alkyl-
2
R
R1 F O N H 158a-r
Ac ce p
te
d
158a: R1 = Bn, R2 = H: 95%, 99% ee 158b: R1 = p-MeOC6H4, R2 = H: 96%, 97% ee 158c: R1 = o-Tol, R2 = H: 87%, 99% ee 158d: R1 = m-Tol, R2 = H: 96%, 96% ee 158e: R1 = p-Tol, R2 = H: 96%, 96% ee 158f: R1 = o-ClC6H4, R2 = H: 82%, 98% ee 158g: R1 = m-ClC6H4, R2 = H: 84%, 97% ee 158h: R1 = p-ClC6H4, R2 = H: 98%, 98% ee 158i: R1 = p-NO2C6H4, R2 = H: 94%, 97% ee 158j: R1 = 1-naphthylmethyl, R2 = H: 90%, 99% ee 158k: R1 = 2-naphthylmethyl, R2 = H: 88%, 97% ee 158l: R1 = 2-thienylmethyl, R2 = H: 85%, 94% ee 158m: R1 = Ph, R2 = H: 85%, 89% ee 158n: R1 = Ph, R2 = Cl: 98%, 93% ee 158o: R1 = Me, R2 = H: 80%, 90% ee 158p: R1 = n-Bu, R2 = H: 82%, 93% ee 158q: R1 = i-Bu, R2 = H: 85%, 93% ee 158r: R1 = allyl, R2 = H: 81%, 95% ee
Scheme 49. Fluorination of 3-substituted oxindoles [90].
89 Page 89 of 135
The catalytic asymmetric α-arylation of carbonyl compounds is also of high interest, because it provides an efficient access to chiral α-aryl compounds regarded as essential motifs in many biologically active natural products and pharmaceutically active compounds [91]. In
ip t
this context, Feng et al. have reported a novel asymmetric catalytic strategy for α-arylation of a wide variety of 3-substituted oxindoles 112a-r with diaryliodonium triflates 159a-h [92].
cr
This nice reaction was promoted by a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand
us
160 bearing tetrahydroisoquinoline backbones in the presence of NaHCO3 and provided a range of chiral oxindole derivatives 161a-y with quaternary carbon centers in generally high
an
yields and enantioselectivities of up to 99% and 99% ee, respectively (Scheme 50). The lowest yields (60-71%) and enantioselectivities (72-84% ee) were observed in the reactions of
M
3-tert-butyl-2-oxindole 112p and 3-allyl-butyl-2-oxindole 112o. Using other metal sources popular in α-arylation, such as CuBr, Cu(OTf)2, or Pd(OAc)2, resulted in poor yields or
d
complicated racemic mixtures. The utility of this nice methodology was demonstrated in the
Ac ce p
te
asymmetric synthesis of an antiproliferative oxindole agent.
90 Page 90 of 135
O
O N H
160 (10 mol%) Sc(OTf)3 (10 mol%)
112a-r R
O
N H
3 Å M.S. CH2Cl2, 35 °C
I+ -
161a-y
us
OTf
R1
R2
NaHCO3
3
Ar
R3
cr
+
O
H N 4 R4 R 4 R = (S)-2-phenylethyl
R1
R2
ON H
+ N O-
ip t
N+
159a-h
Ac ce p
te
d
M
an
161a: R1 = Bn, R2 = R3 = H, Ar = Ph: 89%, 95% ee 161b: R1 = o-Tol, R2 = R3 = H, Ar = Ph: 99%, 91% ee 161c: R1 = m-Tol, R2 = R3 = H, Ar = Ph: 80%, 95% ee 161d: R1 = p-Tol, R2 = R3 = H, Ar = Ph: 98%, 94% ee 161e: R1 = o-ClC6H4, R2 = R3 = H, Ar = Ph: 93%, 92% ee 161f: R1 = m-ClC6H4, R2 = R3 = H, Ar = Ph: 99%, 99% ee 161g: R1 = p-ClC6H4, R2 = R3 = H, Ar = Ph: 84%, 96% ee 161h: R1 = m-BrC6H4, R2 = R3 = H, Ar = Ph: 99%, 99% ee 161i: R1 = m-NO2C6H4, R2 = R3 = H, Ar = Ph: 99%, 98% ee 161j: R1 = p-CNC6H4, R2 = R3 = H, Ar = Ph: 97%, 97% ee 161k: R1 = p-MeOC6H4, R2 = R3 = H, Ar = Ph: 95%, 95% ee 161l: R1 = 2-naphthylmethyl, R2 = R3 = H, Ar = Ph: 81%, 96% ee 161m: R1 = 2-thienylmethyl, R2 = R3 = H, Ar = Ph: 82%, 91% ee 161n: R1 = 2-thienylmethyl, R2 = R3 = H, Ar = Ph: 85%, 94% ee (R) 161o: R1 = allyl, R2 = R3 = H, Ar = Ph: 60%, 72% ee 161p: R1 =t-Bu, R2 = R3 = H, Ar = Ph: 71%, 84% ee 161q: R1 = m-ClC6H4, R2 = 6-Cl, R3 = H, Ar = Ph: 90%, 98% ee 161r: R1 = Bn, R2 = 6-Cl, R3 = H, Ar = Ph: 89%, 90% ee 161s: R1 = Bn, R2 = H, R3 = 4-F, Ar = p-FC6H4: 65%, 94% ee 161t: R1 = Bn, R2 = H, R3 = 4-Cl, Ar = p-ClC6H4: 79%, 96% ee 161u: R1 = Bn, R2 = H, R3 = 4-Br, Ar = p-BrC6H4: 82%, 98% ee 161v: R1 = Bn, R2 = H, R3 = 4-Me, Ar = p-Tol: 76%, 96% ee 161w: R1 = Bn, R2 = R3 = H, Ar = Mes: 80%, 92% ee 161x: R1 = Bn, R2 = H, R3 = 4-Cl, Ar = Mes: 79%, 94% ee 161y: R1 = Bn, R2 = H, R3 = 4-Ph, Ar = Mes: 55%, 90% ee
Scheme 50. α-Arylation of 3-substituted oxindoles [92].
7. Enantioselective scandium-catalyzed aldol reactions
91 Page 91 of 135
The direct catalytic asymmetric aldol reaction is a powerful and atom-economical method for synthesizing chiral β-hydroxy carbonyl compounds. Many metals and organocatalysts for
ip t
reactions of aldehyde electrophiles have been developed in the past decade [93]. Among catalysts early employed either in organic solvent or in water to promote enantioselective
cr
aldol reactions are chiral scandium complexes derived from pybox [94], N,N’-dioxide ligands [95], and bipyridine-alcohol ligands [96]. More recently, Wang et al. reported a convenient
us
enantioselective decarboxylative aldol reaction to access chiral highly functionalized α-
an
hydroxyesters 162a-j from β-ketoacids 163a-d and inactivated aromatic and aliphatic αketoesters 164a-g (Scheme 51) [97]. Good to high yields of up to 95% were achieved along
M
with moderate to good enantioselectivities of 49-84% ee by catalyzing the process with a
d
chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral pybox ligand 134.
O
te
O
N
O
Ph
R1
Ac ce p
OH
163a-d
+
O
R2
O
OEt 164a-g
O
N
N
134 (12 mol%)
Ph OHO
Sc(OTf)3 (10 mol%)
R2 OEt
R1 CHCl3, 0 °C
O 162a-j
162a: R1 = R2 = Ph: 95% yield, 84% ee 162b: R1 = Ph, R2 = p-BrC6H4: 91% yield, 81% ee 162c: R1 = Ph, R2 = p-FC6H4: 90% yield, 78% ee 162d: R1 = Ph, R2 = p-OCF3C6H4: 92% yield, 76% ee 162e: R1 = Ph, R2 = CH2Bn: 93% yield, 77% ee 162f: R1 = Ph, R2 = Me: 88% yield, 60% ee 162g: R1 = Ph, R2 = i-Pr: 91% yield, 56% ee 162h: R1 = p-FC6H4, R2 = Ph: 88% yield, 75% ee 162i: R1 = 2-Naph, R2 = Ph: 93% yield, 59% ee 162j: R1 = Et, R2 = Ph: 81% yield, 49% ee
Scheme 51. Decarboxylative aldol reaction of β-keto acids with α-ketoesters [97]. 92 Page 92 of 135
In addition, a series of novel chiral N,N’-dioxide ligands were recently investigated by Kobayashi and Kitanosono in enantioselective scandium-catalyzed direct aldol reactions using
ip t
aqueous formaldehyde [98]. They selected dioxide 165 as optimal ligand which allowed, in combination with Sc(OTf)3, the reaction of formaldehyde with ketone derivatives, including
cr
simple ketone 166a, thioester 166b, and 2-methyl-1-indanone 166c, to be achieved in water. This remarkably simple process performed at room temperature afforded the corresponding hydroxymethylated
products
167a-c
in
moderate
yields
us
chiral
(23-53%)
and
an
enantioselectivities of 53-75% ee (Scheme 52). In spite of these modest results, it is important to note that this study offered the simplest metalloenzyme-like catalyst system that worked
M
efficiently in water.
d
N+
ON H ( )12
te
O
Ac ce p
N
( )12
165 (5 mol%)
N O
HCHO aq.
166a-b
167a-b R = Ph: 30% yield, 62% ee R = SEt: 23% yield, 53% ee
O
+
OH
R
H2O, 20 or 40 °C pyridine (20 mol%)
R
166c
O
H N
Sc(OTf)3 (8 mol%)
O
+
+ N O-
same conditions
O
OH
HCHO aq.
167c 53% yield, 75% ee
Scheme 52. Aldol reactions of ketones with aqueous formaldehyde [98].
93 Page 93 of 135
8. Enantioselective scandium-catalyzed oxidations
ip t
8.1. Epoxidations
cr
Chiral epoxides constitute key building blocks for the synthesis of natural products and
us
biologically active compounds [99]. Among the different methodologies available for their synthesis, the enantioselective titanium-catalyzed oxidation of allylic alcohols reported by
an
Katsuki and Sharpless in 1980s is still the most efficient one [100]. However, this methodology presents some limitations, such as its rather high catalyst loadings and required
M
anhydrous reaction conditions. With the aim of finding alternative methodologies, enantioselective scandium-catalyzed epoxidations have been developed. As an example, a
d
simple asymmetric epoxidation of α,β-unsaturated carbonyl compounds based on the use of
te
aqueous hydrogen peroxide as green oxidant and a chiral scandium catalyst was reported by Feng et al., in 2012 [101]. Remarkably, this process did not require the presence of additives
Ac ce p
to provide a number of chiral epoxides 168a-u in general excellent yields and enantioselectivities of up to 99% and 99% ee, respectively, from the corresponding α,βunsaturated carbonyl compounds 61a-u by using chiral N,N’-dioxide ligand 97 in combination with Sc(OTf)3 as catalyst system (Scheme 53). In this study, other metal sources, such as Y(OTf)3 and La(OTf)3, were also investigated albeit all giving much lower yields and enantioselectivities. In addition to the mild and environmentally begnin conditions, including a low concentration of hydrogen peroxide used, along with water and air tolerance of the catalyst system, the latter could be recovered and reused efficiently.
94 Page 94 of 135
ON H
O
O R
Ar
+ H2O2
+ N O-
O
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (5 mol%) Sc(OTf)3 (5 mol%)
O R
Ar
THF, 35 °C (30% aq.)
168a-u
cr
61a-u
O
ip t
N+
Ac ce p
te
d
M
an
us
168a: R = Ar = Ph: 99%, 98% ee 168b: R = Ph, Ar = m-MeOC6H4: 83%, 95% ee 168c: R = Ph, Ar = p-Tol: 82%, 99% ee 168d: R = Ph, Ar = p-MeOC6H4: 95%, 98% ee 168e: R = Ph, Ar = p-FC6H4: 99%, 97% ee 168f: R = Ph, Ar = p -ClC6H4: 90%, 96% ee 168g: R = Ph, Ar = p-NO2C6H4: 87%, 99% ee 168h: R = Ph, Ar = 2-furyl: 80%, 92% ee 168i: R = Ph, Ar = 2-Naph: 70%, 95% ee 168j: R = p-Tol, Ar = Ph: 84%, 99% ee 168k: R = p -BrC6H4, Ar = Ph: 99%, 98% ee 168l: R = 1-Naph, Ar = Ph: 99%, 98% ee 168m: R = 2-Naph, Ar = Ph: 99%, 98% ee 168n: R = t -Bu, Ar = Ph: 99%, 96% ee 168o: R = CO2Et, Ar = Ph: 82%, 96% ee 168p: R = CO2Et, Ar = p-Tol: 91%, 86% ee 168q: R = CO2Et, Ar = p-MeOC6H4: 88%, 96% ee 168r: R = CF3, Ar = p-FC6H4: 99%, 99% ee 168s: R = CF 3, Ar = p -MeOC6H4: 99%, 97% ee 168t: R = CCl3, Ar = p-MeOC6H4: 99%, 99% ee 168u: R = CCl3, Ar = 2-furyl: 99%, 95% ee
Scheme 53. Epoxidation of α,β-unsaturated ketones with aqueous hydrogen peroxide [101].
Although great progress has been made in H2O2-efficient epoxidations [102], the epoxidations of trisubstituted olefins using hydrogen peroxide as oxidant are still challenging [103]. In this context, Feng et al. have applied closely related conditions to those of Scheme 53 to the asymmetric epoxidation of 2-arylidene-1,3-diketones 169a-n which led to the corresponding chiral trisubstituted epoxides 170a-n in moderate to good yields (50-85%) albeit excellent enantioselectivities of up to 99% ee (Scheme 54) [104]. The catalyst system
95 Page 95 of 135
used at 10 mol% of catalyst loading was the same as in Scheme 53 (5 mol% in Scheme 53) but the reaction was performed in methanol instead of THF as solvent. The best result (85% yield, 99% ee) was reached with trisubstituted olefin 169b bearing two chlorine substituents
O
+ H2O2
Bz 169a-n
O
us
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (10 mol%) Sc(OTf)3 (10 mol%)
an
Ar
Bz
ON H
+ N O-
MeOH, 30 °C
O
Ar
Bz Bz 170a-n
M
(30% aq.)
cr
N+
ip t
on the aromatic ring while 2-alkylidene-2,3-diketones did not undergo the reaction.
Ac ce p
te
d
170a: Ar = Ph: 74%, 98% ee 170b: Ar = 3,4-Cl2C6H3: 85%, 99% ee 170c: Ar = p-NCC6H4: 71%, 93% ee 170d: Ar = p-NO2C6H4: 58%, 98% ee 170e: Ar = m-CF3C6H4: 53%, 99% ee 170f: Ar = p-CF3C6H4: 55%, 99% ee 170g: Ar = p-FC6H4: 50%, 98% ee 170h: Ar = p-ClC6H4: 60%, 99% ee 170i: Ar = m-BrC6H4: 54%, 98% ee 170j: Ar = p-BrC6H4: 59%, 97% ee 170k: Ar = m-PhOC6H4: 63%, 99% ee 170l: Ar = m-MeOC6H4: 62%, 99% ee 170m: Ar = m-Tol: 63%, 98% ee 170n: Ar = p-Tol: 69%, 97% ee
Scheme 54. Epoxidation of 2-arylidene-1,3-diketones with aqueous hydrogen peroxide [104].
8.2. Baeyer−Villiger reactions
The Baeyer−Villiger reaction is highly valuable for the synthesis of esters or lactones [105]. Especially, the asymmetric Baeyer−Villiger oxidation of racemic cyclic ketones provides a
96 Page 96 of 135
simple and attractive route for the synthesis of optically active lactones [106]. Impressive results have been achieved by using biocatalysts, organocatalysts, and chiral metal complexes. As it is often the case, ring-strained cyclobutanones are more reactive in Baeyer−Villiger
ip t
oxidations than other cyclic ketones, and they have been well-studied. On the other hand, the desymmetrization of 4-alkylcyclohexanones has been less explored in recent years and
cr
remains challenging. In this context, Feng et al. have developed a highly efficient Baeyer−Villiger reaction of meso-cyclohexanones 171a-m with m-chloroperbenzoic acid
us
(MCPBA) performed in the presence of a catalytic amount (5 mol%) of Sc(OTf)3 and chiral
an
N,N’-dioxide ligand 69 [107]. The process afforded the corresponding ε-lactones 171a-m in good yields (71-90%) and high enantioselectivities of up to 95% ee, as illustrated in Scheme
M
55. The enantiocontrol of the reaction was sensitive to neither the electronic properties nor the steric hindrance of substituents on the phenyl ring of 4-aryl-substituted cyclohexanones 172b-
d
h. Moreover, fused-ring-substituted cyclohexanones 172i-j as well as 4-alkyl-substituted
te
cyclohexanones 172k-m provided comparable excellent results (84-95% ee). The synthetic importance of this novel desymmetrization was demonstrated by the transformation of
Ac ce p
product 171k into an important intermediate in the synthesis of an effective inhibitor of acetylcholinesterase. Later, Su and Hu reported theoretical studies (DFT and ONIOM) on the asymmetric Baeyer−Villiger oxidation of 4-phenylcyclohexanone 172a under these conditions which revealed that the first step of the process, corresponding to the addition of MCPBA to the carbonyl group of the ketone, was the rate-determining step [108]. Furthermore, the repulsion between the m-chlorophenyl group of MCPBA and the 2,4,6iPr3C6H2 group of the dioxide ligand, as well as the cyclohexanone and the amino acid skeleton of the ligand, played important roles in the control of the enantioselectivity of the reaction. The combination of scandium/N,N’-dioxide ligand 69 with MCPBA could form a
97 Page 97 of 135
reactive species that could effectively catalyze the reaction with a reasonable activation
O
O +
MCPBA
+
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%)
O
O
us
R
ON H
N O-
cr
N+
ip t
barrier of 86.7 kJ mol-1.
EtOAc, -20 °C
O
*
R
an
171a-m 171a : R = Ph: 86% yield, 95% ee 171b: R = p-Tol: 90% yield, 95% ee 171c : R = m-Tol: 84% yield, 94% ee 171d: R = p-FC6H4: 71% yield, 92% ee 171e: R = m-FC6H4: 84% yield, 94% ee 171f: R = p-ClC6H4: 82% yield, 94% ee 171g: R = m-ClC6H4: 81% yield, 94% ee 171h: R = p-PhC6H4: 80% yield, 94% ee 171i: R = 1-Naph: 84% yield, 95% ee 171j: R = 2-Naph: 87% yield, 94% ee 171k : R = Me: 76% yield, 84% ee (R) 171l: R = i-Pr: 75% yield, 92% ee (R) 171m: R = t-Bu: 81% yield, 94% ee (R)
Ac ce p
te
d
M
172a-m
Scheme 55. Baeyer−Villiger reaction of meso-cyclohexanones through desymmetrization [107].
Related reaction conditions were applied to the Baeyer−Villiger reaction of mesocyclobutanones 173a-f which afforded the corresponding chiral γ-lactones 174a-f in good yields (71-84%) and high enantioselectivities of 87-91% ee ( Scheme 56) [107]. The electronic nature of the substituents in cyclobutanones had nearly no effect on the efficiency and enantioselectivity of the reaction.
98 Page 98 of 135
O
O +
Ar
MCPBA
ON H
N O-
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%) EtOAc, -60 °C
O
Ar
*
ip t
N+
O
174a-f
cr
173a-f
an
us
174a: Ar = Ph: 82% yield, 91% ee (S) 174b: Ar = p-Tol: 84% yield, 90% ee (S) 174c: Ar = m-Tol: 80% yield, 91% ee 174d: Ar = p-MeOC6H4: 78% yield, 91% ee (S) 174e: Ar = p-FC6H4: 71% yield, 87% ee (S) 174f: Ar = p-ClC6H4: 83% yield, 87% ee (S)
Scheme 56. Baeyer−Villiger reaction of meso-cyclobutanones through desymmetrization
M
[107].
d
Another challenge to the catalytic enantioselective Baeyer−Villiger oxidation is its
te
application to the kinetic resolution of racemic cyclic ketones. It was thus significant that the
Ac ce p
Baeyer−Villiger reaction of racemic 2-arylcyclohexanones 175a-g catalyzed by the same catalyst system employed under related conditions was exemplified [107]. Surprisingly, the process afforded only trace amount of expected normal Baeyer−Villiger products 177a-g along with abnormal chiral Baeyer−Villiger products 176a-g as major products generated from the migration of the less-substituted group, and recovered chiral 2-arylcyclohexanones 175a-g (Scheme 57). The enantioselectivities of abnormal Baeyer−Villiger products 176a-g were high to excellent (82-98% ee) as well as those of recovered 2-arylcyclohexanones (8997% ee) while those of normal Baeyer−Villiger products 177a-g were of 72-99% ee. Major products 176a-g and 175a-g were respectively obtained in 44-50% and 45-51% yields by using Al(Oi-Pr)3 as an additive. The best result was achieved in the reaction of 1-
99 Page 99 of 135
naphthylcyclohexanone 175f which afforded unreacted ketone 175f in 99% ee and abnormal
O Ar +
MCPBA
ON H
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%) Al(Oi-Pr)3 EtOAc, -20 or -40 °C
175a-g
Ar
Ar
*
O
O
+
175a-g
*
O
+
O * Ar
an
abnormal BayerBayer-Villiger Villiger product 176a-g product 177a-g
M
= Ph: 46% yield (175a), 48% yield (176a), 3% yield (177a), 94% ee (S) (175a), 94% ee (R) (176a) = p-ClC6H4: 47% yield (175b), 50% yield (176b), 3% yield (177b), 97% ee (S) (175b), 93% ee (R) (176b) = p-BrC6H4: 47% yield (175c), 50% yield (176c), 3% yield (177c), 97% ee (S) (175c), 92% ee (R) (176c) = p-Tol: 51% yield (175d), 44% yield (176d), 4% yield (177d), 89% ee (S) (175d), 91% ee (R) (176d) = p-PhC6H4: 44% yield (175e), 50% yield (176e), 6% yield (177e), 90% ee (S) (175e), 90% ee (R) (176e) = 1-Naph: 49% yield (175f), 46% yield (176f), 5% yield (177f), 99% ee (175f), 98% ee (176f) = 2-Naph: 45% yield (175g), 49% yield (176g), 5% yield (177g), 90% ee (175g), 82% ee (176g)
d
Ar Ar Ar Ar Ar Ar Ar
O
cr
O
N O-
us
N+
ip t
Baeyer−Villiger product 176f in 98% ee with 50% conversion.
Ac ce p
kinetic resolution [107].
te
Scheme 57. Abnormal Baeyer−Villiger reaction of 2-aryl-substituted cyclohexanones through
In 2014, a closely related N,N’-dioxide ligand 113 was applied to the scandium-catalyzed Baeyer−Villiger oxidation of 2-substituted cyclopentanones 178a-g which also occurred through kinetic resolution [109]. As illustrated in Scheme 58, a series of 2-arylcyclopentanones 178a-f were submitted to a combination of this ligand with Sc(OTf)3 in the presence of Al(OEt)3 as additive which afforded in this case the corresponding normal Baeyer−Villiger products 179a-f in high enantioselectivities of 85-98% ee and high conversions (48-54%). These 6-aryl-substituted δ-lactones 179a-f were obtained in all cases with > 95:5 regioselectivity. Indeed, the abnormal Baeyer−Villiger products 180a-f were
100 Page 100 of 135
always produced in less than 5% yield except for the reaction of benzyl-substituted cyclopentanone 178g which provided a 56:44 mixture of the two Baeyer−Villiger products 179g and 180g along with recovered enantioenriched cyclopentanone 178g in low
ip t
enantioselectivity of 14% ee. Comparing these results with those of the preceding study (Scheme 57) dealing with preferential abnormal Baeyer−Villiger oxidations of 2-substituted
cr
cyclohexanones, the authors proposed that the different ring strain and conformations of the 2-substituted cyclic ketones, and the steric hindrance created by the chiral catalyst as well,
us
would account for the migratory aptitude in the circumstances. This work represented the most efficient example of the kinetic resolution of 2-substituted cyclopentanones via
+ N
N+ O
M
an
nonenzymatic asymmetric Baeyer−Villiger oxidation to date.
O-
O-
O
H N Ar
d
N H
+
MCPBA
Al(OEt)3 4 Å M.S. EtOAc, -20 °C
Ac ce p
R
te
O
Ar Ar = 2,6-Et2-4-MeC6H2 113 (5 mol%) Sc(OTf)3 (5 mol%)
178a-g
O
O * 178a-g
R
+
O O *
+
O
R *
R
Baeyer-Villiger abnormal Baeyer product 179a-g -Villiger product 180a-g
R = Ph: 42% yield (178a), 48% yield (179a), 5% yield (180a), 90% ee (178a), 98% ee (179a) R = p-Tol: 45% yield (178b), 48% yield (179b), 5% yield (180b), 90% ee (178b), 94% ee (179b) R = m-Tol: 46% yield (178c), 48% yield (179c), 4% yield (180c), 85% ee (178c), 98% ee (179c) R = p-MeOC6H4: 40% yield (178d), 54% yield (179d), 4% yield (180d), 98% ee (R) (178d), 94% ee (179d) R = p-PhC6H4: 44% yield (178e), 50% yield (179e), 4% yield (180e ), 95% ee (178e), 98% ee (179e) R = 2-Naph: 44% yield (178f), 51% yield (179f), 5% yield (180f), 92% ee (178f), 94% ee (179f) R = Bn: 57% yield (178g), 23% yield (179g), 18% yield (180g), 14% ee (178g), 87% ee (179g)
Scheme 58. Baeyer−Villiger reaction of 2-substituted cyclopentanones [109].
9. Enantioselective scandium-catalyzed reductions
101 Page 101 of 135
The enantioselective reduction of prochiral ketones provides the most efficient access to optically active secondary alcohols. It has been achieved by using a wide range of reducing
ip t
agents including alkali metal borohydrides which are mild, inexpensive, highly selective, and environmentally friendly [110]. The latter have been used in combination of various chiral
cr
metal catalysts to achieve enantioselectivity in these reduction reactions. Nonetheless, the use
us
of simple chiral Lewis acid complexes for asymmetric metal borohydride reduction has been investigated only recently by Feng et al. by using scandium chiral catalysts [111]. As
an
illustrated in Scheme 59, the authors developed the reduction of α,β-unsaturated ketones 181a-k with aqueous potassium borohydride in the presence of a chiral scandium complex in
M
situ generated from Sc(OTf)3 and N,N’-dioxide ligand 182. The process allowed a wide range of chiral allylic alcohols 183a-k to be achieved in remarkable yield of 99% combined with
d
good to high enantioselectivities of up to 95% ee. The catalytic system was expanded to the
te
reduction of saturated ketones but the reactions required prolonged reaction times (8 h instead
Ac ce p
of 1.5 h for enones) and the corresponding chiral secondary alcohols were isolated in moderate enantioselectivities (≤ 86% ee). The role of water was essential to dramatically increase the rate of the reaction, allowing a complete conversion. This work represented the first catalytic enantioselective reduction of prochiral enones and ketones by employing potassium borohydride as the reducing agent.
102 Page 102 of 135
+ N
ON H
O +
O-
O H N Ar' Ar' Ar' = 2,6-i-Pr2-4-t-BuC6H2 182 (10 mol%) Sc(OTf) 3 (10 mol%) KBH4 aq. O
Ar
ip t
N+
OH
Ar
THF, 0 °C
cr
(0.45 equiv) 181a-k
183a-k
M
an
us
183a: Ar = Ph: 99% yield, 90% ee 183b: Ar = m-Tol: 99% yield, 90% ee 183c: Ar = o-MeOC6H4: 99% yield, 95% ee 183d: Ar = m-MeOC6H4: 99% yield, 90% ee 183e: Ar = p-MeOC6H4: 99% yield, 90% ee 183f: Ar = p-PhC6H4: 99% yield, 88% ee 183g: Ar = p-BnC6H4: 99% yield, 94% ee 183h: Ar = p-FC6H4: 99% yield, 88% ee 183i: Ar = m-CF3C6H4: 99% yield, 81% ee 183j: Ar = 2-Naph: 99% yield, 90% ee 183k: Ar = 2-furyl: 99% yield, 90% ee
te
d
Scheme 59. Reduction of α,β-unsaturated ketones with aqueous KBH4 [111].
Ac ce p
Chiral β-amino alcohols are essential structural motifs commonly found in a large number of natural products and pharmaceutical compounds, such as β-adrenergic blocking drugs and agonists for the treatment of cardiovascular disease, antidepressant, asthma, and chronic obstructive pulmonary disease [112]. They can be directly generated through asymmetric reductions of the corresponding α-amino ketones in the presence of chiral metal catalysts. However, the discovery of methods of this type employing safe and cheap reducing agents, and convenient and practical procedures still remains a challenge. In 2014, Feng et al. reported an easy and simple route to these products based on the first enantioselective alkali metal borohydride reduction of α-primary amino ketones catalyzed by a chiral scandium complex derived from Sc(OTf)3 and chiral N,N’-dioxide ligand 184 [113]. As shown in
103 Page 103 of 135
Scheme 60, the reaction of a range of α-primary amino ketones hydrochlorides 185a-h with aqueous potassium borohydride in the presence of 10 mol% of the catalyst system provided, after subsequent N-Boc derivation, the corresponding chiral amino alcohols 186a-h in
N+
+
KBH4 aq.
O-
O
H N Ar' Ar' Ar' = 2,6-Et2C6H3 184 (10 mol%) Sc(OTf)3 (10 mol%)
us
O Ar
O N H
OH
an
1.
+ N -
O
cr
ip t
moderate to high yields (65-90%) and enantioselectivities of 74-90% ee.
Ar *
186a-h
M
NH2HCl (0.75 equiv) THF, -20 to 0 °C 185a-h 2. (Boc)2O (1.2 equiv) K2CO3 (1.2 equiv) 35 °C
NHBoc
Ac ce p
te
d
186a: Ar = Ph: 80% yield, 85% ee 186b: Ar = p-MeOC6H4: 65% yield, 90% ee 186c: Ar = p-EtOC6H4: 90% yield, 74% ee 186d: Ar = p-PhC6H4: 90% yield, 79% ee 186e: Ar = p-FC6H4: 80% yield, 81% ee 186f: Ar = p-ClC6H4: 90% yield, 77% ee 186g: Ar = p-BrC6H4: 90% yield, 74% ee 186h: Ar = 2-Naph: 90% yield, 74% ee
Scheme 60. Reduction of α-amino ketones with aqueous KBH4 [113].
10. Enantioselective scandium-catalyzed Friedel−Crafts reactions
The Friedel−Crafts reaction of aromatic compounds with aldehydes or ketones constitutes one of the most fundamental reactions in organic chemistry [114]; however, its enantioselective catalytic version is still an unexplored field. Based on the fact that the phenol unit occurs widespread in biologically active natural products and pharmaceutically useful
104 Page 104 of 135
molecules [115], an expansion of the scope of phenols in asymmetric Friedel−Crafts reaction is of interest. In this context, Feng et al. have developed enantioselective Friedel−Crafts reactions of phenols 187a-c with (E)-4-oxo-4-arylbutenoates 57a-n which afforded the
ip t
corresponding chiral polyfunctionalized products 188a-q in moderate to high yields (78-97%) and good to high enantioselectivities (88-97% ee) [116]. The process was performed in the
cr
presence of a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand 111 ( Scheme 61). Ester groups had little influence on the enantioselectivity, and somewhat decreased yields
us
were obtained for sterically hindered ester group (products 188c-d). Regardless of the
an
electronic and steric nature, or the position of the substituents on the aromatic ring of (E)-4oxo-4-arylbutenoates 57f-l, the asymmetric Friedel−Crafts reaction proceeded smoothly,
M
providing the desired products 188f-l in high yields (78-97%) and enantioselectivities (8997% ee). The best result was reached in the reaction of 3,4-dimethoxy-substituted (E)-ethyl 4-
d
oxo-4-arylbutenoate 57h. The synthetic utility of the reaction was demonstrated in an easy
Ac ce p
te
conversion of product 188a into a potentially useful biological pyridazinone derivative.
105 Page 105 of 135
N+
N
+
-
O CO2R1
Ar
57a-n + 2
RO
OH
O
OO N H H N R3 R3 R3 = 1-adamantyl R2O 111 (6 mol%) Sc(OTf)3 (5 mol%) O CH2Cl2, 30 °C Ar
OH
CO2R1
cr
R2O
OR2
ip t
O
188a-q 187a-c
Ac ce p
te
d
M
an
us
188a: Ar = Ph, R1 = Et, R2 = Me: 95% yield, 93% ee 188b: Ar = Ph, R1 = R2 = Me: 97% yield, 93% ee 188c: Ar = Ph, R1 = i-Pr, R2 = Me: 78% yield, 92% ee 188d: Ar = Ph, R1 = t-Bu, R2 = Me: 87% yield, 95% ee 188e: Ar = Ph, R1 = Bn, R2 = Me: 96% yield, 92% ee 188f: Ar = m-MeOC6H4, R1 = Et, R2 = Me: 92% yield, 94% ee 188g: Ar = p-MeOC6H4, R1 = Et, R2 = Me: 97% yield, 92% ee 188h: Ar = 3,4-(MeO)2C6H3, R1 = Et, R2 = Me: 78% yield, 97% ee 188i: Ar = o-FC6H4, R1 = Et, R2 = Me: 88% yield, 94% ee 188j: Ar = p-FC6H4, R1 = Et, R2 = Me: 93% yield, 89% ee 188k: Ar = p-BrC6H4, R1 = Et, R2 = Me: 93% yield, 91% ee 188l: Ar = p-NO2C6H4, R1 = Et, R2 = Me: 92% yield, 94% ee 188m: Ar = 2-furyl, R1 = Et, R2 = Me: 86% yield, 88% ee 188n: Ar = 2-thienyl, R1 = Et, R2 = Me: 92% yield, 95% ee 188o: Ar = Ph, R1 = Et, R2 = Me: 87% yield, 89% ee 188p: Ar = Ph, R1 = Et, R2 = i-Pr: 92% yield, 93% ee 188q: Ar = Ph, R1 = R2 = Et: 93% yield, 91% ee
Scheme 61. Friedel−Crafts reaction of phenols with (E)-4-oxo-4-arylbutenoates [116].
Sesamol is a crucial fragment found in a number of biologically active molecules and natural products. Meanwhile, chiral α-amino-substituted sesamol derivatives have emerged as ubiquitous antibacterial and antitumor pharmaceuticals [117]. An easy way to construct these α-amino sesamols in enantiomerically enriched form is the asymmetric aza-Friedel−Crafts reaction with imines. In 2014, very good results were reported by Feng et al. in enantioselective scandium-catalyzed aza-Friedel−Crafts reaction of sesamol with a wide range 106 Page 106 of 135
of aryl imines 190a-o performed in the presence of chiral N,N′-dioxide ligand 189 [118]. As shown in Scheme 62, the corresponding bioactive chiral α-amino-sesamols 191a-o were produced in moderate to high yields (32-97%) with generally high enantioselectivities of up to
ip t
97% ee. The lowest enantioselectivities (83-86% ee) and yields (32-53%) were obtained for the reactions of 2-thienyl- and 2-naphthyl-substituted imine substrates 190l-m. On the other
cr
hand, regardless of the electron-donating or electron-withdrawing substituents on the phenyl
us
ring of imines (Ar), high enantioselectivities (89-97% ee) were obtained for products 191b-j. Generally, substituents on the meta-position of the phenyl ring of imine presented better
an
yields than the ortho- and para-substituted ones. When the tosyl protecting group of the imine was changed to Bs (190n) or a more electron-withdrawing 4-chloro-phenylsulfonyl group
M
(190o), the reactivity as well as the enantioselectivity maintained. Unfortunately, aliphatic
Ac ce p
te
d
aldimines performed sluggishly.
107 Page 107 of 135
+ N -
N
O
O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 189 (13 mol%) Sc(OTf)3 (10 mol%)
Ar 190a-o + OH
O
O N H
O
R
-
OH
O
m-BrC6H4CO2H (10 mol%)
NHR
O
* Ar
toluene, 0 °C
O
ip t
N+
cr
191a-o
sesamol
te
d
M
an
us
191a: Ar = Ph, R = Ts: 93% yield, 94% ee 191b: Ar = o-Tol, R = Ts: 63% yield, 97% ee 191c: Ar = m-Tol, R = Ts: 80% yield, 93% ee 191d: Ar = p-Tol, R = Ts: 72% yield, 91% ee 191e: Ar = o-FC6H4, R = Ts: 83% yield, 96% ee 191f: Ar = m-FC6H4, R = Ts: 97% yield, 95% ee 191g: Ar = p-FC6H4, R = Ts: 90% yield, 95% ee 191h: Ar = m-ClC6H4, R = Ts: 91% yield, 96% ee 191i: Ar = m-CF3C6H4, R = Ts: 90% yield, 96% ee 191j: Ar = p-CF 3C6H4, R = Ts: 71% yield, 89% ee 191k: Ar = 2-furyl, R = Ts: 80% yield, 86% ee 191l: Ar = 2-thienyl, R = Ts: 32% yield, 83% ee 191m: Ar = 2-Naph, R = Ts: 53% yield, 86% ee 191n: Ar = Ph, R = Bs: 85% yield, 92% ee 191o: Ar = Ph, R = p-ClC6H4SO2: 80% yield, 95% ee
Ac ce p
Scheme 62. Friedel−Crafts reaction of sesamol with aryl aldimines [118].
11. Miscellaneous enantioselective scandium-catalyzed reactions
In 2011, Feng et al. reported the first catalytic asymmetric electrophilic addition of αdiazoesters to α-alkyl ketones, consisting in a unique C−N bond formation reaction via αhydrazonation [119]. As shown in Scheme 63, the reaction was catalyzed by a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 9 in the presence of Li2CO3 as an additive. The reaction occurred between ketones 192a-j and αbenzyl-α-diazoacetate 7a, affording the corresponding unexpected chiral alkylhydrazone 108 Page 108 of 135
products 193a-j. Indeed, it was rationally expected that a ring-expansion product 194 would be obtained from the initial nucleophilic addition of the α-diazoester to the C=O bond of the ketone instead of product 193 arisen from electrophilic addition of the α-diazoester. A broad
ip t
scope of ketones was compatible with the mild reaction conditions regardless of the positions and electronic properties of the substituents on the benzene ring of 1-tetralone derivatives
cr
192a and 192c-f since these substrates led to the corresponding products 193a and 193c-f in
us
good to high yields (80-96%) and high enantioselectivities (94-99% ee), except 6-methoxy-1tetralone 192b which displayed a lower reactivity (65% yield) along with good
an
enantioselectivity of 93% ee. In addition, chroman-4-one 192g and thiochroman-4-one 192h were good candidates and yielded the corresponding products 193g and 193h, respectively,
M
with 98% ee in yields of 75 and 90%, respectively. Furthermore, other benzo cyclic ketones, such as 1-indanone 192i incorporating a five-membered ring, was compatible with this
d
method, giving a moderate yield (53%) and good enantioselectivity (89% ee), whereas a
te
higher yield (98%) and enantioselectivity (99% ee) were reached using 1-benzosuberone 192j as the nucleophile. Non-benzo cycloalkanones 192k-o, such as cyclohexanone 192k and 4-
Ac ce p
thiacyclohexanone 192l, were also tolerated in the process, giving the corresponding products 193k-l with moderate yields (70-83%) and enantioselectivities (61-71% ee). Moreover, seven, eight-, and ten-membered aliphatic cyclic ketones delivered products 193m-o albeit with modest enantioselectivities (52-77% ee), although cyclooctanone 193n exhibited relatively lower reactivity (45% yield). It is worth noting that this work described for the first time the electrophilic capability of α-diazoesters in a unique catalytic asymmetric C−N bond formation via α-hydrazonation of unactivated ketones.
