3.12 Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

3.12 Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives B Furman and S Stecko, Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland r 2012 Elsevier Ltd. All rights reserved.

3.12.1 Introduction 3.12.2 Asymmetric Cycloaddition Reactions 3.12.2.1 [2 þ 1] Cycloadditions 3.12.2.2 [2 þ 2] Cycloadditions 3.12.2.3 [3 þ 2] Cycloadditions 3.12.2.4 [4 þ 2] Cycloadditions 3.12.2.4.1 Hetero Diels–Alder reactions 3.12.2.5 Ene Reaction 3.12.3 Stereocontrolled Addition and Substitution Reactions 3.12.3.1 Additions to Imines and Other Electrophiles 3.12.3.2 1,4-Addition Reactions 3.12.3.3 Alkylation of Enolates 3.12.3.4 Aldol Reaction 3.12.4 Rearrangement Reactions 3.12.5 Radical Reactions 3.12.6 Oxidation Reactions 3.12.6.1 Epoxidation Reactions 3.12.6.1.1 Epoxidation of olefins bearing carbohydrate-derived chiral auxiliary 3.12.6.1.2 Epoxidation with carbohydrate-derived oxidants 3.12.6.2 Asymmetric Oxidation of Sulfides 3.12.6.3 Miscellaneous Oxidation 3.12.6.4 Dihydroxylation of Olefins 3.12.7 Reduction Reactions 3.12.7.1 Reduction of Olefins 3.12.7.2 Reduction of Carbonyl Group 3.12.8 Miscellaneous Application of Carbohydrate Auxiliaries 3.12.8.1 Displacement Reactions at Sulfur and Phosphorus 3.12.8.2 Sugars as Ligands for Metal-Catalyzed Processes (Selected Examples) 3.12.8.3 Nazarov Cyclization 3.12.8.4 Photochemical Reactions 3.12.9 Conclusions Acknowledgments References

3.12.1

297 298 298 305 308 313 318 320 320 320 322 324 326 327 329 331 331 332 335 342 343 343 344 344 346 349 349 351 352 353 353 353 353

Introduction

Although the primary significance of carbohydrates rests on their major importance in biology, they represent a unique class of polyfunctional compounds, which can be chemically manipulated in a multitude of ways. In particular, they can be transformed into numerous polymeric, oligomeric, and monomeric molecules of high importance in pharmaceutical, agrochemical, food, and textile industries, to list a few examples. Widely spread research into the chemistry, biochemistry, and biology of carbohydrates has contributed significantly to these sciences and, in consequence, to the modern medicine. Their application in chemical research is particularly interesting. Among the chiral raw materials available from nature, carbohydrates occupy a leading position. Several factors seem to play a decisive role in their status. One of these is the availability of a great variety of structurally diverse carbohydrates and their relatively convenient isolation from numerous and usually inexpensive natural sources. Other valuable features are their high enantiomeric purity and the number of available chiral centers. The synthetic application of carbohydrates in a stereocontrolled organic synthesis has to be considered in context of at least two aspects. Sugars can be employed as starting materials in the target-oriented synthesis (a chiral pool synthetic approach) or, due to their enantiomeric purity, they can serve as stereodifferentiation agents in the formation of a new stereogenic center (a chiral auxiliary approach). The number of available chiral centers or functional groups can be regarded as a major inconvenience because of the protection requirements that increase the number of synthetic steps. The number of carbon atoms present in common sugars,

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298

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

usually four to seven carbon atoms, seems ideal for the elaboration of building blocks according to the modern synthetic strategies. However, many natural product syntheses starting from sugars involve C–C bond cleavage to remove unnecessary carbon atoms (and chiral centers). Although this could be considered a loss of time, money, and a disregard of the atom economy, it is generally compensated by the low cost of naturally occurring carbohydrates. Moreover, due to the high stereodiversity of carbohydrates, it is quite easy to find the most appropriate starting sugar to ensure a good fit between this raw material and the planned target. There are three possibilities in regard to the application of sugars as chiral stereodiscriminating agents in organic synthesis (Figure 1). Most often they are employed as chiral auxiliaries by bonding to reactants, thereby providing a localized asymmetric environment, and they are removed once the new stereogenic centers are established. However, they can be used to render reagent asymmetric and thus can be effective without bonding to the substrates. The third possibility is an application of a carbohydratederived catalyst bearing sugar subunit(s) as a ligand. In this chapter, each of these three approaches for the application of sugars as stereodifferentiating auxiliaries will be discussed.

Sugar-derived chiral reagents

Modern carbohydrate-derived chiral auxillaries

Sugar-linked reactants

Catalysts with sugarderived ligand(s)

Figure 1 Modern carbohydrate-derived chiral auxiliaries.

3.12.2 3.12.2.1

Asymmetric Cycloaddition Reactions [2 þ 1] Cycloadditions

The chiral cyclopropanes are important class of strained small ring compounds. Their diastereoselective and enantioselective preparation has attracted attention for decades.1 One of the reasons is the fact that cyclopropanes are useful intermediates and building blocks in organic synthesis. Moreover, the cyclopropane ring has been found as a key structural element of numerous naturally occurring compounds, especially of the marine origin. Most common methods for the preparation of cyclopropanes from olefins are the Simmons–Smith reaction and rhodium or copper-catalyzed reaction of alkenes with diazoalkanes. A number of chiral auxiliary-based methods has been reported, and many of them enable access to the enantiomerically pure cyclopropyl derivatives after removal of the auxiliary.1e The different chiral auxiliary approaches that have been developed for the reaction with various halomethylmetal reagents can be divided into four general classes, which are depicted in Figures 2 (a)–(d). The carbohydrate-based auxiliaries have been successfully employed in several approaches to the chiral allylic ethers (a) and chiral acetals (b). An interesting and efficient asymmetric synthesis of chiral cyclopropyl derivatives was described by Charette et al.2 The cyclopropanation of allyl b-D-glucopyranosides 1 with diethylzinc/diiodomethane led to the cyclopropane derivatives 2 with a high yield and the diastereomeric ratio better than 100:1. As it was pointed out, the unprotected 2-hydroxyl group at sugar moiety is essential for the efficient diastereofacial differentiation in 1. In the case of the C-2 O-protected b-D-glucopyranosides, the observed diastereoselectivity was poor in the range

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

R1

R1 R2

O

R1

R2

[Aux]

X R3

R3 A Allylic ethers

R

R2

[Aux] R3

B Acetals

R1

2

X

299

X

[Aux]

R3

O

D Enamines or enol ethers

C Unsaturated carbonyl derivatives

Figure 2 Different chiral auxiliary approaches for asymmteric cyclopropanation.

from 2:1 to 3.5:1 only. The hydroxy group at C-2 reacts with diethylzinc and participates in the coordination of Simmons–Smith intermediate with the halomethyl zinc unit (Figure 3).2a,b ‡

BnO BnO

OBn O

R1

Et O

R2

O Zn Zn

R3 I

Figure 3 Transition state for the Simmons–Smith cyclopropanation of allyl D-glucopyranosides.

Moreover, when diethylzinc was used in equimolar amount, rather than a 10-fold excess, the diastereoisomeric ratio dropped dramatically to approximately 3:2. The replacement of b-D-glucose auxiliary by its pseudo-enantiomeric form 3, readily available from L-rhamnose, gave stereoselectively cyclopropanes with the opposite configuration ent-2 (Table 1, entry 2).2a,b Similarly, in the reaction with a-anomeric allyl glucosides corresponding to 1 (4), the high preference of cyclopropanes’ formation with opposite configuration to that of 2 was observed (Table 1, entry 3).2c A cleavage of the chiral auxiliary was accomplished by the ring contraction of the corresponding triflate.3 It is worth noting that Charette, on the basis of assumed stereochemical model of cyclopropanation, proposed simpler auxiliary derived from 1,2-cyclohexanediol (5), obtained via enzymatic resolution. The stereodifferentiation abilities of 5 were comparable with those observed for sugar counterpart (Table 1, entry 4).4 The high diastereoselectivity of cyclopropanation was also observed for b-D-galactopyranose-derived allyl ethers studied by Iglesias-Guerra and coworkers (Table 1, entry 5).5 As noted earlier, the free hydroxyl group at C-2 was essential for assuring a high stereoselectivity of the process. Charette and Coˆte´ have applied this method to the synthesis of all four isomers of coronamic acid, a cyclopropyl amino acid with important agrochemical applications (Scheme 1).6 The (E)-allylic glycoside 7 was subjected to the Simmons–Smith cyclopropanation to afford cyclopropane 8 in a high yield and with perfect diastereoselectivity (499:1). Analogous transformation of (Z)-isomer 9, under the same conditions, proceeded with a lower selectivity. However, lowering the reaction temperature and replacement of CH2I2 by CH2ICl led to 10 in 98% yield and with a 66:1 diastereomeric ratio. After releasing from D-glucose auxiliary, the hydroxymethyl cyclopropanes were converted into desired coronamic acid’s isomers in six steps (Scheme 1). Kang et al.7 described the asymmetric Simmons–Smith reaction of acetal-type substrates (Figure 2(b)) bearing D-fructose unit as a stereodifferentiation auxiliary. The treatment of b-D-fructopyranoside 11 with a,b-unsaturated aldehyde (or its acetal) in the presence of acid promoter led to the transacetalation endo product 12 along with its exo isomer 13 (equation 1).