109 Page 109 of 135
N+ O
+
O-
O-
O
R1
N
O
N H
R3 192a-j
Sc(OTf)3 (2.4-6 mol%)
+ CO2Et
R2
Li2CO3 (10 mol%)
R3
CH2Cl2, 20 °C
N2 7a
R
R2
CO2Et
X ( )n R3
194
Bn
CO2Et
193a-j
O Bn 1
X
H * N N ( )n
an
Bn
O R1
ip t
( )n
cr
X
us
R2
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (2-5 mol%)
Ac ce p
te
d
M
193a: X = CH2, n = 1, R1 = R2 = H, R3 = OMe: 89% yield, 95% ee 193b: X = CH2, n = 1, R1 = R3 = H, R2 = OMe: 65% yield, 93% ee 193c: X = CH2, n = 1, R1 = OMe, R2 = R3 = H: 93% yield, 99% ee 193d: X = CH2, n = 1, R1 = NO2, R2 = R3 = H: 88% yield, 94% ee 193e: X = CH2, n = 1, R1 = Br, R2 = R3 = H: 96% yield, 99% ee 193f: X = CH2, n = 1, R1 = R3 = Me, R2 = H: 80% yield, 99% ee 193g: X = O, n = 1, R1 = R2 = R3 = H: 75% yield, 98% ee 193h: X = S, n = 1, R1 = R2 = R3 = H: 90% yield, 98% ee 193i: X = CH2, n = 0, R1 = R2 = R3 = H: 53% yield, 89% ee 193j: X = CH2, n = 2, R1 = R2 = R3 = H: 98% yield, 99% ee
O
Bn
+
X
( )n
192k-o
O
CO2Et same conditions
N2
X
H * N N ( )n
7a
Bn CO2Et
193k-o
193k: X = CH2, n = 1: 83% yield, 71% ee 193l: X = S, n = 1: 70% yield, 61% ee 193m: X = CH2, n = 2: 81% yield, 74% ee 193n: X = CH2, n = 3: 45% yield, 77% ee 193o: X = CH2, n = 5: 75% yield, 52% ee
Scheme 63. α-Amination of cyclic ketones with α-benzyl-α-diazoacetate [119].
110 Page 110 of 135
Later in 2015, other enantioselective scandium-catalyzed electrophilic aminations were reported by Luan et al. [120]. It involved catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols 195a-s implemented with electrophilic azodicarboxylates 196a-c
ip t
under catalysis with in situ generated chiral pybox scandium complexes of ligands 197 and 134. This process provided the corresponding bicyclic enones 198a-s bearing a nitrogen-
cr
containing quaternary stereocenter in high enantioselectivities (90-98% ee) with good to high yields (81-98%) (Scheme 64). The results from reactions of disubstituted naphthols 195a-j
us
with dibenzyl azodicarboxylate 196a catalyzed by complex of ligand 197 showed that it was possible to vary the substituents on both the 1- and 3-positions of 2-naphthols (Scheme 61,
an
first equation). Thus, the 3-position of naphthols (R2) could be substituted with alkyl groups
M
(195a-c and 195g-h), aromatic groups featuring differential electronic properties (195d-e), heterocycles (195f), and even halogen functionalities (195i-j) while various aliphatic
d
substituents were compatible at the 1-position (R1) of the naphthyl ring without compromising
te
the enantioselectivity. With the aim of extending this methodology to the reaction of monosubstituted 2-naphthols 195k-s with other azodicarboxylates 196b-c, the authors found
Ac ce p
that using related ligand 134 allowed better results to be achieved than by using catalyst derived from ligand 197. Under these conditions, a range of other aminative dearomatization chiral products 198k-s was achieved in comparable excellent yields and enantioselectivities (Scheme 64, second equation). It is important to note that this work constituted the first example of a catalytic asymmetric aminative dearomatization of 2-naphthols.
111 Page 111 of 135
O
N N
N Bn
1
R
OH Cbz N + N 2 Cbz R 195a-j
Bn
197 (6 mol%) Sc(OTf)3 (5 mol%)
NHCbz Cbz N R1 O R2
CH2Cl2, r.t. 198a-j
196a
ip t
O
M
an
us
cr
198a: R1 = R2 = Me: 97% yield, 98% ee 198b: R1 = Me, R2 = Et: 95% yield, 90% ee 198c: R1 = Me, R2 = Bn: 89% yield, 97% ee 198d: R1 = Me, R2 = Ph: 94% yield, 96% ee 198e: R1 = Me, R2 = p-ClC6H4: 91% yield, 96% ee 198f: R1 = Me, R2 = 2-thienyl: 87% yield, 95% ee 198g: R1 = Et, R2 = Me: 93% yield, 93% ee 198h: R1 = allyl, R2 = Bn: 81% yield, 96% ee 198i: R1 = Me, R2 = Br: 84% yield, 92% ee 198j: R1 = Me, R2 = I: 90% yield, 95% ee
O
N
N
d
134 (6 mol%)
2 OH R O2C N + N
2 CO2R2 Ph R O2C HN N R1
O
Sc(OTf)3 (5 mol%)
CO2R2
196b-c
CH2Cl2, r.t. 198k-s
Ac ce p
195k-s
Ph
te
R1
O
N
198k: R1 = R2 = Bn: 98% yield, 98% ee 198l: R1 = CH2p-Tol, R2 = Bn: 97% yield, 98% ee 198m: R1 = CH2-(p-CO2EtC6H4), R2 = Bn: 92% yield, 98% ee 198n: R1 = CH2-(o-BrC6H4), R2 = Bn: 87% yield, 94% ee 198o: R1 = CH2-(p-OCF3C6H4), R2 = Bn: 95% yield, 96% ee 198p: R1 = CH2(2-Naph), R2 = Bn: 85% yield, 96% ee 198q: R1 = Et, R2 = i-Pr: 98% yield, 90% ee 198r: R1 = n-Bu, R2 = i-Pr: 94% yield, 97% ee 198s: R1 = allyl, R2 = i-Pr: 93% yield, 92% ee
Scheme 64. Aminative dearomatizations of mono- and disubstituted 2-naphthols [120].
Later, this type of reactions were also investigated by Feng et al. by using a chiral scandium catalyst derived from N,N’-dioxide ligand 111 [121]. As shown in Scheme 65, the reaction of 112 Page 112 of 135
a range of disubstituted 2-naphthols 195a-k with various azodicarboxylates 196a-d led to the corresponding chiral β-naphthalenone compounds 198a-m bearing a nitrogen-containing quaternary carbon stereocenter in good to excellent yields of up to 99% and high
ip t
enantioselectivities of 88-99% ee. In the case of diethyl azodicarboxylate as substrate, homogeneous excellent results were achieved in terms of yields and enantioselectivities with
cr
an exception for product 198f which was achieved in only 40% yield albeit with an excellent
us
enantioselectivity of 99% ee. Generally, the nature of substituent R2 on the 3-position of the 2-naphthol had little effect on the enantioselectivity. Aliphatic groups, such as methyl, ethyl,
an
n-butyl, benzyl, as well as allyl groups were tolerated, and the corresponding products 198a-e were obtained in 95-98% ee. Remarkably, substrates bearing halogen functionalities also
M
underwent the asymmetric dearomatization reaction well, providing the corresponding products 198g-i in 85-95% yields and 92-97% ees. Moreover, a 3-phenyl-substituted 2-
d
naphthol was also a suitable substrate, affording the dearomatized product 198j in 99% yield
te
and 99% ee. Concerning the influence of the nature of substituent R1, larger substituents decreased the enantioselectivity slightly, but the results were still good (99% yield and 86%
Ac ce p
ee for product 198k with R1 = Et). In addition to diethyl azodicarboxylate, diisopropyl and dibenzyl azodicarboxylates were alternative electrophiles, providing the corresponding products in 93-99% yields and 88-95% ees.
113 Page 113 of 135
N+ O-
O
N H
N
+
O-
O
H N R4
R4 R4 = 1-adamantyl 111 (5 mol%)
R1
CO2R3 R3O2C 1 R N NH O
196a-d
R2 198a-m
5 Å M. S., H2O
cr
195a-k
ip t
OH R3O2C Sc(OTf)3 (5 mol%) N + N CO2R3 CH2Cl2, 30 °C R2
d
M
an
us
198a: R1 = R2 = Me, R3 = Et: 99% yield, 95% ee 198b: R1 = Me, R2 = R3 = Et: 99% yield, 96% ee 198c: R1 = Me, R2 = n-Bu, R3 = Et: 88% yield, 97% ee 198d: R1 = Me, R2 = Bn, R3 = Et: 99% yield, 98% ee 198e: R1 = Me, R2 = allyl, R3 = Et: 73% yield, 98% ee 198f: R1 = Me, R2 = CH2C(Me)=CH2, R3 = Et: 40% yield, 99% ee 198g: R1 = Me, R2 = Cl, R3 = Et: 86% yield, 92% ee 198h: R1 = Me, R2 = Br, R3 = Et: 85% yield, 92% ee 198i: R1 = Me, R2 = I, R3 = Et: 95% yield, 97% ee 198j: R1 = Me, R2 = Ph, R3 = Et: 99% yield, 99% ee 198k: R1 = R3 = Et, R2 = Me: 99% yield, 86% ee 198l: R1 = R2 = Me, R3 = i-Pr: 99% yield, 95% ee 198m: R1 = R2 = Me, R3 = Bn: 93% yield, 88% ee
Ac ce p
te
Scheme 65. Aminative dearomatizations of disubstituted 2-naphthols [121].
In 2014, Hou et al. employed a novel preformed cationic half-sandwich scandium alkyl complex 199 bearing monocyclopentadienyl ligands embedded in chiral binaphthyl backbones to catalyze the enantioselective C−H bond addition of pyridines 200a-l to various alkenes 201a-e [122]. The process afforded a variety of enantioenriched alkylated pyridine derivatives 202a-q in generally high yields of up to 95% and good to high enantioselectivities of up to 96% ee (Scheme 66). The substrate scope was wide since variously substituted pyridines were tolerated, including 2-phenylpyridine 200i for which the C−H bond activation reaction occurred selectively at the pyridine unit rather than at the phenyl group. Furthermore, in addition to simple 1-alkenes, such as 1-hexene 201a, 1-heptene 201n, and 1-octene 201o, allylcyclohexane 201p and allyltrimethylsilane 201q, containing bulky substituents in close 114 Page 114 of 135
proximity to the C−C double bond, were compatible alkylation agents in a similar fashion. Notably, the analogous yttrium and gadolinium complexes showed no activity under similar
ip t
conditions.
N
us
X Sc N
cr
X
an
X = OSi(i-Pr)3 199 (5 mol%) R
N +
R4
R2
R1 R2
toluene, 40 °C
3
R
201a-e
N
R3 202a-q
d
200a-l
R4
[Ph 3C][B(C6F 5)4] (5 mol%)
M
1
Ac ce p
te
202a: R1 = Me, R2 = R3 = H, R4 = n-Bu: 90% yield, 88% ee 202b: R1 = R3 = Me, R2 = H, R4 = n-Bu: 93% yield, 96% ee 202c: R1 = R2 = Me, R3 = H, R4 = n-Bu: 95% yield, 90% ee 202d: R1 = Me, R2 = Br, R3 = H, R4 = n-Bu: 94% yield, 90% ee 202e: R1 = Me, R2 = H, R3 = Cl, R4 = n-Bu: 91% yield, 92% ee 202f: R1 = Et, R2 = R3 = H, R4 = n-Bu: 93% yield, 84% ee 202g: R1 = i-Pr, R2 = R3 = H, R4 = n-Bu: 94% yield, 76% ee 202h: R1 = t-Bu, R2 = R3 = H, R4 = n-Bu: 83% yield, 84% ee 202i: R1 = Ph, R2 = R3 = H, R4 = n-Bu: 94% yield, 84% ee 202j: R1,R2 = (CH2)4, R3 = H, R4 = n-Bu: 93% yield, 84% ee 202k: R1,R2 = (CH2)3, R3 = H, R4 = n-Bu: 63% yield, 86% ee 202l: R1 = I, R2 = R3 = H, R4 = n-Bu: 87% yield, 88% ee 202m: R1 = Me, R2,R3 = (CH=CH)2, R4 = n-Bu: 81% yield, 94% ee 202n: R1 = Me, R2 = R3 = H, R4 = n-Pent: 92% yield, 86% ee 202o: R1 = Me, R2 = R3 = H, R4 = n-Hex: 92% yield, 86% ee 202p: R1 = Me, R2 = R3 = H, R4 = CH2Cy: 94% yield, 82% ee 202q: R1 = Me, R2 = R3 = H, R4 = CH2TMS: 80% yield, 72% ee
Scheme 66. Addition of pyridines to alkenes catalyzed by a preformed chiral half-sandwich scandium catalyst [122].
115 Page 115 of 135
Another preformed scandium tetraazane chiral catalyst 203 was synthesized by Mu et al. and further applied to the catalysis of enantioselective intramolecular hydroamination of alkenes 204a-c in the presence of n-BuLi [123]. As shown in Scheme 67, the corresponding
ip t
chiral pyrrolidines 205a-c were achieved in high yields (90-95%) and low to good enantioselectivities (28-85% ee). Better yields were reached by changing this scandium
N Sc N Cl N Ar Ar Ar = 2,6-Me 2C6H3
an
N
us
cr
catalyst by its yttrium analogue.
M
203 (5 mol%)
R
R
n-BuLi (5 mol%)
H2N
NH
R
* 205a-c
te
204a-c
d
C6D6
R
Ac ce p
205a: R = Me: 90% yield, 85% ee 205b: R,R = (CH2)4: 90% yield, 71% ee 205c: R = Ph: 95% yield, 28% ee
Scheme 67. Intramolecular hydroamination of alkenes catalyzed by a preformed chiral tetraazane scandium catalyst [123].
In 2011, a direct highly diastereo- and enantioselective asymmetric vinylogous Mannichtype reaction of aldimines 206a-o with non-activated natural α-angelica lactone 207 was successfully developed by Feng et al. [124]. The process was catalyzed by a chiral scandium complex in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 97, providing the corresponding δ-amino γ,γ’-disubstituted butenolide carbonyl derivatives 208a-o bearing adjacent quaternary and tertiary stereocenters. As shown in Scheme 68, these products were
116 Page 116 of 135
achieved in moderate to good yields (58-83%), high enantioselectivities (90-97% ee) and moderate to excellent diastereoselectivities (72-98% de). The introduction of an electrondonating methyl group to N-arylimine decreased the enantioselectivity (90% ee) of the
ip t
corresponding product 208c slightly with good yield (82%), while electron-withdrawing chloride group gave the corresponding product 208b with higher diastereo- and
cr
enantioselectivity (92% de and 97% ee) in moderate yield (67%). The enantioselectivity of the reaction was sensitive to the electronic property rather than to the steric hindrance of
us
substituents on the phenyl ring of aromatic aldimines. It is worth noting that substrates with
an
electron-withdrawing substituents provided higher enantioselectivities than those with electron-donating ones (products 208i-k vs products 208d-h). Moreover, fused ring and
M
heteroaromatic aldimines 208l-o were also tolerated, leading to the corresponding products
Ac ce p
te
d
208l-o with enantioselectivities of 93-97% ee.
117 Page 117 of 135
N+
HO + Ar
O
R 206a-o
O
3 Å M.S. 2-Me-THF, 0 °C
207
HO HN
R
Ar O
cr
N
OO H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 97 (6 mol%) Sc(OTf)3 (5 mol%) ON H
ip t
O
+ N
O 208a-o
d
M
an
us
208a: Ar = Ph, R = H: 81% yield, 95% ee, 90% de 208b: Ar = Ph, R = Cl: 67% yield, 97% ee, 92% de 208c: Ar = Ph, R = Me: 82% yield, 90% ee, 86% de 208d: Ar = o-Tol, R = H: 78% yield, 93% ee, 98% de 208e: Ar = m-Tol, R = H: 77% yield, 92% ee, 90% de 208f: Ar = p-Tol, R = H: 83% yield, 92% ee, 90% de 208g: Ar = p-MeOC6H4, R = H: 82% yield, 94% ee, 92% de 208h: Ar = m-MeOC6H4, R = H: 77% yield, 90% ee, 90% de 208i: Ar = p-FC6H4, R = H: 76% yield, 98% ee, 92% de 208j: Ar = p-ClC6H4, R = H: 74% yield, 96% ee, 92% de 208k: Ar = p-BrC6H4, R = H: 58% yield, 97% ee, 92% de 208l: Ar = 1-Naph, R = H: 75% yield, 95% ee, 94% de 208m: Ar = 2-Naph, R = H: 83% yield, 93% ee, 90% de 208n: Ar = 2-furyl, R = H: 62% yield, 95% ee, 72% de 208o: Ar = 2-thienyl, R = H: 82% yield, 97% ee, 92% de
Ac ce p
te
Scheme 68. Vinylogous Mannich-type reaction of α-angelica lactone [124].
Tetrahydroquinoline derivatives bearing a quaternary carbon center at the C4 position exhibit potential biological activities. The Povarov reaction, an inverse electron-demand azaDiels−Alder reaction of N-arylimines with electron-rich alkenes, is one of the most efficient routes to construct this type of privileged backbone [125]. However, most of the reported asymmetric methods provided chiral tetrahydroquinolines with a tertiary stereocenter at the C4 position. In 2011, Feng et al. described the enantioselective scandium-catalyzed Povarov reaction of α-alkyl styrenes 209a-d with N-aryl aldimines 206a-n which afforded the corresponding chiral tetrahydroquinolines 210a-q bearing a quaternary stereogenic center [126]. Performing the process with chiral N,N’-dioxide ligand 9, these important products
118 Page 118 of 135
were obtained in general excellent enantioselectivities of 92 to > 99% ee (Scheme 69). Regardless of the steric hindrance of the substituents on the electron-deficient imines 206b-g, tetrahydroquinolines 210b-g were obtained in good to high yields (76-93%) with good
ip t
diastereoselectivities (86-92% de) and excellent enantioselectivities (92-> 99% ee). On the other hand, the presence of electron-donating substituents on the aromatic imine enriched the
cr
electron density and thus decreased the reactivity. Thus, in the case of imines derived from methyl-substituted benzaldehydes 206h-j, lower yields (51-88% yields) were obtained albeit
us
with high diastereo- and enantioselectivities of 88-90% de and 94-99% ee, respectively. When
an
an electron-donating p-methoxy-substituted imine 206k was employed, an excellent enantioselectivity of 98% ee was also achieved, but the yield was substantially reduced
M
(22%). Imines 206m-n derived from heteroaromatic and aliphatic aldehydes were also suitable substrates to afford the corresponding products 210m-n with high enantioselectivities
Ac ce p
te
d
(95-96% ee) albeit in low yields (33-35%).
119 Page 119 of 135
N+
OO H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (10 mol%) Sc(OTf)3 (10 mol%) ON H
HO
R1
206a-n
R2
R3
R1CHO (0.5 equiv.) MgSO4 CH2Cl2, 30 °C
209a-d
OH
R3
N H
R1
cr
+
R2
ip t
O
N
+ N
210a-q
Ac ce p
te
d
M
an
us
210a : R1 = R2 = Ph, R3 = Me: 75% yield, 96% ee, 88% de 210b: R1 = o-ClC6H4, R2 = Ph, R3 = Me: 93% yield, 92% ee, 86% de 210c: R1 = m-ClC6H4, R2 = Ph, R3 = Me: 76% yield, 95% ee, 90% de 210d: R1 = p-ClC6H4, R2 = Ph, R3 = Me: 82% yield, > 99% ee, 92% de 210e: R1 = p-BrC6H4, R2 = Ph, R3 = Me: 92% yield, > 99% ee, 92% de 210f: R1 = p-FC6H4, R2 = Ph, R3 = Me: 85% yield, 98% ee, 90% de 210g : R1 = p-CF3C6H4, R2 = Ph, R3 = Me: 81% yield, 99% ee, 86% de 210h: R1 = o-Tol, R2 = Ph, R3 = Me: 88% yield, 94% ee, 90% de 210i: R1 = m-Tol, R2 = Ph, R3 = Me: 66% yield, 97% ee, 88% de 210j: R1 = p-Tol, R2 = Ph, R3 = Me: 51% yield, 99% ee, 90% de 210k : R1 = p-MeOC6H4, R2 = Ph, R3 = Me: 22% yield, 98% ee, 82% de 210l: R1 = 2-Naph, R2 = Ph, R3 = Me: 67% yield, > 99% ee, 92% de 210m: R1 = 2-thienyl, R2 = Ph, R3 = Me: 35% yield, 96% ee, 78% de 210n: R1 = Cy, R2 = Ph, R3 = Me: 33% yield, 95% ee, 22% de 210o: R1 = Ph, R2 = p-Tol, R3 = Me: 70% yield, 98% ee, 94% de 210p: R1 = Ph, R2 = p-FC6H4, R3 = Me: 70% yield, 98% ee, 94% de 210q: R1 = R2 = Ph, R3 = Et: 40% yield, 96% ee, 86% de
Scheme 69. Povarov reaction of α-alkyl styrenes with N-aryl aldimines [126].
Finally, Franz et al. have reported scandium-catalyzed enantioselective Hosomi−Sakurai allylations of isatins 6a-j with various substituted allylic silanes 211a-d to give the corresponding chiral 3-allyl-3-hydroxy-2-oxindoles 212a-q bearing a quaternary stereogenic center [127]. These products were obtained in good to high yields and enantioselectivities of up to 99% and 99% ee, respectively, when the reactions were performed with a chiral scandium complex derived from pybox ligand 27 in the presence of TMSCl as activator and NaSbF6 as additive (Scheme 70). This catalyst system was equally efficient for N-substituted 120 Page 120 of 135
as well as unsubstituted NH isatins, and for allyl trimethylsilane as well as substituted allylic silanes. For example, 2-methyl-, 2-phenyl-, and 2-cyclohexyl-substituted allylsilanes proceeded in high yields of up to 99% and enantioselectivities of up to 99% ee (products Furthermore,
the
reaction
conditions
were
also
applicable
to
(E)-
ip t
212n-p).
crotyltrimethylsilane which provided anti-product 212q in 95% yield, 96% ee, albeit with
cr
moderate anti-diastereoselectivity of 66% de. In some cases, the catalyst loading of the
O
O
M
6a-j SiMe3
211a-d
R4
R3
OH R2
d
TMSCl (3 equiv)
NaSbF6 (30 mol%)
te
R3
N
27 (10 mol%) Sc(OTf)3 (10 mol%) 4 Å M.S.
N R1 + R4
an
R2
O
N
N
O
us
process could be reduced as low as 0.05 mol% in comparable results.
MeCN, r.t.
O N R1 212a-q
Ac ce p
212a: R1 = Me, R2 = 5-Cl, R3 = R4 = H: 99% yield, 91% ee 212b: R1 = Me, R2 = 5-Br, R3 = R4 = H: 96% yield, 86% ee 212c: R1 = Me, R2 = 5-F, R3 = R4 = H: 89% yield, 89% ee 212d: R1 = Me, R2 = 4-Cl, R3 = R4 = H: 96% yield, 87% ee 212e: R1 = Me, R2 = H, R3 = R4 = H: 91% yield, 89% ee 212f: R1 = Me, R2 = 5-OMe, R3 = R4 = H: 72% yield, 92% ee 212g: R1 = R2 = R3 = R4 = H: 99% yield, 85% ee 212h: R1 = R3 = R4 = H, R2 = 5-Br: 99% yield, 86% ee 212i: R1 = R3 = R4 = H, R2 = 4-Cl: 99% yield, 82% ee 212j: R1 = R3 = R4 = H, R2 = 7-F: 97% yield, 81% ee 212k: R1 = R3 = R4 = H, R2 = 5-OMe: 99% yield, 80% ee 212l: R1 = R3 = R4 = H, R2 = 5-OCF3: 99% yield, 81% ee 212m: R1 = Ph, R2 = R3 = R4 = H: 97% yield, 89% ee 212n: R1 = R4 = Me, R2 = 5-Br, R3 = H: 95% yield, 97% ee 212o: R1 = Me, R2 = 5-Cl, R3 = H, R4 = Ph: 88% yield, 99% ee 212p: R1 = Me, R2 = 5-Cl, R3 = H, R4 = Cy: 99% yield, 95% ee 212q: R1 = R3 = Me, R2 = 5-Cl, R4 = H: 95% yield, 96% ee, 66% de
Scheme 70. Hosomi−Sakurai allylation of isatins with allylsilanes [127]. 121 Page 121 of 135
12. Conclusions
ip t
This review illustrates well that scandium asymmetric chemistry has become an important component of asymmetric organic synthesis, in particular through its recent impressive
cr
diversification outcomes. It updates the major progress reported since the beginning of 2011
us
in the field of all types of enantioselective transformations promoted by chiral scandium catalysts, well demonstrating the power of these special catalysts to provide a high degree of
an
reactivity and stereoselectivity in a myriad of asymmetric transformations including highly efficient novel domino processes. It demonstrates that since the pioneering studies dealing
M
with enantioselective scandium-catalyzed Diels−Alder reactions reported by Kobayashi in 1994, a large number of highly efficient enantioselective scandium-catalyzed reactions have
d
been developed. Among important recent results, remarkable enantioselectivities have been
te
reported by several groups for a range of unprecedented fascinating scandium-catalyzed domino reactions including multicomponent ones which allowed the synthesis of a wide range
Ac ce p
of complex molecules to be achieved. For example, the group of Feng reported very high enantioselectivities of up to 99% ee for various types of completely novel domino reactions. Remarkable results were also achieved by other groups, such as those of Davies, Ding, Kingsbury, Kesavan, Chi, Shi, Franz, and Cai. In addition, a number of important advances have been independently developed by the groups of Vaccaro, Kobayashi, Wang, and Feng, in the area of asymmetric scandium-catalyzed Michael additions of a range of substrates to α,βunsaturated carbonyl compounds, providing various types of functionalized chiral products in generally remarkable enantioselectivities of up to 99% ee. Among them, several important examples of highly enantioselective Michael additions of thiols to α,β-unsaturated ketones could be nicely performed in water with enantioselectivities of up to 98% ee. Furthermore,
122 Page 122 of 135
important advances in scandium-catalyzed asymmetric chemistry have been reported by several groups in the field of Mannich reaction, [4+2] and [2+2] cycloaddition reactions, ringopening of epoxides, allylation reactions, α-functionalizations of 3-substituted oxindoles,
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Baeyer−Villiger reaction, epoxidation of alkenes, reduction of ketones, aldol reactions, Friedel−Crafts reaction, hydroamination and amination reactions, Povarov reaction, aldol
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reactions performed in water, as well as addition reactions. In most cases, Sc(OTf)3 which is a stable and excellent Lewis acid even in aqueous solutions in contrast with most other Lewis
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acids, was used as precatalyst both in organic solvents or in aqueous solutions. Scandium triflate salt can be easily recovered through extraction with water and reused. This recyclable
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use of scandium complexes is important for green chemistry and will play a key role in future developments of asymmetric scandium catalysis. The success in the firstly reported highly
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enantioselective reactions performed in water, providing potential and unusual tools in organic chemistry, constitutes a foundation for performing organic processes in
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environmentally friendly conditions, and consequently, this field presents significant
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challenges in the future. Furthermore, the ever-growing need for environmentally friendly
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catalytic processes prompted organic chemists to focus on less moisture sensitive metals employed at low catalyst loadings, such as scandium, to develop new catalytic systems to perform reactions, such as C–C bond formations, C–heteroatoms bond formations, or C–H functionalizations. A bright future is undeniable for more sustainable novel and enantioselective scandium-catalyzed transformations and their applications in total synthesis even if the promise of asymmetric catalysis through highly efficient and environmentally friendly chiral scandium complexes remains to be fulfilled.
Graphical Abstract
123 Page 123 of 135
Recent developments in enantioselective scandium-catalyzed transformations
Hélène Pellissier
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1.1.1 Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
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This review collects the major progress in the field of enantioselective transformations promoted by chiral scandium catalysts, covering the literature since the beginning of 2011,
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well illustrating the power of these special catalysts to promote various types of reactions.
124 Page 124 of 135
[Sc]*
R
+
[D]
(C)
E*
[Sc]*
R' +
R *
Nu
Nu
O R
R'
R''
Y R''
Y [Sc]*
X R
+
* * R''' R'
HX
Nu
R' * Nu
R
R
R
[Sc]* + XY
O
R'
R'
*
R'
+
O
R'
[Sc]* O
R''
R
R'' * * X O OH
[Sc]*
+
R'
R O
M
R
H2O2
O R
O
MCPBA
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( )n
OH
Z
X
[Sc]*
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X
( )n
OH Z
Y
R
* R O
Y
+ N2
( )n
R *
+
R'
R' O
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+
*
*
[Sc]*
R
O
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X
Y
X
N H
N H
X
R
*
R'
R
O X
[Sc]*
R'''
+
C X
R'
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B
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+
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A
[Sc]* R X
H N
* ( )n
R' N
Y
Highlights
Recent developments in enantioselective scandium-catalyzed transformations Enantioselective scandium-catalyzed domino reactions Enantioselective scandium-catalyzed Michael additions
125 Page 125 of 135
Enantioselective scandium-catalyzed oxidations
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Miscellaneous enantioselective scandium-catalyzed reactions
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ABBREVIATIONS
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Ar: aryl Bpy: 2,2’-bipyridine
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BINOL: 1,1'-bi-2-naphthol Bn: benzyl
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BNP: Binaphthophosphole Boc: tert-butoxycarbonyl
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Cy: cyclohexyl
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Cbz: benzyloxycarbonyl
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Bs: benzenesulfonyl
DBDMH: 1,3-dibromo-5,5-dimethylhydantoin DCE: dichloroethane
de: diastereomeric excess
DFT: density functional theory
DOSP: N-p-dodecylbenzenesulfonylprolinate ee: enantiomeric excess Hex: hexyl HFIP: hexafluoroisopropanol
126 Page 126 of 135
MCPBA: meta-chloroperbenzoic acid Mes: mesyl M.S.: molecular sieves
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Naph: naphthyl
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NBS: N-bromosuccinimide NFSI: N-fluorobisbenzenesulfonimide
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NHC: N-heterocyclic carbene NIS: N-iodosuccinimide
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Oct: octyl
Pybox: 2,6-bis(2-oxazolyl)pyridine
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TBS: tert-butyldimethylsilyl
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r.t.: room temperature
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Pent: pentyl
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Tf: trifluoromethane sulfonyl THF: tetrahydrofuran TMS: trimethylsilyl Tol: tolyl
Ts: 4-toluenesulfonyl (tosyl)
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S0010-8545(15)30092-8 http://dx.doi.org/doi:10.1016/j.ccr.2016.01.005 CCR 112186
To appear in:
Coordination Chemistry Reviews
Received date: Revised date: Accepted date:
19-11-2015 18-1-2016 20-1-2016
Please cite this article as: H. Pellissier, nRecent developments in enantioselective scandium-catalyzed transformations, Coordination Chemistry Reviews (2016), http://dx.doi.org/10.1016/j.ccr.2016.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent developments in enantioselective
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Hélène Pellissier*
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scandium-catalyzed transformations
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313,
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1. Introduction
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Contents
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13397, Marseille, France
2. Enantioselective scandium-catalyzed domino reactions 3. Enantioselective scandium-catalyzed Michael additions 4. Enantioselective scandium-catalyzed cycloaddition reactions 5. Enantioselective scandium-catalyzed ring-opening reactions 6. Enantioselective scandium-catalyzed α-functionalizations of 3-substituted oxindoles 7. Enantioselective scandium-catalyzed aldol reactions 8. Enantioselective scandium-catalyzed oxidations 8.1. Epoxidations 8.2. Baeyer−Villiger reactions 9. Enantioselective scandium-catalyzed reductions
1 Page 1 of 135
10. Enantioselective scandium-catalyzed Friedel−Crafts reactions 11. Miscellaneous enantioselective scandium-catalyzed reactions 12. Conclusions
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References
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Keywords: Scandium
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Asymmetric catalysis
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Enantioselectivity Chirality
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Enantioselective transformations
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1. Introduction
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*Tel.: +33 4 91 28 27 65. E-mail: [email protected]
The synthesis of chiral compounds is an important and challenging area of contemporary synthetic organic chemistry [1]. Although asymmetric synthesis is sometimes viewed as a subdiscipline of organic chemistry, actually this topical field transcends any narrow classification and pervades essentially all chemistry [2]. The broad utility of synthetic chiral molecules in medicines and materials has made asymmetric catalysis a prominent area of investigation. Indeed, of the methods available for preparing chiral compounds, catalytic asymmetric synthesis has attracted most attention. In particular, asymmetric metal catalysis has emerged as a powerful tool to perform reactions in a highly enantioselective fashion over the past few decades in spite of the common drawbacks of metals, such as moisture 2 Page 2 of 135
sensitivity, recoverability, and toxicity, particularly for heavy metals. [2,3]. On the other hand, because rare earth metal triflates, such as Sc(OTf)3, are water-compatible and recoverable Lewis acids, they have been regarded as new types of Lewis acids. The application of
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scandium complexes in organic chemistry has been scarce for a long time probably due to the less reserve and difficulties in separation until Sc(OTf)3 was first introduced as a promising
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reusable Lewis acid in Diels−Alder reaction by Kobayashi in 1993 [4]. Afterwards, the unique characteristics of Sc(OTf)3 which feature advantages as stability, recovery, and
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reusability have drawn intense attentions in catalytic organic chemistry. In particular, over the past two decades, scandium asymmetric chemistry has become an important component of
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asymmetric organic synthesis. Scandium complexes derived from Sc(OTf)3 constitute a special type of Lewis acids with a unique and extraordinary high catalytic activity in many
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organic reactions which may be attributed to the small ionic radii of scandium compared with other rare earth metal complexes. The combination of the electronic properties of scandium
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with chiral ligands results in a myriad of novel asymmetric organic transformations often
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performed in remarkable enantioselectivities and under convenient experimental conditions.
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Scandium is expected to have the strongest Lewis acidity among rare earth metals, is compatible with water and Lewis bases, and is regarded as one of the standard and, more importantly, environmentally benign Lewis acids. All these advantages have ensured that enantioselective scandium-catalyzed reactions have received continuous ever-growing attention during the two last decades leading to exciting and fruitful research. This interest was initiated by the early success of enantioselective Diels−Alder reactions catalyzed by the first chiral scandium catalyst reported by Kobayashi in 1994 [5]. Ever since, many types of chiral ligands, such as bipyridines, bisoxazolines, bis(oxazolinyl)pyridines, and N,N’-dioxides etc., have been successfully applied in the presence of scandium triflate to catalyze almost all types of asymmetric organic reactions. Among important recent results, remarkable enantioselectivities have been reported by several groups for a range of unprecedented
3 Page 3 of 135
fascinating scandium-catalyzed domino reactions including multicomponent ones. For example, the group of Feng reported very high enantioselectivities of up to 99% ee for various types of completely novel domino reactions. Remarkable results were also achieved by other
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groups, such as those of Davies, Ding, Kingsbury, Kesavan, Chi, Shi, Franz, and Cai. In addition, a number of important advances have been independently developed by the groups
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of Vaccaro, Kobayashi, Wang, and Feng, in the area of asymmetric scandium-catalyzed Michael additions of a range of substrates, providing various types of functionalized chiral
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products in generally remarkable enantioselectivities of up to 99% ee. Furthermore, important advances in scandium-catalyzed asymmetric chemistry have been reported by several groups
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in the field of Mannich reactions, [4+2] and [2+2] cycloaddition reactions, ring-opening of epoxides, allylation reactions, α-functionalizations of oxindoles, Baeyer−Villiger reactions,
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epoxidation of alkenes, reductions of ketones, aldol reactions, Friedel−Crafts reactions, hydroamination and amination reactions, Povarov reactions, as well as addition reactions. The
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goal of this review is to collect the major developments in all types of enantioselective
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scandium-catalyzed transformations published since the beginning of 2011, since this field
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was most recently reviewed by Feng and Liu in a book chapter published in 2011, covering the literature up to 2010 [6]. More generally, the field of reactions catalyzed by (racemic) scandium catalysts among other rare earth complexes has been reviewed by several authors up to 2010 [7]. For the reader’s convenience, the review has been divided into ten parts, dealing successively with enantioselective scandium-catalyzed domino reactions, enantioselective scandium-catalyzed Michael additions, enantioselective scandium-catalyzed cycloaddition reactions, enantioselective scandium-catalyzed ring-opening reactions, enantioselective scandium-catalyzed
α-functionalizations
scandium-catalyzed
aldol
enantioselective
reactions,
scandium-catalyzed
of
3-substituted
enantioselective reductions,
oxindoles,
enantioselective
scandium-catalyzed
enantioselective
oxidations,
scandium-catalyzed
Friedel−Crafts reactions, and miscellaneous enantioselective scandium-catalyzed reactions. 4 Page 4 of 135
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2. Enantioselective scandium-catalyzed domino reactions
Tietze has defined a domino reaction as a process involving two or more bond-forming
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transformations, taking place under the same reaction conditions, without adding additional reagents, catalysts, and additives, in which the subsequent reactions result as a consequence of
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the functionality formed by bond formation or fragmentation in the previous step [8]. The use of these fascinating reactions in organic synthesis is increasing constantly [9], allowing the
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synthesis of a wide range of complex molecules, including natural products and biologically active compounds, through an economically favourable way by using one-pot processes that
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avoid the use of costly and time-consuming protection-deprotection processes, as well as purification procedures of intermediates [10]. The economical interest in combinations of
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asymmetric metal catalytic processes with the concept of domino reactions is obvious, and
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has allowed reaching easily high molecular complexity with often excellent levels of
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stereocontrol with simple operational one-pot procedures, and advantages of savings in solvent, time, energy, and costs. In the last decade, an increasing number of enantioselective domino processes catalyzed by metals have been developed [10k]. The wide variety of these novel highly efficient domino processes well reflects that of metals employed to induce them. Indeed, an increasing number of different metals such as magnesium, titanium, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, gold, zinc, aluminum, as well as tin were effective catalysts. In recent years, chiral scandium catalysts have been successfully applied to various asymmetric domino reactions including multicomponent ones, such as three-component Mannich-type reactions [11], three-component aza-Diels-Alder reactions [12], and three-component allylation reactions [13] among others. A more recent example reported by Kingsbury et al. involved the use of a combination of scandium triflate 5 Page 5 of 135
with a chiral trisoxazoline ligand 1 to promote an enantioselective domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones 2a-d (Scheme 1) [14]. Actually, despite their highly versatile coordination chemistry, the use of oxazoline-containing ligands
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tends to be polarized towards late transition metals; indeed their use with early transition metals and the f-elements is significantly less developed [15]. This type of ligands was first
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employed in molecular lanthanide catalysis as early as 1997 [16], yet there is still a significant void in the literature in this respect. In the domino reaction depicted in Scheme 1, a series of
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chiral arylated medium ring carbocycles 3a-k were rapidly accessed through scandium-
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catalyzed domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones 2a-d with aryldiazoalkanes 4a-g in both high yields and enantioselectivities of up to > 98% and
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97% ee, respectively. The transformation took place by 1,2-rearrangement in Sc-complexed diazonium betaine intermediate 5, cleanly affording the corresponding α-tertiary 2-
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arylcycloalkanone 3a-k in one step with dinitrogen as the only byproduct. As shown in
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Scheme 1, the highest levels of enantioselectivity were reached with cycloheptanones (n = 4)
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compared to the other ring sizes evaluated.
6 Page 6 of 135
O
O N
1 (5.5-11 mol%)
X +
( )n
O
Sc(OTf)3 (5-10 mol%)
Y
N2
toluene, -78 °C
( )n
Z
2a-d
Z
Y
cr
O
N O
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N
4a-g
X 3a-k
d
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3a: n = 1, X = Y = Z = H: > 98% yield, 71% ee 3b: n = 3, X = Y = Z = H: 94% yield, 90% ee 3c: n = 3, X = Y = H, Z = Me: 96% yield, 88% ee 3d: n = 3, X = Z = H, Y = Br: > 98% yield, 89% ee 3e: n = 4, X = Y = Z = H: 94% yield, 94% ee 3f: n = 4, X = Y = H, Z = CF 3: 78% yield, 96% ee 3g: n = 4, X = Z = H, Y = OMe: > 98% yield, 94% ee 3h: n = 4, X = Me, Y = Z = H: 97% yield, 87% ee 3i: n = 4, X = Y = H, Z = Me: > 98% yield, 97% ee 3j: n = 4, X,Y = (CH=CH)2, Z = H: 94% yield, 94% ee 3k: n = 5, X = Y = Z = H: > 98% yield, 86% ee
X Y
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proposed mechanism:
O
Sc(OTf)3/1
X Y
+ N2
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N2 +
( )n
Z
4
2
1,2-rearrangement
addition of diazoalkane
Z
O [Sc]-
( )n 5
Z
O
Y ( )n
X 3
Scheme 1. Domino diazoalkane addition/1,2-rearrangement reaction of cycloalkanones [14].
In recent years, the group of Feng has explored a new type of C2-symmetric ligands, namely chiral N,N’-dioxides synthesized from cheap optically pure amino acids [17]. These particular ligands have two alkyl amine oxide-amide subunits separated by a straight-chain alkyl spacer. 7 Page 7 of 135
They are full of conformationally flexible subunits that challenge the notion of the rigid feature of succesfull ligands. Interestingly, N,N’-dioxides provide an intriguing arsenal of chiral metal complexes for asymmetric catalysis upon coordination with a variety of metal
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precursors. In particular, excellent results have been reported by using these ligands in combination with scandium triflate in a wide range of enantioselective transformations
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including domino reactions [11-13]. As a recent example, enantioselective domino
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diazoalkane addition/1,2-rearrangement reaction of isatins 6a-j with α-alkyl-α-diazoesters 7aw was developed by this group, affording the corresponding highly functionalized C4-
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quaternary 2-quinolone chiral derivatives 8a-af in remarkable yields and enantioselectivities of up to 94% and 99% ee, respectively (Scheme 2) [18]. This asymmetric ring-expansion
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reaction performed well in the presence of chiral N,N’-dioxide ligand 9 used at a catalyst loading as low as 0.05 mol% in combination with Sc(OTf)3. The study of the scope of the
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domino reaction showed that varying the ester group of the α-diazoester (R1) had no adverse
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effect on yield and enantioselectivity (8a-d). The rate and enantioselectivity of the reactions of a series of substituted α-benzyl diazoacetates were uniformly high (94-99% ee for products
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8e-n). The electronic properties, bulkiness, or positions of the substituents on the benzyl group of diazoacetates had very little effect on the reaction outcome. Moreover, 2naphthylmethyl-substituted α-diazoester was also tolerated in the process, providing the corresponding product 8o in 94% yield and 99% ee. The reactions of diazoesters containing an alkyl substituent at the α-position were relatively fast to give the corresponding products 8p-r in 93-97% ee. In these reactions, the catalyst loading could be reduced to 0.05 mol%. Moreover, diazoesters containing substituents bearing functional groups, such as cinnamyl and allyl moieties, also led to the corresponding α-cinnamyl and α-allylic ketone derivatives 8s-t in excellent enantioselectivities (98-99% ee). Furthermore, other α-alkyl diazoesters bearing a terminal substituent, such as an ester, a nitrile, and a silyl ether group also gave very 8 Page 8 of 135
high enantioselectivities of 93-97% ee for the corresponding products 8u-w. The investigation of the scope of the reaction with respect to the isatin substrate showed that the position and electronic nature of the substituents of the isatin (R3) had significant effects on both
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enantioselectivity and reactivity (8x-af). Isatins 8x-aa, which have substituents at the C5 position, gave lower levels of enantioselectivity (80-93% ee) and were less reactive (76-88%
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yield) than isatins with substituents at the C6 and C7 positions (8ab-af). This work
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represented the first catalytic asymmetric ring-expansion reaction of isatins with α-alkyl-α-
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diazoesters.
9 Page 9 of 135
N+
N
O
+
-
O-
O
O
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (0.05-0.2 mol%)
O R2
N2
R3
N Bn 8a-af
CH2Cl2, 30 °C
7a-w [Sc]
addition of diazoalkane
R2 O
R3
N2+ CO2R1 O
1,2-rearrangement
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N Bn
O
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N Bn 6a-j
CO2R1 Sc(OTf)3 (0.05-0.2 mol%)
CO2R1 O
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O +
R3
R2
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N H
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d
M
8a: R1 = Et, R2 = Bn, R3 = H: 91% yield, 99% ee 8b: R1 = Me, R2 = Bn, R3 = H: 89% yield, 99% ee 8c: R1 = i-Pr, R2 = Bn, R3 = H: 90% yield, 99% ee 8d: R1 = t-Bu, R2 = Bn, R3 = H: 91% yield, 97% ee 8e: R1 = Et, R2 = CH2(o-FC6H4), R3 = H: 94% yield, 94% ee 8f: R1 = Et, R2 = CH2(m-Tol), R3 = H: 91% yield, 97% ee 8g: R1 = Et, R2 = CH2(m-FC6H4), R3 = H: 92% yield, 99% ee 8h: R1 = Et, R2 = CH2(m-MeOC6H4), R3 = H: 93% yield, 99% ee 8i: R1 = Et, R2 = CH2(m-PhOC6H4), R3 = H: 91% yield, 99% ee 8j: R1 = Et, R2 = CH2(p-FC6H4), R3 = H: 90% yield, 99% ee 8k: R1 = Et, R2 = CH2(p-ClC6H4), R3 = H: 94% yield, 99% ee 8l: R1 = Et, R2 = CH2(p-BrC6H4), R3 = H: 91% yield, 95% ee 8m: R1 = Et, R2 = CH2(p-PhC6H4), R3 = H: 90% yield, 99% ee 8n: R1 = Et, R2 = CH2(3,4-Cl2C6H3), R3 = H: 94% yield, 99% ee 8o: R1 = Et, R2 = CH2(2-Naph), R3 = H: 94% yield, 99% ee 8p: R1 = Et, R2 = CH2Bn, R3 = H: 71% yield, 97% ee 8q: R1 = Et, R2 = n-Pr, R3 = H: 65% yield, 94% ee 8r: R1 = Et, R2 = n-Bu, R3 = H: 63% yield, 93% ee 8s: R1 = Et, R2 = CH2(E)-CH=CHPh, R3 = H: 83% yield, 99% ee 8t: R1 = Et, R2 = allyl, R3 = H: 84% yield, 98% ee 8u: R1 = Et, R2 = CH2CO2Et, R3 = H: 77% yield, 97% ee 8v: R1 = Et, R2 = (CH2)3CN, R3 = H: 54% yield, 93% ee 8w: R1 = Et, R2 = (CH2)3OTBS, R3 = H: 67% yield, 96% ee 8x: R1 = Et, R2 = Bn, R3 = 5-F: 88% yield, 93% ee 8y: R1 = Et, R2 = Bn, R3 = 5-Cl: 84% yield, 90% ee 8z: R1 = Et, R2 = Bn, R3 = 5-Br: 84% yield, 87% ee 8aa: R1 = Et, R2 = Bn, R3 = 5-I: 76% yield, 80% ee 8ab: R1 = Et, R2 = Bn, R3 = 6-F: 90% yield, 99% ee 8ac: R1 = Et, R2 = Bn, R3 = 6-Br: 89% yield, 98% ee 8ad: R1 = Et, R2 = Bn, R3 = 6-F: 90% yield, 99% ee 8ae: R1 = Et, R2 = Bn, R3 = 7-F: 80% yield, 98% ee 8af: R1 = Et, R2 = Bn, R3 = 7-Me: 82% yield, 96% ee
10 Page 10 of 135
Scheme 2. Domino diazoalkane addition/1,2-rearrangement reaction of isatins [18].
Later in 2015, these authors applied the same catalyst system to promote related
ip t
enantioselective domino intramolecular diazoalkane addition/1,2-rearrangement reaction of ketones [19]. As shown in Scheme 3, the intramolecular reaction of a series of simple ketones
cr
bearing an α-diazoester 10a-s afforded, through diazoalkane addition followed by 1,2-
us
rearrangement reaction, the corresponding cyclic β-ketoesters 11a-s in good to excellent yields (63-96%) and enantioselectivities of up to 96% ee. The reactions were generally
an
performed with 0.5 mol% of catalyst loading and were not affected by moisture and oxygen. Varying the ester group of the 2-diazo-6-ketoalkanoate 10 affected the enantioselectivity
M
slightly. Meanwhile, the methyl ester gave better yield than the ethyl and tert-butyl esters (11a-c), thus indicating that enhancing the steric hindrance on the ester group hampered the
d
yield. The influence of position and electronic nature of substituents on the phenyl group (R2
te
= aryl) was investigated, showing that almost all substrates with a substituent on the meta- or
Ac ce p
para-position of this phenyl group provided the corresponding β-ketoesters 11d-l in excellent enantioselectivities (91-96% ee) and good yields (80-96%). Notably, condensed-ring and heteroaromatic ketone substrates were tolerated under the current system, producing the corresponding products 11n-p with high yields (87-95%) and enantioselectivities (80-95% ee). In addition, the scope of the process was extended to aliphatic ketones 10q-s which required only 0.05 mol% of catalyst loading to afford the corresponding domino products 11q-s in good yields (80-94%) albeit lower enantioselectivities of 66-86% ee (Scheme 3). Notably, these results constituted the first intramolecular homologation of simple ketones with α-diazoesters which provided a novel and efficient method for the construction of αalkyl/alkyl-substituted 2-oxocyclopentanecarboxylates with a chiral all-carbon quaternary center. 11 Page 11 of 135
+ N
N+ O-
O
O-
O
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (0.05-0.5 mol%) N2
R2
O
Sc(OTf)3 (0.05-0.5 mol%) CO2R1
2
OR1
R
us
CH2Cl2, 20 or 30 °C 10a-s
O
cr
O
ip t
N H
11a-s
R2
O-
CO2R1
1,2-rearrangement
an
addition of diazoalkane
N2+
Ac ce p
te
d
M
11a: R1 = Et, R2 = Ph: 81% yield, 93% ee 11b: R1 = Me, R2 = Ph: 86% yield, 95% ee 11c: R1 = t-Bu, R2 = Ph: 63% yield, 92% ee 11d: R1 = Me, R2 = m-Tol: 84% yield, 96% ee 11e : R1 = Me, R2 = m-MeOC6H4: 88% yield, 96% ee 11f: R1 = Me, R2 = m-(CH2=CH)C6H4: 82% yield, 95% ee 11g: R1 = Me, R2 = p-Tol: 86% yield, 92% ee 11h: R1 = Me, R2 = p-(t-Bu)C6H4: 88% yield, 94% ee 11i: R1 = Me, R2 = p-MeOC6H4: 96% yield, 92% ee 11j: R1 = Me, R2 = p-FC6H4: 85% yield, 91% ee 11k: R1 = Me, R2 = p-ClC6H4: 85% yield, 93% ee 11l: R1 = Me, R2 = p-BrC6H4: 80% yield, 93% ee 11m: R1 = Me, R2 = 3,5-Me 2C6H3: 65% yield, 92% ee 11n: R1 = Me, R2 = 2-Naph: 87% yield, 95% ee 11o: R1 = Me, R2 = 2-furyl: 95% yield, 84% ee 11p: R1 = Me, R2 = 2-thienyl: 93% yield, 80% ee 11q: R1 = R2 = Me: 80% yield, 66% ee 11r: R1 = Me, R2 = n-Bu: 94% yield, 86% ee 11s : R1 = Me, R2 = n-Hex: 89% yield, 85% ee
Scheme 3. Domino intramolecular diazoalkane addition/1,2-rearrangement reaction of ketones [19].
12 Page 12 of 135
In the last few years, an explosive number of multiple-catalyst systems for various organic transformations have been developed [20]. This novel methodology is particularly adapted to enantioselective domino reactions, allowing a rapid and economic construction of highly
ip t
functionalized chiral molecules from simple and readily available starting materials in onepot. Moreover, a reaction catalyzed by two different catalysts at the same time can allow a
cr
reactivity and a selectivity to be achieved otherwise not possible by using a single catalyst alone. The main problem, however, lies in finding the proper catalyst which should not only
us
be compatible with the other catalysts but also tolerates reagents, solvent and intermediates
an
generated during the course of the reaction. In particular, the development of multimetallic catalytic systems and their application to asymmetric catalysis has become an emerging area
M
in modern organic synthesis [21]. In this context, an asymmetric domino reaction involving diazoesters was developed by Davies et al., in 2011 [22]. It evolved through successive formation, and
ene
reaction
rearrangement, of
allylic
alcohols
oxy-Cope 12a-h
with
te
rearrangement/tautomerization,
[2,3]-sigmatropic
d
oxygen-ylide
vinyldiazoacetates 13a-e to give a series of chiral highly functionalized cyclopentanes 14a-l
Ac ce p
bearing four stereogenic centers in moderate to good yields (48-95%) along with enantioselectivities of 64-92% ee (Scheme 4). This remarkable process employed a combination of Rh2(S-DOSP)4 and Sc(OTf)3 as catalyst system which worked through relay catalysis. Therefore, the chiral rhodium catalyst induced the oxygen-ylide formation of 15, which was converted into 16 through [2,3]-sigmatropic rearrangement (Scheme 4). The latter was then submitted to oxy-Cope rearrangement to give intermediate 17 which tautomerized to afford 18. Finally, under scandium catalysis, ketoester 18 underwent an ene reaction to produce the final cyclopentane 14. The steric tolerance of the process was probed through substrates with various linear as well as branched alkyl chains (products 14a-d). All aliphatic substituents proved efficient substrates for the reaction even those bearing function groups,
13 Page 13 of 135
such as olefin, silyl ether, and phenyl (products 14e-h). Moreover, the reaction conditions tolerated aliphatic as well as aromatic vinyldiazoacetates which allowed the introduction of different functionality at the C4-position of the final cyclopentane to be achieved.
ip t
Remarkably, in all cases of substrates studied, the diastereoselectivity of the one-pot reaction
Ac ce p
te
d
M
an
us
cr
was > 90% de.
14 Page 14 of 135
C12H25
Rh2(S-DOSP)4 (1 mol%)
R1
+
R2
MeO2C
Sc(OTf)3 (20 mol%)
N2
OH
CO2Me
R2
13a-e
12a-h
OH
R1
cr
heptane, 0 to 80 °C
ip t
O S H O Rh O N O Rh
14a-l
> 90% de
te
d
M
an
us
14a: R1 = Me, R2 = Ph: 95% yield, 82% ee 14b: R1 = i-Pr, R2 = Ph: 67% yield, 80% ee 14c: R1 = i-Bu, R2 = Ph: 73% yield, 80% ee 14d: R1 = n-Hex, R2 = Ph: 80% yield, 78% ee 14e: R1 = CH2CH=CH2, R2 = Ph: 86% yield, 76% ee 14f: R1 = CH2OTBS, R2 = Ph: 65% yield, 78% ee 14g: R1 = CH2OTMS, R2 = Ph: 59% yield, 84% ee 14h: R1 = Bn, R2 = Ph: 42% yield, 87% ee 14i: R1 = Me, R2 = p-CF3C6H4: 63% yield, 78% ee 14j: R1 = Me, R2 = p-MeOC6H4: 94% yield, 87% ee 14k: R1 = Me, R2 = p-BrC6H4: 48% yield, 92% ee 14l: R1 = Me, R2 = Et: 63% yield, 64% ee proposed mechanism:
Ac ce p
OH
R1
+
R2
12
[2,3]-sigmatropic rearrangement
MeCO2
oxygen-ylide formation
N2
Rh +H O
2
R
CO2Me
R1
Rh2(S-DOSP)4
13
15
MeCO2
oxy-Cope rearrangement
OH
MeCO2
R2
OH
R2
R1
17
16 tautomerization
MeCO2
R1
O
R2 18
ene reaction R1
Sc(OTf)3
MeO2C
R2
OH
R1 14
15 Page 15 of 135
Scheme 4. Rh- and Sc-catalyzed domino oxygen-ylide formation/[2,3]-sigmatropic rearrangement/oxy-Cope rearrangement/tautomerization/ene reaction of allylic alcohols with
ip t
vinyldiazoacetates [22].
4-Aminobenzopyrans and related compounds are one of the common subunits of natural
cr
products, which can also be used as drugs. Therefore, considerable attention has been devoted
Feng
et
al.
have
developed
novel
us
to develop highly efficient methods for constructing this fused cyclic structure. In this context, enantioselective
scandium-catalyzed
domino
an
addition/ketalization reaction of salicylaldimines 19a-q with 2,3-dihydro-2H-furan 20 to afford the corresponding chiral cis-aminobenzopyrans 21a-q with excellent yields (up to
M
98%), diastereoselectivities (> 90% de), and enantioselectivities of up 99% ee [23]. Various salicylaldimines 19a-h (R1 = H) substituted at the N-aryl ring reacted with furan 20 in the
d
presence of N,N’-dioxide ligand 22 to give the corresponding cis-4-aminobenzopyrans 21a-h
te
in excellent outcomes (Scheme 5). The position of the substituent on the N-aryl ring of salicylaldimines (R2) had an evident effect on the enantioselectivities. Indeed, substrates with
Ac ce p
the substituent on the para-position afforded better results than those with the substituent on the ortho- or meta-position (21b-d). On the other hand, the electronic effect of the substituent on the N-aryl ring of salicylaldimines had no evident influence on the stereoselectivities (21dh). However, a dramatic decrease in enantioselectivities was observed for the salicylaldimines derived from substituted salicylaldehydes (R1 ≠ H) except for substrate 19i (R1 = 4-OMe, R2 = H) which provided 91% ee. To explain these results, the authors proposed a steric hindrance between the substrates and chiral ligand 22, and reasoned that chiral ligands with relative small steric hindrance could be suitable for these substrates. Investigating a series of chiral N,N’-dioxide ligands with different amide subunits, ligand 23, derived from L-pipecolic acid and (S)-2-phenylethanamine, was suitable for subtrates substituted (R1 ≠ H) on the
16 Page 16 of 135
salicyladehyde moiety (19j-q). As shown in Scheme 5, enantioselectivities of 90-93% ee were
( )n N+ N H R3
+ ( )n
O-
O
H N R3
cr
O-
O
N
ip t
achieved for a range of variously substituted chiral cis-aminobenzopyrans 21j-q.
22 (R3 = Ph2 CH, n = 1) or 23 (R3 = (S)-2-phenylethyl, n = 2)
R2
(5 mol%)
us
N
Sc(OTf )3 (5.5 mol%)
R1
+ OH
O
N
R1
+
O
te
OH
M
R2
d
[Sc]
20
an
19a-q
5 Å M.S.
CHCl3 , -20 °C
HN
R2 H
R1 O H 21a-q
O
Ac ce p
> 90% de with ligand 22: 21a: R 1 = R 2 = H: 97% yield, 97% ee 21b: R 1 = H, R 2 = 2-Cl: 97% yield, 82% ee 21c: R 1 = H, R 2 = 3-Cl: 85% yield, 85% ee 21d: R 1 = H, R 2 = 4-Cl: 83% yield, 97% ee 21e: R 1 = H, R 2 = 4-F: 87% yield, 97% ee 21f: R1 = H, R2 = 4-CF 3: 87% yield, 91% ee 21g: R 1 = H, R 2 = 4-Me: 98% yield, 95% ee 21h: R 1 = H, R 2 = 4-MeO: 94% yield, 99% ee 21i: R1 = 4-MeO, R2 = H: 85% yield, 91% ee with ligand 23: 21j: R1 = 5-Cl, R 2 = H: 83% yield, 92% ee 21k: R 1 = 5-Me, R 2 = H: 92% yield, 90% ee 21l: R1 = 5-MeO, R2 = H: 84% yield, 92% ee 21m: R1 = 5-Cl, R2 = 4-MeO: 86% yield, 92% ee 21n: R 1 = 5-Br, R2 = 4-MeO: 95% yield, 93% ee 21o: R 1 = 5-Me, R2 = 4-MeO: 97% yield, 91% ee 21p: R 1 = 5-Cl, R2 = 4-F: 96% yield, 92% ee 21q: R 1 = 5-Me, R2 = 4-F: 87% yield, 90% ee
17 Page 17 of 135
Scheme 5. Domino addition/ketalization reaction of salicylaldimines with 2,3-dihydro-2Hfuran [23].
ip t
2,3-Dihydroquinazolinone constitutes a privileged scaffold because of its extensive pharmacological activities. In 2012, Prakash and Kesavan reported a highly enantioselective
cr
synthesis of 2,3-dihydroquinazolinones 24a-n based on a scandium-catalyzed domino imine
us
formation/intramolecular amidation reaction of 2-aminobenzamides 25a-b with aldehydes 26a-m performed in the presence of pybox ligand 27 [24]. As shown in Scheme 6, a range of
an
chiral 2,3-dihydroquinazolinones 24a-n were generated in general excellent yields and enantioselectivities of up to 96% and 98% ee by using 2.5 mol% of ligand 27 in combination
M
with 1 mol% of Sc(OTf)3 at ambient temperature. Variously substituted aromatic aldehydes provided similar excellent results at room temperature while aliphatic aldehydes required
d
lowering the reaction temperature to -20 °C to achieve the corresponding products 24m-n in
te
good enantioselectivities (86-92% ee). This process represented the first metal-catalyzed highly enantioselective synthesis of 2,3-dihydroquinazolinones through intramolecular
Ac ce p
amidation of imines in very good yields.
18 Page 18 of 135
O
O
N
N
NH2 NH2 25a-b
27 (2.5 mol%) Sc(OTf)3 (1 mol%)
+ O
4 Å M.S.
O
O X
X N
NH
us
NH2
cr
CH2Cl2, r.t. or -20 °C
R H 26a-m
ip t
X
O
N
N H
R
R
an
24a-n
Ac ce p
te
d
M
at r.t.: 24a: R = Ph, X = H: 94% yield, 98% ee 24b: R = 2-Naph, X = H: 92% yield, 98% ee 24c: R = m-FC6H4, X = H: 91% yield, 98% ee 24d: R = m-BrC6H4, X = H: 94% yield, 80% ee 24e : R = p-FC6H4, X = H: 92% yield, 90% ee 24f: R = p-BrC6H4, X = H: 90% yield, 94% ee 24g: R = p-CNC6H4, X = H: 88% yield, 90% ee 24h: R = p-PhC6H4, X = H: 95% yield, 96% ee 24i: R = p-PhC6H4, X = Cl: 96% yield, 97% ee 24j: R = p-(CF3CO)C6H4, X = Cl: 94% yield, 95% ee 24k : R = 3,4-(MeO)2C6H3, X = H: 90% yield, 95% ee 24l: R = p-EtC6H4, X = H: 91% yield, 86% ee at -20 °C: 24m: R = n-Hex, X = H: 86% yield, 92% ee 24n: R = n-Pr, X = H: 80% yield, 86% ee
Scheme 6. Domino imine formation/intramolecular amidation reaction of 2-aminobenzamides with aldehydes in the presence of a pybox ligand [24].
Later in 2015, this process was reinvestigated by Cai et al. by using fluorous chiral bisoxazoline ligand 28 at 5 mol% of catalyst loading in combination with 1 mol% of Sc(OTf)3 [25]. Bisoxazoline 28 was selected as optimal ligand among a variety of chiral bisoxazoline derivatives. As shown in Scheme 7, the reaction of 2-aminobenzamide 25a with a variety of
19 Page 19 of 135
aldehydes 26a-o afforded the corresponding chiral 2,3-dihydroquinazolinones 24a-o in high yields (76-94%) along with enantioselectivities of 87-98% ee. Substituted benzaldehydes bearing either electronically poor, neutral, or rich group had remarkable differences in
ip t
enantioselectivities of this reaction although the corresponding products 24a-k were obtained in generally high yields and good to high enantioselectivities (76-94% yield, 87-98% ee). The
cr
scope of the methodology was extended to an heteroaromatic aldehyde, a α,β-unsaturated
us
aldehyde, and an aliphatic aldehyde to give the corresponding products 24l, 24n, and 24o in good enantioselectivities of 87, 94, and 89% ee, respectively. One advantage of using
Ac ce p
te
d
M
without significant loss of enantioselectivity.
an
fluorinated ligand 28 is that it could be easily recovered and reused at least three times
20 Page 20 of 135
C 8F17 O
O
O NH2
N
N
NH 2
Ph
25a
28 (5 mol%)
O
ip t
Sc(OTf )3 (1 mol%)
+
4 Å M.S. CH 2Cl2, r.t.
H O
26a-o
NH R
us
24a-o N H
cr
R
Ph
Ac ce p
te
d
M
an
24a : R = Ph: 84% yield, 97% ee 24b: R = p-ClC6 H4 : 89% yield, 98% ee 24c : R = p-CF3C6H4 : 94% yield, 97% ee 24d: R = p-NO2 C6H4: 92% yield, 98% ee 24e : R = p-MeOC 6H 4: 86% yield, 92% ee 24f: R = p-Me2NC 6H4 : 83% yield, 93% ee 24g: R = p-Tol: 86% yield, 95% ee 24h: R = m-BrC 6H 4: 84% yield, 88% ee 24i: R = o-BrC 6H 4: 91% yield, 89% ee 24j: R = m-NO2C6H 4: 81% yield, 91% ee 24k : R = o-NO2C 6H 4: 90% yield, 92% ee 24l: R = 2-pyridinyl: 82% yield, 87% ee 24m: R = 1-Naph: 79% yield, 92% ee 24n: R = (E)-PhCH=CH: 76% yield, 94% ee 24o: R = Cy: 90% yield, 89% ee
Scheme 7. Domino imine formation/intramolecular amidation reaction of 2-aminobenzamide with aldehydes in the presence of a fluorinated bisoxazoline ligand [25].
In another context, Franz et al. recently reported the first catalytic asymmetric [3+2] annulation of unsaturated carbonyl compounds with allylsilanes [26]. This evolved through enantioselective scandium-catalyzed domino Michael/1,2-silyl shift/cyclization reaction of a variety of alkylidene oxindoles 29a-k with allyltriisopropylsilane 30 to give the corresponding highly functionalized chiral spirocyclopentanes 31a-k bearing three stereogenic centers in high yields, diastereo-, and enantioselectivities of up to 97%, 98% de , 21 Page 21 of 135
and 99% ee, respectively (Scheme 8). The reaction was catalyzed by 10 mol% of Sc(OTf)3 and pybox ligand 27 in the presence of NaBArF as additive. It began with the Michael addition of allyltriisopropylsilane 30 to alkylidene oxindole 29 to give intermediate 32, which
ip t
was subsequently submitted to a 1,2-silyl shift followed by cyclization reaction to finally provide spirocyclopentane 31. The role of NaBArF was attributed to the formation of a
cr
cationic scandium complex. Very good results were achieved with various ester and nitrile substrates 29a-f and 29h-k while phenyl-substituted alkylidene 29g required a higher catalyst
us
loading (20 mol% instead of 10 mol%) and extended reaction times (4 days), to afford the corresponding spirocyclopentane 31g in moderate enantioselectivity of 68% ee. In addition to
afforded
the
corresponding
products
31h-i
in
both
excellent
yields
and
M
also
an
N-acetylated alkylidene oxindoles 29a-g, chelating oxindoles containing urea and Cbz groups
enantioselectivities of 80-83% and 92-96% ee, respectively. The NH spirooxindoles 31j-k
d
could be accessed by simple deprotection of the corresponding N-acyl oxindoles with KHCO3
Ac ce p
te
and H2O2 in high yields (80-88%) and enantioselectivities of 92-98% ee.
22 Page 22 of 135
R
O
X
O
N N
N
O N Z Y 29a-k +
ip t
27 (10 mol%) Sc(OTf) 3 (10 mol%) 4 Å M.S., NaBArF
Si(i-Pr)3
CH 2Cl2, r.t.
cr
30 Si(i-Pr) 3 R O
Y
N Z
an
Y
N Z
X
Si(i-Pr)3 O [Sc]
us
R X
32
31a-k
Ac ce p
te
d
M
31a: R = CO2Et, X = H, Y = F, Z = Ac: 82% yield, 94% de, 92% ee 31b: R = CO 2Et, X = Y = H, Z = Ac: 92% yield, 90% de, 96% ee 31c: R = CO2Et, X = OMe, Y = H, Z = Ac: 75% yield, 96% de, 96% ee 31d: R = CO 2t -Bu, X = F, Y = H, Z = Ac: 80% yield, 70% de, 99% ee 31e: R = CO2Me, X = F, Y = H, Z = Ac: 95% yield, 80% de, 96% ee 31f: R = CN, X = F, Y = H, Z = Ac: 92% yield, 90% de, 96% ee 31g: R = Ph, X = Y = H, Z = Ac: 72% yield, 84% de, 68% ee (with 20 mol% of catalyst and reaction run of 4 days) 31h: R = CO 2Et, X = F, Y = H, Z = CONHPh: 97% yield, 88% de, 98% ee 31i: R = CO2 Et, X = F, Y = H, Z = Cbz: 83% yield, 98% de, 96% ee 31j: R = CO2 Bn, X = F, Y = Z = H: 80% yield, 94% de, 92% ee 31k: R = CO2Et, X = F, Y = Z = H: 88% yield, 90% de, 98% ee
Scheme 8. Domino Michael/1,2-silyl shift/cyclization reaction of alkylidene oxindoles with allyltriisopropylsilane [26].
The chiral spirocyclic-3,3’-oxindole unit is encountered in a large variety of natural products and pharmaceutical candidates with a wide spectrum of biological activities [27]. To access even more complex and functionalized chiral products of this type, Feng et al. very recently described a novel enantioselective scandium-catalyzed domino 1,5-hydride shift/ring closure reaction of alkylidene oxindoles 33a-m which allowed a wide range of chiral spirooxindole tetrahydroquinolines 34a-m bearing contiguous quaternary or tertiary carbon 23 Page 23 of 135
stereocenters to be achieved in good to excellent yields (73-97%) and good to high enantioselectivities (85-94% ee) (Scheme 9) [28]. In the presence of N,N’-dioxide ligand 9 (10 mol%) in combination with Sc(OTf)3 (10 mol%), alkylidene oxindole 33 underwent a 1,5-
ip t
hydride shift to give intermediate 35 which was subsequently submitted to ring closure reaction to provide final product 34. Remarkably, in all cases of substrates, the
cr
diastereoselectivity of the reaction was > 90% de. Oxindole derivatives with N-Me, N-Boc, and N-Bn protecting groups were tolerated with no influence on the diastereo- and
Ac ce p
te
d
M
an
us
enantioselectivity.
24 Page 24 of 135
+ N
N+ O-
O
O-
O
N H
R3 R4
H
R1
H
Sc(OTf)3 (10 mol%)
X
X
O Z
O
DCE, 35 °C
N R2
R4
Y
R1
Z
33a-m
N R2
35
N R3 H O R4
Y Z
N R2
34a-m > 90% de
an
X
us
Y
R3 N
ip t
( )n N
cr
R1
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (10 mol%)
Ac ce p
te
d
M
34a: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH=CH)2: 97% yield, 91% ee 34b: R1 = X = Y = Z = H, R2 = Boc, R3,R4 = (CH=CH)2: 93% yield, 91% ee 34c: R1 = X = Y = Z = H, R2 = Bn, R3,R4 = (CH=CH)2: 89% yield, 90% ee 34d: R1 = X = Z = H, Y = Cl, R2 = Me, R3,R4 = (CH=CH)2: 80% yield, 85% ee 34e: R1 = X = Z = H, Y = Br, R2 = Me, R3,R4 = (CH=CH)2: 84% yield, 88% ee 34f: R1 = X = Y = H, Z = F, R2 = Me, R3,R4 = (CH=CH)2: 87% yield, 87% ee 34g: R1 = Y = Z = H, X = R2 = Me, R3,R4 = (CH=CH)2: 83% yield, 90% ee 34h: R1 = Y = Z = H, X = MeO, R2 = Me, R3,R4 = (CH=CH)2: 73% yield, 89% ee 34i: R1 = Y = Z = H, X = F, R2 = Me, R3,R4 = (CH=CH)2: 92% yield, 87% ee 34j: R1 = Br, X = Y = Z = H, R2 = Me, R3,R4 = (CH=CH)2: 92% yield, 90% ee 34k: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH=C(OMe))2: 93% yield, 94% ee 34l: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH2)3: 83% yield, 92% ee 34m: R1 = X = Y = Z = H, R2 = Me, R3,R4 = (CH2)4: 78% yield, 91% ee
Scheme 9. Domino 1,5-hydride shift/ring closure reaction of alkylidene oxindoles [28].
Chiral dihydropyrrole frameworks are a privileged structural unit in a number of natural compounds with important biological activities and also a key building block in the synthesis of complex molecules [29]. In 2015, Feng et al. reported a novel asymmetric approach to this type
of
products
based
on
enantioselective
scandium-catalyzed
domino
ring-
opening/cyclization/dehydration reaction of cyclopropyl ketones 36a-p with primary amines
25 Page 25 of 135
37a-h [30]. As shown in Scheme 10, the process employed a catalyst system composed by 10 mol% of Sc(OTf)3 and 10 mol% of N,N’-dioxide ligand 38 which was used in the presence of LiCl as an additive. The reaction began with the ring-opening of cyclopropyl ketone 36 with
ip t
primary amine 37 to give intermediate 39 which further underwent cyclization reaction followed by dehydration to give the final 2,4,5-trisubstituted 2,3-dihydropyrrole 40. As shown
cr
in Scheme 10, a series of cyclopropyl ketones 36a-p reacted smoothly with phenylamine 37a 3 (R = Ph), providing the corresponding chiral products 40a-p in good to excellent
1
us
enantioselectivities (66-96% ee) and poor to excellent yields (16-98%). Both electron-rich and
an
electron-deficient aryl groups at the 2-position (R ) of cyclopropyl ketones had a small effect on the enantioselectivity (40b-k). The reaction tolerated naphthyl-substituted cyclopropyl
M
ketones which gave the corresponding products 40l-m in high enantioselectivities (94-96% ee) and excellent yields (97-98%). On the other hand, a lower enantioselectivity of 66% ee
d
1 was obtained in the reaction of methyl-substituted cyclopropyl ketone (R = Me) 36p. In
te
addition to phenyl amine, various other aromatic primary amines provided high enantioselectivities of 90-97% ee (40q-v) while cyclopropyl amine 37h led to the
Ac ce p
corresponding product 40w in lower enantioselectivity (87% ee). Other aliphatic amines, including cyclopentanamine, 2-methylpropan-2-amine, and phenylmethanamine, did not provide the desired dihydropyrrole products. Importantly, this methodology also constituted an effective procedure for the kinetic resolution of 2-substituted cyclopropyl ketones which were recovered in enantioselectivities of up to 95% ee.