O O R1

EtO OEt

O

+ HO HO

O O

OR2

PPTS C6H6, Δ

11

O

OR2

OO

O

OR2

OO

+

ð1Þ H

H R1

yield 80−90% dr 1.1−1.8 : 1 (endo:exo)

O

O

12 (endo)

R1 13 (exo)

Generally, endo-acetals afforded best selectivity, especially when O-3 was protected with bulky group (R2), providing (2R,3R)hydroxymethyl cyclopropanes with up to 85% ee (Table 2, entry 1). The corresponding exo-acetals underwent the

300

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Table 1

Carbohydrate-based allyl ether type chiral auxiliaries for Simmons–Smith cyclopropanation

Entry

Chiral auxiliary

1

RO RO RO

Conditions

R1

O

R2

O

OH

Et2Zn (10 equivalent) CH2l2 (10 equivalent) PhMe

Yield (ee)

Product of cleavage

R1

495% (498%)

Reference 2a,b

R2

HO

R3

R3

R: Bn. Bz, Piv

2

1 R1

2

R2

O

O

OBn OBn

HO

R3

Et2Zn (10 equivalent) CH2l2 (10 equivalent) PhMe

R1

495% (498%)

2a,b

R2

HO R3

3

ent-2 3

BnO BnO BnO

O R1

OH O

R2

Et2Zn (10 equivalent) CH2l2 (10 equivalent) MTBE

R1

83  93% (92–94%)

2c

R2

HO R3

R3

4

ent-2 R1

4

OH

4

R2

HO R3 2

Ph O O

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2

R1

O BnO

R1

90  98% (493%)

R3

5 5

Et2Zn (3 equivalent) CH2l2 (3 equivalent) PhMe

R2

O

5

R2

HO R3

R2

O

OH

R1

90  95% (84–100%)

2 R3

6

cyclopropanation process with the lower stereoselectivity (Table 2, entry 2). In these cases, the R2 group in 13 cannot shield either side of alkene as efficiently as in the endo-isomer 12. Kang also noted that the D-psicopyranose (3-epi-11) induced a significantly lower diastereoselectivity under standard cyclopropanation conditions, effectively precluding its application as a chiral auxiliary.7 Recently, Iglesias-Guerra and coworkers8 have investigated the application of D-glucose, D-xylose, and L-rhamnose as chiral auxiliaries for the asymmetric cyclopropanation of acetal-type olefins. The acetals were obtained from (E)-cinnamaldehyde diethoxy acetal and a-methyl-(E)-cinnamaldehyde diethoxy acetal. Generally, the diastereomeric excess observed for reactions of (E)-cinnamaldehyde sugar-acetal was higher than that observed for the a-methyl-(E)-cinnamaldehyde analogs. The diastereoselectivity of cyclopropanation reaction of a-L-rhamnopyranose-derived acetals 14 and 15 depended on the configuration of the acetal carbon.8a The higher diastereoselectivity was observed for the endo-isomer 15 (Table 2, entries 3 and 4), as in the case of Kang’s fructopyranose-derived auxiliaries. Stereoselectivity for acetals with a-D-glucofuranose unit was very different depending on the functionalization on C-3 atom of the carbohydrate; a higher asymmetric induction was observed for 16a with the 3-hydroxy group free, whereas its O-protected counterpart (16b) provided only a slight stereodifferentiation of double bond faces (Table 2, entry 5).8a In the group of compounds with a six-membered acetal ring, the stereoselectivity of cyclopropanation process depended on the configuration of the carbohydrate moiety (Table 2, entries 6–8). The a-D-xylofuranose-based acetals 18 provided higher diastereoselectivity than compounds bearing the a-D-glucopyranose auxiliary 17.8a,b Generally, the former acetal gave the best results for a series of both five- and six-membered acetals. To summarize, the observed stereoselectivity for Kang and Iglesias-Guerras’ approach was lower than that typically observed using Charette’s method, probably due to a greater conformational flexibility and a less effective complexation of zinc ion by the sugar moiety. In comparison, much higher levels of diastereoselectivity have been realized using the tartaric acid-based chiral auxiliary 19 (see Table 2, entry 9).9 The cyclopropanation of olefins using the transition metal-catalyzed decomposition of diazoalkanes is one of the most extensively studied reactions of the organic chemistry arsenal.1,10

BnO BnO

7

BnO BnO

Et2Zn(4 equivalent) CH2I2(5 equivalent)

OBn TIPSO O O OH

TIPSO SugO

CH2Cl2, −30 °C Et

OBn TIPSO O O OH

Et2Zn (4 equivalent) CH2ICl (5 equivalent) CH2Cl2, −60 °C

10

82%

HOOC

83%

NHBoc HOOC

Et

(−)-Allo-coronamic acid

Et 5 steps

(2 steps from 8, 75%)

NHBoc HOOC

42%

5 steps TIPSO HO

dr >66:1 yield 98%

41%

TIPSO

Et

(−)-Coronamic acid

NHBoc HOOC

Et

(+)-Allo-coronamic acid

RuCl3, NaIO4 Et

91%

HOOC

Et 5 steps

(2 steps from 10, 80%) Scheme 1 The synthesis of all four isomers of the coronamic acid.

64%

NHBoc HOOC

Et

(+)-Coronamic acid

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Et

TIPSO RuCl3, NaIO4

Et

TIPSO SugO

5 steps

Et

dr >99:1 yield 93%

8

9

TIPSO HO

Et

301

302

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Table 2

Carbohydrate-based acetal-type chiral auxiliaries for Simmons–Smith cyclopropanation

Entry Olefin

1

Chiral auxiliary

R1

EtO

O OEt

O

R1: Ph, Me, n-C5H11, BnOCH2 R2: Me, Bn, CH2Ar

O

OR2

OO 12

H

Conditions

Yield (ee)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) DCE  20 1C to 0 1C

85–90%

Product of cleavage (R)

Reference

(R)

R1

OH

7

OH

7

(64–85%)

R1

2

O

O

O

OR2

H

13

OO

Et2Zn (5 equivalent)

82–88%

CH2l2 (10 equivalent) DCE  20 1C to 0 1C

(33–54%)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2  15 1C to r.t.

81% (26%)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2  15 1C to r.t.

75% (56.5%)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2  15 1C to r.t.

64–66%

(S)

(S)

R1

R1 3

EtO

Ph OEt

OMe O

BnO O

O 14

R

Ph

OMe

4

O

BnO O

O 15

OH

8a

R Ph

OH

8a

R Ph

Ph

5

H O

O O

O O

R1O Ph 16a R1: H 16b R1: Bn

(49% for 16a)

OH (R)

Ph

(from 16a)

(4.8% for 16b)

OH

16a R1: H 16b R1: H

Ph 6

Ph

8a

(R)

O O BnO

Et2Zn (5 equivalent) CH2l2 (10 R1 OMe equivalent) CH2Cl2 R 1 : OH, OBn, NHAc 17  15 1C-r.t.

O

(from 16b) OH

62–76% (R)

(20–46%)

8a

(R)

Ph

(Continued )

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives Table 2

Continued

Entry Olefin

Chiral auxiliary

R1

7

R1

R2

EtO

O O

R2 OEt R1 : H, alkyl R2 : H, alkyl, aryl

O

O O

EtO

O

H

O H 18a R: H 18b R: alkyl

8

O

H

O O

H

OEt 18c

R1

9

303

R1 2

2

O

R

R

O

COOR

O COOR

19

Conditions

Yield (ee)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2  15 1C to r.t.

85–87%

Product of cleavage

Reference

OH

8a,b

(R)

(R1: H, 80–100%)

R2

( R)

R1

(R1: alkyl, 50–76%)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) CH2Cl2  15 1C to r.t.

79% (67%)

Et2Zn (5 equivalent) CH2l2 (10 equivalent) Hexane  20 1C to r.t.

50–95%

OH

8b

R1

9

2

R

CHO

(93–97%)

The copper- and rhodium-catalyzed cyclopropanation of sugar-derived enol ethers 20 and 21 was investigated by Schumacher and Reissig (equation 2).11 In the presence of Cu(acac)2, the reaction of carbohydrate enol 20 with methyl diazoacetate afforded a mixture of cis- and trans-cyclopropanes 22 and 23 in the ratio 1:4. The minor cis-product 22 was obtained with 95% de, whereas the de of the major isomer 23 did not exceed 5%. A similar result was obtained when Rh2(OAc)4 was applied as a catalyst. Change of catalyst system to CuOTf/24 complex enhanced the stereoselectivity of the cyclopropanation to afford the trans-cyclopropane 23 almost exclusively (yield 74%, 22:23 ratioo3:97) and with de up to 60%.

O

O O

O

O

catalyst

O N2

O or

COOR

O

O

COOR

O

22 20

OSug +

DCE

O O

OSug

COOR

ð2Þ

23

21 O

O N

N

24

The same trend was observed in the case of enol ether 21. In the presence of CuOTf/24, the cyclopropane 23 was obtained as a major isomer (yield 54%, 22:23 ratio 12:88) with 65% de Replacement of methyl diazoacetate by its t-butyl congener led to the increase of the reaction yield and the trans-isomer was formed exclusively. Unfortunately, for both enol ethers 20 and 21, the authors did not report the absolute configuration of major cyclopropane derivatives nor did they provide a detailed discussion of the stereochemical outcome of reported reactions (especially the mechanism by which both the carbohydrate moiety and bis(oxazoline) ligand cooperate).