26 Page 26 of 135
N+
COR2 36a-p
OO H N Ar Ar Ar = 2,4,6-i-Pr3C6H2
+ R3NH2 37a-h
R3 N
38 (10 mol%) Sc(OTf)3 (10 mol%) LiCl (1 equiv) CHCl2CHCl2, 35 °C
R3H2N
R2
R1
O
R1
R2
ip t
R1
ON H
COR2
40a-w
cr
COR2
+
us
O
N
COR2
an
39
Ac ce p
te
d
M
40a: R1 = R2 = R3 = Ph: 82% yield, 91% ee 40b : R1 = p-Tol, R2 = R3 = Ph: 95% yield, 91% ee 40c: R1 = p-MeOC6H4, R2 = R3 = Ph: 96% yield, 92% ee 40d : R1 = p-FC6H4, R2 = R3 = Ph: 94% yield, 95% ee 40e: R1 = p-BrC6H4, R2 = R3 = Ph: 88% yield, 95% ee 40f: R1 = m-Tol, R2 = R3 = Ph: 96% yield, 92% ee 40g: R1 = m-MeOC6H4, R2 = R3 = Ph: 81% yield, 94% ee 40h: R1 = o-Tol, R2 = R3 = Ph: 92% yield, 94% ee 40i: R1 = o-MeOC6H4, R2 = R3 = Ph: 95% yield, 92% ee 40j: R1 = 3,4-Cl2C6H3, R2 = R3 = Ph: 66% yield, 96% ee 40k: R1 = 3,4-(MeO)2C6H3, R2 = R3 = Ph: 98% yield, 92% ee 40l: R1 = 1-Naph, R2 = R3 = Ph: 98% yield, 96% ee 40m: R1 = 2-Naph, R2 = R3 = Ph: 97% yield, 94% ee 40n : R1 = R3 = Ph, R2 = p-Tol: 63% yield, 96% ee 40o: R1 = R3 = Ph, R2 = Me: 59% yield, 73% ee 40p : R1 = Me, R2 = R3 = Ph: 16% yield, 66% ee 40q: R1 = R2 = Ph, R3 = p-Tol: 86% yield, 92% ee 40r: R1 = R2 = Ph, R3 = p-FC6H4: 95% yield, 90% ee 40s : R1 = R2 = Ph, R3 = p-BrC6H4: 85% yield, 96% ee 40t: R1 = R2 = Ph, R3 = p-NO2C6H4: 96% yield, 95% ee 40u: R1 = R2 = Ph, R3 = m-ClC6H4: 96% yield, 96% ee 40v: R1 = R2 = Ph, R3 = o-ClC6H4: 46% yield, 97% ee 40w: R1 = R2 = Ph, R3 = Cy: 41% yield, 87% ee
Scheme 10. Domino ring-opening/cyclization/dehydration reaction of cyclopropyl ketones with primary amines [30].
27 Page 27 of 135
In 2012, Franz et al. reported a nice synthesis of chiral biologically interesting spirooxindoles on the basis of a catalytic asymmetric [3+2] annulation of allylsilanes 41a-d with isatins 6a-h [31]. The reaction was promoted by a combination of ScCl2(SbF6) with
ip t
chiral pybox ligand 27 in the presence of TMSCl as additive. The domino process between allylsilanes and isatins began with allylation which afforded intermediates 42 which were
cr
further submitted to 1,2-silyl migration to provide intermediates 43. The latter then underwent cyclization to afford the final chiral spirooxindoles 44a-k in moderate to good yields,
us
remarkable enantioselectivities of 97-99% ee, along with complete diastereoselectivity in
an
almost all cases of substrates (Scheme 11). The best yields were reached in the case of using
Ac ce p
te
d
M
allyltriisopropylsilane.
28 Page 28 of 135
O O
(R4)2R3Si
O N R1 6a-h
27 (10 mol%) ScCl2(SbF6) (10 mol%)
O R2
4 Å M.S. TMSCl (3 equiv)
SiR3(R4)2
CH2Cl2, r.t.
41a-d
O
N R1 44a-k
cr
+
N
N
ip t
R2
O
N
proposed mechanism:
2
O
R
6
+
(R4)2R3Si
allylation
Ac ce p
N R1
te
O
d
M
an
us
44a: R1 = Me, R2 = 5-Br, R3 = R4 = i-Pr: 71% yield, 99% ee, > 99% de 44b: R1 = Me, R2 = 5-Cl, R3 = R4 = i-Pr: 74% yield, 99% ee, > 99% de 44c: R1 = Me, R2 = 4-Cl, R3 = R4 = i-Pr: 62% yield, 99% ee, 42% de 44d: R1 = Me, R2 = 5-F, R3 = R4 = i-Pr: 67% yield, 99% ee, > 99% de 44e: R1 = Bn, R2 = 5-OCF3, R3 = R4 = i-Pr: 82% yield, 99% ee, > 99% de 44f: R1 = PMB, R2 = 5-F, R3 = R4 = i-Pr: 55% yield, 99% ee, > 99% de 44g: R1 = Me, R2 = H, R3 = R4 = i-Pr: 47% yield, 99% ee, > 99% de 44h: R1 = Ph, R2 = H, R3 = R4 = i-Pr: 81% yield, 97% ee, > 99% de 44i: R1 = Me, R2 = 5-Br, R3 = p-MeOC6H4, R4 = i-Pr: 20% yield, 99% ee, > 90% de 44j: R1 = Me, R2 = 5-Br, R3 = CHPh2, R4 = Me: 34% yield, 99% ee, > 90% de 44k: R1 = Me, R2 = 5-Br, R3 = o-MeOC6H4, R4 = Me: 13% yield, 99% ee, > 90% de
O
2
R
O N R1
SiR3(R4)2
42
41
SiR3(R4)2 SiR3(R4)2
1,2-silyl migration
R2
cyclization
O R2
O
O N R1
O N R1
44
43
Scheme 11. Domino allylation/1,2-silyl migration/cyclization reaction of allylsilanes with isatins [31].
29 Page 29 of 135
Enantioselective organocatalytic processes have reached maturity in recent years with an impressive and steadily increasing number of studies [32]. The ability of organocatalysts to promote a wide range of reactions by different activation modes makes organocatalysis ideal
ip t
for its application in domino reactions. First introduced by Krische et al. in 2003 [33], the combination of catalysts from different disciplines, such as organocatalysis, and metal
cr
catalysis, has attracted increasing attention in the synthetic community in the past several years, allowing enable unprecedented transformations not currently possible by use of any
us
catalysis alone, and making current synthetic methods more economical and practical [20]. Although the combination of transition metal catalysis with organocatalysis has allowed a
an
range of novel and useful reactions to be achieved, the development of domino reactions induced by a combination of two types of catalysts still remains a challenge. While the
M
organocatalysis is dominated by Lewis base catalysts, such as amines, carbenes, and tertiary phosphines, a metal catalyst usually has an empty coordination site to interact and activate a
d
substrate. The challenge in combining an organocatalyst and a metal catalyst is in part to
te
avoid the deactivation of catalyst by Lewis acid/base interaction. In this area, Chi et al.
Ac ce p
recently reported the first use of scandium in cooperative N-heterocyclic carbene (NHC) catalysis [34]. As shown in Scheme 12, the combination of Sc(OTf)3 and Mg(OTf)2 with chiral NHC catalyst 45 allowed a novel enantioselective domino γ-addition/cyclization reaction of enals 46a-k with trifluoromethyl ketones 47a-h to be achieved in good to high yields and enantioselectivities of up to 82% and 94% ee, respectively. The reaction afforded a wide range of chiral unsaturated δ-lactones 48a-r through the first oxidative generation of vinyl enolates for γ-functionalization of enals under NHC catalysis. A postulated reaction pathway is illustrated in Scheme 12 to explain the results. The vinyl enolate intermediate 51 likely arose from γ-deprotonation of the oxidatively generated unsaturated intermediate 50, although direct oxidation of the enal γ-carbon of the homoenolate intermediate 49 leading to
30 Page 30 of 135
51 could not be completely ruled out. Vinyl enolate 51 then underwent nucleophilic addition to ketone 47, affording product 48. The Sc(III) Lewis acid, which is known to have good affinities for carbonyl oxygens and carboxylates, likely was involved in multisite coordination
ip t
to bring the ketone electrophile into close proximity with intermediate 51 and the chiral NHC catalyst, as illustrated by 52. This coordination amplified the otherwise weak chiral induction
Ac ce p
te
d
M
an
us
cr
by the chiral NHC catalyst.
31 Page 31 of 135
O N N
N
BF4 Mes
45 (20 mol%)
O
O O R2
F3C
+
t-Bu
O
R1 46a-k
O
t-Bu THF, 0 °C or r.t.
K2CO3 (50 mol%)
O
cr
H
ip t
Sc(OTf)3 (10 mol%) Mg(OTf)2 (10 mol%) t-Bu t-Bu
CF3
R1
R2 48a-r
us
47a-h
Ac ce p
te
d
M
an
48a: R1 = R2 = Ph: 81% yield, 94% ee 48b: R1 = p-Tol, R2 = Ph: 76% yield, 91% ee 48c: R1 = p-MeOC6H4, R2 = Ph: 82% yield, 90% ee 48d: R1 = p-BrC6H4, R2 = Ph: 76% yield, 88% ee 48e: R1 = p-ClC6H4, R2 = Ph: 74% yield, 90% ee 48f: R1 = 2-Naph, R2 = Ph: 67% yield, 90% ee 48g: R1 = 1-thienyl, R2 = Ph: 76% yield, 84% ee 48h: R1 = 1-furyl, R2 = Ph: 78% yield, 84% ee 48i: R1 = 1-pyridinyl, R2 = Ph: 81% yield, 86% ee 48j: R1 = (E)-PhCH=CH, R2 = Ph: 65% yield, 79% ee 48k: R1 = (E)-(p-Tol)CH=CH, R2 = Ph: 71% yield, 77% ee 48l: R1 = Ph, R2 = p-Tol: 61% yield, 93% ee 48m: R1 = Ph, R2 = p-BrC6H4: 74% yield, 91% ee 48n: R1 = Ph, R2 = p-ClC6H4: 76% yield, 91% ee 48o: R1 = Ph, R2 = 1-thienyl: 75% yield, 90% ee 48p: R1 = Ph, R2 = Me: 52% yield, 80% ee 48q: R1 = Ph, R2 = CO2Et: 64% yield, 60% ee 48r: R1 = Ph, R2 = 1-thienyl: 75% yield, 90% ee
proposed mechanism:
O
2
Mes
R
O
CF 3
N N N
O
O
H
O Mes
O CF3
R1 48
N N
46
R2
R1
N
1 OH R
O
1
R
45 49
53
[O] Mes N N N O
Mes
H
O
R1
N N O
R1 [Sc] O
CF3 R
F3C 52
N
Mes
O
N N
2
O Sc(OTf)3
R2 47
50 N O
1
R
O 51
K2CO3
32 Page 32 of 135
Scheme 12. Multicatalyzed domino γ-addition/cyclization reaction of enals with trifluoromethyl ketones [34].
ip t
Inspired by these pioneering results, Wang et al. employed a closely related chiral NHC catalyst 54 in combination with Sc(OTf)3 to promote asymmetric domino γ-
cr
addition/cyclization reaction of enals 46a-l with β-bromo-α-ketoesters 55a-m to provide the
us
corresponding chiral unsaturated δ-lactones 56a-w (Scheme 13) [35]. When the reaction was performed in the presence of CsOAc as a base, a wide range of these highly functionalized
an
products were achieved at room temperature in good yields (67-88%), general excellent diastereoselectivity of > 90% de, and high enantioselectivities of 85-98% ee when starting from enals bearing various aromatic or heteroaromatic substituents (R ). Replacement of a β-
M
1
(hetero)aryl group by a vinyl substituent gave the corresponding product 56v in 83% yield, >
d
90% de, and 89% ee while the use of a methyl group resulted in a slow conversion (< 10% at
te
r.t., 67% yield at 50°C) and a moderate enantioselectivity of 40% ee for product 56w but with 2
Ac ce p
always an excellent diastereoselectivity of > 90% de. The nature of the substituent (R ) at the γ-position of β-bromo-α-ketoesters 55a-m had no influence on the results since they were homogeneous for (hetero)aromatic and aliphatic groups. This process constituted the first intermolecular dynamic kinetic resolution of α-ketoesters through cooperative catalysis by an NHC catalyst with a Lewis acid.
33 Page 33 of 135
O N
BF4 Ar
O
R2
O
O
O
O +
H
R1
O
O
toluene, r.t.
O
O
cr
t-Bu t-Bu CsOAc (50 mol%)
55a-m
ip t
54 (20 mol%) Ar = 2,6-Et2C6H3 Sc(OTf)3 (10 mol%) t-Bu t-Bu
O
Br
N N
Br
2
us
R
46a-l
56a-w
R1
an
> 90% de
1
2
Ac ce p
te
d
M
56a: R = Ph, R = p-Tol: 81% yield, 92% ee 56b: R1 = Ph, R2 = p-MeOC6H4: 80% yield, 85% ee 56c: R1 = Ph, R2 = p-FC6H4: 79% yield, 90% ee 56d: R1 = Ph, R2 = p-CF3C6H4: 86% yield, 93% ee 56e: R1 = Ph, R2 = m-ClC6H4: 82% yield, 90% ee 56f: R1 = Ph, R2 = o-FC6H4: 80% yield, 92% ee 56g: R1 = Ph, R2 = 2-Naph: 83% yield, 90% ee 56h: R1 = Ph, R2 = 2-thienyl: 83% yield, 86% ee 56i: R1 = Ph, R2 = CH=CH2: 70% yield, 87% ee 56j: R1 = Ph, R2 = Cy: 85% yield, 91% ee 56k: R1 = Ph, R2 = Et: 76% yield, 90% ee 56l: R1 = Ph, R2 = H: 77% yield, 91% ee 56m: R1 = p-Tol, R2 = Ph: 79% yield, 92% ee 56n: R1 = p-MeOC6H4, R2 = Ph: 70% yield, 94% ee 56o: R1 = p-FC6H4, R2 = Ph: 80% yield, 91% ee 56p: R1 = p-ClC6H4, R2 = Ph: 81% yield, 85% ee 56q: R1 = p-BrC6H4, R2 = Ph: 84% yield, 90% ee 56r: R1 = p-NO2C6H4, R2 = Ph: 85% yield, 96% ee 56s: R1 = 2-Naph, R2 = Ph: 80% yield, 93% ee 56t: R1 = 3-pyridyl, R2 = Ph: 88% yield, 98% ee 56u: R1 = 2-thienyl, R2 = Ph: 75% yield, 90% ee 56v: R1 = allyl, R2 = Ph: 83% yield, 89% ee 56w: R1 = Me, R2 = Ph: 67% yield, 40% ee (50 °C)
Scheme 13. Multicatalyzed domino γ-addition/cyclization reaction of enals with β-bromo-αketoesters [35].
34 Page 34 of 135
Even though the history of multicomponent reactions dates back to the second half of 19
th
century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in the last decades with the work of Ugi that the concept of multicomponent reaction has emerged as a powerful
ip t
tool in synthetic chemistry [36]. Multicomponent reactions are defined as domino reactions involving at least three substrates and, consequently, constitute a subgroup of domino
cr
reactions [9b,37]. In spite of the recent emergence of organocatalysis, enantioselective metalcatalyzed multicomponent reactions represent the majority of catalytic enantioselective
us
multicomponent reactions. A range of various metal catalysts, such as copper, rhodium, gold, platinum, palladium, cobalt, ruthenium, scandium, magnesium, titanium, zinc, aluminum,
an
nickel, silver, iridium, as well as tin have been demonstrated to induce a wide number of types of these powerful one-pot reactions. In the last few years, chiral scandium catalysts have also
M
been successfully applied to induce various types of enantioselective multicomponent reactions, such as asymmetric three-component chloroamination reaction of α,β-unsaturated
d
γ-ketoesters 57a-m [38]. As shown in Scheme 14, these substrates reacted with TsNCl2 and
te
TsNH2 in the presence of a combination of Sc(OTf)3 with N,N’-dioxide ligand 58 as catalyst
Ac ce p
system to give the corresponding chiral chloroaminated products 59a-m generally in high yields (up to 98%) and enantioselectivities (92-99% ee) along with moderate to high diastereoselectivities (66-98% de). The lowest yield (65%) was observed in the case of substrate 57d bearing a bulky tert-butyl group. The diastereoselectivity was influenced by the electronic property of the substituents at the aromatic group (Ar). Indeed, generally the substrates with an electron-donating group gave the desired products (59f-g) with a high diastereoselectivity (96% de), while electron-withdrawing substituents on the phenyl group reduced the stability of the chloronium intermediate 60 (Scheme 14) which resulted in a relatively lower diastereoselectivity (66-86% de for 59h-k). Notably, this process employed a remarkably low catalyst loading of only 0.05 mol%.
35 Page 35 of 135
+ N O-
N+
O Ar
ON H
O
H N R'
R' R' = 1-adamantyl 58 (0.05 mol%) Sc(OTf)3 (0.05 mol%)
CO2R 57a-m + TsNCl2
4 Å M.S. + TsNH2
O Ar
cr
CH2Cl2, 35 °C O Ar
+ CO2R Cl
an
60
TsNH2
us
TsNCl2
NHTs * * CO R 2 Cl 59a-m
ip t
O
Ac ce p
te
d
M
59a: Ar = R = Ph: 93% yield, 92% ee, 97% de 59b: Ar = Ph, R = Et: 98% yield, 97% ee, 92% de 59c: Ar = Ph, R = Me: 98% yield, 96% ee, 90% de 59d: Ar = Ph, R = t-Bu: 65% yield, 96% ee, 94% de 59e: Ar = Ph, R = Bn: 98% yield, 95% ee, 92% de 59f: Ar = p-MeOC6H4, R = Et: 97% yield, 99% ee, 96% de 59g: Ar = p-Tol, R = Et: 99% yield, 97% ee, 96% de 59h: Ar = p-ClC6H4, R = Et: 96% yield, 98% ee, 86% de 59i: Ar = p-BrC6H4, R = Et: 95% yield, 93% ee, 74% de 59j: Ar = p-NO2C6H4, R = Et: 95% yield, 93% ee, 66% de 59k: Ar = m-NO2C6H4, R = Et: 93% yield, 94% ee, 86% de 59l: Ar = 2-Naph, R = Et: 96% yield, 97% ee, 90% de 59m: Ar = 2-furyl, R = Et: 95% yield, 98% ee, 98% de
Scheme 14. Three-component chloroamination reaction of α,β-unsaturated γ-ketoesters [38].
The scope of this nice methodology was extended to a range of α,β-unsaturated ketones 61a-q which provided under the same reaction conditions the corresponding α-chloro-βamino-ketone derivatives 62a-q as almost single anti-diastereomers (up to > 98% de) in nearly quantitative yields and remarkable enantioselectivities of up to 99% ee (Scheme 15) [38]. To explain the anti-configuration of the products, the formation of bridged chloronium ion intermediate 63 can be proposed (Scheme 15). Thus, a possible mechanism was that the highly reactive species TsNHCl was generated from TsNH2 and TsNCl2 upon the promotion 36 Page 36 of 135
of molecular sieves initially. Then, a N,N’-dioxide-Sc(III) complex mediated the formation of the chiral chloronium ion intermediate 63, which was followed by nucleophilic attack of
Ac ce p
te
d
M
an
us
cr
ip t
nitrogen to deliver final product 62 (Scheme 15).
37 Page 37 of 135
N+
O Ar 61a-q
ON H
OO H N R' R' R' = 1-adamantyl 58 (0.05 mol%) Sc(OTf)3 (0.05 mol%)
NHTsO R
+ TsNCl2
Ar
4 Å M.S. CH2Cl2, 35 °C
+ TsNH2
Cl 62a-q
cr
R
+
ip t
O
N
Ac ce p
te
d
M
an
us
62a: R = Ar = Ph: 99% yield, 98% ee, > 98% de 62b: R = Ph, Ar = p-Tol: 99% yield, 98% ee, > 98% de 62c: R = Ph, Ar = m-Tol: 99% yield, 96% ee, > 98% de 62d: R = Ph, Ar = p-FC6H4: 99% yield, 97% ee, > 98% de 62e: R = Ph, Ar = p-ClC6H4: 96% yield, 98% ee, > 98% de 62f: R = Ph, Ar = p-MeOC6H4: 92% yield, 98% ee, > 98% de 62g: R = Ph, Ar = p-NO2C6H4: 91% yield, 97% ee, 90% de 62h: R = Ph, Ar = m-NO2C6H4: 96% yield, 95% ee, > 98% de 62i: R = Ph, Ar = 2-Naph: 99% yield, 98% ee, > 98% de 62j: R = Ph, Ar = 2-furyl: 99% yield, 99% ee, > 98% de 62k: R = m-Tol, Ar = Ph: 99% yield, 97% ee, 94% de 62l: R = p-Tol, Ar = Ph: 97% yield, 97% ee, 96% de 62m: R = p-FC6H4, Ar = Ph: 99% yield, 98% ee, > 98% de 62n: R = m-MeOC6H4, Ar = Ph: 99% yield, 96% ee, > 98% de 62o: R = p-PhC6H4, Ar = Ph: 88% yield, 97% ee, > 98% de 62p: R = 2-Naph, Ar = Ph: 96% yield, 98% ee, > 98% de 62q: R = (E)-PhCH=CH, Ar = Ph: 95% yield, 98% ee, 94% de
possible mechanism: TsNCl2
+ TsNH2
4 Å M.S.
TsNHCl +
O
p-Tol O S O NH
[Sc]
Sc(OTf)3/58
O R
Ar Ar
61
R Cl 63
O
NHTs
Ar
R Cl 62
38 Page 38 of 135
Scheme 15. Three-component chloroamination reaction of α,β-unsaturated ketones [38].
In 2011, the same authors also developed highly efficient enantioselective iodoamination
ip t
reactions of α,β-unsaturated ketones 64a-o with N-iodosuccinimide (NIS) and TsNH2 in the presence of 0.5 mol% of a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral
cr
N,N’-dioxide ligand 65 [39]. As shown in Scheme 16, the three-component process allowed a
us
range of trans-α-iodo-β-amino products 66a-o to be achieved most of the time as single diastereomers (> 98% de) in very good yields of up to 97% and remarkable
an
enantioselectivities of up to 98% ee. Interestingly, these excellent results were obtained regardless of the electronic nature or position of the substituents on the phenyl rings (66b-g
M
and 66j-l). Moreover, naphthyl-, cinnamyl-, and furyl-substituted chalcones were also suitable substrates for the reaction, providing the corresponding products 66n, 66o, and 66m in 98%
d
ee. TsNHI species, generated from the reaction between NIS and TsNH2 in the presence of
te
molecular sieves, was confirmed by the authors as the active species in the iodoamination
Ac ce p
process involved in the formation of the key iodonium ion intermediates.
39 Page 39 of 135
ON H
O
O
H N R3 R3 3 R = BnCH2 65 (0.5 mol%) Sc(OTf)3 (0.5 mol%)
R2 64a-o + NIS + TsNH2
TsNH
O
R1
R2
4 Å M.S., dark
I
CH2Cl2, 23 °C
66a-o
cr
O R1
+ N O-
ip t
N+
te
d
M
an
us
66a: R1 = R2 = Ph: 96%, 96% ee, > 98% de 66b: R1 = o-Tol, R2 = Ph: 95%, 98% ee, > 98% de 66c: R1 = m-Tol, R2 = Ph: 96%, 98% ee, > 98% de 66d: R1 = p-Tol, R2 = Ph: 86%, 98% ee, > 98% de 66e: R1 = p-FC6H4, R2 = Ph: 85%, 97% ee, > 98% de 66f: R1 = p-ClC6H4, R2 = Ph: 95%, 98% ee, > 98% de 66g: R1 = p-MeOC6H4, R2 = Ph: 90%, 95% ee, > 90% de 66h: R1 = Me, R2 = Ph: 86%, 94% ee, > 98% de 66i: R1 = H, R2 = Ph: 90%, 90% ee 66j: R1 = Ph, R2 = p-Tol: 93%, 97% ee, > 98% de 66k: R1 = Ph, R2 = p-FC6H4: 97%, 97% ee, > 98% de 66l: R1 = Ph, R2 = p-MeOC6H4: 91%, 98% ee, > 98% de 66m: R1 = Ph, R2 = 2-furyl: 90%, 98% ee, > 98% de 66n: R1 = Ph, R2 = 2-Naph: 92%, 98% ee, > 98% de 66o: R1 = Ph, R2 = (E)-PhCH=CH: 93%, 98% ee, > 98% de
Ac ce p
Scheme 16. Three-component iodoamination reaction of α,β-unsaturated ketones [39].
The same reaction conditions were applied to the asymmetric iodoamination of a variety of α,β-unsaturated γ-ketoesters 57a-k which afforded the corresponding chiral β-iodo-α-amino acid derivatives 67a-k as almost single trans-diastereomers (> 90% de) in excellent enantioselectivities of 95-98% ee and very high yields except in the cases of substrates with bulky groups on the ester moiety (75-83% yields for products 67c-d) [39]. On the other hand, both the steric hindrance of ester moieties and the electronic properties of the substituents on the aromatic ring had little influence on the diastereoselectivities always > 90% de (Scheme 17).
40 Page 40 of 135
+ N
N+ O-
O
O-
O
Ar
OR O
65 (0.5 mol%)
57a-k
O
Sc(OTf)3 (0.5 mol%) Ar
+ NIS 4 Å M.S., dark + TsNH2
CH2Cl2, 23 °C
NHTs OR * * I O
cr
R'
O
H N R' R' = BnCH2
ip t
N H
us
67a-k
M
an
67a: Ar = Ph, R = Me: 96%, 96% ee, 96% de 67b: Ar = Ph, R = Et: 96%, 98% ee, 98% de 67c: Ar = Ph, R = i-Pr: 83%, 96% ee, 98% de 67d: Ar = Ph, R = t-Bu: 75%, 97% ee, > 98% de 67e: Ar = R = Ph: 90%, 97% ee, > 90% de 67f: Ar = Ph, R = Bn: 94%, 97% ee, 96% de 67g: Ar = p-MeOC6H4, R = Et: 92%, 95% ee, 94% de 67h: Ar = p-Tol, R = Et: 89%, 96% ee, 96% de 67i: Ar = p-FC6H4, R = Et: 97%, 97% ee, 96% de 67j: Ar = p-BrC6H4, R = Et: 88%, 97% ee, 96% de 67k: Ar = m-MeOC6H4, R = Et: 90%, 98% ee, > 90% de
te
d
Scheme 17. Three-component iodoamination reaction of α,β-unsaturated γ-ketoesters [39].
Ac ce p
In another context, a three-component asymmetric Mannich reaction of silyl ketene imines 68a-f was reported by these authors by using a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 69 [40]. As shown in Scheme 18, substrates 71a-f reacted with imines in situ generated from aldehydes 26a-m and aminophenol 70 to give the corresponding chiral β-amino nitriles 71a-r bearing vicinal tertiary and quaternary stereogenic centers in high yields of up to 96%, high enantioselectivities of up to 97% ee, and moderate to excellent diastereoselectivities of 60-98% de. Indeed, a wide range of aldehydes were suitable substrates for the reaction of α-methyl-α-aryl silyl ketene imines derived from electron-rich as well as electron-deficient aromatic aldehydes. The diastereoselectivity was slightly influenced by the position of the substituents on the aromatic ring of the aldehydes. 41 Page 41 of 135
Generally, ortho-substituted aromatic aldehydes gave the desired products 71b and 71h-i with better diastereoselectivity (90-94% de) than the meta-substituted ones (78-80% de for products 71c and 71e). Both excellent diastereo- and enantioselectivities were also achieved
ip t
(96% ee, 94-96% de) for products 71j-k derived from fused-ring aromatic aldehydes while 3furyl and cyclohexyl aldehydes provided the corresponding products 71l-m in lower
cr
stereoselectivities (77% ee and 60% de for 71l, 89% ee and 80% de for 71m). On the other hand, linear aliphatic aldehydes were unreactive. Concerning the scope of the aryl group of
us
the silyl ketene imines, electron-rich as well as electron-poor silyl ketene imines provided the
an
corresponding β-amino nitriles 71n-r in good yields (80-95%) and high diastereo- and
Ac ce p
te
d
M
enantioselectivities of 82-98% de, and 90-93% ee, respectively.
42 Page 42 of 135
+ N
N+ O-
O
O-
O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2
O + H2N Ar +
OH
69 (10 mol%) Sc(OTf)3 (10 mol%)
OH 70
i-PrNH2 (20 mol%)
TBS
EtOAc, -20 °C
NH R
C N
cr
R H 26a-m
ip t
N H
Ar
C N
71a-r
us
68a-f
Ac ce p
te
d
M
an
71a: R = Ar = Ph: 92% yield, 95% ee, 84% de 71b: R = o-Tol, Ar = Ph: 77% yield, 95% ee, 94% de 71c: R = m-Tol, Ar = Ph: 85% yield, 94% ee, 80% de 71d: R = p-Tol, Ar = Ph: 94% yield, 93% ee, 88% de 71e: R = m-MeOC6H4, Ar = Ph: 94% yield, 89% ee, 78% de 71f: R = p-MeOC6H4, Ar = Ph: 79% yield, 97% ee, 90% de 71g: R = p-ClC6H4, Ar = Ph: 95% yield, 94% ee, 80% de 71h: R = o-ClC6H4, Ar = Ph: 95% yield, 94% ee, 90% de 71i: R = o-BrC6H4, Ar = Ph: 96% yield, 93% ee, 90% de 71j: R = 1-Naph, Ar = Ph: 91% yield, 96% ee, 96% de 71k: R = 2-Naph, Ar = Ph: 88% yield, 96% ee, 94% de 71l: R = 3-furyl, Ar = Ph: 87% yield, 77% ee, 60% de 71m: R = Cy, Ar = Ph: 65% yield, 89% ee, 80% de 71n: R = Ph, Ar = m-Tol: 88% yield, 92% ee, 82% de 71o: R = Ph, Ar = p-MeOC6H4: 80% yield, 90% ee, 88% de 71p: R = Ph, Ar = p-ClC6H4: 95% yield, 92% ee, 96% de 71q: R = Ph, Ar = o-BrC6H4: 87% yield, 93% ee, 98% de 71r: R = Ph, Ar = p-BrC6H4: 88% yield, 92% ee, 88% de
Scheme 18. Three-component Mannich reaction of silyl ketene imines [40].
Intramolecular
versions
of
asymmetric
scandium-catalyzed
two-component
halogenoaminations have been recently reported by Shi et al. For example, these authors have described an efficient enantioselective domino bromination/aminocyclization reaction of allyl N-tosylcarbamates 72a-o with N-bromosuccinimide (NBS) as bromine source to afford the corresponding chiral functionalized oxazolidinones 73a-o [41]. In all cases, the reactions proceeded regioselectively to give the 5-exo products as single diastereomers. The process, catalyzed by a combination of Sc(OTf)3 and Trost ligand 74, allowed a variety of these 43 Page 43 of 135
products to be achieved in generally good yields of up to 90% and high enantioselectivities of up to 97% ee (Scheme 19). The substituents (R1) on the olefin could be linear (products 73ad) or branched alkyl groups (products 73e-f). Moreover, various functional groups, such as
ip t
OBn, OAc, OTs, CN, Cl, and NHBoc, could be present in the side chains (products 73g-l). Other chiral ligands were investigated thus demonstrating that the phosphine group and its
cr
position were crucial for maintaining good yield and enantioselectivity of the reaction.
an
H N
us
Furthermore, it was assumed that the phosphine could be involved in the activation of NBS.
PPh2
O O
O
R1
72a-o NBS
Ac ce p
+
NHTs
Sc(OTf)3 (2-5 mol%)
te
O
74 (2-5 mol%)
d
R2
PPh2
M
N H
toluene/CH2Cl2, -50 °C
O O
NTs R1 R2
Br
73a-o > 99% de
73a: R1 = Et, R2 = H: 88% yield, 96% ee 73b: R1 = n-Bu, R2 = H: 80% yield, 96% ee 73c: R1 = n-Hex, R2 = H: 90% yield, 96% ee 73d: R1 = CH2Bn, R2 = H: 83% yield, 93% ee 73e: R1 = CH2Cp, R2 = H: 77% yield, 96% ee 73f: R1 = Cy, R2 = H: 71% yield, 96% ee 73g: R1 = CH2OBn, R2 = H: 80% yield, 94% ee 73h: R1 = (CH2)3OAc, R2 = H: 80% yield, 97% ee 73i: R1 = (CH2)3OTs, R2 = H: 75% yield, 97% ee 73j: R1 = (CH2)3CN, R2 = H: 75% yield, 96% ee 73k: R1 = (CH2)3Cl, R2 = H: 87% yield, 96% ee 73l: R1 = (CH2)3NHBoc, R2 = H: 50% yield, 92% ee 73m: R1 = R2 = Me: 81% yield, 83% ee 73n: R1 = n-Bu, R2 = Me: 83% yield, 91% ee 73o: R1 = i-Bu, R2 = Me: 87% yield, 88% ee
Scheme 19. Domino bromination/aminocyclization reaction of allyl N-tosylcarbamates [41]. 44 Page 44 of 135
In 2015, a related methodology was reported by the same group, dealing with asymmetric domino bromination/aminocyclization reaction of homoallylic N-tosylcarbamates 75a-i [42].
ip t
In this case, the bromine source was N-bromoacetamide and the optimal catalyst was derived from a novel chiral monophosphine 76 and Sc(OTf)3. In these conditions, a wide variety of
cr
chiral oxazinanones 77a-i were produced through highly enantioselective 6-exobromoaminocyclization in moderate yields albeit remarkable enantioselectivities of up to >
us
99% ee (Scheme 20). The substrates could bear various functional groups, including OBn, Cl,
M
an
and N3 among others, in the side chains (75e-g).
H N
PPh2
O O
te
d
N H
O
NHTs
O
Ac ce p
R
75a-i
+ MeCONHBr
NO2 76 (10 mol%)
Sc(OTf)3 (10 mol%)
O O
NTs R
CH2Cl2, -15 °C
Br 77a-i
77a: R = Me: 58% yield, 99% ee 77b: R = Et: 57% yield, > 99% ee 77c: R = n-Pent: 57% yield, > 99% ee 77d: R = CH2Cy: 54% yield, 99% ee 77e: R = (CH2)2OBn: 48% yield, 97% ee 77f: R = (CH2)2Cl: 45% yield, 99% ee 77g: R = (CH2)2N3: 48% yield, 98% ee 77h: R = allyl: 59% yield, 98% ee 77i: R = H: 72% yield, 64% ee
Scheme
20.
Domino
bromination/aminocyclization
reaction
of
homoallylic
N-
tosylcarbamates [42].
45 Page 45 of 135
In addition, these authors recently developed an efficient regio- and enantioselective 6-endo bromoaminocyclization of 2,4-dienyl N-tosylcarbamates 78a-n using 1,3-dibromo-5,5-
ip t
dimethylhydantoin (DBDMH) as the bromine source and a chiral phosphine oxide/Sc(OTf)3 complex as catalyst employed at 5 mol% of catalyst loading [43]. As shown in Scheme 21,
cr
the domino process afforded a range of chiral 5-bromo-1,3-oxazinan-2-ones 79a-n bearing various functional groups, such as OMe, OAc, and N3, in good yields (up to 91%) and general
us
excellent enantioselectivities of 92-99% ee. The substituents on the diene could be linear
an
(78b-d) or branched alkyl groups (78e). Moreover, aryl-substituted (78i-k) and trisubstituted dienes (78l-n) were also effective substrates for the reaction. While much lower yield (28%)
M
and enantioselectivity (84% ee) were obtained for product 79a when using chiral diphosphine ligand 74, the use of the corresponding phosphine oxide ligand 80 allowed these excellent
Ac ce p
te
d
results to be achieved. An additive, such as NaCl, was crucial for the reaction.
46 Page 46 of 135
H N OO O O O O
NHTs
78a-n
Sc(OTf)3 (5 mol%)
NTs R2
O
2
R
Br
N
cr
+
R1
NaCl (1.2 equiv)
O
CHCl3, -50 °C
N Br
Br
3
R
79a-n
us
R
O
80 (5 mol%)
R3 1
PPh2
ip t
N H
PPh2
an
O DBDMH
Ac ce p
te
d
M
79a: R1 = Me, R2 = R3 = H: 91% yield, 97% ee 79b: R1 = Et, R2 = R3 = H: 83% yield, 96% ee 79c: R1 = n-Pr, R2 = R3 = H: 87% yield, 95% ee 79d: R1 = n-Bu, R2 = R3 = H: 79% yield, 93% ee 79e: R1 = i-Pr, R2 = R3 = H: 84% yield, 95% ee 79f: R1 = CH2OMe, R2 = R3 = H: 77% yield, 97% ee 79g: R1 = CH2OAc, R2 = R3 = H: 71% yield, 95% ee 79h: R1 = CH2N3, R2 = R3 = H: 65% yield, 95% ee 79i: R1 = Ph, R2 = R3 = H: 61% yield, 95% ee 79j: R1 = p-ClC6H4, R2 = R3 = H: 71% yield, 95% ee 79k : R1 = p-FC6H4, R2 = R3 = H: 68% yield, 97% ee 79l: R1 = R2 = Me, R3 = H: 79% yield, 92% ee 79m: R1 = R3 = Me, R2 = H: 81% yield, 98% ee 79n: R1,R3 = (CH2)4, R2 = H: 64% yield, 99% ee
Scheme 21. Domino bromination/aminocyclization reaction of 2,4-dienyl N-tosylcarbamates [43].
Closely related conditions were also applied by these authors to the asymmetric domino bromination/aminocyclization reaction of 2-benzofuranylmethyl N-tosylcarbamates 81a-n with DBDMH [44]. As shown in Scheme 22, the process afforded a novel class of chiral spiro benzofuran oxazolidinones 82a-n in good to excellent yields of 62-97% and remarkable enantioselectivities of 91-97% ee when using Na2CO3 as an additive. Homogeneous results 47 Page 47 of 135
were achieved for a range of 2-benzofuranylmethyl N-tosylcarbamates 81a-n containing various electron-rich or electron-deficient substituents at the C4, C5, and C6 positions. The utility of the process was shown by the transformation of some products into other
OO O O N H
1
R
PPh2 PPh2
NHTs
2
R
Sc(OTf)3 (5 mol%)
81a-n
Na2CO3 (1.2 equiv)
M
+
80 (5 mol%)
O
O
R3
an
O
O
us
H N
cr
ip t
functionalized chiral spiro benzofuran oxazolidinones without loss of optical purity.
O N Ts
R3
O
82a-n
te
O DBDMH
O
d
Br
N
Br
R2
CHCl3, -60 °C
N Br
R1
Ac ce p
82a: R1 = R2 = R3 = H: 90% yield, 94% ee 82b : R1 = F, R2 = R3 = H: 80% yield, 94% ee 82c: R1 = Br, R2 = R3 = H: 87% yield, 96% ee 82d : R1 = R3 = H, R2 = Me: 89% yield, 94% ee 82e: R1 = R3 = H, R2 = t-Bu: 90% yield, 97% ee 82f: R1 = R3 = H, R2 = F: 97% yield, 94% ee 82g: R1 = R3 = H, R2 = Cl: 93% yield, 92% ee 82h: R1 = R3 = H, R2 = Br: 82% yield, 93% ee 82i: R1 = R3 = H, R2 = I: 62% yield, 91% ee 82j: R1 = R2 = H, R3 = F: 83% yield, 93% ee 82k: R1 = R2 = H, R3 = Cl: 91% yield, 91% ee 82l: R1 = R2 = H, R3 = Br: 91% yield, 93% ee 82m: R1 = H, R2 = R3 = F: 95% yield, 91% ee 82n : R1 = R3 = Me, R2 = Cl: 88% yield, 96% ee
Scheme 22. Domino bromination/aminocyclization reaction of 2-benzofuranylmethyl Ntosylcarbamates [44].
3. Enantioselective scandium-catalyzed Michael additions 48 Page 48 of 135
Although firstly reported by Komnenos in 1883 [45], the nucleophilic 1,4-addition of stabilized carbon nucleophiles to electron-poor olefins, generally α,β-unsaturated carbonyl
ip t
compounds, is known as the Michael addition. More generally, Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereocontrolled formation of
cr
carbon−carbon and carbon−heteroatom bonds [46], as has been demonstrated by the huge
us
number of examples in which it has been applied as a key strategic transformation in total synthesis. Although base catalysis is commonly known as a very efficient and high-yielding
an
process in Michael reactions, the strongly basic conditions are often a limiting factor since they can lead to a number of side- and subsequent reactions generating by-products. In order
M
to circumvent these drawbacks, catalysis by metals which work formally under neutral conditions, has attracted the attention of the chemists in this area as a mild and efficient
d
alternative to base catalysis [46b,f,k,l,]. Actually, the catalysis of the Michael reaction by transition metals was first reported in 1972 by Saegusa et al. who treated malonates and
te
diketones with various α,β-unsaturated carbonyl compounds and derivatives using achiral
Ac ce p
copper complexes [47]. The first asymmetric Michael addition catalyzed by a chiral scandium complex was described in 1997 by Katsuki and Kitajima [48]. It involved the addition of 2(trimethylsilyloxy)furans to give the corresponding chiral butenolides achieved by using Sc(OTf)3 and 3,3’-bis(diethylaminomethyl)-1,1’-bi-2-naphthol as catalyst system. Ever since, various other ligands have been investigated in a range of scandium-catalyzed Michael additions of β-ketoesters, malonates, hydroxylamines, or thiols to α,β-unsaturated carbonyl compounds, among which N,N’-dioxides [49], pybox derivatives [50], and BNP ligands [51]. A recent example was reported by Vaccaro et al. dealing with enantioselective scandiumcatalyzed addition of thiols 83a-e to α,β-unsaturated ketones 64a-f [52]. As shown in Scheme 23, this process was performed in water with a catalyst system composed of 1 mol% of
49 Page 49 of 135
Sc(OTf)3 and 2 mol% of chiral bipyridine ligand 84. It provided the corresponding chiral βketo sulfides (R)-85a-m in satisfactory yields of up to 93% and good to high enantioselectivities of up to 97% ee (Scheme 23). Other Lewis acids derived from the same
ip t
ligand, including Yb(OTf)3, In(OTf)3, and Bi(NO3)3, all resulted in lower yields and enantioselectivities. The substrate scope showed that in contrast to all aliphatic thiols which
cr
provided very good results in general, thiophenol 83d led to a moderate enantioselectivity of
us
52% ee. Highly enantioenriched products were obtained with both aryl- and alkyl-substituted enones (Scheme 23). An advantage of this methodology was that the catalyst system could be
an
recovered and recycled with no loss in enantioselectivity. Notably, this work represented the
M
first Lewis acid-catalyzed enantioselective sulfa-Michael addition performed in water.
d
N
N
O
te
t-Bu
3
R1 + R SH
Ac ce p
R2
64a-f
83a-e
t-Bu
OH HO 84 (2 mol%) SR3 O
Sc(OTf) 3 (1 mol%) H2O, 30 °C
R2
R1 85a-m
85a: R1 = Me, R2 = Ph, R3 = n-Bu: 93% yield, 94% ee 85b: R1 = Me, R2 = Ph, R3 = t-Bu: 93% yield, 97% ee 85c: R1 = Me, R2 = Ph, R3 = c-Pent: 83% yield, 97% ee 85d: R1 = Me, R2 = R3 = Ph: 81% yield, 52% ee 85e: R1 = Me, R2 = p-ClC6H4, R3 = Bn: 87% yield, 90% ee 85f: R1 = Me, R2 = p-NO2C6H4, R3 = Bn: 88% yield, 89% ee 85g: R1 = Me, R2 = n-Pent, R3 = Bn: 82% yield, 94% ee 85h: R1 = R2 = Ph, R3 = Bn: 73% yield, 92% ee 85i: R1 = Me, R2 = p-ClC6H4, R3 = t-Bu: 79% yield, 97% ee 85j: R1 = R2 = Ph, R3 = t-Bu: 60% yield, 97% ee 85k: R1 = Me, R2 = p-ClC6H4, R3 = c-Pent: 75% yield, 95% ee 85l: R1 = Me, R2 = n-Pr, R3 = c-Pent: 71% yield, 76% ee 85m: R1 = R2 = Ph, R3 = c-Pent: 84% yield, 96% ee
Scheme 23. Michael reaction of thiols with α,β-unsaturated ketones [52]. 50 Page 50 of 135
These reactions were also independently investigated by Kobayashi et al. at room temperature by using a combination of Sc(OTf)3 with an even lower catalyst loading (1.2
ip t
mol%) of the enantiomer of ligand 84 (ent-84) in water [53]. Using 10 mol% of pyridine as an additive allowed better yields of up to 92% and enantioselectivities of up to 97% ee to be
cr
achieved for a range of β-keto sulfides (S)-85a-j arising from Michael reactions of the
us
corresponding thiols 83a-e with α,β-unsaturated ketones 64a-f. As in the preceding work (Scheme 21), a much lower enantioselectivity (44% ee) was obtained in the case of reaction
an
of thiophenol to give product (S)-85g while general high enantioselectivities were observed
d
M
from aliphatic thiols.
N
N
Ac ce p
O
te
t-Bu
3 R1 + R SH
R2
64a-f
83a-e
OH
t-Bu HO
ent-84 (1.2 mol%) SR3 O
Sc(OTf)3 (1 mol%) pyridine (10 mol%) H2O, r.t.
R2
R1 85a-j
85a: R1 = Me, R2 = Ph, R3 = Bn: 92% yield, 93% ee 85b: R1 = R2 = Ph, R3 = Bn: 83% yield, 94% ee 85c : R1 = Me, R2 = n-Pent, R3 = Bn: 65% yield, 85% ee 85d: R1 = Et, R2 = Me, R3 = Bn: 84% yield, 84% ee 85e : R1 = Ph, R2 = Me, R3 = Bn: 88% yield, 90% ee 85f: R1 = Me, R2 = p-ClC6H4, R3 = Bn: 82% yield, 92% ee 85g: R1 = R2 = R3 = Ph: 92% yield, 44% ee 85h: R1 = R2 = Ph, R3 = Et: 80% yield, 97% ee 85i: R1 = R2 = Ph, R3 = i-Pr: 81% yield, 86% ee 85j: R1 = R2 = Ph, R3 = c-Pent: 91% yield, 93% ee
Scheme 24. Michael reaction of thiols with α,β-unsaturated ketones [53].
51 Page 51 of 135
Closely related reaction conditions were later applied by these authors to the Michael addition of benzylmercaptan 83a to indanone- and tetralone-derived enones 86a-g [54]. As shown in Scheme 25, a range of chiral functionalized indanone- and tetralone products 87a-g
ip t
were achieved in moderate to good yields of up to 90%, generally high enantioselectivities of up to 98% ee, along with moderate to high syn-diastereoselectivities of up to 94% de by using
cr
6 mol% of chiral ligand ent-84 in combination with 5 mol% of Sc(OTf)3. General high syn/anti ratios were obtained in the case of using tetralone-derived enones as substrates 86a-d
us
and 86f-g while indanone-derived enone 86e provided only 36% de (Scheme 25). Lower
an
yields (26-37%) were obtained in the case of tetrasubstituted tetralone products 87f-g. Higher yields and selectivities were reached performing the reactions in water than in organic
d
M
solvents.
te
N
N
t-Bu
R3
Ac ce p
O
R2 + BnSH
R1
( )n
86a-g
t-Bu
OH HO ent-84 (6 mol%)
83a
O
SBn R2
Sc(OTf)3 (5 mol%)
3
R pyridine (20 mol%) H2O, r.t.
R1
( )n 87a-g
87a : R1 = R3 = H, R2 = Ph, n = 1: 90% yield, 80% de, 96% ee 87b: R1 = R3 = H, R2 = p-MeOC6H4, n = 1: 75% yield, 90% de, 97% ee 87c : R1 = R3 = H, R2 = p-ClC6H4, n = 1: 56% yield, 88% de, 97% ee 87d: R1 = OMe, R2 = Ph, R3 = H, n = 1: 83% yield, 94% de, 98% ee 87e : R1 = R3 = H, R2 = Ph, n = 0: 75% yield, 36% de, 97% ee 87f: R1 = H, R2 = R3 = Me, n = 1: 37% yield, 92% ee 87g: R1 = MeO, R2 = R3 = Me, n = 1: 26% yield, 94% ee
Scheme 25. Michael reaction of benzylmercaptan with tetralone- and indanone-derived enones [54].
52 Page 52 of 135
Earlier in 2011, Feng et al. described enantioselective scandium-catalyzed Michael additions of 4-substituted pyrazolones 88a-e to 4-oxo-4-arylbutenoates 57a-i to give the
ip t
corresponding 4-disubstituted pyrazolones 89a-m [55]. As shown in Scheme 26, these Michael products bearing a quaternary stereogenic center were produced in generally high
cr
yields and enantioselectivities of up to 97% and 95% ee, respectively, in combination with
us
moderate to high diastereoselectivities (64-90% de) in the presence of a scandium catalyst derived from chiral N,N’-dioxide ligand 90 and Sc(OTf)3. The more sterically hindered
an
isopropyl 4-oxo-4-arylbutenoate exhibited better diastereo- and enantioselectivities than ethyl 4-oxo-4-arylbutenoate (products 89a-b), and the reaction proceeded well for many differently
M
substituted 4-oxo-4-arylbutenoates and 4-substituted pyrazolones, independently of the electron-donating or electron-withdrawing character of the substituents. Moreover,
Ac ce p
te
products 89h-i with good results.
d
heteroaromatic and fused-ring substrates were also applicable, giving the corresponding
53 Page 53 of 135
R1
O
ON H
O
+ N O-
O
H N Ar'
Ar' Ar' = 2,4,6-Me3C6H2 90 (5.5 mol%) Sc(OTf)3 (5 mol%)
Ph N N 88a-e +
O Ar
O
CO2R2 R1 O
EtOH, 30 °C N 89a-m
N
Ph
cr
CO2R2
Ar
ip t
N+
57a-i
te
d
M
an
us
89a: R1 = Bn, Ar = Ph, R2 = Et: 95%, 86% ee, 64% de 89b: R1 = Bn, Ar = Ph, R2 = i-Pr: 83%, 90% ee, 80% de 89c: R1 = Bn, Ar = p-Tol, R2 = i-Pr: 91%, 92% ee, 74% de 89d: R1 = Bn, Ar = p-FC6H4, R2 = i-Pr: 85%, 94% ee, 72% de 89e: R1 = Bn, Ar = p-ClC6H4, R2 = i-Pr: 95%, 93% ee, 76% de 89f : R1 = Bn, Ar = p-MeOC6H4, R2 = i-Pr: 85%, 92% ee, 70% de 89g: R1 = Bn, Ar = m-ClC6H4, R2 = i-Pr: 83%, 92% ee, 86% de 89h: R1 = Bn, Ar = 2-thienyl, R2 = i-Pr: 95%, 90% ee, 60% de 89i: R1 = Bn, Ar = 2-Naph, R2 = i-Pr: 97%, 91% ee, 78% de 89j: R1 = p-Tol, Ar = Ph, R2 = i-Pr: 91%, 95% ee, 80% de 89k: R1 = 2-furanylmethyl, Ar = Ph, R2 = i-Pr: 95%, 95% ee, 90% de 89l: R1 = Et, Ar = Ph, R2 = i-Pr: 97%, 93% ee, 90% de 89m: R1 = Me, Ar = Ph, R2 = i-Pr: 92%, 86% ee, 86% de
Ac ce p
Scheme 26. Michael reaction of 4-substituted pyrazolones with 4-oxo-4-arylbutenoates [55].
Over the past decade, tremendous progress has been achieved in the catalytic asymmetric aza-Michael reaction, since the resulting chiral β-amino carbonyl compounds are both biologically and synthetically of great importance [56]. As a result, numerous attractive nitrogen nucleophiles were attempted. In this context, benzoyl hydrazine has been added to α,β-unsaturated ketones 92a-t by Feng et al. in the presence of Sc(OTf)3 and another N,N’dioxide chiral ligand 91 [57]. The interest in using hydrazine is not only due to its derivatives having pharmacological activities, but also to the challenging issue of regioselectivity between two competitive amines. Thus, this process afforded the corresponding aza-Michael products 93a-t through regioselective addition of the nonactivated amine moiety of the 54 Page 54 of 135
hydrazine in moderate to high yields of up to 87% and good to high enantioselectivities (8497% ee). As shown in Scheme 27, the electron-withdrawing as well as electron-donating substituents at the aromatic R were tolerated under these mild reaction conditions with
ip t
excellent enantioselectivity and yield (93b-g). In contrast, the corresponding aryl (Ar)substituted analogs furnished the desired products 93k-p with moderate yields and unequal
cr
enantioselectivities, due to the electronic effect of functional groups. The process tolerated fused-ring, styryl or multi-substituted and heteroaromatic-substituted substrates, providing the
us
corresponding Michael products 93h-j and 93q-t in moderate yields with up to 97% ee. The
an
absolute configuration was determined to be S in the case of product 93k through X-ray analysis. This work constituted the first catalytic asymmetric aza-Michael reaction through
M
the nonactivated amine moiety of benzoyl hydrazine toward chalcones achieved highly
Ac ce p
te
d
enantio- and regioselectively.
55 Page 55 of 135
N+ O
O-
N
+
O-
O H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 Ph O 91 (6 mol%) HN NH O Sc(OTf)3 (5 mol%)
Ar
R + Ph
N H
NH2
4 Å M.S.
92a-t
CH2Cl2, 25 °C
Ar
*
R
93a-t
cr
O
O
ip t
N H
Ac ce p
te
d
M
an
us
93a: Ar = R = Ph: 78% yield, 93% ee 93b: Ar = Ph, R = p-FC6H4: 81% yield, 95% ee 93c: Ar = Ph, R = p-ClC6H4: 77% yield, 96% ee 93d: Ar = Ph, R = m-FC6H4: 75% yield, 89% ee 93e : Ar = Ph, R = p-MeOC6H4: 74% yield, 94% ee 93f: Ar = Ph, R = p-Tol: 71% yield, 94% ee 93g: Ar = Ph, R = m-Tol: 70% yield, 94% ee 93h: Ar = Ph, R = 2-thienyl: 75% yield, 90% ee 93i: Ar = Ph, R = 2-Naph: 68% yield, 90% ee 93j: Ar = Ph, R = (E)-PhCH=CH: 87% yield, 86% ee 93k: Ar = p-ClC6H4, R = Ph: 69% yield, 84% ee (S) 93l: Ar = p-Tol, R = Ph: 62% yield, 91% ee 93m: Ar = m-Tol, R = Ph: 71% yield, 91% ee 93n: Ar = o-Tol, R = Ph: 67% yield, 94% ee 93o: Ar = p-MeOC6H4, R = Ph: 64% yield, 97% ee 93p: Ar = p-PhC6H4, R = Ph: 51% yield, 94% ee 93q: Ar = 3-thienyl, R = Ph: 42% yield, 88% ee 93r: Ar = 1-Naph, R = Ph: 75% yield, 97% ee 93s: Ar = 2-Naph, R = Ph: 64% yield, 91% ee 93t: Ar = 2,3-Cl2C6H3, R = Ph: 60% yield, 85% ee
Scheme 27. Aza-Michael reaction of benzoyl hydrazine with α,β-unsaturated ketones [56].
Catalytic asymmetric addition of azoles to electron-deficient olefins provided a protocol for the introduction of optically active azole moieties that can be found in many drugs. However, only a few examples of this type of methodology exist. Among them, enantioselective scandium-catalyzed aza-Michael addition of 1H-benzotriazole 94 to α,β-unsaturated ketones 61a-v reported by Feng et al., which afforded the corresponding N-1 products 95a-v in both excellent yields of up to 99% and enantioselectivities of up to 99% ee (Scheme 28) [58]. 56 Page 56 of 135
These results were achieved by using chiral N,N’-dioxide ligand 96 which was selected among a variety of other N,N’-dioxides. The electronic nature and the position of the substituents at the aromatic ring of R or Ar had little influence on the enantioselectivity (95b-
ip t
m and 95p-r). The electronic and stereochemical effects of the β-aromatic substituents were greater than those of the aromatic substituents of the carbonyl moiety. Notably, when the β-
cr
substituent R was an unsaturated cinnamyl group or an aliphatic cyclohexyl group, the
us
corresponding Michael products 95n-o were obtained in moderate yields (45-60%) with 82 and 88% ee, respectively. Good to high enantioselectivities (80-95% ee) were also achieved
Ac ce p
te
d
M
an
with substrates bearing heteroaromatic substituents (61t-v).
57 Page 57 of 135
N+ O-
O
+ N O-
O
O R
N Ar +
N H
5 Å M.S. CHCl3, -20 °C
94
N
N R *
O
Ar
95a-v
us
61a-v
Sc(OTf)3 (2.5 mol%)
N
N
cr
H N Ar' Ar' Ar' = p-ClC6H4 96 (2.5 mol%)
ip t
N H
Ac ce p
te
d
M
an
95a: R = Ar = Ph: 99% yield, 96% ee 95b: R = o-ClC6H4, Ar = Ph: 65% yield, 88% ee 95c: R = m-ClC6H4, Ar = Ph: 99% yield, 97% ee 95d: R = p-ClC6H4, Ar = Ph: 99% yield, 97% ee 95e: R = p-FC6H4, Ar = Ph: 88% yield, 97% ee 95f: R = p-BrC6H4, Ar = Ph: 98% yield, 96% ee 95g: R = m-NO2C6H4, Ar = Ph: 87% yield, 98% ee 95h: R = p-NO2C6H4, Ar = Ph: 80% yield, 99% ee 95i: R = p-CNC6H4, Ar = Ph: 60% yield, 98% ee 95j: R = m-Tol, Ar = Ph: 99% yield, 95% ee 95k: R = p-Tol, Ar = Ph: 98% yield, 93% ee 95l: R = p-MeOC6H4, Ar = Ph: 90% yield, 85% ee 95m: R = 2-Naph, Ar = Ph: 65% yield, 96% ee 95n: R = (E)-PhCH=CH, Ar = Ph: 45% yield, 82% ee 95o: R = Cy, Ar = Ph: 60% yield, 88% ee 95p: R = Ph, Ar = p-ClC6H4: 99% yield, 97% ee 95q: R = Ph, Ar = p-NO2C6H4: 99% yield, 95% ee 95r: R = Ph, Ar = p-MeOC6H4: 99% yield, 95% ee 95s: R = Ph, Ar = 2-Naph: 96% yield, 96% ee 95t: R = 2-thienyl, Ar = Ph: 50% yield, 80% ee 95u: R = Ph, Ar = 2-thienyl: 35% yield, 95% ee 95v: R = Ph, Ar = 2-furyl: 98% yield, 92% ee
Scheme 28. Aza-Michael reaction of 1-H-benzotriazole with α,β-unsaturated ketones [58].
More recently, a chiral scandium catalyst in situ generated from ScCl3•6H2O and chiral N,N’-dioxide ligand 97 was applied to develop enantioselective aza-Michael reactions of pyrazole 99 with α-substituted vinyl ketones 98a-n to provide in excellent yields the corresponding optically active pyrazole derivatives 100a-n [59]. As shown in Scheme 29, 58 Page 58 of 135
general high enantioselectivities of 89-94% ee were achieved for vinyl ketones 98a-m bearing an aromatic α-substituent (R ) while substrate 98n having a methyl group (R = Me) gave a 2
2
R2 R1
O2N
R1
H
R2
N N
NO2
CHCl3, 2N HCl, 30 °C
100a-n
100a: R1 = H, R2 = Ph: 99%, 93% ee 100b: R1 = 4-F, R2 = Ph: 87%, 94% ee 100c: R1 = 4-Cl, R2 = Ph: 86%, 94% ee 100d: R1 = 4-Br, R2 = Ph: 98%, 94% ee 100e: R1 = 4-Me, R2 = Ph: 91%, 92% ee 100f: R1 = 4-MeO, R2 = Ph: 97%, 90% ee 100g: R1 = H, R2 = o-ClC6H4: 99%, 94% ee 100h: R1 = H, R2 = p-ClC6H4: 98%, 91% ee 100i: R1 = H, R2 = o-BrC6H4: 99%, 93% ee 100j: R1 = H, R2 = m-BrC6H4: 99%, 93% ee 100k: R1 = H, R2 = m-BrC6H4: 99%, 90% ee 100l: R1 = 4-Me, R2 = p-FC6H4: 99%, 90% ee 100m: R1 = 4-OMe, R2 = 2-Naph: 93%, 89% ee 100n: R1 = H, R2 = Me: 93%, 60% ee
Ac ce p
te
d
99
N
ScCl3(6H2O) (10 mol%)
O
an
H N
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3 97 (10 mol%)
M
98a-n
cr
O
+
ON H
O
us
+ N O-
N+
ip t
lower enantioselectivity of 60% ee. The use of HCl(aq.) as additive accelerated the process.
Scheme 29. Aza-Michael reaction of a pyrazole with α-substituted vinyl ketones [59].
The butenolide skeleton ranks among one of the most ubiquitous structural motifs found in naturally occurring products and biologically active compounds [60]. In 2011, Feng et al. developed a very efficient synthesis of chiral γ-substituted butenolides 101a-u based on
59 Page 59 of 135
enantio- and regioselective scandium-catalyzed Michael reaction of 2-silyloxyfuran 102 with chalcones 103a-u [61]. A broad range of these fuctionalized products were achieved as single anti-diastereomers with complete γ-regioselectivity, almost quantitative yields in general, and
ip t
good to high enantioselectivities of 82-94% ee (Scheme 30). The process was catalyzed by a combination of 5 mol% of Sc(OTf)3 and the same quantity of chiral N,N’-dioxide ligand 104
cr
in a mixture of ethyl propionate and tert-butanol as solvent. It is notable that this catalyst system exhibited a remarkably broad substrate scope under exclusive diastereocontrol without
us
any side product from α-addition. Regardless of the electronic properties or steric hindrance
an
of the substituent (Ar1) at the β-phenyl group of the chalcones, excellent enantioselectivities were observed (101b-m). The catalyst was also applicable to heterocyclic systems, which
Ac ce p
te
d
M
delivered the corresponding Michael products 104n-o with 90-92% ee.
60 Page 60 of 135
N+ O-
O
+ N O-
O
N H
O Ar1
Ar2
TBSO +
O
O O
Sc(OTf)3 (5 mol%)
O
t-BuOH/ethyl propionate, 0 °C 102
Ar1
Ar2
101a-u
cr
103a-u
ip t
H N Ar3 Ar3 3 Ar = 2,6-Et2C6H3 104 (5 mol%)
Ac ce p
te
d
M
an
us
> 98% de 101a: Ar1 = Ar2 = Ph: 99% yield, 90% ee 101b: Ar1 = p-Tol, Ar2 = Ph: 99% yield, 87% ee 101c: Ar1 = m-Tol, Ar2 = Ph: 97% yield, 90% ee 101d: Ar1 = o-Tol, Ar2 = Ph: 99% yield, 90% ee 101e: Ar1 = p-MeOC6H4, Ar2 = Ph: 98% yield, 90% ee 101f: Ar1 = m-MeOC6H4, Ar2 = Ph: 99% yield, 91% ee 101g: Ar1 = p-FC6H4, Ar2 = Ph: 98% yield, 90% ee 101h: Ar1 = p-ClC6H4, Ar2 = Ph: 92% yield, 90% ee 101i: Ar1 = m-ClC6H4, Ar2 = Ph: 95% yield, 92% ee 101j: Ar1 = p-BrC6H4, Ar2 = Ph: 99% yield, 91% ee 101k: Ar1 = m-BrC6H4, Ar2 = Ph: 96% yield, 92% ee 101l: Ar1 = p-CNC6H4, Ar2 = Ph: 99% yield, 92% ee 101m: Ar1 = m-CF3C6H4, Ar2 = Ph: 98% yield, 94% ee 101n: Ar1 = 2-thienyl, Ar2 = Ph: 99% yield, 92% ee 101o: Ar1 = 3-thienyl, Ar2 = Ph: 99% yield, 90% ee 101p: Ar1 = Ph, Ar2 = p-Tol: 99% yield, 88% ee 101q: Ar1 = Ph, Ar2 = m-Tol: 96% yield, 84% ee 101r: Ar1 = Ar2 = p-MeOC6H4: 92% yield, 82% ee 101s: Ar1 = p-BrC6H4, Ar2 = p-Tol: 92% yield, 88% ee 101t: Ar1 = m-BrC6H4, Ar2 = p-Tol: 99% yield, 91% ee 101u: Ar1 = m-CF 3C6H4, Ar2 = p-Tol: 99% yield, 89% ee
Scheme 30. Michael reaction of a 2-silyloxyfuran with chalcones [61].
In addition, chiral γ,γ-disubstituted butenolides 105a-o were highly efficiently synthesized through enantioselective Michael addition of β,γ-unsaturated butenolides 106a-c to α,βunsaturated γ-ketoesters 107a-m upon catalysis with a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand 108 [62]. These highly functionalized products were achieved in
61 Page 61 of 135
moderate to good yields of up to 93%, good to high diastereoselectivities of up to > 90% de, and high to excellent enantioselectivities of up to 97% ee (Scheme 31). Ligand 108 was selected among a variety of N,N’-dioxides, as well as Sc(OTf)3 as most efficient Lewis acid
ip t
among a series of other precatalysts including Ni(OTf)2, Cu(OTf)2, La(OTf)3, and Y(OTf)3 which gave either no products or poor enantioselectivities (< 27% ee). Under the optimized
cr
reaction conditions, the ester group (R2) of substrate 107 exhibited an influence on both diastereo- and enantioselectivities (products 105a-c). The bulkier alkyl group (t-butyl) gave
us
slightly better diastereo- and enantioselectivities than methyl and ethyl groups. The stereocontrol of the reaction was sensitive to neither the electronic property nor the steric
an
hindrance of substituents on the phenyl ring (R1) of aromatic α,β-unsaturated γ-ketoesters
M
107, however, generally the meta-substituted substrates gave lower yields than the ortho- and para-substituted ones (Scheme 31). The substrate scope could be extended to fused-ring and
d
heteroaromatic substrates 107j-l with good diastereo- and enantioselectivities of up to 88% de
te
and 95% ee, respectively. Notably, good results (86% de, 90% ee) were also reached with aliphatic α,β-unsaturated γ-ketoester 107m. The steric hindrance of the alkyl group from
Ac ce p
methyl to ethyl and n-C10H21 was investigated, showing that the diastereo- and enantioselectivity of the process increased (92% ee and 86% de for product 105a, 97% ee and > 90% de for product 105n, and 96% ee and > 90% de for product 105o, respectively).
62 Page 62 of 135
ON H
O Ar R
Ar = 2,6-Me2-4-(t-Bu)C6H2 108 (5 mol%) O Sc(OTf)3 (5 mol%)
O 106a-c
+
OO *
MeOAc, 4 Å M.S., 0 °C R1
O R1
O
H N Ar
CO2R2
R3
2 * CO2R
105a-o
cr
O
3
+ N O-
ip t
N+
107a-m
Ac ce p
te
d
M
an
us
105a: R1 = Ph, R2 = t-Bu, R3 = Me: 85%, 92% ee, 86% de 105b: R1 = Ph, R2 = R3 = Me: 88%, 89% ee, 74% de 105c: R1 = Ph, R2 = Et, R3 = Me: 83%, 86% ee, 75% de 105d: R1 = o-Tol, R2 = t-Bu, R3 = Me: 92%, 89% ee, > 90% de 105e: R1 = m-Tol, R2 = t-Bu, R3 = Me: 59%, 89% ee, 82% de 105f: R1 = p-Tol, R2 = t-Bu, R3 = Me: 64%, 96% ee, 86% de 105g: R1 = o-MeOC6H4, R2 = t-Bu, R3 = Me: 84%, 90% ee, > 90% de 105h: R1 = p-MeOC6H4, R2 = t-Bu, R3 = Me: 86%, 95% ee, 90% de 105i: R1 = m-MeOC6H4, R2 = t-Bu, R3 = Me: 68%, 87% ee, 78% de 105j: R1 = 1-Naph, R2 = t-Bu, R3 = Me: 69%, 82% ee, 88% de 105k: R1 = 2-Naph, R2 = t-Bu, R3 = Me: 72%, 95% ee, 82% de 105l: R1 = 2-thienyl, R2 = t-Bu, R3 = Me: 93%, 83% ee, 82% de 105m: R1 = Cy, R2 = t-Bu, R3 = Me: 57%, 90% ee, 86% de 105n: R1 = Ph, R2 = t-Bu, R3 = Et: 50%, 97% ee, > 90% de 105o: R1 = Ph, R2 = t-Bu, R3 = n-C10H21: 63%, 96% ee, > 90% de
Scheme 31. Michael reaction of β,γ-unsaturated butenolides with α,β-unsaturated γ-ketoesters [62].
The catalytic asymmetric conjugate addition of carbon nucleophiles to alkynyl carbonyl compounds is an efficient way to construct versatile and useful building blocks because the newly formed C=C bond can be further functionalized. In contrast to extensive and fruitful studies on enantioselective 1,4-addition reactions of electron-deficient alkenes, investigations of conjugate additions of electron-deficient alkynes are still limited. The difficulty in controlling both E/Z selectivity and enantioselectivity is probably the reason for this limited
63 Page 63 of 135
amount of studies. Generally, the predominant product of these reactions is the thermodynamically stable E isomer. In 2012, Feng et al. reported enantioselective scandiumcatalyzed Michael reactions of alkynones 109a-l with a 4-substituted pyrazolone 88a which
ip t
afforded highly stereoselectively the corresponding thermodynamically unstable Z products 110a-l bearing a quaternary stereogenic center in high enantiomeric and geometric control
cr
[63]. As shown in Scheme 32, these highly Z-selective additions were catalyzed by a combination of Sc(OTf)3 (5 mol%) and 6 mol% of chiral N,N’-dioxide ligand 111, providing
us
a series of functionalized optically active 4-alkenyl-pyrazol-5-ones 110a-l in high yields of up to 95%, high diastereoselectivities of up to > 90% de, and excellent enantioselectivities of up
an
to 99% ee. This catalyst system showed a remarkably broad substrate scope, since a wide range of aromatic, aliphatic, and heterocyclic alkynone derivatives 109a-l provided
Ac ce p
te
d
M
homogeneous excellent results.
64 Page 64 of 135
N+ O-
O
+ N O-
R 109a-l
Sc(OTf)3 (5 mol%)
+ Bn
R
O O
CHCl3, 0 or 25 °C Ph N N
Ph
Bn N N
cr
110a-l
ip t
H N Ar Ar Ar = 1-adamantyl 111 (6 mol%)
O
O
O
N H
88a
d
M
an
us
110a: R = o-Tol: 95% yield, Z/ E = 91:9, 99% ee 110b: R = m-Tol: 93% yield, Z/ E = 93:7, 97% ee 110c: R = p-Tol: 90% yield, Z/ E = 95:5, 98% ee 110d: R = o-FC6H4: 93% yield, Z/ E = 91:9, 96% ee 110e: R = p-FC6H4: 93% yield, Z/ E = 89:11, 96% ee 110f: R = p-ClC6H4: 92% yield, Z/E = 94:6, 96% ee 110g: R = o-MeOC6H4: 93% yield, Z/ E > 95:5, 98% ee 110h: R = 4-F-3-OPhC6H3: 92% yield, Z/E = 88:2, 91% ee 110i: R = 2-Naph: 91% yield, Z/ E > 95:5, 98% ee 110j: R = 2-thienyl: 92% yield, Z/E = 89:11, 96% ee 110k: R = Cy: 90% yield, Z/ E = 88:12, 97% ee 110l: R = n-Pent: 85% yield, Z/E = 92:8, 98% ee
Ac ce p
te
Scheme 32. Michael reaction of alkynones with a 4-substituted pyrazolone [63].
In the same area, these authors also developed enantioselective Michael reactions of alkynones 109a-i with 3-substituted oxindoles 112a-h through catalysis with a scandium complex derived from Sc(OTf)3 and another chiral N,N’-dioxide ligand 113 [64]. As shown in Scheme 33, the reactions were again highly Z-stereoselective since the corresponding enone derivatives 114a-p with a vinyl-substituted quaternary stereogenic center were achieved in very high Z/E ratios of 89:11 to > 95:5. Remarkable yields of up to 99% along with enantioselectivities of 93-99% ee were obtained for a range of substrates, such as 3aryloxindoles bearing electron-donating as well as electron-withdrawing aryl groups and oxindoles bearing 3-thienyl or 3-condensed ring substituent (products 114f-g). Furthermore,
65 Page 65 of 135
the process tolerated a series of alkynones with aromatic as well as aliphatic substituents.
+ N
N+ -
O-
O
O
ip t
Notably, the catalyst loading could be reduced to 0.5 mol%.
R3 109a-i +
Sc(OTf)3 (0.5-5 mol%)
R2
O
R3 R2
R1 O
THF, 30 °C
N H 112a-h
O
N H 114a-p
an
4 Å M.S.
R1
cr
O
us
H N Ar Ar Ar = 2,6-Et2-4-MeC6H2 113 (0.6-6 mol%)
O
N H
Ac ce p
te
d
M
114a: R1 = 5-Me, R2 = R3 = Ph: 96% yield, Z/E > 95:5, 94% ee 114b: R1 = 5-Cl, R2 = R3 = Ph: 98% yield, Z/ E > 95:5, 99% ee 114c: R1 = H, R2 = p-FC6H4, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114d: R1 = H, R2 = p-ClC6H4, R3 = Ph: 99% yield, Z/ E = 94:6, 99% ee 114e: R1 = H, R2 = m-Tol, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114f: R1 = H, R2 = 2-thienyl, R3 = Ph: 93% yield, Z/ E > 95:5, 99% ee 114g: R1 = H, R2 = 2-Naph, R3 = Ph: 99% yield, Z/ E > 95:5, 99% ee 114h: R1 = H, R2 = Bn, R3 = Ph: 94% yield, Z/ E = 95:5, 96% ee 114i: R1 = 5-Me, R2 = Ph, R3 = p-Tol: 98% yield, Z/ E > 95:5, 98% ee 114j: R1 = 5-Me, R2 = Ph, R3 = p-FC6H4: 97% yield, Z/ E > 95:5, 99% ee 114k: R1 = 5-Me, R2 = Ph, R3 = p-BrC6H4: 97% yield, Z/ E > 95:5, 99% ee 114l: R1 = 5-Me, R2 = Ph, R3 = p-CF3C6H4: 97% yield, Z/ E > 95:5, 94% ee 114m: R1 = 5-Me, R2 = Ph, R3 = 2-Naph: 96% yield, Z/ E > 95:5, 98% ee 114n: R1 = 5-Me, R2 = Ph, R3 = 2-thienyl: 98% yield, Z/ E = 89:11, 93% ee 114o: R1 = 5-Me, R2 = Ph, R3 = Cy: 90% yield, Z/ E = 90:10, 98% ee 114p: R1 = 5-Me, R2 = Ph, R3 = n-Pent: 90% yield, Z/E > 95:5, 96% ee
Scheme 33. Michael reaction of alkynones with 3-substituted oxindoles [64].
In 2015, a series of 3-substituted oxindoles 112a-m were reacted with linear dienyl ketones 115a-c in the presence of a catalytic amount of Sc(OTf)3 and chiral N,N’-dioxide ligand 9 to give regioselectively the corresponding chiral oxindoles 116a-u with quaternary stereocenters 66 Page 66 of 135
through 1,6-addition [65]. In the case of 1,6-addition of δ-unsubstituted dienyl ketones 115a-b (R3 = H), the corresponding Michael products 116a-n were achieved in moderate to good yields of 63-89% along with high enantioselectivities of 92-99% ee. As shown in Scheme 34,
ip t
the electronic properties of the substituents on the aromatic ring (Ar) had only little effect on the enantioselectivity of the reaction. Similarly, both the electronic nature and the position of
cr
the substituents R2 at the aromatic ring of oxindole substrates had a limited influence on the enantioselectivity (116b-h). Substrates bearing a condensed-ring or heteroaromatic-ring
us
substituent as R2 were also applicable, affording the corresponding products 116i-k with 96-
an
99% ee. The scope of this methodology was also successfully applied to the 1,6-addition of 3substituted oxindoles 112o-u to δ-methyl-substituted dienyl ketone 115c (R3 = Me) by simply
M
changing the solvent from chloroform to THF, providing the corresponding enantiopure Michael adducts 116o-u with a very high general diastereoselectivity of up to > 90% de, and
d
good yields of up to 87% (Scheme 34). Again, both the electronic properties and the steric
te
hindrance of the substituent R2 of the oxindole substrate had no obvious effect on the
Ac ce p
enantioselectivity and diastereoselectivity of the process.