304

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Recently, Ferriera et al.12 have applied carbohydrate-derived diazoacetates in metal-catalyzed cyclopropanation of styrene (Scheme 2). The reactions of diazoacetates 25a–e, leading to the cis- 26 and trans-adducts 27, were carried out either in the presence of Rh2(OAc)4 or CuOTf-fluorous bis(oxazoline) 28 complex. Regardless of whether Ru(II) or Cu(I) catalyst was applied, the diastereomeric excess of the main product 27 was similar. According to authors, such a result suggests that chelating sugar moiety is responsible for control of the diastereoselectivity in the cyclopropanation. In the case of copper(I) catalyst, higher trans/ cis ratios were achieved similar to Schumacher and Reissig11 observations. The best cis/trans selectivity and diastereomeric excess were obtained for the D-ribose-derived diazoacetate 25a (26/27 ratio 5:95, for 26 53% de, for 27 60% de), however, regrettably, the yield was poor (20% when Ru(II) was used and 30% in presence of copper(I) catalyst).

O OSug N2

Ph

catalyst

+

Ph +

CH2Cl2

COOSug

25a-e

COOSug

26 C8F17(H2C)3 (CH2)3C8F17

O

OMe O

O

O

O

N

N

28

O

O

O

25a

25b

O

O O

O

O

O

O O

O

25c

O

O

O

O O

27

O

O

O

25d

25e

Scheme 2 The carbohydrate-derived diazoacetates in metal-catalyzed cyclopropanation of styrene.

Carbohydrates, alongside their application as a chiral auxiliary in the classical way, have also been used as structural elements of chiral ligands for enantioselective metal-mediated reactions. For example, the carbohydrate-derived ligands were employed during the asymmetric cyclopropanation of olefins with diazoacetates. The diamine and diimine ligands 29–32 derived from a-D-glucose and a-D-mannose were used in the Cu(MeCN)4BF4 mediated cyclopropanation of styrene with ethyl diazoacetate.13 Although the yield of this process was often very good (75–90%), the observed cis/trans selectivity was moderate (from 3:2 to 7:3 trans/cis) and the enantiomeric excess was found to be poor (up to 55% ee for trans-adduct and up to 40% ee for cis-one).

O

O O

Ph

OBn

O N 29

30

NH HN Ar

Ar 31

OMe

O

N

N Ar

O

Ph OMe

O

NH HN Ar

O O

Ph OBn

O

N Ar

Ar

O O

Ph

Ar

Ar 32

Boysen and colleagues14 introduced C2-symmetrical bis(oxazoline)-BOX ligand 33 derived from the D-glucosamine and applied it in the copper-catalyzed cyclopropanation of styrene derivatives with diazoacetates (Scheme 3). The reasonable selectivity (up to 7:3) and a good enantiomeric excess (up to 82% ee) were achieved with ethyl diazoester whereas the bulky t-butyl diazoester decreased the trans selectivity as well as both the yield and ee Recent studies revealed the strong steric and configurational effects of position 3 of the sugar unit on the asymmetric induction of cyclopropanation.14b

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O AcO

O

O N AcO

305

O

N

OAc

AcO

OAc

OAc

33 CuOTf-0.5 C6H6

N2

+

COOR

(1.1 mol%)

Ph

Ph

COOR

+

trans-(1S,2S) R: Et

Ph

COOR

cis-(1S,2R)

yield 60% (trans/cis 70:30) 82% ee 82% ee

R: t-Bu yield 60% (trans/cis 50:50) 74% ee 68% ee Ph N2

Ph

+

COOR

Ph

Ph

COOR

(S)-enantiomer R: Et

yield 85%, 75% ee

R: t-Bu yield 75% 79% ee Scheme 3 The cyclopropanation of styrene derivatives with diazoacetates in the presence of glucose-derived C2-symmetrical bis(oxazoline)-BOX/ copper(I) complex.

3.12.2.2

[2 þ 2] Cycloadditions

The cyclobutanes,15 oxetanes,16 azetidines,17 b-lactones,16 and b-lactams17 are all four-membered ring compounds regarded as important buildings blocks in organic synthesis. They are also widely found as structural elements of a vast number of bioactive compounds. These two reasons make the stereocontrolled methods for their formation an intensively scrutinized field of research. The common routes of the synthesis of these strained species involve the cyclization and cycloaddition reactions. According to the Woodward–Hoffman rules, the concerted thermal [2 þ 2] cycloadditions are symmetry-forbidden, but should proceed via supra-antara-facial approach of the reactants. The [2 þ 2] cycloaddition reactions of ketenes and related reactive intermediates proceed by a stepwise mechanism. However, the photochemically induced [2 þ 2] cycloadditions are symmetry allowed. One method of the formation of oxetane ring is the photocycloaddition of olefins to carbonyl compounds known as Paterno–Bu¨chi reaction. The examples of an asymmetric variant of this process, assisted by the carbohydrate-based auxiliaries are limited. Several sugar-bound phenyl glyoxylic esters were tested by Scharf and coworkers18 However, in a photo-induced reaction with furan, only the D-arabinopyranose derivative 34 furnished oxetanes 35 and 36 with a good diastereoselectivity (equation 3).

Ph O

O O O

O

O hv yield 80%

Ph

O

34

O

O

O

O

+

SugOOC Ph 35

COOSug Ph

ð3Þ

36 dr 1:9

Lower diastereoselectivity was also observed during the photochemical cycloaddition of furan to a-D-ribohexofuranoso-3-ulose derivative investigated by Zamojski and Jarosz.19 Kunz and Ganz described an approach to the nonracemic cyclobutanes, starting from vinyl D-galactopyranosides and 20 D-glucofuranosides. Dichloroketene, generated from trichloroacetyl chloride in the presence of Zn/Cu metal couple, reacted with 37 at room temperature to give a 4:1 mixture of diastereoisomeric cyclobutanones 38. These products were found to be highly

306

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

unstable and could be isolated only after subsequent stereoselective reduction of carbonyl function with NaBH4. Similar transformations of 3-O-alkenyl D-glucofuranoside 39 yielded corresponding cyclobutanols with a selectivity ranging from 2:1 to 5:1. PivO PivO

PivO

OPiv O

PivO

O OPiv 37

R1O

OPiv O

O OPiv

38

O

O

O

BzO

R1O

Cl Cl

O

O O

OBz

R2

OBz

BzO BzO BzO

OBz O

40

O

O

41

39

The same process was investigated by Frauenrath and coworkers.21 The 1-O-vinyl protected a- and b-D-glucopyranosides, a-D-ribopyranoside as well as the b-D-mannopyranoside derivatives were chosen as the substrates in order to study the influence of different carbohydrate residues, anomeric configurations, and protecting group schemes. In all cases, the major diastereoisomer resulted from an addition of the dichloroketene from the si-face of the olefin in the 1-O-vinyl glycosides, as observed in Kunz’s examples. The generally observed diastereoselectivity for the glucopyranosides was moderate. However, a good diastereoselectivity was found for the 1-O-vinyl a-D-ribopyranoside 40, and, in particular, for 1-O-vinyl b-D-mannopyranoside 41. The [2 þ 2] cycloaddition of ketenes to imines, known as Staudinger reaction, is a key method of the formation of 2-azetidinone ring – the fundamental structural element of numerous bioactive compounds, particularly the b-lactam antibiotics.17,22 Several examples of asymmetric Staudinger reactions, where the stereoinformation originates from the carbohydrate auxiliary, are known. The sugar-based chiral auxiliary can be bound either to imine or to the ketene reagent. Borer and Balogh23 used D-glucal-derived chiral carboxylic acid 42 as a ketene precursor in the reaction with cinnamaldehydederived imine 43 (Scheme 4). However, the corresponding cis-b-lactam 45, obtained after the acid-catalyzed removal of the sugar auxiliary from 44, displayed only 70% enantiomeric enrichment.

AcO

OAc O

Ph +

O O 42

OH

PMP

(COCl)2, DMF Et3N

AcO

OAc O Ph

O

N 43

44 O

AcOH/H2O THF

N PMP

Ph

HO N O

PMP 45

70% ee Scheme 4 Synthesis of b-lactams via asymmetric Staudinger reaction.

Ko¨ll and coworkers24 applied the D-xylose-derived oxazolidinones for a highly stereoselective [2 þ 2] cycloaddition to imines. Treatment of acid 46 with the Mukaiyama reagent 47 led to the ketene, which after the reaction with imines furnished cis-b-lactams 48 with an outstanding diastereoselectivity and in good yield (Scheme 5). In further experiments, authors revealed that under the same conditions, the 3-thiazoline-derived cyclic imines of type 49, possessing the fixed cis geometry of the double bond, led to the formation of corresponding bicyclic trans-b-lactams 50 exclusively. Unfortunately, authors were unable to assign the absolute configuration of compounds 50.24 Jun and coworkers25 applied the D-mannitol-derived oxazolidinone chiral auxiliaries 51 for the asymmetric Staudinger reaction. However, these auxiliaries displayed poor stereodifferentiation properties and afforded cis-lactams (as a major product) along with trans-isomers. Chiral imines, derived from nonracemic amines, have also been successfully applied in the asymmetric Staudinger synthesis of b-lactams. In most examples, chiral amines derived from the D-glucosamine or D-galactosoamine were used.26 These examples will be discussed in detail in Chapter 4.14 which discusses application of aminosugars as chiral auxiliaries. An alternative method of stereocontrolled formation of a 2-azetidinone ring is the reaction of electron-deficient isocyanates with chiral electron-rich alkenes such as vinyl ethers or acetates.17,27 The commonly used reactive chlorosulfonyl isocyanate (CSI)28 undergoes stereospecific syn-addition to alkenes via concerted mechanism.29 The chlorosulfonyl group can then be reductively removed from the nitrogen atom. Enol ethers incorporating nonanomeric hydroxyl (e.g., 52a–e) are not conventionally used as a chiral auxiliary, since the subsequent removal of sugar moiety requires the use of destructive oxidative methods. Nevertheless, it is worth to examine the stereochemical course of such cycloaddition reactions, as documented by Chmielewski and coworkers30 In the presence of sodium carbonate as a base, CSI was reacted with 3-O-vinyl derivatives of 1,2-O-isopropylidene-a-Dglucofuranose and a-D-xylofuranose with the efficient stereocontrol. Reactions of 5,6-O-isopropylidene D-glucofuranose 52a (Scheme 6) demonstrated a weak selectivity and a low yield,30a similarly as it was observed by Ganz and Kunz in reactions with dichloroketene. In contrast, the reaction with the 5,6-ditosylo derivative 52d gave exclusively (40 R)-azetidinone 53d. For the D-xylo series of vinyl ethers, protecting of O-5 with tosyl (52b) or tri(i-propyl)benzenosulfonyl (TIBS, 52c) groups resulted in a low

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

N

MeO MeO

N O

+ COOH

O

46

Cl

MeO

I

O N

R1

R2

R1:

Ph, R2: Bn, PMP

MeO

2 N R

N

Et3N CH2Cl2

Ph

O

O

47

307

O

H

R1

O 48 yields 58−71% dr >99:1

O H S

S

N

R R 49 Scheme 5

D-Xylose-derived

N*

HOOC

N

O

N

O

O

R R

O

O

O

R R

R R

50 (relative configuration)

51

oxazolidinones as chiral auxiliaries for stereoselective [2 þ 2] cycloaddition to imines.

diastereoselectivity of corresponding lactams 53b–c, whereas the triphenylsilyl derivative 52e gave exclusively the (40 R)-azetidinone 53e. Single products were also obtained in the case of 5-O-trityl protected xylofuranose 1-butynyl ethers 52f–g.30c Generally, the large substituents at C-5 of the furanose ring effectively shielded the re-face of the vinyl moiety (Schemes 6, 54) resulting in the diastereoselective formation of b-lactams 53.30a,b R1

R2O

O

(i) CSI, Na2CO3 (ii) Red-Al

O

R1

O

O

R

HO

(R)

NH O

‡

OR2 O

O

O

O

O

N

O

52a–e

O

SO2Cl 53a–e

O

O

O

O O

O 52a

O

52b 52c 52d 52e

R1 H H CH2OTs H

R2 Ts TIBS Ts SiPh3

54

de (%) 33 54 >95 >95

TIBS: 2,4,6-tri(i-propyl)benzenosulfoyl

O TrO O

O O

52f E-isomer 52g Z-isomer

Scheme 6 Cycloaddition of chlorosulfonyl isocyanate (CSI) to 3-O-vinyl-glycofuranoses.

The [2 þ 2] cycloaddition of CSI to 5-O-vinyl derivatives of 1,2-O-isopropylidene-a-D-glucofuranoses 55a-f showed that, in this case, the stereoselectivity of the reaction can be controlled (Scheme 7).30b,d The presence of a small substituent at the C-3 carbon atom on the top of the furanose ring (R1), afforded excellent asymmetric induction preferentially forming 4-alkoxy-2-azetidinones 56a–f with (S)-configuration at C-40 carbon atom. Such an outcome indicates that the attack of isocyanate occurs from the face occupied by R1 group. In addition, the TIBS group effectively blocks the si-face of olefin that corresponds to the preferable formation of (S)-isomer as a major diastereoisomer (Schemes 7, 57). Chmielewski and coworkers31 also demonstrated that vinyl ether 58 (derived from L-tartaric acid and structurally related to 55) also provides a high stereocontrol of cycloaddition of CSI (Scheme 8). The high stereoselectivity and formation of single products were also observed for the enol ethers 59 and 60 bearing sugar units representing pseudo-enantiomeric relation (Scheme 8).32 A comparison of steady-state NOE coefficients measured for vinyl-substituted isopropyl ethers with conformations generated by a

308

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

molecular mechanics program allowed a characterization of the most favorable ground state conformations. Bearing in mind the Hammond postulate, the authors could propose consisted stereochemical model of [2 þ 2] cycloaddition of CSI to vinyl ethers.32c

O

O

(i) CSI, Na2CO3 (ii) Red-Al

O

TIBSO

TIBSO R1 R2

R2

O

O O

‡

(S)

(S)

(S)

R1

H

O (R) (R)

HN

O

H

TIBSO H

(R)

H

O

H

O N O

55a–f

56a–f 55a 55b 55c 55d 55e 55f

R1

R2

OBz CH2SMe OBn OMe H H

H 4 H 38 H 72 H 92 H >95 CH2SMe >95

O

R1

O R2 O SO2Cl

57

de (%)

Scheme 7 Cycloaddition of chlorosulfonyl isocyanate (CSI) to 5-O-vinyl-glycofuranoses.

O O

(i) CSI, Na2CO3 (ii) Red-Al

O

H O

NH O

O

TIBSO

OSug

de 91%

TrO O

NH

O

TIBSO

58

OSug

TrO

O

O

O

O

NH

O 59

60

O

OEt

Scheme 8 Stereocontrolled cycloadditions of CSI to vinyl ethers and alkoxyallenes.

The [2 þ 2] cycloaddition of CSI to chiral alkoxyallenes leads to 3-alkylidene-2-azetidinones, a structural motif present in many antibiotics and b-lactamase inhibitors.33 The same group also investigated the reactions of sugar-derived alkoxyallenes (e.g., 61). These reactions were also sterically controlled, but proceeded with a significantly lower asymmetric induction in comparison with that found for the corresponding vinyl ethers (equation 4).34 O TrO

O O

O

O (i) CSI, Na2CO3 (ii) Red-Al

O

TrO O H

O NH

ð4Þ

O 61 de 40%

3.12.2.3

[3 þ 2] Cycloadditions

The 1,3-dipolar cycloaddition reactions are the powerful tool in the synthesis of five-membered heterocycles. These reactions proceed via concerted suprafacial mechanism which ensures the complete stereochemical information transfer from substrates to

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

309

the products. With these reactions, up to four stereogenic centers can be created in a single step.35 Stereodifferentiating groups can be introduced either in the 1,3-dipole or in the dipolarophile. Among various 1,3-dipoles, the nitrones are particularly important.36 Their functionality, stability (in most cases), simple synthesis, and reactivity make them a powerful and useful reagents, which found a number of applications in the synthetic organic chemistry including target-oriented synthesis.36,37 The cycloaddition of nitrones to alkenes or alkynes leads to the formation of isoxazolidines or isoxazolines, respectively, being important precursors of b-amino alcohols, b-amino aldehydes, or b-amino acids, for example. There are several stereochemical aspects concerned with the reactions of nitrones with olefins. Some nitrones, particularly those having alkoxycarbonyl function at the carbon atom of the double bond can undergo (E)/(Z)-isomerization to cause formation of diastereoisomeric cycloadducts. In addition, the cycloaddition of nitrones to olefins may proceed via either endo- or exo-transition states. Carbohydrates are wildly used in nitrone/olefin cycloaddition reactions. The sugar unit may be attached either to sp2-carbon atom or to nitrogen. The former case (C-glycosyl nitrones) is typical for the chiral pool synthetic approach in target-oriented synthesis and many of this type sugar-derived nitrones are known.36–39 Commonly, the latter approach (N-glycosyl nitrones) is applied when carbohydrate unit acts as a classical chiral auxiliary. A detailed study on the cycloaddition reactions involving N-glycosyl nitrones (e.g., D-mannofuranosylnitrone 61) was carried out by Vasella’s group.40 The reactions with methyl methacrylate led to the corresponding N-glycosyl-isoxazolidines type 62 with a high diastereoselectivity (equation 5).40a,b The preferred formation of (5S)-diastereoisomer was explained on the basis of kinetic anomeric effect, which increased the reactivity of certain conformers. Attack of the dipolarophile follows with a high selectivity from the direction of the furanose C1–O bond (from behind the nitrone as written in equation 5). Such a direction of attack is preferred because the delocalization of the n orbital developing on the nitrogen atom (in 62) into the s orbital of the ring C–O bond can occur at an early phase in the transition state (kinetic exo-anomeric effect).109 In contrast to reactions of 61, the diastereoselectivity for D-ribo analog is lower.40b

O

O R

O O O R H

N O

61a R: H 61b R: Me

R

R

COOMe *Sug N O (5S)

ð5Þ

62a R: H, yield 97%, (5S):(5R) = 87.5:12.5 62b R: Me, yield 98%, (5S):(5R) = 95:5