67 Page 67 of 135
+ N O-
R2
R1
O O
N H 112a-m +
ON H
O
H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 9 (6 mol%) Sc(OTf)3 (5 mol%)
R1
R2
Ar
Ar
O
N H
4 Å M. S. CHCl3 or THF, 30 °C
O
cr
R3
*
*
O
R3
ip t
N+
116a-u
us
115a-b
Ac ce p
te
d
M
an
116a: R1 = R3 = H, R2 = Bn, Ar = p-MeOC6H4: 67% yield, 97% ee 116b: R1 = R3 = H, R2 = m-BrC6H4, Ar = Ph: 72% yield, 96% ee 116c: R1 = R3 = H, R2 = m-BrC6H4, Ar = p-MeOC6H4: 72% yield, 96% ee 116d: R1 = R3 = H, R2 = m-NO2C6H4, Ar = p-MeOC6H4: 79% yield, 96% ee 116e: R1 = R3 = H, R2 = m-Tol, Ar = p-MeOC6H4: 63% yield, 97% ee 116f: R1 = R3 = H, R2 = p-BrC6H4, Ar = p-MeOC6H4: 79% yield, 96% ee 116g: R1 = R3 = H, R2 = p-CNC6H4, Ar = p-MeOC6H4: 81% yield, 96% ee 116h: R1 = R3 = H, R2 = Ar = p-MeOC6H4: 68% yield, 98% ee 116i: R1 = R3 = H, R2 = 2-naphthylmethyl, Ar = p-MeOC6H4: 85% yield, 96% ee 116j: R1 = R3 = H, R2 = 2-thienylmethyl, Ar = p-MeOC6H4: 80% yield, 99% ee 116k: R1 = R3 = H, R2 = 2-furanylmethyl, Ar = p-MeOC6H4: 84% yield, 98% ee 116l: R1 = R3 = H, R2 = Me, Ar = p-MeOC6H4: 80% yield, 92% ee 116m: R1 = R3 = H, R2 = Ph, Ar = p-MeOC6H4: 89% yield, 94% ee (S) 116n: R1 = R3 = H, R2 = 2-Naph, Ar = p-MeOC6H4: 80% yield, 93% ee 116o: R1 = H, R2 = Bn, R3 = Me, Ar = p-MeOC6H4: 83% yield, > 99% ee, > 90% de 116p: R1 = H, R2 = m-Tol, R3 = Me, Ar = p-MeOC6H4: 74% yield, > 99% ee, > 90% de 116q: R1 = H, R2 = m-BrC6H4, R3 = Me, Ar = p-MeOC6H4: 80% yield, 99% ee, 90% de 116r: R1 = H, R2 = Ar = p-MeOC6H4, R3 = Me: 78% yield, > 99% ee, > 90% de 116s: R1 = H, R2 = 2-naphthylmethyl, R3 = Me, Ar = p-MeOC6H4: 87% yield, > 99% ee, > 90% de 116t: R1 = H, R2 = 2-thienylmethyl, R3 = Me, Ar = p-MeOC6H4: 80% yield, > 99% ee, > 90% de 116u: R1 = H, R2 = R3 = Me, Ar = p-MeOC6H4: 72% yield, > 99% ee, 80% de
Scheme 34. Michael reaction of dienyl ketones with 3-substituted oxindoles [65].
In 2015, the same authors reported enantioselective Michael addition of 3-substituted oxindoles 112a-m to N-(2-t-butylphenyl)maleimide 117 in the presence of a scandium catalyst in situ generated from chiral N,N’-dioxide ligand 69 and Sc(OTf)3 [66]. As shown in
68 Page 68 of 135
Scheme 35, when the reaction was performed in the presence of K2HPO4, a range of chiral atropoisomeric succinimides 118a-m bearing adjacent quaternary and tertiary centers were afforded in remarkable yields of up to 99%, enantio- and diastereoselectivities of up to 99%
ip t
ee and > 90% de, respectively. Excellent results were reached for various 3-substituted benzyl oxindoles 112a-h as well as for oxindoles 112i-k substituted by heteroaromatic or fused-ring.
cr
Lower diastereo- and enantioselectivities of 50-80% de and 88-89% ee, respectively, were
N+ R R2
+
O t-Bu
Ac ce p
N O 117
O
K2HPO4 (3 equiv) CH2Cl2, 30 °C
H N R2 1
R
Sc(OTf)3 (10 mol%)
te
N H 112a-m
O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 69 (10 mol%)
d
O
ON H
+ N O-
M
O
1
an
us
obtained in the case of reactions of 3-phenyl oxindole 112l and 3-methyl oxindole 112m.
O
N
O t-Bu
118a-m
118a: R1 = Bn, R2 = H: 99% yield, 97% ee, > 90% de 118b: R1 = o-BrC6H4CH2, R2 = H: 99% yield, 96% ee, > 90% de 118c: R1 = m-BrC6H4CH2, R2 = H: 98% yield, 98% ee, > 90% de 118d: R1 = p-BrC6H4CH2, R2 = H: 94% yield, 96% ee, > 90% de 118e: R1 = p-ClC6H4CH2, R2 = H: 87% yield, 95% ee, > 90% de 118f: R1 = m-NO2C6H4CH2, R2 = H: 99% yield, 97% ee, > 90% de 118g: R1 = p-MeOC6H4CH2, R2 = H: 99% yield, 97% ee, > 90% de 118h: R1 = p-TolCH2, R2 = H: 99% yield, 97% ee, > 90% de 118i: R1 = 2-furanylmethyl, R2 = H: 93% yield, 94% ee, > 90% de 118j: R1 = 2-thienylmethyl, R2 = H: 93% yield, 95% ee, > 90% de 118k: R1 = 2-naphthylmethyl, R2 = H: 99% yield, 97% ee, > 90% de 118l: R1 = Ph, R2 = H: 96% yield, 89% ee, 80% de 118m: R1 = Me, R2 = H: 91% yield, 88% ee, 50% de
69 Page 69 of 135
Scheme 35. Michael reaction of N-(2-t-butylphenyl)maleimide with 3-substituted oxindoles
ip t
[66].
Although impressive progress in the metal-catalyzed asymmetric Michael additions has
cr
been made in the past decades, there remains a great challenge in the diastereoselectivity issue of these reactions, especially those involving nitroalkanes with α,β-unsaturated ketones. In
us
this context, Wang et al. have employed an in situ generated scandium catalyst from Sc(OTf)3 and novel chiral C2-symmetric tridentate Schiff base ligand 119 to promote the first
an
enantioselective Michael reaction of nitroalkanes 120a-b with 2-enoyl-pyridine N-oxides 121a-n [67]. This novel process allowed a range of chiral Michael products 122a-o to be
M
achieved in good yields of up to 89%, moderate to good anti-diastereoselectivities of 50-92% de, and high enantioselectivities of 91-95% ee (Scheme 36). 2-Enoyl-pyridine N-oxides 121a-
d
m and 121o with (hetero)aromatic substituents as well as substrates such as 121n bearing an
te
aliphatic substituent were tolerated. To illustrate the synthetic utility of this process, one of
Ac ce p
the products was converted into a biologically active analogue of nicotine. It is important to note that the level of diastereoselectivity reached in these reactions was unprecedented in the asymmetric 1,4-addition of nitroalkanes to α,β-unsaturated ketones.
70 Page 70 of 135
CF3 F3C OH HO N
Bn NH
R2
HN
O
O 119 (15 mol%)
121a-n
Sc(OTf)3 (15 mol%)
+ R1
O N
O
R2
R1
NO2
Cs2CO3 (15 mol%)
NO2
ip t
O
cr
O N
N
Bn
THF, r.t.
122a-o
us
120a-b
Ac ce p
te
d
M
an
122a: R1 = Me, R2 = Ph: 87% yield, 93% ee, 84% de 122b: R1 = Me, R2 = p-FC6H4: 86% yield, 93% ee, 80% de 122c: R1 = Me, R2 = p-ClC6H4: 76% yield, 92% ee, 82% de 122d: R1 = Me, R2 = p-BrC6H4: 72% yield, 95% ee, 84% de 122e: R1 = Me, R2 = p-Tol: 84% yield, 92% ee, 82% de 122f: R1 = Me, R2 = p-MeOC6H4: 89% yield, 91% ee, 80% de 122g: R1 = Me, R2 = m-MeOC6H4: 86% yield, 95% ee, 78% de 122h: R1 = Me, R2 = m-NO2C6H4: 64% yield, 91% ee, 60% de 122i: R1 = Me, R2 = m-FC6H4: 81% yield, 91% ee, 66% de 122j: R1 = Me, R2 = o-FC6H4: 79% yield, 93% ee, 80% de 122k: R1 = Me, R2 = 2,4-(MeO)2C6H3: 89% yield, 92% ee, 84% de 122l: R1 = Me, R2 = 2-Naph: 84% yield, 95% ee, 78% de 122m: R1 = Me, R2 = 2-furyl: 76% yield, 92% ee, 50% de 122n: R1 = Me, R2 = n-Hex: 69% yield, 95% ee, 92% de 122o: R1 = Et, R2 = Ph: 72% yield, 93% ee, 80% de
Scheme 36. Michael reaction of nitroalkanes with 2-enoyl-pyridine N-oxides [67].
Recently, Yoon et al. reported the first highly enantioselective intermolecular reaction of αamino radicals achieved through cooperative photoredox and Lewis acid catalysis [68]. This process began with the in situ generation of these radicals from the corresponding αsilylamines 123a-g (Scheme 37) in the presence of Ru(bpy)3Cl2 under irradiation with fluorescent light. These radicals were then submitted to asymmetric conjugate addition to α,βunsaturated ketones 124a-j bearing a pyrazolidinone moiety. A range of chiral γaminocarbonyl products 125a-s were achieved in moderate to excellent yields (35-96%) and good to high enantioselectivities of 85-96% ee when using an in situ generated scandium catalyst from pybox ligand 126 and Sc(OTf)3. A variety of electron-withdrawing para 71 Page 71 of 135
substituents (R1 = F, Cl, Br) were easily accommodated on the N-aryl moiety of α-silylamines 123b-d (90-96% yields, 92-94% ee for products 125b-d) while modestly electron-donating substituents (R1 = Me) slowed the rate of the reaction (79% yield) without affecting the enantioselectivity (product 125e). High enantioselectivities (92-96% ee) were also reached with substrates having substituents in ortho and meta substituents (products 125f-g).
ip t
Generally, N-alkyl-N-aryl α-silylamines were employed but a good result was also achieved with a N,N-diaryl α-silylamine (R4 = Ph) giving the corresponding product 125h in 93% yield
cr
and 91% ee. Sterically bulky N-alkyl-N-aryl α-silylamines (R4 = Bn, i-Pr) reacted sluggishly in the reaction, providing the corresponding products 125i-j in 33-60% yields albeit with
us
excellent enantioselectivities (94-95% ee). Concerning the Michael acceptors, aliphatic as well as aromatic ones bearing both electron-poor and electron-rich substituents provided
an
comparable high enantioselectivities (91-96% ee). A marginally diminished enantioselectivity of 85% ee was obtained for ortho-substituted product 125r. To expand the utility of this methodology, an efficient removal of the pyrazolidinone auxiliary was achieved from some
Ac ce p
te
d
M
products without erosion of the enantioselectivity.
72 Page 72 of 135
O
R1
R3
O
N N
TMS
N
i-Bu
i-Bu 126 (20 mol%)
R4 N
Sc(OTf)3 (15 mol%)
R2 123a-g
Ru(bpy)3Cl2 (2 mol%)
+ O R5
O
R1
Bu4NCl (30 mol%)
R5
O N N
R3
Et
R2
MeCN, visible light
125a-s
cr
N N
O
ip t
R4 N
Et
us
124a-j
Ac ce p
te
d
M
an
125a: R1 = R2 = R3 = H, R4 = R5 = Me: 87% yield, 93% ee 125b: R1 = F, R2 = R3 = H, R4 = R5 = Me: 94% yield, 94% ee 125c: R1 = Cl, R2 = R3 = H, R4 = R5 = Me: 96% yield, 93% ee 125d: R1 = Br, R2 = R3 = H, R4 = R5 = Me: 90% yield, 92% ee 125e: R1 = Me, R2 = R3 = H, R4 = R5 = Me: 79% yield, 91% ee 125f: R1 = R3 = H, R2 = OMe, R4 = R5 = Me: 85% yield, 92% ee 125g: R1 = R2 = H, R3 = F, R4 = R5 = Me: 80% yield, 96% ee 125h: R1 = R2 = R3 = H, R4 = Ph, R5 = Me: 93% yield, 91% ee 125i: R1 = R2 = R3 = H, R4 = Bn, R5 = Me: 60% yield, 94% ee 125j: R1 = R2 = R3 = H, R4 = i-Pr, R5 = Me: 33% yield, 95% ee 125k: R1 = R2 = R3 = H, R4 = Me, R5 = n-Pr: 76% yield, 93% ee 125l: R1 = R2 = R3 = H, R4 = Me, R5 = i-Pr: 71% yield, 93% ee 125m: R1 = R2 = R3 = H, R4 = Me, R5 = CH2OBn: 75% yield, 91% ee 125n: R1 = R2 = R3 = H, R4 = Me, R5 = t-Bu: 35% yield, 96% ee 125o: R1 = R2 = R3 = H, R4 = Me, R5 = Ph: 74% yield, 93% ee 125p: R1 = R2 = R3 = H, R4 = Me, R5 = p-ClC6H4: 63% yield, 91% ee 125q: R1 = R2 = R3 = H, R4 = Me, R5 = p-MeOC6H4: 83% yield, 94% ee 125r: R1 = R2 = R3 = H, R4 = Me, R5 = o-MeOC6H4: 81% yield, 85% ee 125s: R1 = R2 = R3 = H, R4 = Me, R5 = 2-furyl: 83% yield, 91% ee
proposed mechanism: R4 N
R1
R3
O
TMS
R2 123a-g
R1 Ru(bpy)3Cl2
N N Et
R3 Michael
2
R
R4 N R1
R5
R4 N
photoredox activation
[Sc]* O
R5
O
O N N
R3
Et
2
R
125a-s
73 Page 73 of 135
Scheme 37. Michael reaction of α-amino radicals with α,β-unsaturated ketones [68].
ip t
4. Enantioselective scandium-catalyzed cycloaddition reactions
cr
Cycloaddition reactions which form multiple bonds, rings, and stereocenters are particularly
us
important tools for the efficient assembly of complex molecular structures [69]. Of the many families of reactions discovered over the past century, cycloaddition reactions hold a
an
prominent place in the arsenal of synthetic methods currently available to organic chemists and the research activity in this field shows no signs of abatement [70]. Among
M
cycloadditions, the 1,3-dipolar cycloaddition (Huisgen cycloaddition [71]) is a classic reaction in organic chemistry consisting of the reaction of a dipolarophile with a 1,3-dipolar compound
d
that allows the production of important 5-membered heterocycles. This reaction represents
te
one of the most productive fields of modern synthetic organic chemistry. Indeed, catalytic methods encompassing metal carbene intermediates constitute a vast array of transformations
Ac ce p
that offer the synthetic chemist great scope in the synthesis of many complex molecules [72]. Among the metals used to catalyze cycloadditions [73], scandium has been recently used by Zhang and Li in an enantioselective [3+2] cycloaddition of alkyne 127 with N-tosylaziridine 128 to give the corresponding chiral highly substituted 3-pyrroline 129 [74]. The latter was produced in 80% yield with a moderate enantioselectivity of 70% ee when using chiral pybox ligand 27 in combination with Sc(OTf)3 as catalyst system (Scheme 38).
74 Page 74 of 135
O
Ph 128
N
N
CO2Et 27 (5.5 mol%)
CO2Et
Ph
Ts N
Sc(OTf)3 (5 mol%)
CO2Et
+ p-MeOC6H4
MeO
CO2Et p-MeOC6H4
4 Å M.S.
OMe
CH2Cl2, r.t.
129
cr
127
ip t
Ts N
O
N
80% yield, 70% ee
an
us
Scheme 38. [3+2] Cycloaddition of an alkyne with an N-tosylaziridine [74].
The importance of optically active β-lactones as versatile chiral synthons underscores
M
current research efforts for developing novel catalytic enantioselective methods, among which the asymmetric [2+2] cycloaddition between ketenes and carbonyl compounds appears to be
d
the most elegant. In 2014, Feng et al. developed highly efficient [2+2] cycloadditions of
te
disubstituted ketenes 130a-l with substituted isatins 6a-i to give the corresponding chiral βlactones 131a-t [75]. This process was catalyzed by a chiral scandium complex in situ
Ac ce p
generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 9, and provided a range of chiral spiro cycloadducts bearing two contiguous quaternary stereogenic centers as almost single diastereomers (> 98% de) in high yields of up to 99%, and generally excellent enantioselectivities of up to 98% ee (Scheme 39). Remarkably, in most cases of substrates, the catalyst loading could be reduced as low as 0.2-0.5 mol%. Studying the substrate scope of the reaction, the authors demonstrated its generality and functional group tolerance. For example, the substituent on the aryl group (Ar1) of aryl alkyl ketenes had little or no effect on the stereoselectivity.
75 Page 75 of 135
O
+ O
H N Ar2 Ar2 2 Ar = 2,6-i-Pr2C6H3 9 (0.2-2 mol%)
O R2
ON H
N O-
O N Bn 6a-i
O O
Sc(OTf)3 (0.2-2 mol%)
+
R
N Bn
cr
CH2Cl2, 30 °C
C O
Ar1 O
2
3 Å M.S.
Ar1
R1
ip t
N+
131a-t
R1
> 98% de
us
130a-l
Ac ce p
te
d
M
an
131a: Ar1 = Ph, R1 = Et, R2 = H: 96% yield, 95% ee 131b: Ar1 = Ph, R1 = n-Pr, R2 = H: 95% yield, 88% ee 131c: Ar1 = Ph, R1 = n-Bu, R2 = H: 97% yield, 91% ee 131d: Ar1 = o-FC6H4, R1 = Et, R2 = H: 90% yield, 96% ee 131e: Ar1 = m-FC6H4, R1 = Et, R2 = H: 91% yield, 95% ee 131f: Ar1 = p-FC6H4, R1 = Et, R2 = H: 95% yield, 96% ee 131g: Ar1 = o-MeOC6H4, R1 = Et, R2 = H: 77% yield, 86% ee 131h: Ar1 = m-MeOC6H4, R1 = Et, R2 = H: 96% yield, 97% ee 131i: Ar1 = p-MeOC6H4, R1 = Et, R2 = H: 87% yield, 96% ee 131j: Ar1 = p-Tol, R1 = Et, R2 = H: 91% yield, 98% ee 131k: Ar1 = p-ClC6H4, R1 = Et, R2 = H: 99% yield, 96% ee 131l: Ar1 = 2-Naph, R1 = Et, R2 = H: 95% yield, 97% ee 131m: Ar1 = Ph, R1 = Et, R2 = 6-F: 80% yield, 96% ee 131n: Ar1 = Ph, R1 = Et, R2 = 5-F: 95% yield, 85% ee 131o: Ar1 = Ph, R1 = Et, R2 = 6-Br: 90% yield, 80% ee 131p: Ar1 = Ph, R1 = Et, R2 = 7-F: 90% yield, 98% ee 131q: Ar1 = Ph, R1 = Et, R2 = 7-Cl: 84% yield, 97% ee 131r: Ar1 = Ph, R1 = Et, R2 = 7-Br: 96% yield, 97% ee 131s: Ar1 = Ph, R1 = Et, R2 = 7-Me: 79% yield, 98% ee 131t: Ar1 = Ph, R1 = Et, R2 = 7-CF 3CO: 80% yield, 96% ee
Scheme 39. [2+2] Cycloaddition of ketenes with isatins [75].
The asymmetric hetero-Diels−Alder reaction is one of the most efficient synthetic methodologies for the regio- and stereoselective construction of chiral six-membered heterocycles [76]. In recent years, several examples of these reactions have used chiral scandium catalysts. For example, Desimoni et al. have developed enantioselective hetero-
76 Page 76 of 135
Diels−Alder cycloaddition of 4-aryl-2-oxo-3-butenoates 132a-b with 1-trialkylsiloxy-1cyclohexenes 133a-b catalyzed by a combination of Sc(OTf)3 and chiral pybox ligand 134 in the presence of HFIP as an additive [77]. The corresponding almost enantiopure cycloadducts
ip t
135a-d were obtained in moderate to good yields (53-73%) as major diastereomers bearing a
N N
Ph + O 132a-b
OSiRR'2 133a-b
Ph 134 (10 mol%) Sc(OTf)3 (10 mol%) 3 Å M.S. HFIP (1.7 equiv) CH2Cl2, -20 °C
M
MeO2C
N
H
an
Ar
O
us
O
cr
trans ring junction with moderate diastereoselectivities of 14-66% de (Scheme 40).
R'2RSiO
Ar
O
CO2Me
135a-d major
te
d
135a: Ar = Ph, R = R' = Me: 55% yield, 98% ee, 14% de 135b: Ar = p-BrC6H4, R = R' = Me: 62% yield, 99% ee, 56% de 135c: Ar = Ph, R = t-Bu, R' = Me: 73% yield, 99% ee, 66% de 135d: Ar = p-BrC6H4, R = t-Bu, R' = Me: 53% yield, 98% ee, 42% de
Ac ce p
Scheme 40. Hetero-Diels−Alder cycloaddition of 4-aryl-2-oxo-3-butenoates with 1trialkylsiloxy-1-cyclohexenes [77].
Chiral dihydrocoumarin derivatives have attracted much attention due to their pharmacological and physiological activities. Consequently, significant efforts have been devoted to the asymmetric synthesis of these fascinating molecules. Among them, enantioselective inverse-electron-demand hetero-Diels−Alder cycloadditions of o-quinones 136a-b with azlactones 137a-p were recently developed by Feng et al. by using a chiral scandium catalyst [78]. Among a series of N,N’-dioxides investigated, L-ramipril-derived ligand 138 was selected as optimal to achieve the corresponding chiral functionalized 3,4dihydrocoumarins 139a-p bearing nitrogen atom substituents as almost single diastereomers 77 Page 77 of 135
(> 90% de) in good yields of up to 94% and generally high enantioselectivities of up to 96% ee, as illustrated in Scheme 41. Under these mild reaction conditions, a wide range of azlactones with either electron-withdrawing or electron-donating substituents on the phenyl
ip t
ring in the R1 group were tolerated. Interestingly, only moderate enantioselectivities were reached by using other metals as precatalysts, such as Ni(OTf)2 or Yb(OTf)3 (19-24% ee vs
cr
74% ee with Sc(OTf)3 under similar conditions). This work constituted the first use of
an
us
azlactones in the inverse-electron-demand hetero-Diels−Alder reaction with o-quinones.
N+ ON H
Ar
136a-b +
O
R2
M
O
Sc(OTf)3 (10 mol%)
O
d
O
+
O H N Ar' Ar' Ar' = 2,6-Me2-4-t-BuC6H2 138 (10.5 mol%)
O O
N O-
O
N
O
Ac ce p
R1 137a-p
te
imidazole (15 mol%) THF, 35 °C
O
Ar
O R2 NHCOR1
139a-p > 90% de
139a: R1 = Ph, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139b: R1 = p-FC6H4, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139c: R1 = p-ClC6H4, R2 = Bn, Ar = p-MeOC6H4: 89% yield, 94% ee 139d: R1 = p-BrC6H4, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 91% ee 139e: R1 = p-NCC6H4, R2 = Bn, Ar = p-MeOC6H4: 64% yield, 92% ee 139f: R1 = p-CF3C6H4, R2 = Bn, Ar = p-MeOC6H4: 68% yield, 92% ee 139g: R1 = p-Tol, R2 = Bn, Ar = p-MeOC6H4: 90% yield, 93% ee 139h: R1 = Ar = p-MeOC6H4, R2 = Bn: 85% yield, 90% ee 139i: R1 = p-NO2C6H4, R2 = Bn, Ar = p-MeOC6H4: 94% yield, 96% ee 139j: R1 = m-ClC6H4, R2 = Bn, Ar = p-MeOC6H4: 88% yield, 91% ee 139k: R1 = R2 = Bn, Ar = p-MeOC6H4: 63% yield, 94% ee 139l: R1 = Ph, R2 = p-FC6H4, Ar = p-MeOC6H4: 42% yield, 91% ee 139m: R1 = Ph, R2 = p-BrC6H4, Ar = p-EtOC6H4: 91% yield, 91% ee 139n: R1 = Ph, R2 = MeS(CH2)2, Ar = p-MeOC6H4: 75% yield, 82% ee 139o: R1 = Ph, R2 = Me, Ar = p-MeOC6H4: 71% yield, 77% ee 139p: R1 = Ph, R2 = H, Ar = p-MeOC6H4: 70% yield, 91% ee
78 Page 78 of 135
Scheme 41. Hetero-Diels−Alder cycloaddition of o-quinones with azlactones [78].
ip t
5. Enantioselective scandium-catalyzed ring-opening reactions
cr
The asymmetric nucleophilic addition of meso-epoxides is an efficient method to construct chiral 1,2-difunctional compounds, such as 1,2-diol monoethers, 1,2-amino alcohols, or 1,2-
us
thioalcohols. In the past decade, scandium complexes of chiral bipyridine ligands have been successfully applied to the reactions of alcohols, amines, including N-heterocycles and
an
indoles, as well as thiols with racemic epoxides [79]. In the last few years, another type of ligands, such as chiral N,N’-dioxides, have led to very good results in these reactions. For
M
example, ligand 140 was used by Feng et al. in enantioselective scandium-catalyzed ringopening of epoxides 141a-d with pyrazole derivatives 142a-f to give the corresponding chiral
d
β-pyrazole-substituted alcohols 143a-i as single diastereomers (98% de) in moderate to
te
quantitative yields and high enantioselectivities of 87-99% ee (Scheme 42) [80]. Meso-
Ac ce p
epoxides with electron-withdrawing or electron-donating substituents at the meta- and paraposition of the aryl group allowed the maintenance of the high enantioselectivity and complete syn-diastereoselectivity (143g-i). Moreover, a range of variously substituted pyrazole derivatives provided comparable excellent results (143b-f). The importance of this nice reaction is related to the fact that pyrazole is a motif found in a number of small molecules possessing diverse chemical, biological, and pharmaceutical activities [81].
79 Page 79 of 135
ON H
O Ar'
O
141a-d R1
R3 OH
N N
Ar
H N
3 Å M.S. CH2Cl2, 35 °C
N R2
O
H N Ar'
Ar' = 3,5-Me2C6H3 140 (5.25 mol%) Sc(OTf)3 (5 mol%)
Ar
+
+
Ar
R2
R1
cr
Ar
N O-
ip t
N+
143a-i
3
98% de
us
R 142a-f
d
M
an
143a: R1 = R2 = R3 = H, Ar = Ph: 99% yield, 87% ee 143b: R1 = R3 = Me, R2 = H, Ar = Ph: 96% yield, 95% ee 143c: R1 = R3 = H, R2 = NO2, Ar = Ph: 88% yield, 89% ee 143d: R1 = R3 = Et, R2 = NO2, Ar = Ph: 54% yield, 87% ee 143e: R1 = R3 = Me, R2 = Br, Ar = Ph: 95% yield, 95% ee 143f: R1,R2 = (CH=CH)2, R3 = H, Ar = Ph: 87% yield, 99% ee 143g: R1 = R3 = Me, R2 = Br, Ar = p-FC6H4: 99% yield, 95% ee 143h: R1 = R3 = Me, R2 = Br, Ar = m-MeOC6H4: 99% yield, 96% ee 143i: R1 = R3 = Me, R2 = H, Ar = m-MeOC6H4: 99% yield, 92% ee
Ac ce p
te
Scheme 42. Ring-opening of epoxides with pyrazole derivatives [80].
While tremendous advances have been made in asymmetric synthesis, the resolution of racemates is still the most important industrial approach to the synthesis of chiral compounds [82]. The use of enzymes for the kinetic resolution of racemic substrates to afford enantiopure compounds in high enantioselectivity and good yield has long been a popular strategy in synthesis. However, transition metal-mediated (and more recently organocatalyzed) kinetic resolutions have gained popularity within the synthetic community over the last two decades due to the progress made in the development of chiral catalysts for asymmetric reactions. Indeed, many catalytic nonenzymatic procedures have been developed providing high enantioselectivity and yield for both products and recovered starting materials [83]. A kinetic resolution of 2,3-epoxy 3-aryl ketones 144a-m was recently reported by Feng et al. through 80 Page 80 of 135
enantioselective scandium-catalyzed ring-opening with pyrazole derivatives 142a-e to give the corresponding chiral β-pyrazole-substituted alcohols 145a-q [84]. As shown in Scheme 43, the reaction was catalyzed by a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand
ip t
with a two-carbonic linkage 146, providing these opened products in moderate yields (3251%) and high enantioselectivities of up to 97% ee along with the recovered epoxides 144a-m
cr
in very high enantioselectivities of up to > 99% ee and yields of up to 65%. In this reaction, the molecular sieves were indispensable part of the catalytic system. Regardless of the 1
2
us
electronic nature or position of the substituents on the aryl rings of Ar and Ar of the racemic
an
epoxides 144a-m reacting with pyrazole derivative 142a (R1 = R3 = Me, R2 = NO2), the kinetic resolution process occurred smoothly with high yields and enantioselectivities. In all cases of
Ac ce p
te
d
M
reactions, single diastereomers were achieved in up to > 90% de.
81 Page 81 of 135
+ N
ON H
O
O-
O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2
O
R1
O Ar2
Ar1
H N N
+ R2
146 (10 mol%) Sc(OTf)3 (5 mol%) 3 Å M.S.
R3
R3
R1 Ar
CH2Cl2, 35 °C
N
N
O
1
Ar OH
142a-e
145a-q
O
+
2
O Ar2
Ar1
144a-m
cr
144a-m
R2
ip t
N+
> 90% de
te
d
M
an
us
Ar 1 = Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 47% yield (145a), 95% ee (145a), 49% yield (144a), 94% ee (144a) Ar 1 = p-ClC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145b), 94% ee (145b), 49% yield (144a), 95% ee (144a) Ar 1 = p-FC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2 : 48% yield (145c), 96% ee (145c ), 51% yield (144a), 91% ee (144a ) Ar 1 = p-Tol, Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145d), 91% ee (145d), 43% yield (144a), > 99% ee (144a) Ar 1 = p-PhOC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = NO2: 50% yield (145e), 91% ee (145e), 46% yield (144a), > 99% ee (144a) Ar 1 = m-PhOC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2: 42% yield (145f), 93% ee (145f), 53% yield (144a), 83% ee (144a) Ar 1 = m-ClC6H4, Ar2 = Ph, R1 = R3 = Me, R2 = NO2 : 32% yield (145g), 97% ee (145g), 63% yield (144a), 54% ee (144a) Ar 1 = Ph, Ar2 = p-ClC6H4, R1 = R3 = Me, R2 = NO2: 50% yield (145h), 95% ee (145h), 49% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-FC6H4, R1 = R3 = Me, R2 = NO2 : 51% yield (145i), 95% ee (145i), 49% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-BrC6H4, R1 = R3 = Me, R2 = NO2 : 51% yield (145j), 96% ee (145j), 51% yield (144a), > 99% ee (144a) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = Me, R2 = NO2 : 50% yield (145k), 97% ee (145k), 49% yield (144a) > 99% ee (144a) Ar 1 = Ph, Ar2 = p-PhOC6H4, R1 = R3 = Me, R2 = NO2: 50% yield (145l), 91% ee (145l), 46% yield (144a ), > 99% ee (144a) Ar 1 = Ph, Ar2 = 2-thienyl, R1 = R3 = Me, R2 = NO2 : 35% yield (145m), 82% ee (145m), 65% yield (144a), 44% ee (144a) Ar 1 = Ar2 = Ph, R1 = R3 = Me, R2 = Br: 49% yield (145n), 90% ee (145n), 50% yield (144b), 91% ee (144b) Ar 1 = p-PhOC6H4, Ar 2 = Ph, R1 = R3 = Me, R2 = H: 40% yield (145o), 88% ee (145o), 49% yield (144c), 90% ee (144c) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = H, R2 = NO2 : 44% yield (145p), 95% ee (145p), 50% yield (144d), 90% ee (144d) Ar 1 = Ph, Ar2 = p-CF3C6H4, R1 = R3 = R2 = H: 40% yield (145q), 57% ee (145q), 50% yield (144e), 84% ee (144e)
Ac ce p
Scheme 43. Ring-opening of 2,3-epoxy 3-aryl ketones with pyrazole derivatives [84].
Earlier, Bhanage et al. employed a chiral scandium catalyst, derived from (R)-BINOL, Sc(OTf)3, and N-methylmorpholine, to promote enantioselective ring-opening of mesoepoxide 141a with a series of aromatic amines such as anilines 147a-i to afford the corresponding chiral β-amino alcohols 148a-i [85]. The latter were obtained in good yields of up to 92% along with moderate to high enantioselectivities of 64-94% ee (Scheme 44). This novel catalytic system had competitive advantages, such as short reaction times (10-22 h), no additives, and no expensive chiral ligands requiring a multistep synthesis under harsh reaction conditions.
82 Page 82 of 135
(R)-BINOL (12 mol%)
NH2
Ph
Sc(OTf)3 (10 mol%)
+
Ph
N-methylmorpholine (24 mol%)
Ph
R Ph
CH2Cl2, 0 °C 141a
OH
R N H
ip t
O
148a-i
147a-i
an
us
cr
148a: R = H: 91% yield, 94% ee 148b: R = 2-Me: 86% yield, 76% ee 148c: R = 4-Me: 90% yield, 82% ee 148d: R = 2-OMe: 81% yield, 67% ee 148e: R = 4-OMe: 89% yield, 88% ee 148f: R = 3-F-4-OMe: 92% yield, 83% ee 148g: R = 4-Br: 87% yield, 68% ee 148h: R = 2,4,6-(Me)3: 78% yield, 64% ee 148i: R = 2,3-(CH=CH)2: 90% yield, 74% ee
M
Scheme 44. Ring-opening of epoxides with anilines [85].
d
In another context, cyclopropyl ketones have been successfully submitted to ring-opening
te
with various nucleophiles in the presence of a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 38, which provided a novel route to optically active
Ac ce p
γ-substituted carbonyl compounds [86]. For example, a range of aromatic as well as aliphatic thiols 83a-n were reacted with cyclopropyl ketones 150a-g in the presence of this catalyst system and LiCl in 1,1,2,2-tetrachloroethane at 60°C. The process afforded the corresponding chiral sulfides 149a-s in generally good to high yields and enantioselectivities of up to 98% and 95% ee, respectively (Scheme 45). This work represented the first example of one catalytic system working for the ring-opening reaction of donor-acceptor cyclopropanes.
83 Page 83 of 135
ON H
O
N O-
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 38 (11 mol%) Ar1
COAr2 150a-g
+
S
Sc(OTf)3 (10 mol%)
RSH
Ar1 *
LiCl (1 equiv) 83a-n
CHCl2CHCl2, 60 °C
R
COAr2
COAr2
149a-s
cr
COAr2
ip t
N+
Ac ce p
te
d
M
an
us
149a: Ar1 = Ar2 = R = Ph: 94% yield, 92% ee 149b: Ar1 = Ar2 = Ph, R = o-Tol: 95% yield, 92% ee 149c: Ar1 = Ar2 = Ph, R = p-Tol: 97% yield, 91% ee 149d: Ar1 = Ar2 = Ph, R = p-MeOC6H4: 95% yield, 89% ee 149e: Ar1 = Ar2 = Ph, R = p-FC6H4: 84% yield, 91% ee 149f: Ar1 = Ar2 = Ph, R = p-BrC6H4: 90% yield, 92% ee 149g: Ar1 = Ar2 = Ph, R = m-ClC6H4: 90% yield, 93% ee 149h: Ar1 = Ar2 = Ph, R = o-ClC6H4: 83% yield, 92% ee 149i: Ar1 = Ar2 = Ph, R = 1-Naph: 98% yield, 90% ee 149j: Ar1 = Ar2 = Ph, R = 2-Naph: 95% yield, 91% ee 149k: Ar1 = Ar2 = Ph, R = 1-thienyl: 74% yield, 90% ee 149l: Ar1 = Ar2 = Ph, R = Cy: 90% yield, 91% ee 149m: Ar1 = Ar2 = Ph, R = t-Bu: 55% yield, 86% ee 149n: Ar1 = p-Tol, Ar2 = Ph, R = p-ClC6H4: 83% yield, 91% ee 149o: Ar1 = m-Tol, Ar2 = Ph, R = p-ClC6H4: 94% yield, 93% ee 149p: Ar1 = p-FC6H4, Ar2 = Ph, R = p-ClC6H4: 88% yield, 93% ee 149q: Ar1 = m-ClC6H4, Ar2 = Ph, R = p-ClC6H4: 62% yield, 95% ee 149r: Ar1 = 2-Naph, Ar2 = Ph, R = p-ClC6H4: 92% yield, 88% ee 149s: Ar1 = Ph, Ar2 = p-FC6H4, R = p-ClC6H4: 85% yield, 95% ee
Scheme 45. Ring-opening of cyclopropyl ketones with thiols [86].
The scope of the preceding reaction was extended to other nucleophiles, such as alcohols 152a-h and carboxylic acids 152i-m (Scheme 46) [86]. By reaction with cyclopropyl ketone 151a, they led to the corresponding chiral alcohols 153a-h and esters 153i-m, respectively, in moderate to high yields (62-94%) along with enantioselectivities of 50-92% ee for the first ones, and high yields (90-99%) combined with moderate to good enantioselectivities of 6983% ee for the second ones.
84 Page 84 of 135
ON H
O
N O-
+ O
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 38 (11 mol%)
Ph
+
RXH
COPh 152a-m
CHCl2CHCl2, 60 °C
COPh
COPh
153a-m
us
151a
Ph *
LiCl (1 equiv)
R
cr
COPh
X
Sc(OTf)3 (10 mol%)
ip t
N+
te
d
M
an
153a: X = O, R = Me: 69% yield, 91% ee 153b: X = O, R = Et: 78% yield, 92% ee 153c: X = O, R = n-Oct: 78% yield, 91% ee 153d: X = O, R = Bn: 60% yield, 90% ee 153e: X = O, R = c-Bu: 72% yield, 92% ee 153f: X = O, R = c-Pent: 94% yield, 92% ee 153g: X = O, R = Cy: 78% yield, 91% ee 153h: X = O, R = Ph: 62% yield, 50% ee 153i: X = COO, R = Me: 90% yield, 76% ee 153j: X = COO, R = n-Hept: 98% yield, 82% ee 153k: X = COO, R = Bn: 99% yield, 83% ee 153l: X = COO, R = Ph: 96% yield, 69% ee 153m: X = COO, R = Cy: 99% yield, 72% ee
Ac ce p
Scheme 46. Ring-opening of cyclopropyl ketones with alcohols and carboxylic acids [86].
6. Enantioselective scandium-catalyzed α-functionalizations of 3-substituted oxindoles
Oxindoles constitute an important structural motif in the library of natural products and biologically active drugs. The enantioselective construction of 3-functionalized oxindoles is among the most attractive and valuable synthetic targets due to the unique properties of such a structural motif [87]. In addition to enantioselective Michael additions of carbon nucleophiles to 3-substituted oxindoles described in Schemes 33-35 [64-66], other scandium-catalyzed asymmetric reactions have been recently reported to construct C-N, C-S, and C-C bonds at the
85 Page 85 of 135
C3 position of oxindoles. As an exemple, Feng et al. have developed enantioselective hydroxyamination reaction of 3-substituted oxindoles 112a-j with nitrosoarenes 154a-e performed in the presence of a chiral scandium catalyst in situ generated from Sc(OTf)3 and
ip t
chiral N,N’-dioxide ligand 97 [88]. While other rare earth metal sources, such as La(OTf)3, Lu(OTf)3, and Sm(OTf)3, only resulted in trace amounts of products, the use of Sc(OTf)3
cr
allowed a range of N-nitroso aldol products 155a-n to be achieved in generally very good yields and enantioselectivities of up to 98% and 98% ee, respectively (Scheme 47).
us
Remarkably, the reactions were complete in only 20 to 60 minutes. In all cases of substrates,
an
the yields were > 89% except for 2-methyl-nitrosobenzene for which the corresponding
M
product 155l was obtained in only 66% yield.