In related cycloadditions, the prochiral nitrone of type 61 (such as, e.g., the nitrone derived from acetaldehyde) did not show high diastereoselectivity with regard to the configuration at C-3 of the isoxazolidine. This effect could be traced back to the low configurative stability of the nitrone itself. Nitrone 61 and its pseudo-enantiomeric ribofuranosyl analogs with N-protected 40c L-vinylglycine esters were employed in a double diastereodifferentiation. Although 61 gave the diastereomeric isoxazolidines in a ratio of only 3:1, the L-vinylglycine esters and the D-ribose analog apparently form a ‘matching pair’ and react to give a single stereoisomer. This double asymmetric induction system was further applied by Whitney and Mzengeza during the synthesis of antibiotic acivicin.41 These studies were further extended to allow the asymmetric synthesis of proline analogs.42 Thus, the N-glycosyl-isoxazolidines 63 were prepared by reacting N-glycosyl-C-alkoxycarbonyl nitrones 65, obtained in situ from corresponding oxime 64 and glyoxylate, with ethylene (Scheme 9).43 The diastereoisomeric isoxazolidines 63a and 63b were separated and utilized in the synthesis of 5-oxaproline esters 66 and amides 67 (Scheme 9).42 In a similar fashion, Vasella and Voeffray43 performed the synthesis of analogs of captopril 68, for example, its epimer 69. In these cases, the ribose-derived oxime was utilized as the precursor of the cycloaddition component.43 Vasella and Voeffray neatly demonstrated the versatility and usefulness of their method in the synthesis of 1-deoxynojirimycin 70.44 The corresponding isoxazolidine 71 was obtained in the reaction of D-mannofuranosylnitrone, derived from oxime 64, and furan (Scheme 10). The promising results demonstrated by Vasella’s chiral sugar-derived nitrones encouraged other groups to continue further development of this methodology. For example, Goti’s group45 applied Vasella’s approach in the enantioselective synthesis of isoxazolidines. N-Glycosyl nitrones have also been used as a precursors in the synthesis of (2S)-4-oxopipecolic acid (an unusual amino acid),46 hydroxypyroglutamic acids,47 and other amino acids48 or in synthesis of (þ)-negamycin 72 and ()-3-epi-negamycin 7349 to name just a few examples. In 2005, an efficient synthetic route to isoxazolidinyl analogs of tiazofurin (75) was developed by Merino et al.50 Tiazofurin 74 is a thiazole-containing C-nucleoside that has demonstrated a significant activity in vitro against a number of model tumor systems.51 The key step consisted of using the N-ribosyl nitrone as starting material, in which the carbohydrate unit acted both as a chiral auxiliary and as a N-protecting group.

310

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

OH

O O

ROOC

OR

OH

O

O

O

N

O

O O

O

N

ethylene

O

O

O

COOR N Sug

O

+

63a 64

COOR N Sug 63b

65

O

N R1

O

COOR2

66

COOH

N N R

COOH

N

CONH2 O

67

O

SH

SH

68

69

Scheme 9 1,3-Dipolar cycloaddition of N-glycosyl-C-alkoxycarbonyl nitrones to ethylene.

(i) OHC-COOt-Bu (ii) furan 64

t-BuOOC

t-BuOOC

(i) OsO4 (ii) acetone, H+

H O

O

40%

O

O

O H

H

OH

HO

Sug N

Sug N 38%

OH

H

N H

O

71

OH

70

Scheme 10 The synthesis of 1-deoxynojirimycin.

Very recently, Bode and coworkers52 demonstrated the utility of both D-mannose- and D-gulose-derived N-glycosyl nitrones in the asymmetric synthesis of enantiopure isoxazolidinone monomers for the synthesis of b3-oligopeptides. OH

NH2 O

H2N

OH N H

N

COOH

NH2 O

H2N

N H

S

S

O N HO

OH 74

COOH

(−)-73

(+)-72

HO

N

CONH2

N

HO

CONH2

N O H 75

In 2004 Tamura et al.53 synthesized (þ)-(3R,5S)-3-hydroxycotinine 76, the main metabolite of nicotine found in urine of smokers, by cycloaddition of N-(L-gulosyl)-C-(3-pyridyl)nitrone 77 with (2S)-N-(acryloyl)bornane-10,2 sultam (78) (Scheme 11). The reaction of nitrone 77 with (2S)-78 in refluxing CH2Cl2 afforded cycloadduct 79 as the major product, along with a small amount of other isomers, with a high selectivity 9:1, respectively. However, the cycloaddition of nitrone 77 to (2R)-78 furnished a complex mixture of cycloadducts. These results clearly showed the combination of nitrone 77 and (2R)-78 to be a mismatched pair and that of nitrone 77 and (2S)-78 to be a matched pair. The cycloadduct 79 underwent the hydrolytic removal of the L-gulosyl group by treatment with hydrochloric acid to give N-deprotected isoxazolidine, which was further elaborated to (þ)-76 (Scheme 11). The Vasella-type nitrones were also applied in the preparation of modified nucleosides, particularly the isoxazolidinyl nucleosides.54 For example, the reaction of N-furanosyl nitrone 80 with vinyl acetate gave the 1:1 mixture of two isoxazolidines epimeric at C-5 but with a high diastereofacial selectivity. After separation of isomers, an introduction of thymidine unit and removal of the sugar auxiliary afforded N,O-nucleoside 81, unsubstituted at the nitrogen atom (Scheme 12).54a Fisˇera et al.55 revealed that the unprotected nitrones like 82 derived from D-glucopyranosyl oxime can also be used in the [3 þ 2] cycloaddition reactions. The reaction of 82 with N-arylmaleimides gave the anti-isoxazolidines 83 as major isomers (equation 6). The syn-diastereoisomers 84 were formed with a diastereomeric excess of more than 90% only when Ar2 group was

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

N

O H O O

OH

O

XS O H O N

H

(2S)-78

O

O H

N

N N

O

O

O

77

O

N

COXS

O (+)−76

79

N

XS:

311

O S O Scheme 11 Tamura’s synthesis of (þ)-(3R,5S)-3-hydroxycotinine 76.

1:1 mixture at C-5 OAc O 5 O N

EtOOC O

OAc

N

[Si]O

O O

[Si]O

18 h 80%

O

COOEt O

O H

H N

N O

N

O

EtOOC

O 81

80 [Si]: SiPh2t-Bu Scheme 12 [3 þ 2] cycloaddition of N-furanosyl nitrone 80 with vinyl acetate.

2,6-disubstituted. The hydrogen bond between the nitrone oxygen and the hydroxyl group at C-2 was implied in effective control of the dipole conformation and ultimately the stereoselectivity of cycloaddition.

HO HO

OH O OH 82

O O N

Ar2 N

O

H

O

H

Ar1

N Ar2

Sug N Ar1

H 83

O

O

O

O

N Ar2

Sug N Ar1

H

ð6Þ

O

84

The intramolecular 1,3-dipolar cycloaddition of N-glycosyl alkenylnitrone was reported by Tamura et al.48 The N-mannosylnitrone 85 treated with (E)-p-methoxycinnamyl alcohol in the presence of a catalytic amount of TiCl4 underwent transesterification to afford nitrone 86, followed by the in situ intramolecular cycloaddition to give isoxazolidine 87 as a single isomer in 75% yield (Scheme 13). Next, this cycloadduct was utilized as a building block in the preparation of aminoacyl side chain of nikkomycin Bz 88. The cycloaddition of azomethine ylides to olefins provides a convenient access to pyrrolidines, which are useful synthetic intermediates. Moreover, a pyrrolidine ring is present in numerous bioactive compounds of natural origin. Many pyrrolidines are also versatile chiral auxiliaries or ligands in chiral catalysis (see Chapter 4.17). Roussi and coworkers56 reported the synthesis of highly reactive ylides by deprotonation of conformationally locked N-oxides 89a and 89b bearing sugar-derived chiral auxiliary. Deprotonation of N-oxide 89a in the presence of (E)-stilbene gave pyrrolidines 90a and 91a in 40% yield, whereas the reaction of 89b provided the mixture of 90b and 91b in 60% yield (Scheme 14). In both cases, the resulting pyrrolidines were accompanied by amines 92a,b arising from the decomposition of unstabilized ylides. The stereoselectivity of cycloadditions was moderate (c. 70%). It is interesting to note that the reaction of 89a favored formation of the (3R,4R) product 90a, whereas the derivative 90b led to the (3S,4S)-diastereoisomer 91b as a major product. This selectivity reversal was rationalized by the minimization of electronic interaction between sugar’s oxygen atoms and negative terminus of the dipoles in the corresponding transitions states. The pyrrolidines were released from the auxiliary by the treatment with CHCl3/aqueous NaOH followed by the basic hydrolysis. The auxiliary sugars were recovered as the 2,3-anhydro derivatives ready for reuse, in a nearly quantitative yield. As it was mentioned at the beginning of this subchapter, the carbohydrate-derived auxiliaries can also be linked to the dipolarophile. For example, a highly selective [3 þ 2] cycloadditions were achieved using acryloyl esters of chiro-inositol derivatives as the chiral auxiliaries.57 The ester 93 reacted with nitrile oxides to give (S)-isoxazolines 94 with diastereoisomeric excess of 90% (equation 7). The chiral auxiliary was removed by reduction of ester group. The author suggested that observed stereochemical outcome was result of an approach of 1,3-dipole to s-cis conformer of 93 providing corresponding (S)-cycloadduct, whereas minor isomer came from cycloaddition to the s-trans conformer. In both cases, the bulky silyloxy group prevents the attack from the re-face of the olefin double bond.

312

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

O

O

OH

N

O

O

MeO

MeOOC

O O

O

TiCl4

O

O

O

85

O

PMP N

O

O

O O

H

O

O

O

O

86

H N

PMP

O

O

87

COOHOH HN

OH

H2 N

O

O

O N

HO

NH O OH

88

Scheme 13 The intramolecular 1,3-dipolar cycloaddition of N-glycosyl alkenylnitrone. The preparation of aminoacyl side chain of nikkomycin Bz 88.

Sug

N

O

Ph

Ph

LDA

Ph

N

Sug

Ph +

N Sug Ph

89a,b

N Sug

OH O

O O

89a Sug:

Ph 89b Sug:

Sug

N

H

Ph 90a,b

Ph

+

91a,b

O O

92a,b

O

OMe

OH

OMe

Scheme 14 An application of sugar-derived auxiliaries for a stereocontrolled cycloaddition of azomethine ylides.

O

Ph Si O O

O O

O

ð7Þ

O

O s-cis

94 yields 54−95%

N R

93

R

(S)

C6H6, r.t. O

O N

Sug O

The 1,3-dipolar cycloadditions to sugar-derived acrylates were also investigated by Biao and coworkers58 The acryloyl ester 95, derived from glucose, and aromatic nitrile oxides provided corresponding isoxazolines 96 with a moderate diastereoselectivity up to 70% (equation 8). In this case, the re-side of double bond of 95 is more readily accessible than the si-side, which is blocked by the bulky 5,6-isopropylidene group.

O O

O

O

Ar

N O

N O

O

Ar O

O

O

O 95

96 upto 70% de

ð8Þ Sug

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

313

Another example of 1,3-dipolar cycloaddition performed using the sugar-derived chiral dipolarophile was reported by Tadano and coworkers.59 Benzonitrile N-oxide and pivalonitrile N-oxide were reacted with methyl 4-O-acryloyl-6-deoxy-2,3-di-O(t-butyldimethylsilyl)-a-D-glucopyranoside 97, furnishing the respective cycloadducts in excellent yield, each as a single diastereoisomer. (equation 9). O

O R

O

O (Si)O

N O

N

97 (Si): SiMe2t-Bu

O O

O

(Si)O OMe

ð9Þ

R: Ph: yield 96%; de 98% R: Piv: yield 90%; de 98%

O

O O

O O

98a

O

O (Si)O

R

(Si)O OMe

O

O

O

O O

O

O

O O 98b

O

O 98c

Cycloaddition of nitrile oxides to vinyl ethers was investigated by Rollin and coworkers.60 Among the studied carbohydratederived vinyl ethers 98a–c, a particularly high diastereoselectivity was observed for the D-fructo derivative 98a.

3.12.2.4

[4 þ 2] Cycloadditions

The Diels–Alder reaction is a standard method for the six-membered ring formation.61 In principle, it allows the formation of four contiguous asymmetric centers in one step. The relative stereochemistry of the reaction is well defined because it proceeds via a well ordered cyclic transition state arising from the suprafacial–suprafacial interaction, with preference of endo approach. Therefore, the asymmetric version of this reaction represents an attractive tool for the diastereoselective synthesis of configurationally defined compounds.62 The Diels–Alder reaction are found among the most popular and successful applications of carbohydrate auxiliaries, particularly when they are attached to the dienophile.63 Kunz and coworkers64 performed Diels–Alder reactions with acrylate esters of dihydro-D-glucal 99 and dihydro-L-rhamnal 100. The cycloadditions of these acrylates with various dienes are highly selective when conducted at 0 1C in the presence of titanium promoters. The pseudo-enantiomeric esters 101 and 102 are precursors of the enantiomeric bicyclo[2,2,2]oct-2-enes. The titanium promoters play an important role in these reactions. The catalyst coordinates both the acrylate ester and the 4-O-pivaloyl protection, so that either the re-face or the si-face of acrylate is accessible, respectively (Scheme 15). A similar approach to the enantiomerically enriched norbornene derivatives was developed by Tadano et al.65 who employed the 6-deoxy-a-D-glucopyranosides, as chiral templates. Under the Lewis acid-promotion, the 2,3-di-O-pivaloyl derivative 103 provided adduct 104 with an excellent endo/exo selectivity and good p-facial selectivity. However under the thermal conditions, the 4-O-acryloyl ester 103 produced adduct 105 having both lower endo/exo selectivity and p-facial selectivity. The reductive removal of carbohydrate templates from the endo-adducts led to the isomeric (2S)- and (2R)-enriched 5-norbornene-2-methanols (Scheme 16). The same group explored the EtAlCl2-promoted Diels–Alder reactions with furan using other sugar templates.66 The Diels–Alder reaction of D-gluco-2-O-acryloyl ester 106, produced an endo-adduct 107 predominantly, whereas the reaction of the D-manno-2-O-acryloyl ester 108, under the same reaction conditions, led to an endo-adduct 109. Substrates 106 and 108 differ from each other in the configuration at C-2 carbon atom. This difference dramatically influenced the facial selectivity of the diene approach. The adducts 107 and 109 contain the enantiomeric 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid, compounds frequently used as chiral building blocks for natural products synthesis Scheme 17.67 Nouguier and coworkers68 found that the acrylate esters derived from the 1,3:2,4-di-O-methylene acetals of arabitol or xylitol reacted stereoselectively with cyclopentadiene in the presence of EtAlCl2. For example, the D-arabitol-derived compound 110 gave the (R)-adduct 111 in a 99% yield. Authors suggested that the high selectivity was a conseguace of the formation of aluminum chelate involving one of the dioxane rings and the carbonyl atom (Scheme 18). The importance of chelation was indicated by the fact that the noncatalyzed reaction was less selective. The synthesis and the utility of various methylene protected glucosides have also been reported by this group.69 The Lewis acid promoted Diels–Alder reactions of acrylate ester derived from monobenzylated isosorbide 112 and cyclopentadiene provided exclusively the endo-adduct in a good yield and with a high diastereoselectivity.70 The authors found that

314

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

PivO

OPiv O O

TiCl4, 0 °C

PivO H O 2 O

OPiv O Ti

Ti

O

88%

O

O O

100 99

O

O

(2R):(2S) 90:10 O Ti O

O O

OPiv

OPiv O 2

TiCl4, 0 °C 74%

O 102

O 101

H

(2R):(2S) 7:93

Scheme 15 Sugar-bonded acylate esters as dipolarophiles for asymmetric Diels–Alder reaction.

(R)

EtAlCl2

R*

O

CH2Cl2, −78 °C 79%

O

O PivO

COOR* 104 endo : exo >95 : 5 de 80%

OMe OPiv (S)

CH2Cl2, r.t. 74%

103

COOR* 105 endo : exo 89 : 11 de 74%

Scheme 16 Tadano’s approach to enantiomerically enriched norbornene derivatives.

O

BnO O OMe O

BnO PivO

O

O EtAlCl2

CH2Cl2, −78 °C 88%

106

O

BnO O BnO

108

O

O EtAlCl2

OMe O

PivO

COOR* 107 endo:exo 91:9 de 96%

COOR*

CH2Cl2, −78 °C 89%

109 endo:exo > 95:5 de 98%

Scheme 17 The EtAlCl2-promoted Diels–Alder reactions with furan using sugar-2-O-acryloyl esters.

O

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

O

EtAlCl2

O

O

si-face

H

O

O

O

−60 °C, 3 h 99%

O

315

O

O

O

O

Al OO O O

O

O

111

110

endo:exo 97:3 de >99 Scheme 18 Nouguier’s approach for stereocontrolled synthesis of norbornene derivatives.

depending on the nature of used Lewis acid, the opposite direction of asymmetric induction of cycloaddition could be observed. In the presence of chelating Lewis acids such as SnCl4, the (S)-endo product 113 was favored, whereas monodentate acids like EtAlCl2 or BF3  Et2O, afforded primarily the (R)-endo product 114 (Scheme 19).

O O

H O

SnCl4 COOR*

CH2Cl2, 20 °C 77%

O H

OBn

EtAlCl2 Et2O, 20 °C 60%

112

113

COOR*

114

Scheme 19 The Lewis acid promoted Diels–Alder reactions of acrylate ester derived from monobenzylated isosorbide 112 and cyclopentadiene.

As mentioned above, the metal coordination played a key role in determining the facial selectivity of sugar-linked dienophiles. In the presence of EtAlCl2, 4-methylbenzyl b-L-arabinose 115 bearing the tricarbonylchromium moiety reacted with isoprene to afford cycloadducts 116 in a good yield and with excellent selectivity (90% de) (equation 10). The same reaction with the noncomplexed counterpart showed an inferior diastereoselectivity (56% de).71 The authors attributed this purely to the diminished bulk and the increased flexibility of the phenyl ligand.