N+
O
ON H
+ N O-
O
2
R1
R
te
d
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (5 mol%) Sc(OTf)3 (3.3 mol%)
ArNO
Ac ce p
O
+
N H
112a-j
154a-e
R2
Ar R1 N OH O
MeCCl3, 30 °C
N H 155a-n
155a: Ar = Ph, R1 = Me, R2 = H: 92%, 95% ee 155b: Ar = Ph, R1 = Et, R2 = H: 91%, 92% ee 155c: Ar = Ph, R1 = n-Pr, R2 = H: 92%, 90% ee 155d: Ar = Ph, R1 = allyl, R2 = H: 98%, 94% ee 155e: Ar = Ph, R1 = Bn, R2 = H: 97%, 95% ee 155f: Ar = Ph, R1 = p-MeOC6H4, R2 = H: 94%, 97% ee 155g: Ar = Ph, R1 = p-PhOC6H4, R2 = H: 95%, 95% ee 155h: Ar = Ph, R1 = p-BrC6H4, R2 = H: 93%, 97% ee 155i: Ar = Ph, R1 = 2-naphthylmethyl, R2 = H: 95%, 98% ee 155j: Ar = Ph, R1 = 2-thienylmethyl, R2 = H: 89%, 92% ee 155k: Ar = m-ClC6H4, R1 = Me, R2 = H: 92%, 94% ee 155l: Ar = o-Tol, R1 = Me, R2 = H: 66%, 92% ee 155m: Ar = m-Tol, R1 = Me, R2 = H: 90%, 88% ee 155n: Ar = p-MeOC6H4, R1 = Me, R2 = H: 95%, 92% ee
86 Page 86 of 135
Scheme 47. Hydroxyamination of 3-substituted oxindoles [88].
The same authors also demonstrated that 3-substituted oxindoles 112a-u reacted with
ip t
readily available N-(phenylthio)phthalimide 156 as sulfur source to give a wide range of chiral 3-phenylthio-substituted oxindoles 157a-u under mild reaction conditions, as illustrated
cr
in Scheme 48 [89]. These products were generally produced in both high to excellent yields
us
and enantioselectivities of 85-98% and 87-> 99% ee, respectively, when the process was performed in the presence of Sc(OTf)3 as scandium source, chiral N,N’-dioxide ligand 97, and
an
a Brønsted base such as Na2CO3. The reaction did not occur in the absence of this base. They assumed that the reaction was initiated by the formation of an enolate anion formed via base-
M
promoted deprotonation of the 3-substituted oxindole. This enolate subsequently reacted with the sulfenylation reagent 156 to afford the final product. It is worth noting that this work
Ac ce p
te
d
constituted the first enantioselective synthesis of 3-thiooxindoles.
87 Page 87 of 135
N+ O
97 (3 or 5 mol%) Sc(OTf)3 (3 or 5 mol%)
2
R
O
N H
cr
Na2CO3, 4 Å M.S. CH2Cl2, 35 °C
O
R1 SPh
ip t
O N H 112a-u +
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3
R1
R2
ON H
+ N O-
157a-u
N SPh
us
O 156
Ac ce p
te
d
M
an
with 3 mol% of catalyst: 157a: R1 = p-MeOC6H4, R2 = H: 98%, 97% ee 157b: R1 = p-NO2C6H4, R2 = H: 95%, 92% ee 157c: R1 = 1-naphthylmethyl, R2 = H: 98%, 97% ee 157d: R1 = 2-naphthylmethyl, R2 = H: 95%, 97% ee 157e: R1 = 2-thienylmethyl, R2 = H: 85%, 94% ee 157f: R1 = Me, R2 = H: 83%, 87% ee 157g: R1 = n-Bu, R2 = H: 89%, 98% ee 157h: R1 = i-Bu, R2 = H: 91%, 98% ee 157i: R1 = allyl, R2 = H: 85%, 95% ee 157j: R1 = MeCO2CH2, R2 = H: 98%, 96% ee with 5 mol% of catalyst: 157k: R1 = Ph, R2 = H: 95%, 99% ee 157l: R1 = o-Tol, R2 = H: 92%, > 99% ee 157m: R1 = m-Tol, R2 = H: 93%, 99% ee 157n: R1 = p-Tol, R2 = H: 94%, 99% ee 157o: R1 = p-FC6H4, R2 = H: 97%, 98% ee 157p: R1 = p-ClC6H4, R2 = H: 91%, 97% ee 157q: R1 = 1-Naph, R2 = H: 91%, 99% ee 157r: R1 = Ph, R2 = 5-Me: 90%, 99% ee 157s: R1 = Ph, R2 = 5-OMe: 97%, 98% ee 157t: R1 = Ph, R2 = 5-F: 93%, 97% ee 157u: R1 = Ph, R2 = 7-F: 88%, 93% ee
Scheme 48. Sulfenylation of 3-substituted oxindoles [89].
In addition, excellent results were reported by these authors for enantioselective scandiumcatalyzed fluorination of 3-substituted oxindoles 112a-r with N-fluorobisbenzenesulfonimide (NFSI) as fluorination agent [90]. As shown in Scheme 49, the use of a catalyst system 88 Page 88 of 135
composed by Sc(OTf)3, chiral N,N’-dioxide ligand 97, and Na2CO3 allowed a series of chiral 3-aryl- and 3-alkyl-3-fluoro-2-oxindoles 158a-r to be achieved in good yields of up to 98% and general excellent enantioselectivities of up to 99% ee. The highest enantioselectivities
ON H
O
O
H N Ar Ar Ar = 2,6-(i-Pr)2C6H3 97 (5 mol%)
R1
R
O + NFSI
an
2
us
+ N O-
N+
cr
substituted ones 112o-r provided enantioselectivities of 90-95% ee.
Sc(OTf)3 (5 mol%) Na2CO3
M
N H 112a-r
CHCl3, 0 °C
ip t
were generally reached for (hetero)aryl-substituted substrates 112b-l (94-99% ee) while alkyl-
2
R
R1 F O N H 158a-r
Ac ce p
te
d
158a: R1 = Bn, R2 = H: 95%, 99% ee 158b: R1 = p-MeOC6H4, R2 = H: 96%, 97% ee 158c: R1 = o-Tol, R2 = H: 87%, 99% ee 158d: R1 = m-Tol, R2 = H: 96%, 96% ee 158e: R1 = p-Tol, R2 = H: 96%, 96% ee 158f: R1 = o-ClC6H4, R2 = H: 82%, 98% ee 158g: R1 = m-ClC6H4, R2 = H: 84%, 97% ee 158h: R1 = p-ClC6H4, R2 = H: 98%, 98% ee 158i: R1 = p-NO2C6H4, R2 = H: 94%, 97% ee 158j: R1 = 1-naphthylmethyl, R2 = H: 90%, 99% ee 158k: R1 = 2-naphthylmethyl, R2 = H: 88%, 97% ee 158l: R1 = 2-thienylmethyl, R2 = H: 85%, 94% ee 158m: R1 = Ph, R2 = H: 85%, 89% ee 158n: R1 = Ph, R2 = Cl: 98%, 93% ee 158o: R1 = Me, R2 = H: 80%, 90% ee 158p: R1 = n-Bu, R2 = H: 82%, 93% ee 158q: R1 = i-Bu, R2 = H: 85%, 93% ee 158r: R1 = allyl, R2 = H: 81%, 95% ee
Scheme 49. Fluorination of 3-substituted oxindoles [90].
89 Page 89 of 135
The catalytic asymmetric α-arylation of carbonyl compounds is also of high interest, because it provides an efficient access to chiral α-aryl compounds regarded as essential motifs in many biologically active natural products and pharmaceutically active compounds [91]. In
ip t
this context, Feng et al. have reported a novel asymmetric catalytic strategy for α-arylation of a wide variety of 3-substituted oxindoles 112a-r with diaryliodonium triflates 159a-h [92].
cr
This nice reaction was promoted by a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand
us
160 bearing tetrahydroisoquinoline backbones in the presence of NaHCO3 and provided a range of chiral oxindole derivatives 161a-y with quaternary carbon centers in generally high
an
yields and enantioselectivities of up to 99% and 99% ee, respectively (Scheme 50). The lowest yields (60-71%) and enantioselectivities (72-84% ee) were observed in the reactions of
M
3-tert-butyl-2-oxindole 112p and 3-allyl-butyl-2-oxindole 112o. Using other metal sources popular in α-arylation, such as CuBr, Cu(OTf)2, or Pd(OAc)2, resulted in poor yields or
d
complicated racemic mixtures. The utility of this nice methodology was demonstrated in the
Ac ce p
te
asymmetric synthesis of an antiproliferative oxindole agent.
90 Page 90 of 135
O
O N H
160 (10 mol%) Sc(OTf)3 (10 mol%)
112a-r R
O
N H
3 Å M.S. CH2Cl2, 35 °C
I+ -
161a-y
us
OTf
R1
R2
NaHCO3
3
Ar
R3
cr
+
O
H N 4 R4 R 4 R = (S)-2-phenylethyl
R1
R2
ON H
+ N O-
ip t
N+
159a-h
Ac ce p
te
d
M
an
161a: R1 = Bn, R2 = R3 = H, Ar = Ph: 89%, 95% ee 161b: R1 = o-Tol, R2 = R3 = H, Ar = Ph: 99%, 91% ee 161c: R1 = m-Tol, R2 = R3 = H, Ar = Ph: 80%, 95% ee 161d: R1 = p-Tol, R2 = R3 = H, Ar = Ph: 98%, 94% ee 161e: R1 = o-ClC6H4, R2 = R3 = H, Ar = Ph: 93%, 92% ee 161f: R1 = m-ClC6H4, R2 = R3 = H, Ar = Ph: 99%, 99% ee 161g: R1 = p-ClC6H4, R2 = R3 = H, Ar = Ph: 84%, 96% ee 161h: R1 = m-BrC6H4, R2 = R3 = H, Ar = Ph: 99%, 99% ee 161i: R1 = m-NO2C6H4, R2 = R3 = H, Ar = Ph: 99%, 98% ee 161j: R1 = p-CNC6H4, R2 = R3 = H, Ar = Ph: 97%, 97% ee 161k: R1 = p-MeOC6H4, R2 = R3 = H, Ar = Ph: 95%, 95% ee 161l: R1 = 2-naphthylmethyl, R2 = R3 = H, Ar = Ph: 81%, 96% ee 161m: R1 = 2-thienylmethyl, R2 = R3 = H, Ar = Ph: 82%, 91% ee 161n: R1 = 2-thienylmethyl, R2 = R3 = H, Ar = Ph: 85%, 94% ee (R) 161o: R1 = allyl, R2 = R3 = H, Ar = Ph: 60%, 72% ee 161p: R1 =t-Bu, R2 = R3 = H, Ar = Ph: 71%, 84% ee 161q: R1 = m-ClC6H4, R2 = 6-Cl, R3 = H, Ar = Ph: 90%, 98% ee 161r: R1 = Bn, R2 = 6-Cl, R3 = H, Ar = Ph: 89%, 90% ee 161s: R1 = Bn, R2 = H, R3 = 4-F, Ar = p-FC6H4: 65%, 94% ee 161t: R1 = Bn, R2 = H, R3 = 4-Cl, Ar = p-ClC6H4: 79%, 96% ee 161u: R1 = Bn, R2 = H, R3 = 4-Br, Ar = p-BrC6H4: 82%, 98% ee 161v: R1 = Bn, R2 = H, R3 = 4-Me, Ar = p-Tol: 76%, 96% ee 161w: R1 = Bn, R2 = R3 = H, Ar = Mes: 80%, 92% ee 161x: R1 = Bn, R2 = H, R3 = 4-Cl, Ar = Mes: 79%, 94% ee 161y: R1 = Bn, R2 = H, R3 = 4-Ph, Ar = Mes: 55%, 90% ee
Scheme 50. α-Arylation of 3-substituted oxindoles [92].
7. Enantioselective scandium-catalyzed aldol reactions
91 Page 91 of 135
The direct catalytic asymmetric aldol reaction is a powerful and atom-economical method for synthesizing chiral β-hydroxy carbonyl compounds. Many metals and organocatalysts for
ip t
reactions of aldehyde electrophiles have been developed in the past decade [93]. Among catalysts early employed either in organic solvent or in water to promote enantioselective
cr
aldol reactions are chiral scandium complexes derived from pybox [94], N,N’-dioxide ligands [95], and bipyridine-alcohol ligands [96]. More recently, Wang et al. reported a convenient
us
enantioselective decarboxylative aldol reaction to access chiral highly functionalized α-
an
hydroxyesters 162a-j from β-ketoacids 163a-d and inactivated aromatic and aliphatic αketoesters 164a-g (Scheme 51) [97]. Good to high yields of up to 95% were achieved along
M
with moderate to good enantioselectivities of 49-84% ee by catalyzing the process with a
d
chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral pybox ligand 134.
O
te
O
N
O
Ph
R1
Ac ce p
OH
163a-d
+
O
R2
O
OEt 164a-g
O
N
N
134 (12 mol%)
Ph OHO
Sc(OTf)3 (10 mol%)
R2 OEt
R1 CHCl3, 0 °C
O 162a-j
162a: R1 = R2 = Ph: 95% yield, 84% ee 162b: R1 = Ph, R2 = p-BrC6H4: 91% yield, 81% ee 162c: R1 = Ph, R2 = p-FC6H4: 90% yield, 78% ee 162d: R1 = Ph, R2 = p-OCF3C6H4: 92% yield, 76% ee 162e: R1 = Ph, R2 = CH2Bn: 93% yield, 77% ee 162f: R1 = Ph, R2 = Me: 88% yield, 60% ee 162g: R1 = Ph, R2 = i-Pr: 91% yield, 56% ee 162h: R1 = p-FC6H4, R2 = Ph: 88% yield, 75% ee 162i: R1 = 2-Naph, R2 = Ph: 93% yield, 59% ee 162j: R1 = Et, R2 = Ph: 81% yield, 49% ee
Scheme 51. Decarboxylative aldol reaction of β-keto acids with α-ketoesters [97]. 92 Page 92 of 135
In addition, a series of novel chiral N,N’-dioxide ligands were recently investigated by Kobayashi and Kitanosono in enantioselective scandium-catalyzed direct aldol reactions using
ip t
aqueous formaldehyde [98]. They selected dioxide 165 as optimal ligand which allowed, in combination with Sc(OTf)3, the reaction of formaldehyde with ketone derivatives, including
cr
simple ketone 166a, thioester 166b, and 2-methyl-1-indanone 166c, to be achieved in water. This remarkably simple process performed at room temperature afforded the corresponding hydroxymethylated
products
167a-c
in
moderate
yields
us
chiral
(23-53%)
and
an
enantioselectivities of 53-75% ee (Scheme 52). In spite of these modest results, it is important to note that this study offered the simplest metalloenzyme-like catalyst system that worked
M
efficiently in water.
d
N+
ON H ( )12
te
O
Ac ce p
N
( )12
165 (5 mol%)
N O
HCHO aq.
166a-b
167a-b R = Ph: 30% yield, 62% ee R = SEt: 23% yield, 53% ee
O
+
OH
R
H2O, 20 or 40 °C pyridine (20 mol%)
R
166c
O
H N
Sc(OTf)3 (8 mol%)
O
+
+ N O-
same conditions
O
OH
HCHO aq.
167c 53% yield, 75% ee
Scheme 52. Aldol reactions of ketones with aqueous formaldehyde [98].
93 Page 93 of 135
8. Enantioselective scandium-catalyzed oxidations
ip t
8.1. Epoxidations
cr
Chiral epoxides constitute key building blocks for the synthesis of natural products and
us
biologically active compounds [99]. Among the different methodologies available for their synthesis, the enantioselective titanium-catalyzed oxidation of allylic alcohols reported by
an
Katsuki and Sharpless in 1980s is still the most efficient one [100]. However, this methodology presents some limitations, such as its rather high catalyst loadings and required
M
anhydrous reaction conditions. With the aim of finding alternative methodologies, enantioselective scandium-catalyzed epoxidations have been developed. As an example, a
d
simple asymmetric epoxidation of α,β-unsaturated carbonyl compounds based on the use of
te
aqueous hydrogen peroxide as green oxidant and a chiral scandium catalyst was reported by Feng et al., in 2012 [101]. Remarkably, this process did not require the presence of additives
Ac ce p
to provide a number of chiral epoxides 168a-u in general excellent yields and enantioselectivities of up to 99% and 99% ee, respectively, from the corresponding α,βunsaturated carbonyl compounds 61a-u by using chiral N,N’-dioxide ligand 97 in combination with Sc(OTf)3 as catalyst system (Scheme 53). In this study, other metal sources, such as Y(OTf)3 and La(OTf)3, were also investigated albeit all giving much lower yields and enantioselectivities. In addition to the mild and environmentally begnin conditions, including a low concentration of hydrogen peroxide used, along with water and air tolerance of the catalyst system, the latter could be recovered and reused efficiently.
94 Page 94 of 135
ON H
O
O R
Ar
+ H2O2
+ N O-
O
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (5 mol%) Sc(OTf)3 (5 mol%)
O R
Ar
THF, 35 °C (30% aq.)
168a-u
cr
61a-u
O
ip t
N+
Ac ce p
te
d
M
an
us
168a: R = Ar = Ph: 99%, 98% ee 168b: R = Ph, Ar = m-MeOC6H4: 83%, 95% ee 168c: R = Ph, Ar = p-Tol: 82%, 99% ee 168d: R = Ph, Ar = p-MeOC6H4: 95%, 98% ee 168e: R = Ph, Ar = p-FC6H4: 99%, 97% ee 168f: R = Ph, Ar = p -ClC6H4: 90%, 96% ee 168g: R = Ph, Ar = p-NO2C6H4: 87%, 99% ee 168h: R = Ph, Ar = 2-furyl: 80%, 92% ee 168i: R = Ph, Ar = 2-Naph: 70%, 95% ee 168j: R = p-Tol, Ar = Ph: 84%, 99% ee 168k: R = p -BrC6H4, Ar = Ph: 99%, 98% ee 168l: R = 1-Naph, Ar = Ph: 99%, 98% ee 168m: R = 2-Naph, Ar = Ph: 99%, 98% ee 168n: R = t -Bu, Ar = Ph: 99%, 96% ee 168o: R = CO2Et, Ar = Ph: 82%, 96% ee 168p: R = CO2Et, Ar = p-Tol: 91%, 86% ee 168q: R = CO2Et, Ar = p-MeOC6H4: 88%, 96% ee 168r: R = CF3, Ar = p-FC6H4: 99%, 99% ee 168s: R = CF 3, Ar = p -MeOC6H4: 99%, 97% ee 168t: R = CCl3, Ar = p-MeOC6H4: 99%, 99% ee 168u: R = CCl3, Ar = 2-furyl: 99%, 95% ee
Scheme 53. Epoxidation of α,β-unsaturated ketones with aqueous hydrogen peroxide [101].
Although great progress has been made in H2O2-efficient epoxidations [102], the epoxidations of trisubstituted olefins using hydrogen peroxide as oxidant are still challenging [103]. In this context, Feng et al. have applied closely related conditions to those of Scheme 53 to the asymmetric epoxidation of 2-arylidene-1,3-diketones 169a-n which led to the corresponding chiral trisubstituted epoxides 170a-n in moderate to good yields (50-85%) albeit excellent enantioselectivities of up to 99% ee (Scheme 54) [104]. The catalyst system
95 Page 95 of 135
used at 10 mol% of catalyst loading was the same as in Scheme 53 (5 mol% in Scheme 53) but the reaction was performed in methanol instead of THF as solvent. The best result (85% yield, 99% ee) was reached with trisubstituted olefin 169b bearing two chlorine substituents
O
+ H2O2
Bz 169a-n
O
us
H N Ar' Ar' Ar' = 2,6-(i-Pr)2C6H3 97 (10 mol%) Sc(OTf)3 (10 mol%)
an
Ar
Bz
ON H
+ N O-
MeOH, 30 °C
O
Ar
Bz Bz 170a-n
M
(30% aq.)
cr
N+
ip t
on the aromatic ring while 2-alkylidene-2,3-diketones did not undergo the reaction.
Ac ce p
te
d
170a: Ar = Ph: 74%, 98% ee 170b: Ar = 3,4-Cl2C6H3: 85%, 99% ee 170c: Ar = p-NCC6H4: 71%, 93% ee 170d: Ar = p-NO2C6H4: 58%, 98% ee 170e: Ar = m-CF3C6H4: 53%, 99% ee 170f: Ar = p-CF3C6H4: 55%, 99% ee 170g: Ar = p-FC6H4: 50%, 98% ee 170h: Ar = p-ClC6H4: 60%, 99% ee 170i: Ar = m-BrC6H4: 54%, 98% ee 170j: Ar = p-BrC6H4: 59%, 97% ee 170k: Ar = m-PhOC6H4: 63%, 99% ee 170l: Ar = m-MeOC6H4: 62%, 99% ee 170m: Ar = m-Tol: 63%, 98% ee 170n: Ar = p-Tol: 69%, 97% ee
Scheme 54. Epoxidation of 2-arylidene-1,3-diketones with aqueous hydrogen peroxide [104].
8.2. Baeyer−Villiger reactions
The Baeyer−Villiger reaction is highly valuable for the synthesis of esters or lactones [105]. Especially, the asymmetric Baeyer−Villiger oxidation of racemic cyclic ketones provides a
96 Page 96 of 135
simple and attractive route for the synthesis of optically active lactones [106]. Impressive results have been achieved by using biocatalysts, organocatalysts, and chiral metal complexes. As it is often the case, ring-strained cyclobutanones are more reactive in Baeyer−Villiger
ip t
oxidations than other cyclic ketones, and they have been well-studied. On the other hand, the desymmetrization of 4-alkylcyclohexanones has been less explored in recent years and
cr
remains challenging. In this context, Feng et al. have developed a highly efficient Baeyer−Villiger reaction of meso-cyclohexanones 171a-m with m-chloroperbenzoic acid
us
(MCPBA) performed in the presence of a catalytic amount (5 mol%) of Sc(OTf)3 and chiral
an
N,N’-dioxide ligand 69 [107]. The process afforded the corresponding ε-lactones 171a-m in good yields (71-90%) and high enantioselectivities of up to 95% ee, as illustrated in Scheme
M
55. The enantiocontrol of the reaction was sensitive to neither the electronic properties nor the steric hindrance of substituents on the phenyl ring of 4-aryl-substituted cyclohexanones 172b-
d
h. Moreover, fused-ring-substituted cyclohexanones 172i-j as well as 4-alkyl-substituted
te
cyclohexanones 172k-m provided comparable excellent results (84-95% ee). The synthetic importance of this novel desymmetrization was demonstrated by the transformation of
Ac ce p
product 171k into an important intermediate in the synthesis of an effective inhibitor of acetylcholinesterase. Later, Su and Hu reported theoretical studies (DFT and ONIOM) on the asymmetric Baeyer−Villiger oxidation of 4-phenylcyclohexanone 172a under these conditions which revealed that the first step of the process, corresponding to the addition of MCPBA to the carbonyl group of the ketone, was the rate-determining step [108]. Furthermore, the repulsion between the m-chlorophenyl group of MCPBA and the 2,4,6iPr3C6H2 group of the dioxide ligand, as well as the cyclohexanone and the amino acid skeleton of the ligand, played important roles in the control of the enantioselectivity of the reaction. The combination of scandium/N,N’-dioxide ligand 69 with MCPBA could form a
97 Page 97 of 135
reactive species that could effectively catalyze the reaction with a reasonable activation
O
O +
MCPBA
+
H N Ar Ar Ar = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%)
O
O
us
R
ON H
N O-
cr
N+
ip t
barrier of 86.7 kJ mol-1.
EtOAc, -20 °C
O
*
R
an
171a-m 171a : R = Ph: 86% yield, 95% ee 171b: R = p-Tol: 90% yield, 95% ee 171c : R = m-Tol: 84% yield, 94% ee 171d: R = p-FC6H4: 71% yield, 92% ee 171e: R = m-FC6H4: 84% yield, 94% ee 171f: R = p-ClC6H4: 82% yield, 94% ee 171g: R = m-ClC6H4: 81% yield, 94% ee 171h: R = p-PhC6H4: 80% yield, 94% ee 171i: R = 1-Naph: 84% yield, 95% ee 171j: R = 2-Naph: 87% yield, 94% ee 171k : R = Me: 76% yield, 84% ee (R) 171l: R = i-Pr: 75% yield, 92% ee (R) 171m: R = t-Bu: 81% yield, 94% ee (R)
Ac ce p
te
d
M
172a-m
Scheme 55. Baeyer−Villiger reaction of meso-cyclohexanones through desymmetrization [107].
Related reaction conditions were applied to the Baeyer−Villiger reaction of mesocyclobutanones 173a-f which afforded the corresponding chiral γ-lactones 174a-f in good yields (71-84%) and high enantioselectivities of 87-91% ee ( Scheme 56) [107]. The electronic nature of the substituents in cyclobutanones had nearly no effect on the efficiency and enantioselectivity of the reaction.
98 Page 98 of 135
O
O +
Ar
MCPBA
ON H
N O-
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%) EtOAc, -60 °C
O
Ar
*
ip t
N+
O
174a-f
cr
173a-f
an
us
174a: Ar = Ph: 82% yield, 91% ee (S) 174b: Ar = p-Tol: 84% yield, 90% ee (S) 174c: Ar = m-Tol: 80% yield, 91% ee 174d: Ar = p-MeOC6H4: 78% yield, 91% ee (S) 174e: Ar = p-FC6H4: 71% yield, 87% ee (S) 174f: Ar = p-ClC6H4: 83% yield, 87% ee (S)
Scheme 56. Baeyer−Villiger reaction of meso-cyclobutanones through desymmetrization
M
[107].
d
Another challenge to the catalytic enantioselective Baeyer−Villiger oxidation is its
te
application to the kinetic resolution of racemic cyclic ketones. It was thus significant that the
Ac ce p
Baeyer−Villiger reaction of racemic 2-arylcyclohexanones 175a-g catalyzed by the same catalyst system employed under related conditions was exemplified [107]. Surprisingly, the process afforded only trace amount of expected normal Baeyer−Villiger products 177a-g along with abnormal chiral Baeyer−Villiger products 176a-g as major products generated from the migration of the less-substituted group, and recovered chiral 2-arylcyclohexanones 175a-g (Scheme 57). The enantioselectivities of abnormal Baeyer−Villiger products 176a-g were high to excellent (82-98% ee) as well as those of recovered 2-arylcyclohexanones (8997% ee) while those of normal Baeyer−Villiger products 177a-g were of 72-99% ee. Major products 176a-g and 175a-g were respectively obtained in 44-50% and 45-51% yields by using Al(Oi-Pr)3 as an additive. The best result was achieved in the reaction of 1-
99 Page 99 of 135
naphthylcyclohexanone 175f which afforded unreacted ketone 175f in 99% ee and abnormal
O Ar +
MCPBA
ON H
+ O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 69 (5 mol%) Sc(OTf)3 (5 mol%) Al(Oi-Pr)3 EtOAc, -20 or -40 °C
175a-g
Ar
Ar
*
O
O
+
175a-g
*
O
+
O * Ar
an
abnormal BayerBayer-Villiger Villiger product 176a-g product 177a-g
M
= Ph: 46% yield (175a), 48% yield (176a), 3% yield (177a), 94% ee (S) (175a), 94% ee (R) (176a) = p-ClC6H4: 47% yield (175b), 50% yield (176b), 3% yield (177b), 97% ee (S) (175b), 93% ee (R) (176b) = p-BrC6H4: 47% yield (175c), 50% yield (176c), 3% yield (177c), 97% ee (S) (175c), 92% ee (R) (176c) = p-Tol: 51% yield (175d), 44% yield (176d), 4% yield (177d), 89% ee (S) (175d), 91% ee (R) (176d) = p-PhC6H4: 44% yield (175e), 50% yield (176e), 6% yield (177e), 90% ee (S) (175e), 90% ee (R) (176e) = 1-Naph: 49% yield (175f), 46% yield (176f), 5% yield (177f), 99% ee (175f), 98% ee (176f) = 2-Naph: 45% yield (175g), 49% yield (176g), 5% yield (177g), 90% ee (175g), 82% ee (176g)
d
Ar Ar Ar Ar Ar Ar Ar
O
cr
O
N O-
us
N+
ip t
Baeyer−Villiger product 176f in 98% ee with 50% conversion.
Ac ce p
kinetic resolution [107].
te
Scheme 57. Abnormal Baeyer−Villiger reaction of 2-aryl-substituted cyclohexanones through
In 2014, a closely related N,N’-dioxide ligand 113 was applied to the scandium-catalyzed Baeyer−Villiger oxidation of 2-substituted cyclopentanones 178a-g which also occurred through kinetic resolution [109]. As illustrated in Scheme 58, a series of 2-arylcyclopentanones 178a-f were submitted to a combination of this ligand with Sc(OTf)3 in the presence of Al(OEt)3 as additive which afforded in this case the corresponding normal Baeyer−Villiger products 179a-f in high enantioselectivities of 85-98% ee and high conversions (48-54%). These 6-aryl-substituted δ-lactones 179a-f were obtained in all cases with > 95:5 regioselectivity. Indeed, the abnormal Baeyer−Villiger products 180a-f were
100 Page 100 of 135
always produced in less than 5% yield except for the reaction of benzyl-substituted cyclopentanone 178g which provided a 56:44 mixture of the two Baeyer−Villiger products 179g and 180g along with recovered enantioenriched cyclopentanone 178g in low
ip t
enantioselectivity of 14% ee. Comparing these results with those of the preceding study (Scheme 57) dealing with preferential abnormal Baeyer−Villiger oxidations of 2-substituted
cr
cyclohexanones, the authors proposed that the different ring strain and conformations of the 2-substituted cyclic ketones, and the steric hindrance created by the chiral catalyst as well,
us
would account for the migratory aptitude in the circumstances. This work represented the most efficient example of the kinetic resolution of 2-substituted cyclopentanones via
+ N
N+ O
M
an
nonenzymatic asymmetric Baeyer−Villiger oxidation to date.
O-
O-
O
H N Ar
d
N H
+
MCPBA
Al(OEt)3 4 Å M.S. EtOAc, -20 °C
Ac ce p
R
te
O
Ar Ar = 2,6-Et2-4-MeC6H2 113 (5 mol%) Sc(OTf)3 (5 mol%)
178a-g
O
O * 178a-g
R
+
O O *
+
O
R *
R
Baeyer-Villiger abnormal Baeyer product 179a-g -Villiger product 180a-g
R = Ph: 42% yield (178a), 48% yield (179a), 5% yield (180a), 90% ee (178a), 98% ee (179a) R = p-Tol: 45% yield (178b), 48% yield (179b), 5% yield (180b), 90% ee (178b), 94% ee (179b) R = m-Tol: 46% yield (178c), 48% yield (179c), 4% yield (180c), 85% ee (178c), 98% ee (179c) R = p-MeOC6H4: 40% yield (178d), 54% yield (179d), 4% yield (180d), 98% ee (R) (178d), 94% ee (179d) R = p-PhC6H4: 44% yield (178e), 50% yield (179e), 4% yield (180e ), 95% ee (178e), 98% ee (179e) R = 2-Naph: 44% yield (178f), 51% yield (179f), 5% yield (180f), 92% ee (178f), 94% ee (179f) R = Bn: 57% yield (178g), 23% yield (179g), 18% yield (180g), 14% ee (178g), 87% ee (179g)
Scheme 58. Baeyer−Villiger reaction of 2-substituted cyclopentanones [109].
9. Enantioselective scandium-catalyzed reductions
101 Page 101 of 135
The enantioselective reduction of prochiral ketones provides the most efficient access to optically active secondary alcohols. It has been achieved by using a wide range of reducing
ip t
agents including alkali metal borohydrides which are mild, inexpensive, highly selective, and environmentally friendly [110]. The latter have been used in combination of various chiral
cr
metal catalysts to achieve enantioselectivity in these reduction reactions. Nonetheless, the use
us
of simple chiral Lewis acid complexes for asymmetric metal borohydride reduction has been investigated only recently by Feng et al. by using scandium chiral catalysts [111]. As
an
illustrated in Scheme 59, the authors developed the reduction of α,β-unsaturated ketones 181a-k with aqueous potassium borohydride in the presence of a chiral scandium complex in
M
situ generated from Sc(OTf)3 and N,N’-dioxide ligand 182. The process allowed a wide range of chiral allylic alcohols 183a-k to be achieved in remarkable yield of 99% combined with
d
good to high enantioselectivities of up to 95% ee. The catalytic system was expanded to the
te
reduction of saturated ketones but the reactions required prolonged reaction times (8 h instead
Ac ce p
of 1.5 h for enones) and the corresponding chiral secondary alcohols were isolated in moderate enantioselectivities (≤ 86% ee). The role of water was essential to dramatically increase the rate of the reaction, allowing a complete conversion. This work represented the first catalytic enantioselective reduction of prochiral enones and ketones by employing potassium borohydride as the reducing agent.
102 Page 102 of 135
+ N
ON H
O +
O-
O H N Ar' Ar' Ar' = 2,6-i-Pr2-4-t-BuC6H2 182 (10 mol%) Sc(OTf) 3 (10 mol%) KBH4 aq. O
Ar
ip t
N+
OH
Ar
THF, 0 °C
cr
(0.45 equiv) 181a-k
183a-k
M
an
us
183a: Ar = Ph: 99% yield, 90% ee 183b: Ar = m-Tol: 99% yield, 90% ee 183c: Ar = o-MeOC6H4: 99% yield, 95% ee 183d: Ar = m-MeOC6H4: 99% yield, 90% ee 183e: Ar = p-MeOC6H4: 99% yield, 90% ee 183f: Ar = p-PhC6H4: 99% yield, 88% ee 183g: Ar = p-BnC6H4: 99% yield, 94% ee 183h: Ar = p-FC6H4: 99% yield, 88% ee 183i: Ar = m-CF3C6H4: 99% yield, 81% ee 183j: Ar = 2-Naph: 99% yield, 90% ee 183k: Ar = 2-furyl: 99% yield, 90% ee
te
d
Scheme 59. Reduction of α,β-unsaturated ketones with aqueous KBH4 [111].
Ac ce p
Chiral β-amino alcohols are essential structural motifs commonly found in a large number of natural products and pharmaceutical compounds, such as β-adrenergic blocking drugs and agonists for the treatment of cardiovascular disease, antidepressant, asthma, and chronic obstructive pulmonary disease [112]. They can be directly generated through asymmetric reductions of the corresponding α-amino ketones in the presence of chiral metal catalysts. However, the discovery of methods of this type employing safe and cheap reducing agents, and convenient and practical procedures still remains a challenge. In 2014, Feng et al. reported an easy and simple route to these products based on the first enantioselective alkali metal borohydride reduction of α-primary amino ketones catalyzed by a chiral scandium complex derived from Sc(OTf)3 and chiral N,N’-dioxide ligand 184 [113]. As shown in
103 Page 103 of 135
Scheme 60, the reaction of a range of α-primary amino ketones hydrochlorides 185a-h with aqueous potassium borohydride in the presence of 10 mol% of the catalyst system provided, after subsequent N-Boc derivation, the corresponding chiral amino alcohols 186a-h in
N+
+
KBH4 aq.
O-
O
H N Ar' Ar' Ar' = 2,6-Et2C6H3 184 (10 mol%) Sc(OTf)3 (10 mol%)
us
O Ar
O N H
OH
an
1.
+ N -
O
cr
ip t
moderate to high yields (65-90%) and enantioselectivities of 74-90% ee.
Ar *
186a-h
M
NH2HCl (0.75 equiv) THF, -20 to 0 °C 185a-h 2. (Boc)2O (1.2 equiv) K2CO3 (1.2 equiv) 35 °C
NHBoc
Ac ce p
te
d
186a: Ar = Ph: 80% yield, 85% ee 186b: Ar = p-MeOC6H4: 65% yield, 90% ee 186c: Ar = p-EtOC6H4: 90% yield, 74% ee 186d: Ar = p-PhC6H4: 90% yield, 79% ee 186e: Ar = p-FC6H4: 80% yield, 81% ee 186f: Ar = p-ClC6H4: 90% yield, 77% ee 186g: Ar = p-BrC6H4: 90% yield, 74% ee 186h: Ar = 2-Naph: 90% yield, 74% ee
Scheme 60. Reduction of α-amino ketones with aqueous KBH4 [113].
10. Enantioselective scandium-catalyzed Friedel−Crafts reactions
The Friedel−Crafts reaction of aromatic compounds with aldehydes or ketones constitutes one of the most fundamental reactions in organic chemistry [114]; however, its enantioselective catalytic version is still an unexplored field. Based on the fact that the phenol unit occurs widespread in biologically active natural products and pharmaceutically useful
104 Page 104 of 135
molecules [115], an expansion of the scope of phenols in asymmetric Friedel−Crafts reaction is of interest. In this context, Feng et al. have developed enantioselective Friedel−Crafts reactions of phenols 187a-c with (E)-4-oxo-4-arylbutenoates 57a-n which afforded the
ip t
corresponding chiral polyfunctionalized products 188a-q in moderate to high yields (78-97%) and good to high enantioselectivities (88-97% ee) [116]. The process was performed in the
cr
presence of a combination of Sc(OTf)3 and chiral N,N’-dioxide ligand 111 ( Scheme 61). Ester groups had little influence on the enantioselectivity, and somewhat decreased yields
us
were obtained for sterically hindered ester group (products 188c-d). Regardless of the
an
electronic and steric nature, or the position of the substituents on the aromatic ring of (E)-4oxo-4-arylbutenoates 57f-l, the asymmetric Friedel−Crafts reaction proceeded smoothly,
M
providing the desired products 188f-l in high yields (78-97%) and enantioselectivities (8997% ee). The best result was reached in the reaction of 3,4-dimethoxy-substituted (E)-ethyl 4-
d
oxo-4-arylbutenoate 57h. The synthetic utility of the reaction was demonstrated in an easy
Ac ce p
te
conversion of product 188a into a potentially useful biological pyridazinone derivative.