O

O O

O O O

O

si-face

115

Cr(CO)3

(i) isoprene Et2AlCl, −20 °C, 8h

O

O O O

H O

(ii) pyridine

ð10Þ

77% 116 de 90%

The N-acryloyl and N-cinnamoyl D-galactosyl-1,3-oxazolidine-2-ones 117 were converted to the corresponding cycloadducts 118 on reaction with cyclopentadiene in the presence of EtAlCl2 (equation 11).72 The Diels–Alder reactions proceeded with excellent endo selectivity and with high diastereoselectivity. The auxiliaries were removed using lithium benzyloxide. Unfortunately, under these conditions, the spirooxazolidine fragment was epimerized at the spiro-carbon atom, preventing its efficient reuse. The 1,3-oxazin-2-ones 119 and 120 derived from the 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid73a and the 2,3:4,5di-O-isopropylidene-b-D-fructopyranose,73b respectively did not undergo this adverse reaction. These auxiliaries proved to be equally effective as the D-galactosyl-spirooxazolidinone, and could be recovered without loss of optical purity.

316

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

O

O O

O N

O

Et2AlCl

O

O

−78 °C

O

O O N

O O

O

O

R

R 117a R: H 117b R: Ph

O

ð11Þ

118a R: H; 83% endo:exo 98:2; de 80% (endo) 118b R: Ph; 99% endo:exo 98:2; de 92% (endo)

O

O O O

O O

O

N

O

OOO O O

R 119

O

N

O O

R 120

Horton et al.74 reported a highly stereoselective, thermal cycloaddition of the D-arabinose-derived (Z)-dienophile 121 with cyclopentadiene (Scheme 20). The diene reacted with the re-face of the dienophile, which was assigned to a steric blocking of the dienophile si-face by the sugar chain. H H AcO H H R*

COOMe H OAc OAc CH2OAc

H H R* COOMe

toluene, 130 °C 81%

de 90%

121

re-face R* H

AcO

H

H COOMe

H

OAc

COOMe

R* A(1,3) Scheme 20 The thermal cycloaddition of the D-arabinose-derived (Z)-dienophile 121 with cyclopentadiene.

The D-galacto (E)-nitroolefin 122 when subjected to the thermal [4 þ 2] cycloaddition with 1-acetoxy-buta-1,3-diene furnished adduct 123 with the complete regio- (endo-) and diastereofacial selectivity (Scheme 21).75 In this case, attack of the diene must occur at the less hindered face of the nitroolefin. These results confirm observations by Frank et al.76 that the diastereofacial selectivity in Diels–Alder reactions is a predictable function of the configuration of the chiral center adjacent to the dienophile double bond. Although in most cases the dienophile is attached to the carbohydrate auxiliary for practical reasons, the examples of reactions with carbohydrate modified dienes are also reported. The thermal reaction of the glucofuranosyl butadienyl ether 124 with butyl glyoxylate, leading to disaccharides 125, can be considered as the first sugar auxiliary-controlled Diels–Alder reaction described in the literature (equation 12).77 Interestingly, this methodology was applied to the synthesis of the blood group A antigenic determinant.78

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

317

NO2 H

H

OAc

OAc R* AcO H AcO H H OAc CH2OAc

si-face

OAc

H

H NO2

NO2

toluene

OAc

H(C3)

105 °C, 24 h

R∗

75%

C4

123

H(C2)

122 Scheme 21 The thermal [4 þ 2] cycloaddition 1-acetoxy-buta-1,3-diene with The D-galacto (E )-nitroolefin 122.

O O

O

O

O

OBu

O

O

O

60 °C, 3d 93%

O

O

O

O

O

O

ð12Þ

O BuOOC

124

125 endo:exo 78:22 de 54% (endo)

The hydrophilic nature of unprotected monosaccharides makes carbohydrate auxiliaries attractive for the reactions conducted in aqueous solvents. Since 1985 the Lubineau group has published a large number of reports dealing mainly with dienes that were rendered water soluble through the temporary introduction of a sugar moiety.79 The efficiency of Diels–Alder reactions between these compounds and standard dienophiles was significantly enhanced in aqueous solutions, despite the presence of the hydrophilic sugar group in the diene. The sugar moiety can be removed after the completion of Diels–Alder reaction. Lubineau also studied the hetero Diels–Alder reactions of glyoxylic acid and its sodium salt in some detail. These reactions were also shown to benefit considerably from the use of water as a solvent. More conventional Diels–Alder reactions of butadienyl glucosides have been intensively examined by Stoodley and coworkers.80 For instance, at ambient temperature the cycloaddition of glucosyl analogs of Danishefsky’s diene (126a,b) with p-benzoquinone resulted in the formation of adducts 127a,b predominately (equation 13). In order to undergo the Diels–Alder reaction, the s-cis geometry of the diene has to be adopted. The dienophile approaches the sterically less hindered top face of a diene of type 126 to avoid an unfavorable syn-1,3-interaction between the C-10 -O-10 bond in the sugar group (Figure 4).

O

OTMS R

O

H

OTMS

O O O

OAc OAc

OAc OAc

20 °C, 20 h

O

H

O

R O

AcO

OAc

ð13Þ

OAc OAc

126a R: H

127a R: H, 46%, de 78%

126b R: Me

127b R: Me, 69%, de >90%

The minor cycloadduct arises from the addition to either the top face of the unfavorable s-cis conformer of type 126-III or the bottom face of the preferred conformer of type 126-I (Figure 4). The methodology described above was recently applied to the asymmetric total synthesis of ()-4-epi-shikimic acid81 and anthracylines.82 Utilizing the D-glucose chiral auxiliary on the dienophile as an alternative stereodirecting moiety was investigated in attempted anthracyclinone syntheses (equation 14).83 Thus, the 5-glucopyranosyloxy-1,4-naphthoquinone 128 reacted with Danishefsky’s diene to give the cycloadduct 129 in a 92% yield and with the full regio- and stereoselectivity.

318

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Approach of dienophile TMSO R OAc O H H AcO H O H H OAc AcO

R OAc O H H AcO H O H H OAc AcO

126−I

OTMS

OTMS OAc O R H H AcO H O H H OAc AcO 126−III

126−II

Figure 4 Dipolarophile approach in Diels–Alder reactions of butadienyl glucosides.

OAc AcO AcO

OAc OAc

AcO OTMS

O

O

O

O

O

OH

128

3.12.2.4.1

O

H

CH2Cl2, 20 °C 20 h 92%

OMe OH

AcO

+

O

OAc

OTMS

H

O

ð14Þ

OMe

129

Hetero Diels–Alder reactions

The Diels–Alder reactions, in which carbon–heteroatom bonds are formed, are useful for the synthesis of heterocyclic compounds. Numerous examples of the hetero Diels–Alder reactions are cited in the recent monograph by Tietze and Kettschau, including some which involve carbohydrates.84 Kresze and Vasella85 developed the sugar-derived nitroso dienophiles 130 and 131 which bear a stereogenic center directly attached to the reactive moiety (Scheme 22). Single cycloadducts 132 and 133 were obtained in the reaction of 130 and 131 with cyclohexadiene. The carbohydrate moieties were cleaved from the cycloadducts by in situ methanolysis, and were recovered as the aldonolactones 134 or 135. The dihydrooxazines made by this route, have proven their synthetical potential in syntheses of aminocyclitols86 and aza-sugars, namely 5-amino-D-allose derivatives.87

O

O

H N ·HCl O

NO Cl

O

O

O

−20 °C 70%

TrO

O

−20 °C 96%

131

O

O

O

132 134

H N ·HCl O

NO Cl

O

O

+

>96% ee

130

O

O O

TrO O

O

+ O

O

133 >96% ee

135

Scheme 22 Hetero Diels–Alder reaction of sugar-derived nitroso dienophiles.

Compared with the reaction with cyclohexadiene, the diastereoselectivity of the Diels–Alder reaction of 130 with cyclopentadiene was found to be lower under variety of reaction conditions.88 The hetero Diels–Alder reaction of nitrosoalkenes with the electron-rich olefins has been known for a long time.89 A detailed mechanistic study carried out by Reissig et al.90 has provided an evidence that this inverse electron demand cycloaddition is a

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

319

concerted process. Reissig and coworkers91 have shown that the reactive nitroso olefins undergo a facile cycloadditions with a sugar-derived vinyl ether 136 giving the chiral 4,5-dihydro-6H-1,2-oxazine derivative 137 (equation 15). The authors found that the (E)-enol ethers reacted much faster and with a higher stereoselectivity than the respective (Z)-isomers. O

O O

O Ph

O

N

O O

O 73% O

O

ð15Þ

O

O

136

O

N

Ph

O

137 trans:cis 98:2 de >99% (trans)

Glycosyl imines are not very reactive dienophiles in the aza-Diels–Alder reactions. However, they can be subjected to cycloaddition reactions after activation with suitable Lewis acids.92 N-Galactosyl imines 138 were shown to react with isoprene in the presence of zinc chloride to give cycloadducts 139 with the complete regioselectivity and diastereoselection up to 10:1 (equation 16). PivO

OPiv O

PivO

PivO R

N

OPiv

N

PivO

ZnCl2 Et2O

H

OPiv O

ð16Þ

OPiv

4−20 °C

138

R

139

During the reactions of N-galactosyl imines 138 with Danishefsky’s diene, a tandem Mannich–Michael reaction sequence was observed resulting in a highly stereoselective formation of 2,3-dihydro-4-pyridones 139 (Scheme 23).93 OTMS PivO

OPiv O

PivO

(i) MeO R

N

OPiv

PivO ZnCl2

PivO

THF, −20 °C

H

(ii) aqueous PivO HCl OMe PivO

OPiv O

H N OPiv

R

O

OPiv O N OPiv

O

138

R

140 de up to 95%

Scheme 23 A tandem Mannich–Michael reaction of N-galactosyl imines 138 with Danishefsky’s diene.