105 Page 105 of 135
N+
N
+
-
O CO2R1
Ar
57a-n + 2
RO
OH
O
OO N H H N R3 R3 R3 = 1-adamantyl R2O 111 (6 mol%) Sc(OTf)3 (5 mol%) O CH2Cl2, 30 °C Ar
OH
CO2R1
cr
R2O
OR2
ip t
O
188a-q 187a-c
Ac ce p
te
d
M
an
us
188a: Ar = Ph, R1 = Et, R2 = Me: 95% yield, 93% ee 188b: Ar = Ph, R1 = R2 = Me: 97% yield, 93% ee 188c: Ar = Ph, R1 = i-Pr, R2 = Me: 78% yield, 92% ee 188d: Ar = Ph, R1 = t-Bu, R2 = Me: 87% yield, 95% ee 188e: Ar = Ph, R1 = Bn, R2 = Me: 96% yield, 92% ee 188f: Ar = m-MeOC6H4, R1 = Et, R2 = Me: 92% yield, 94% ee 188g: Ar = p-MeOC6H4, R1 = Et, R2 = Me: 97% yield, 92% ee 188h: Ar = 3,4-(MeO)2C6H3, R1 = Et, R2 = Me: 78% yield, 97% ee 188i: Ar = o-FC6H4, R1 = Et, R2 = Me: 88% yield, 94% ee 188j: Ar = p-FC6H4, R1 = Et, R2 = Me: 93% yield, 89% ee 188k: Ar = p-BrC6H4, R1 = Et, R2 = Me: 93% yield, 91% ee 188l: Ar = p-NO2C6H4, R1 = Et, R2 = Me: 92% yield, 94% ee 188m: Ar = 2-furyl, R1 = Et, R2 = Me: 86% yield, 88% ee 188n: Ar = 2-thienyl, R1 = Et, R2 = Me: 92% yield, 95% ee 188o: Ar = Ph, R1 = Et, R2 = Me: 87% yield, 89% ee 188p: Ar = Ph, R1 = Et, R2 = i-Pr: 92% yield, 93% ee 188q: Ar = Ph, R1 = R2 = Et: 93% yield, 91% ee
Scheme 61. Friedel−Crafts reaction of phenols with (E)-4-oxo-4-arylbutenoates [116].
Sesamol is a crucial fragment found in a number of biologically active molecules and natural products. Meanwhile, chiral α-amino-substituted sesamol derivatives have emerged as ubiquitous antibacterial and antitumor pharmaceuticals [117]. An easy way to construct these α-amino sesamols in enantiomerically enriched form is the asymmetric aza-Friedel−Crafts reaction with imines. In 2014, very good results were reported by Feng et al. in enantioselective scandium-catalyzed aza-Friedel−Crafts reaction of sesamol with a wide range 106 Page 106 of 135
of aryl imines 190a-o performed in the presence of chiral N,N′-dioxide ligand 189 [118]. As shown in Scheme 62, the corresponding bioactive chiral α-amino-sesamols 191a-o were produced in moderate to high yields (32-97%) with generally high enantioselectivities of up to
ip t
97% ee. The lowest enantioselectivities (83-86% ee) and yields (32-53%) were obtained for the reactions of 2-thienyl- and 2-naphthyl-substituted imine substrates 190l-m. On the other
cr
hand, regardless of the electron-donating or electron-withdrawing substituents on the phenyl
us
ring of imines (Ar), high enantioselectivities (89-97% ee) were obtained for products 191b-j. Generally, substituents on the meta-position of the phenyl ring of imine presented better
an
yields than the ortho- and para-substituted ones. When the tosyl protecting group of the imine was changed to Bs (190n) or a more electron-withdrawing 4-chloro-phenylsulfonyl group
M
(190o), the reactivity as well as the enantioselectivity maintained. Unfortunately, aliphatic
Ac ce p
te
d
aldimines performed sluggishly.
107 Page 107 of 135
+ N -
N
O
O
H N Ar' Ar' Ar' = 2,4,6-i-Pr3C6H2 189 (13 mol%) Sc(OTf)3 (10 mol%)
Ar 190a-o + OH
O
O N H
O
R
-
OH
O
m-BrC6H4CO2H (10 mol%)
NHR
O
* Ar
toluene, 0 °C
O
ip t
N+
cr
191a-o
sesamol
te
d
M
an
us
191a: Ar = Ph, R = Ts: 93% yield, 94% ee 191b: Ar = o-Tol, R = Ts: 63% yield, 97% ee 191c: Ar = m-Tol, R = Ts: 80% yield, 93% ee 191d: Ar = p-Tol, R = Ts: 72% yield, 91% ee 191e: Ar = o-FC6H4, R = Ts: 83% yield, 96% ee 191f: Ar = m-FC6H4, R = Ts: 97% yield, 95% ee 191g: Ar = p-FC6H4, R = Ts: 90% yield, 95% ee 191h: Ar = m-ClC6H4, R = Ts: 91% yield, 96% ee 191i: Ar = m-CF3C6H4, R = Ts: 90% yield, 96% ee 191j: Ar = p-CF 3C6H4, R = Ts: 71% yield, 89% ee 191k: Ar = 2-furyl, R = Ts: 80% yield, 86% ee 191l: Ar = 2-thienyl, R = Ts: 32% yield, 83% ee 191m: Ar = 2-Naph, R = Ts: 53% yield, 86% ee 191n: Ar = Ph, R = Bs: 85% yield, 92% ee 191o: Ar = Ph, R = p-ClC6H4SO2: 80% yield, 95% ee
Ac ce p
Scheme 62. Friedel−Crafts reaction of sesamol with aryl aldimines [118].
11. Miscellaneous enantioselective scandium-catalyzed reactions
In 2011, Feng et al. reported the first catalytic asymmetric electrophilic addition of αdiazoesters to α-alkyl ketones, consisting in a unique C−N bond formation reaction via αhydrazonation [119]. As shown in Scheme 63, the reaction was catalyzed by a chiral scandium catalyst in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 9 in the presence of Li2CO3 as an additive. The reaction occurred between ketones 192a-j and αbenzyl-α-diazoacetate 7a, affording the corresponding unexpected chiral alkylhydrazone 108 Page 108 of 135
products 193a-j. Indeed, it was rationally expected that a ring-expansion product 194 would be obtained from the initial nucleophilic addition of the α-diazoester to the C=O bond of the ketone instead of product 193 arisen from electrophilic addition of the α-diazoester. A broad
ip t
scope of ketones was compatible with the mild reaction conditions regardless of the positions and electronic properties of the substituents on the benzene ring of 1-tetralone derivatives
cr
192a and 192c-f since these substrates led to the corresponding products 193a and 193c-f in
us
good to high yields (80-96%) and high enantioselectivities (94-99% ee), except 6-methoxy-1tetralone 192b which displayed a lower reactivity (65% yield) along with good
an
enantioselectivity of 93% ee. In addition, chroman-4-one 192g and thiochroman-4-one 192h were good candidates and yielded the corresponding products 193g and 193h, respectively,
M
with 98% ee in yields of 75 and 90%, respectively. Furthermore, other benzo cyclic ketones, such as 1-indanone 192i incorporating a five-membered ring, was compatible with this
d
method, giving a moderate yield (53%) and good enantioselectivity (89% ee), whereas a
te
higher yield (98%) and enantioselectivity (99% ee) were reached using 1-benzosuberone 192j as the nucleophile. Non-benzo cycloalkanones 192k-o, such as cyclohexanone 192k and 4-
Ac ce p
thiacyclohexanone 192l, were also tolerated in the process, giving the corresponding products 193k-l with moderate yields (70-83%) and enantioselectivities (61-71% ee). Moreover, seven, eight-, and ten-membered aliphatic cyclic ketones delivered products 193m-o albeit with modest enantioselectivities (52-77% ee), although cyclooctanone 193n exhibited relatively lower reactivity (45% yield). It is worth noting that this work described for the first time the electrophilic capability of α-diazoesters in a unique catalytic asymmetric C−N bond formation via α-hydrazonation of unactivated ketones.
109 Page 109 of 135
N+ O
+
O-
O-
O
R1
N
O
N H
R3 192a-j
Sc(OTf)3 (2.4-6 mol%)
+ CO2Et
R2
Li2CO3 (10 mol%)
R3
CH2Cl2, 20 °C
N2 7a
R
R2
CO2Et
X ( )n R3
194
Bn
CO2Et
193a-j
O Bn 1
X
H * N N ( )n
an
Bn
O R1
ip t
( )n
cr
X
us
R2
H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (2-5 mol%)
Ac ce p
te
d
M
193a: X = CH2, n = 1, R1 = R2 = H, R3 = OMe: 89% yield, 95% ee 193b: X = CH2, n = 1, R1 = R3 = H, R2 = OMe: 65% yield, 93% ee 193c: X = CH2, n = 1, R1 = OMe, R2 = R3 = H: 93% yield, 99% ee 193d: X = CH2, n = 1, R1 = NO2, R2 = R3 = H: 88% yield, 94% ee 193e: X = CH2, n = 1, R1 = Br, R2 = R3 = H: 96% yield, 99% ee 193f: X = CH2, n = 1, R1 = R3 = Me, R2 = H: 80% yield, 99% ee 193g: X = O, n = 1, R1 = R2 = R3 = H: 75% yield, 98% ee 193h: X = S, n = 1, R1 = R2 = R3 = H: 90% yield, 98% ee 193i: X = CH2, n = 0, R1 = R2 = R3 = H: 53% yield, 89% ee 193j: X = CH2, n = 2, R1 = R2 = R3 = H: 98% yield, 99% ee
O
Bn
+
X
( )n
192k-o
O
CO2Et same conditions
N2
X
H * N N ( )n
7a
Bn CO2Et
193k-o
193k: X = CH2, n = 1: 83% yield, 71% ee 193l: X = S, n = 1: 70% yield, 61% ee 193m: X = CH2, n = 2: 81% yield, 74% ee 193n: X = CH2, n = 3: 45% yield, 77% ee 193o: X = CH2, n = 5: 75% yield, 52% ee
Scheme 63. α-Amination of cyclic ketones with α-benzyl-α-diazoacetate [119].
110 Page 110 of 135
Later in 2015, other enantioselective scandium-catalyzed electrophilic aminations were reported by Luan et al. [120]. It involved catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols 195a-s implemented with electrophilic azodicarboxylates 196a-c
ip t
under catalysis with in situ generated chiral pybox scandium complexes of ligands 197 and 134. This process provided the corresponding bicyclic enones 198a-s bearing a nitrogen-
cr
containing quaternary stereocenter in high enantioselectivities (90-98% ee) with good to high yields (81-98%) (Scheme 64). The results from reactions of disubstituted naphthols 195a-j
us
with dibenzyl azodicarboxylate 196a catalyzed by complex of ligand 197 showed that it was possible to vary the substituents on both the 1- and 3-positions of 2-naphthols (Scheme 61,
an
first equation). Thus, the 3-position of naphthols (R2) could be substituted with alkyl groups
M
(195a-c and 195g-h), aromatic groups featuring differential electronic properties (195d-e), heterocycles (195f), and even halogen functionalities (195i-j) while various aliphatic
d
substituents were compatible at the 1-position (R1) of the naphthyl ring without compromising
te
the enantioselectivity. With the aim of extending this methodology to the reaction of monosubstituted 2-naphthols 195k-s with other azodicarboxylates 196b-c, the authors found
Ac ce p
that using related ligand 134 allowed better results to be achieved than by using catalyst derived from ligand 197. Under these conditions, a range of other aminative dearomatization chiral products 198k-s was achieved in comparable excellent yields and enantioselectivities (Scheme 64, second equation). It is important to note that this work constituted the first example of a catalytic asymmetric aminative dearomatization of 2-naphthols.
111 Page 111 of 135
O
N N
N Bn
1
R
OH Cbz N + N 2 Cbz R 195a-j
Bn
197 (6 mol%) Sc(OTf)3 (5 mol%)
NHCbz Cbz N R1 O R2
CH2Cl2, r.t. 198a-j
196a
ip t
O
M
an
us
cr
198a: R1 = R2 = Me: 97% yield, 98% ee 198b: R1 = Me, R2 = Et: 95% yield, 90% ee 198c: R1 = Me, R2 = Bn: 89% yield, 97% ee 198d: R1 = Me, R2 = Ph: 94% yield, 96% ee 198e: R1 = Me, R2 = p-ClC6H4: 91% yield, 96% ee 198f: R1 = Me, R2 = 2-thienyl: 87% yield, 95% ee 198g: R1 = Et, R2 = Me: 93% yield, 93% ee 198h: R1 = allyl, R2 = Bn: 81% yield, 96% ee 198i: R1 = Me, R2 = Br: 84% yield, 92% ee 198j: R1 = Me, R2 = I: 90% yield, 95% ee
O
N
N
d
134 (6 mol%)
2 OH R O2C N + N
2 CO2R2 Ph R O2C HN N R1
O
Sc(OTf)3 (5 mol%)
CO2R2
196b-c
CH2Cl2, r.t. 198k-s
Ac ce p
195k-s
Ph
te
R1
O
N
198k: R1 = R2 = Bn: 98% yield, 98% ee 198l: R1 = CH2p-Tol, R2 = Bn: 97% yield, 98% ee 198m: R1 = CH2-(p-CO2EtC6H4), R2 = Bn: 92% yield, 98% ee 198n: R1 = CH2-(o-BrC6H4), R2 = Bn: 87% yield, 94% ee 198o: R1 = CH2-(p-OCF3C6H4), R2 = Bn: 95% yield, 96% ee 198p: R1 = CH2(2-Naph), R2 = Bn: 85% yield, 96% ee 198q: R1 = Et, R2 = i-Pr: 98% yield, 90% ee 198r: R1 = n-Bu, R2 = i-Pr: 94% yield, 97% ee 198s: R1 = allyl, R2 = i-Pr: 93% yield, 92% ee
Scheme 64. Aminative dearomatizations of mono- and disubstituted 2-naphthols [120].
Later, this type of reactions were also investigated by Feng et al. by using a chiral scandium catalyst derived from N,N’-dioxide ligand 111 [121]. As shown in Scheme 65, the reaction of 112 Page 112 of 135
a range of disubstituted 2-naphthols 195a-k with various azodicarboxylates 196a-d led to the corresponding chiral β-naphthalenone compounds 198a-m bearing a nitrogen-containing quaternary carbon stereocenter in good to excellent yields of up to 99% and high
ip t
enantioselectivities of 88-99% ee. In the case of diethyl azodicarboxylate as substrate, homogeneous excellent results were achieved in terms of yields and enantioselectivities with
cr
an exception for product 198f which was achieved in only 40% yield albeit with an excellent
us
enantioselectivity of 99% ee. Generally, the nature of substituent R2 on the 3-position of the 2-naphthol had little effect on the enantioselectivity. Aliphatic groups, such as methyl, ethyl,
an
n-butyl, benzyl, as well as allyl groups were tolerated, and the corresponding products 198a-e were obtained in 95-98% ee. Remarkably, substrates bearing halogen functionalities also
M
underwent the asymmetric dearomatization reaction well, providing the corresponding products 198g-i in 85-95% yields and 92-97% ees. Moreover, a 3-phenyl-substituted 2-
d
naphthol was also a suitable substrate, affording the dearomatized product 198j in 99% yield
te
and 99% ee. Concerning the influence of the nature of substituent R1, larger substituents decreased the enantioselectivity slightly, but the results were still good (99% yield and 86%
Ac ce p
ee for product 198k with R1 = Et). In addition to diethyl azodicarboxylate, diisopropyl and dibenzyl azodicarboxylates were alternative electrophiles, providing the corresponding products in 93-99% yields and 88-95% ees.
113 Page 113 of 135
N+ O-
O
N H
N
+
O-
O
H N R4
R4 R4 = 1-adamantyl 111 (5 mol%)
R1
CO2R3 R3O2C 1 R N NH O
196a-d
R2 198a-m
5 Å M. S., H2O
cr
195a-k
ip t
OH R3O2C Sc(OTf)3 (5 mol%) N + N CO2R3 CH2Cl2, 30 °C R2
d
M
an
us
198a: R1 = R2 = Me, R3 = Et: 99% yield, 95% ee 198b: R1 = Me, R2 = R3 = Et: 99% yield, 96% ee 198c: R1 = Me, R2 = n-Bu, R3 = Et: 88% yield, 97% ee 198d: R1 = Me, R2 = Bn, R3 = Et: 99% yield, 98% ee 198e: R1 = Me, R2 = allyl, R3 = Et: 73% yield, 98% ee 198f: R1 = Me, R2 = CH2C(Me)=CH2, R3 = Et: 40% yield, 99% ee 198g: R1 = Me, R2 = Cl, R3 = Et: 86% yield, 92% ee 198h: R1 = Me, R2 = Br, R3 = Et: 85% yield, 92% ee 198i: R1 = Me, R2 = I, R3 = Et: 95% yield, 97% ee 198j: R1 = Me, R2 = Ph, R3 = Et: 99% yield, 99% ee 198k: R1 = R3 = Et, R2 = Me: 99% yield, 86% ee 198l: R1 = R2 = Me, R3 = i-Pr: 99% yield, 95% ee 198m: R1 = R2 = Me, R3 = Bn: 93% yield, 88% ee
Ac ce p
te
Scheme 65. Aminative dearomatizations of disubstituted 2-naphthols [121].
In 2014, Hou et al. employed a novel preformed cationic half-sandwich scandium alkyl complex 199 bearing monocyclopentadienyl ligands embedded in chiral binaphthyl backbones to catalyze the enantioselective C−H bond addition of pyridines 200a-l to various alkenes 201a-e [122]. The process afforded a variety of enantioenriched alkylated pyridine derivatives 202a-q in generally high yields of up to 95% and good to high enantioselectivities of up to 96% ee (Scheme 66). The substrate scope was wide since variously substituted pyridines were tolerated, including 2-phenylpyridine 200i for which the C−H bond activation reaction occurred selectively at the pyridine unit rather than at the phenyl group. Furthermore, in addition to simple 1-alkenes, such as 1-hexene 201a, 1-heptene 201n, and 1-octene 201o, allylcyclohexane 201p and allyltrimethylsilane 201q, containing bulky substituents in close 114 Page 114 of 135
proximity to the C−C double bond, were compatible alkylation agents in a similar fashion. Notably, the analogous yttrium and gadolinium complexes showed no activity under similar
ip t
conditions.
N
us
X Sc N
cr
X
an
X = OSi(i-Pr)3 199 (5 mol%) R
N +
R4
R2
R1 R2
toluene, 40 °C
3
R
201a-e
N
R3 202a-q
d
200a-l
R4
[Ph 3C][B(C6F 5)4] (5 mol%)
M
1
Ac ce p
te
202a: R1 = Me, R2 = R3 = H, R4 = n-Bu: 90% yield, 88% ee 202b: R1 = R3 = Me, R2 = H, R4 = n-Bu: 93% yield, 96% ee 202c: R1 = R2 = Me, R3 = H, R4 = n-Bu: 95% yield, 90% ee 202d: R1 = Me, R2 = Br, R3 = H, R4 = n-Bu: 94% yield, 90% ee 202e: R1 = Me, R2 = H, R3 = Cl, R4 = n-Bu: 91% yield, 92% ee 202f: R1 = Et, R2 = R3 = H, R4 = n-Bu: 93% yield, 84% ee 202g: R1 = i-Pr, R2 = R3 = H, R4 = n-Bu: 94% yield, 76% ee 202h: R1 = t-Bu, R2 = R3 = H, R4 = n-Bu: 83% yield, 84% ee 202i: R1 = Ph, R2 = R3 = H, R4 = n-Bu: 94% yield, 84% ee 202j: R1,R2 = (CH2)4, R3 = H, R4 = n-Bu: 93% yield, 84% ee 202k: R1,R2 = (CH2)3, R3 = H, R4 = n-Bu: 63% yield, 86% ee 202l: R1 = I, R2 = R3 = H, R4 = n-Bu: 87% yield, 88% ee 202m: R1 = Me, R2,R3 = (CH=CH)2, R4 = n-Bu: 81% yield, 94% ee 202n: R1 = Me, R2 = R3 = H, R4 = n-Pent: 92% yield, 86% ee 202o: R1 = Me, R2 = R3 = H, R4 = n-Hex: 92% yield, 86% ee 202p: R1 = Me, R2 = R3 = H, R4 = CH2Cy: 94% yield, 82% ee 202q: R1 = Me, R2 = R3 = H, R4 = CH2TMS: 80% yield, 72% ee
Scheme 66. Addition of pyridines to alkenes catalyzed by a preformed chiral half-sandwich scandium catalyst [122].
115 Page 115 of 135
Another preformed scandium tetraazane chiral catalyst 203 was synthesized by Mu et al. and further applied to the catalysis of enantioselective intramolecular hydroamination of alkenes 204a-c in the presence of n-BuLi [123]. As shown in Scheme 67, the corresponding
ip t
chiral pyrrolidines 205a-c were achieved in high yields (90-95%) and low to good enantioselectivities (28-85% ee). Better yields were reached by changing this scandium
N Sc N Cl N Ar Ar Ar = 2,6-Me 2C6H3
an
N
us
cr
catalyst by its yttrium analogue.
M
203 (5 mol%)
R
R
n-BuLi (5 mol%)
H2N
NH
R
* 205a-c
te
204a-c
d
C6D6
R
Ac ce p
205a: R = Me: 90% yield, 85% ee 205b: R,R = (CH2)4: 90% yield, 71% ee 205c: R = Ph: 95% yield, 28% ee
Scheme 67. Intramolecular hydroamination of alkenes catalyzed by a preformed chiral tetraazane scandium catalyst [123].
In 2011, a direct highly diastereo- and enantioselective asymmetric vinylogous Mannichtype reaction of aldimines 206a-o with non-activated natural α-angelica lactone 207 was successfully developed by Feng et al. [124]. The process was catalyzed by a chiral scandium complex in situ generated from Sc(OTf)3 and chiral N,N’-dioxide ligand 97, providing the corresponding δ-amino γ,γ’-disubstituted butenolide carbonyl derivatives 208a-o bearing adjacent quaternary and tertiary stereocenters. As shown in Scheme 68, these products were
116 Page 116 of 135
achieved in moderate to good yields (58-83%), high enantioselectivities (90-97% ee) and moderate to excellent diastereoselectivities (72-98% de). The introduction of an electrondonating methyl group to N-arylimine decreased the enantioselectivity (90% ee) of the
ip t
corresponding product 208c slightly with good yield (82%), while electron-withdrawing chloride group gave the corresponding product 208b with higher diastereo- and
cr
enantioselectivity (92% de and 97% ee) in moderate yield (67%). The enantioselectivity of the reaction was sensitive to the electronic property rather than to the steric hindrance of
us
substituents on the phenyl ring of aromatic aldimines. It is worth noting that substrates with
an
electron-withdrawing substituents provided higher enantioselectivities than those with electron-donating ones (products 208i-k vs products 208d-h). Moreover, fused ring and
M
heteroaromatic aldimines 208l-o were also tolerated, leading to the corresponding products
Ac ce p
te
d
208l-o with enantioselectivities of 93-97% ee.
117 Page 117 of 135
N+
HO + Ar
O
R 206a-o
O
3 Å M.S. 2-Me-THF, 0 °C
207
HO HN
R
Ar O
cr
N
OO H N Ar' Ar' Ar' = 2,6-i-Pr2C6H3 97 (6 mol%) Sc(OTf)3 (5 mol%) ON H
ip t
O
+ N
O 208a-o
d
M
an
us
208a: Ar = Ph, R = H: 81% yield, 95% ee, 90% de 208b: Ar = Ph, R = Cl: 67% yield, 97% ee, 92% de 208c: Ar = Ph, R = Me: 82% yield, 90% ee, 86% de 208d: Ar = o-Tol, R = H: 78% yield, 93% ee, 98% de 208e: Ar = m-Tol, R = H: 77% yield, 92% ee, 90% de 208f: Ar = p-Tol, R = H: 83% yield, 92% ee, 90% de 208g: Ar = p-MeOC6H4, R = H: 82% yield, 94% ee, 92% de 208h: Ar = m-MeOC6H4, R = H: 77% yield, 90% ee, 90% de 208i: Ar = p-FC6H4, R = H: 76% yield, 98% ee, 92% de 208j: Ar = p-ClC6H4, R = H: 74% yield, 96% ee, 92% de 208k: Ar = p-BrC6H4, R = H: 58% yield, 97% ee, 92% de 208l: Ar = 1-Naph, R = H: 75% yield, 95% ee, 94% de 208m: Ar = 2-Naph, R = H: 83% yield, 93% ee, 90% de 208n: Ar = 2-furyl, R = H: 62% yield, 95% ee, 72% de 208o: Ar = 2-thienyl, R = H: 82% yield, 97% ee, 92% de
Ac ce p
te
Scheme 68. Vinylogous Mannich-type reaction of α-angelica lactone [124].
Tetrahydroquinoline derivatives bearing a quaternary carbon center at the C4 position exhibit potential biological activities. The Povarov reaction, an inverse electron-demand azaDiels−Alder reaction of N-arylimines with electron-rich alkenes, is one of the most efficient routes to construct this type of privileged backbone [125]. However, most of the reported asymmetric methods provided chiral tetrahydroquinolines with a tertiary stereocenter at the C4 position. In 2011, Feng et al. described the enantioselective scandium-catalyzed Povarov reaction of α-alkyl styrenes 209a-d with N-aryl aldimines 206a-n which afforded the corresponding chiral tetrahydroquinolines 210a-q bearing a quaternary stereogenic center [126]. Performing the process with chiral N,N’-dioxide ligand 9, these important products
118 Page 118 of 135
were obtained in general excellent enantioselectivities of 92 to > 99% ee (Scheme 69). Regardless of the steric hindrance of the substituents on the electron-deficient imines 206b-g, tetrahydroquinolines 210b-g were obtained in good to high yields (76-93%) with good
ip t
diastereoselectivities (86-92% de) and excellent enantioselectivities (92-> 99% ee). On the other hand, the presence of electron-donating substituents on the aromatic imine enriched the
cr
electron density and thus decreased the reactivity. Thus, in the case of imines derived from methyl-substituted benzaldehydes 206h-j, lower yields (51-88% yields) were obtained albeit
us
with high diastereo- and enantioselectivities of 88-90% de and 94-99% ee, respectively. When
an
an electron-donating p-methoxy-substituted imine 206k was employed, an excellent enantioselectivity of 98% ee was also achieved, but the yield was substantially reduced
M
(22%). Imines 206m-n derived from heteroaromatic and aliphatic aldehydes were also suitable substrates to afford the corresponding products 210m-n with high enantioselectivities
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te
d
(95-96% ee) albeit in low yields (33-35%).
119 Page 119 of 135
N+
OO H N Ar Ar Ar = 2,6-i-Pr2C6H3 9 (10 mol%) Sc(OTf)3 (10 mol%) ON H
HO
R1
206a-n
R2
R3
R1CHO (0.5 equiv.) MgSO4 CH2Cl2, 30 °C
209a-d
OH
R3
N H
R1
cr
+
R2
ip t
O
N
+ N
210a-q
Ac ce p
te
d
M
an
us
210a : R1 = R2 = Ph, R3 = Me: 75% yield, 96% ee, 88% de 210b: R1 = o-ClC6H4, R2 = Ph, R3 = Me: 93% yield, 92% ee, 86% de 210c: R1 = m-ClC6H4, R2 = Ph, R3 = Me: 76% yield, 95% ee, 90% de 210d: R1 = p-ClC6H4, R2 = Ph, R3 = Me: 82% yield, > 99% ee, 92% de 210e: R1 = p-BrC6H4, R2 = Ph, R3 = Me: 92% yield, > 99% ee, 92% de 210f: R1 = p-FC6H4, R2 = Ph, R3 = Me: 85% yield, 98% ee, 90% de 210g : R1 = p-CF3C6H4, R2 = Ph, R3 = Me: 81% yield, 99% ee, 86% de 210h: R1 = o-Tol, R2 = Ph, R3 = Me: 88% yield, 94% ee, 90% de 210i: R1 = m-Tol, R2 = Ph, R3 = Me: 66% yield, 97% ee, 88% de 210j: R1 = p-Tol, R2 = Ph, R3 = Me: 51% yield, 99% ee, 90% de 210k : R1 = p-MeOC6H4, R2 = Ph, R3 = Me: 22% yield, 98% ee, 82% de 210l: R1 = 2-Naph, R2 = Ph, R3 = Me: 67% yield, > 99% ee, 92% de 210m: R1 = 2-thienyl, R2 = Ph, R3 = Me: 35% yield, 96% ee, 78% de 210n: R1 = Cy, R2 = Ph, R3 = Me: 33% yield, 95% ee, 22% de 210o: R1 = Ph, R2 = p-Tol, R3 = Me: 70% yield, 98% ee, 94% de 210p: R1 = Ph, R2 = p-FC6H4, R3 = Me: 70% yield, 98% ee, 94% de 210q: R1 = R2 = Ph, R3 = Et: 40% yield, 96% ee, 86% de
Scheme 69. Povarov reaction of α-alkyl styrenes with N-aryl aldimines [126].
Finally, Franz et al. have reported scandium-catalyzed enantioselective Hosomi−Sakurai allylations of isatins 6a-j with various substituted allylic silanes 211a-d to give the corresponding chiral 3-allyl-3-hydroxy-2-oxindoles 212a-q bearing a quaternary stereogenic center [127]. These products were obtained in good to high yields and enantioselectivities of up to 99% and 99% ee, respectively, when the reactions were performed with a chiral scandium complex derived from pybox ligand 27 in the presence of TMSCl as activator and NaSbF6 as additive (Scheme 70). This catalyst system was equally efficient for N-substituted 120 Page 120 of 135
as well as unsubstituted NH isatins, and for allyl trimethylsilane as well as substituted allylic silanes. For example, 2-methyl-, 2-phenyl-, and 2-cyclohexyl-substituted allylsilanes proceeded in high yields of up to 99% and enantioselectivities of up to 99% ee (products Furthermore,
the
reaction
conditions
were
also
applicable
to
(E)-
ip t
212n-p).
crotyltrimethylsilane which provided anti-product 212q in 95% yield, 96% ee, albeit with
cr
moderate anti-diastereoselectivity of 66% de. In some cases, the catalyst loading of the
O
O
M
6a-j SiMe3
211a-d
R4
R3
OH R2
d
TMSCl (3 equiv)
NaSbF6 (30 mol%)
te
R3
N
27 (10 mol%) Sc(OTf)3 (10 mol%) 4 Å M.S.
N R1 + R4
an
R2
O
N
N
O
us
process could be reduced as low as 0.05 mol% in comparable results.
MeCN, r.t.
O N R1 212a-q
Ac ce p
212a: R1 = Me, R2 = 5-Cl, R3 = R4 = H: 99% yield, 91% ee 212b: R1 = Me, R2 = 5-Br, R3 = R4 = H: 96% yield, 86% ee 212c: R1 = Me, R2 = 5-F, R3 = R4 = H: 89% yield, 89% ee 212d: R1 = Me, R2 = 4-Cl, R3 = R4 = H: 96% yield, 87% ee 212e: R1 = Me, R2 = H, R3 = R4 = H: 91% yield, 89% ee 212f: R1 = Me, R2 = 5-OMe, R3 = R4 = H: 72% yield, 92% ee 212g: R1 = R2 = R3 = R4 = H: 99% yield, 85% ee 212h: R1 = R3 = R4 = H, R2 = 5-Br: 99% yield, 86% ee 212i: R1 = R3 = R4 = H, R2 = 4-Cl: 99% yield, 82% ee 212j: R1 = R3 = R4 = H, R2 = 7-F: 97% yield, 81% ee 212k: R1 = R3 = R4 = H, R2 = 5-OMe: 99% yield, 80% ee 212l: R1 = R3 = R4 = H, R2 = 5-OCF3: 99% yield, 81% ee 212m: R1 = Ph, R2 = R3 = R4 = H: 97% yield, 89% ee 212n: R1 = R4 = Me, R2 = 5-Br, R3 = H: 95% yield, 97% ee 212o: R1 = Me, R2 = 5-Cl, R3 = H, R4 = Ph: 88% yield, 99% ee 212p: R1 = Me, R2 = 5-Cl, R3 = H, R4 = Cy: 99% yield, 95% ee 212q: R1 = R3 = Me, R2 = 5-Cl, R4 = H: 95% yield, 96% ee, 66% de
Scheme 70. Hosomi−Sakurai allylation of isatins with allylsilanes [127]. 121 Page 121 of 135
12. Conclusions
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This review illustrates well that scandium asymmetric chemistry has become an important component of asymmetric organic synthesis, in particular through its recent impressive
cr
diversification outcomes. It updates the major progress reported since the beginning of 2011
us
in the field of all types of enantioselective transformations promoted by chiral scandium catalysts, well demonstrating the power of these special catalysts to provide a high degree of
an
reactivity and stereoselectivity in a myriad of asymmetric transformations including highly efficient novel domino processes. It demonstrates that since the pioneering studies dealing
M
with enantioselective scandium-catalyzed Diels−Alder reactions reported by Kobayashi in 1994, a large number of highly efficient enantioselective scandium-catalyzed reactions have
d
been developed. Among important recent results, remarkable enantioselectivities have been
te
reported by several groups for a range of unprecedented fascinating scandium-catalyzed domino reactions including multicomponent ones which allowed the synthesis of a wide range
Ac ce p
of complex molecules to be achieved. For example, the group of Feng reported very high enantioselectivities of up to 99% ee for various types of completely novel domino reactions. Remarkable results were also achieved by other groups, such as those of Davies, Ding, Kingsbury, Kesavan, Chi, Shi, Franz, and Cai. In addition, a number of important advances have been independently developed by the groups of Vaccaro, Kobayashi, Wang, and Feng, in the area of asymmetric scandium-catalyzed Michael additions of a range of substrates to α,βunsaturated carbonyl compounds, providing various types of functionalized chiral products in generally remarkable enantioselectivities of up to 99% ee. Among them, several important examples of highly enantioselective Michael additions of thiols to α,β-unsaturated ketones could be nicely performed in water with enantioselectivities of up to 98% ee. Furthermore,
122 Page 122 of 135
important advances in scandium-catalyzed asymmetric chemistry have been reported by several groups in the field of Mannich reaction, [4+2] and [2+2] cycloaddition reactions, ringopening of epoxides, allylation reactions, α-functionalizations of 3-substituted oxindoles,
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Baeyer−Villiger reaction, epoxidation of alkenes, reduction of ketones, aldol reactions, Friedel−Crafts reaction, hydroamination and amination reactions, Povarov reaction, aldol
cr
reactions performed in water, as well as addition reactions. In most cases, Sc(OTf)3 which is a stable and excellent Lewis acid even in aqueous solutions in contrast with most other Lewis
us
acids, was used as precatalyst both in organic solvents or in aqueous solutions. Scandium triflate salt can be easily recovered through extraction with water and reused. This recyclable
an
use of scandium complexes is important for green chemistry and will play a key role in future developments of asymmetric scandium catalysis. The success in the firstly reported highly
M
enantioselective reactions performed in water, providing potential and unusual tools in organic chemistry, constitutes a foundation for performing organic processes in
d
environmentally friendly conditions, and consequently, this field presents significant
te
challenges in the future. Furthermore, the ever-growing need for environmentally friendly
Ac ce p
catalytic processes prompted organic chemists to focus on less moisture sensitive metals employed at low catalyst loadings, such as scandium, to develop new catalytic systems to perform reactions, such as C–C bond formations, C–heteroatoms bond formations, or C–H functionalizations. A bright future is undeniable for more sustainable novel and enantioselective scandium-catalyzed transformations and their applications in total synthesis even if the promise of asymmetric catalysis through highly efficient and environmentally friendly chiral scandium complexes remains to be fulfilled.
Graphical Abstract
123 Page 123 of 135
Recent developments in enantioselective scandium-catalyzed transformations
Hélène Pellissier
ip t
1.1.1 Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397, Marseille, France
cr
This review collects the major progress in the field of enantioselective transformations promoted by chiral scandium catalysts, covering the literature since the beginning of 2011,
Ac ce p
te
d
M
an
us
well illustrating the power of these special catalysts to promote various types of reactions.
124 Page 124 of 135
[Sc]*
R
+
[D]
(C)
E*
[Sc]*
R' +
R *
Nu
Nu
O R
R'
R''
Y R''
Y [Sc]*
X R
+
* * R''' R'
HX
Nu
R' * Nu
R
R
R
[Sc]* + XY
O
R'
R'
*
R'
+
O
R'
[Sc]* O
R''
R
R'' * * X O OH
[Sc]*
+
R'
R O
M
R
H2O2
O R
O
MCPBA
te
( )n
OH
Z
X
[Sc]*
Ac ce p O
X
( )n
OH Z
Y
R
* R O
Y
+ N2
( )n
R *
+
R'
R' O
d
+
*
*
[Sc]*
R
O
an
X
Y
X
N H
N H
X
R
*
R'
R
O X
[Sc]*
R'''
+
C X
R'
ip t
B
cr
+
us
A
[Sc]* R X
H N
* ( )n
R' N
Y
Highlights
Recent developments in enantioselective scandium-catalyzed transformations Enantioselective scandium-catalyzed domino reactions Enantioselective scandium-catalyzed Michael additions
125 Page 125 of 135
Enantioselective scandium-catalyzed oxidations
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Miscellaneous enantioselective scandium-catalyzed reactions
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ABBREVIATIONS
us
Ar: aryl Bpy: 2,2’-bipyridine
an
BINOL: 1,1'-bi-2-naphthol Bn: benzyl
M
BNP: Binaphthophosphole Boc: tert-butoxycarbonyl
Ac ce p
Cy: cyclohexyl
te
Cbz: benzyloxycarbonyl
d
Bs: benzenesulfonyl
DBDMH: 1,3-dibromo-5,5-dimethylhydantoin DCE: dichloroethane
de: diastereomeric excess
DFT: density functional theory
DOSP: N-p-dodecylbenzenesulfonylprolinate ee: enantiomeric excess Hex: hexyl HFIP: hexafluoroisopropanol
126 Page 126 of 135
MCPBA: meta-chloroperbenzoic acid Mes: mesyl M.S.: molecular sieves
ip t
Naph: naphthyl
cr
NBS: N-bromosuccinimide NFSI: N-fluorobisbenzenesulfonimide
us
NHC: N-heterocyclic carbene NIS: N-iodosuccinimide
an
Oct: octyl
Pybox: 2,6-bis(2-oxazolyl)pyridine
te
TBS: tert-butyldimethylsilyl
d
r.t.: room temperature
M
Pent: pentyl
Ac ce p
Tf: trifluoromethane sulfonyl THF: tetrahydrofuran TMS: trimethylsilyl Tol: tolyl
Ts: 4-toluenesulfonyl (tosyl)
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