Oxa-Diels–Alder reactions between Danishefsky’s diene and sugar-based 2-oxybenzaldehyde 141, under the BF.3Et2O catalysis, gave 9:1 mixture of dihydropyridones (S)-142 and (R)-142 after acidic work-up (equation 17).94 As in the case of pyridones 140, cycloadducts 142 were formed via an aldol-cyclocondensation sequence. H O O R∗

O

OTMS OAc

+

(i) BF3 Et2O THF, 2 h (ii) TFA

OAc OAc OAc 141

H (2S)

OMe

O

ð17Þ

OR* O

70% 142 (2S):(2R) 9:1

In following up the work of Danishefsky95 on the cycloaddition of aldehydes to dienes bearing various menthyl auxiliaries, Stoodley and coworkers96 have used butadienyl glycosides 143 with the aim to synthesize (1B1)-linked disaccharides. The reaction

320

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

was performed with p-nitrobenzaldehyde in the presence of an europium salt since benzaldehyde itself did not react. A reasonable induction was obtained in the presence of the chiral ()-Eu(hfc)3 as a matched pair to give 144 as the major product (equation 18). OTBDMS O (−)-Eu(hfc)3 (5 mol%)

O R∗

OAc

O

O2N OTBDMS

+ 39%

ð18Þ

O

NO2

OAc

OR*

OAc OAc 144 143

3.12.2.5

de 60%

Ene Reaction

Sugar-derived auxiliaries have also been applied as stereodifferentiation elements in the ene reaction. For example, the carbohydrate-derived a-chloronitrosyl reagents 130 and 131,97 when subjected to a reaction with cyclopentene at room temperature, produced chiral hydroxylamines 145 in good yield and with good enantioselectivity (Scheme 24). Both enantiomers of product were accessible by changing the chiral reagent. Several examples of reactions of cyclic and acyclic olefins were presented.97 A simple separation of the protected sugar by extraction allows recycling of the chiral starting material. O

NO

O

O NHOH

Cl O

Cl

O TrO

NO

O

O

130

NHOH

O

131

hexane, r.t. 48 h 76%

hexane, r.t. 7 days, 70%

(S)-145

(R)-145

er 97:3

er 91:9

Scheme 24 An asymmetric ene reaction.

3.12.3 3.12.3.1

Stereocontrolled Addition and Substitution Reactions Additions to Imines and Other Electrophiles

Numerous applications of N-glycosyl aldimines in natural product synthesis and, in particular, alkaloids98 have been reviewed in the recent years, these topics will only be discussed briefly here and only some exemplary transformations will be presented in this chapter. The stereodifferentiating ability of N-galactosyl imines 138 was first shown in Strecker synthesis.99 In the presence of zinc chloride in isopropanol, chiral imines 138 reacted with trimethylsilylcyanide to give corresponding amino nitriles 146 in almost quantitative yield and with a high diastereomeric excess (R:S from 7:1 to 15:1) (equation 19). The diastereofacial differentiation in this reaction has been explained by the formation of zinc chelate complex 147. The coordination of the Lewis acid to both imine nitrogen and carbonyl oxygen of the equatorial C2-pivaloyl group effectively shields the re-face of the imine, resulting in the nucleophilic attack at the si-face.

OPivOPiv O N PivO OPiv 138

R H

TMSCN, ZnCl2 i-PrOH

OPivOPiv O H N PivO OPiv

PivO PivO

Cl Cl Zn OPiv O O N

CN

O

si-face R

ð19Þ H

R H 146 (R):(S) from 7:1 to 15:1

147 re-face

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

321

Other nucleophiles have also been added to N-glycosyl aldimines, including O-silyl ketene acetals,100 bis-O-silyl ketene acetals,101 diethylphosphite,102 tributylallylstannane,103 and allyltrimethysilane,104 to afford the enantiomerically enriched products. Very recently, Li and Meng105 reported a highly diastereoselective InCl3-catalyzed aza-Friedel-Crafts reaction of substituted indoles with aldimines 148 generated from Kunz’s amine (Scheme 25). The reaction afforded the desired product 149 in a good yield and with up to a 19:1 diastereomeric ratio. The sugar auxiliary could not be cleaved under the traditional acidic conditions. It was removed successfully after unmasking of the O-pivaloyl groups using MeOH/MeONa and subsequent treatment with AcOH/ H2O, to yield the 3-indolyl aryl methylamine derivatives 150 possessing high optical purity.

NO2 PivO PivO Sug =

OPiv

N H

NO2

OPiv O N

NO2

CH2Cl2 H

(i) MeOH/Na

HN Sug

InCl3 92%

N H 149

148

H2N

(ii) AcOH, H2O 90%

N H 150 96% ee

Scheme 25 The diastereoselective InCl3-catalyzed aza-Friedel-Crafts reaction of substituted indoles with aldimines 148.

Krishna et al.106 investigated the use of sugar-derived aldehydes 151 as chiral electrophiles with an activated olefin in the Baylis–Hillman reaction (equation 20). The observed stereoselectivity was explained by favored attack of the zwitterion at the si-face of the aldehyde, resulting in a predominance of the (S)-isomer. The stereochemistry of the newly created center is consistent with the nonchelation Felkin–Anh model.107 OH O + H

DABCO

EWG

EWG

R*

dioxane:water (1:1) r.t., 15 h

R* 151

56−82%

ð20Þ

de 36−85% O

O

OMe

O

R* =

O

MeO

O

O

O

O O

O O

Vasella and coworkers108 intensively studied additions of nucleophiles to N-glycosylnitrones. The authors showed that the addition of lithium dimethyl phosphite to N-mannofuranosyl nitrones 56 afforded N-hydroxy-N-glycosylaminophosphonates 57 with a high asymmetric induction (equation 21). The stereochemical outcome of the reaction was rationalized in terms of the kinetic anomeric effect.109 Steric factors were also considered responsible, in part, for the selective anti-attack at the (Z)-configured nitrone double bond furnishing the (S)-configured product (Figure 5).

O O

O

OBn

N O

O

152

O

LiPO3Me2 THF, −25°C 30 s

O

OBn

Me2O3P O

O

N OH

O

O

ð21Þ

153 dr 94:6

The methodology developed by Vasella has been recently applied to the synthesis of (þ)-(R)-zileuton,110 a potent and selective 5-lipoxygenase inhibitor.111

322

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

O O

O O O H

O

O O O H

N O H

H

N O

OBn

O-exo

OBn anti-attack

O-endo

Figure 5 Stereochemical outcome of the addition of nucleophiles to N-glycosylnitrones.

Roush and coworkers developed a highly stereoselective synthesis of syn 1,2-diols via the reactions of chiral aldehydes and the allylstannane reagent 154 that incorporates a mannosyl unit as a chiral auxiliary.112 The stereogenic center present in the aldehyde was an important element in these reactions, since achiral aldehydes afforded only a poor selectivity. The chiral reagent 154 displayed the especially useful diastereoselectivity in BF.3Et2O-promoted matched double asymmetric induction with chiral aldehydes, for example, (S)-155 and led to all-syn-configured 156 as the major product (Scheme 26). When the enantiomeric aldehyde (R)-155 was used, a similar diastereomeric ratio in favor of the anti,syn-product 157 was observed. This result indicated that the enantioselectivity of the chiral stannane was sufficient to completely overcome the intrinsic diastereofacial bias of (R)-155 in this mismatched pair situation. The stereochemical outcome of the reaction was explained by the preferred Felkin–Anh approach of the Lewis acid-aldehyde complex to the si-face of the enol ether, which was essentially perpendicular to the pyran C–O bond as a consequence of the exo-anomeric effect.

TBSO R* O

O

H

O

O

Me (S)-155

OH

154

CHO

BF3·Et2O

TBSO

CH2Cl2, −78 °C

Me

70%

OR*

156

O

dr 18:1

O

154 SnBu3

CHO

TBSO

Me

154

OH

BF3·Et2O CH2Cl2, −78 °C

(R)-155

TBSO Me

80%

OR*

157 dr 16:1 Scheme 26 The stereoselective synthesis of syn 1,2-diols via reactions of chiral aldehydes and the sugar-derived allylstannane reagent.

In a similar fashion, Yamamoto et al.,113 employed the carbohydrate-derived allylstannanes 158 for the asymmetric a-hydroxyallylation of achiral aldehydes. In this case, the best asymmetric induction (92%) was observed in the AlCl3-promoted reaction of 158 with benzaldehyde (equation 22). TBDPSO

TBDPSO O

O

PhCHO, AlCl3 CH2Cl2, −78 °C

SnBu3 158

Ph

10 min 52%

O

O

ð22Þ

HO syn:anti 97:3 de 92% (syn)

The reaction of allyltributyltin with a sugar-derived a-alkoxyaldehyde 159a was highly stereoselective when mediated by MgBr2 at  60 1C. When the triisopropylsilyl ether 159b was used, the corresponding isomeric alcohol was obtained with lower selectivity. It is presumed that the chelation-controlled reaction takes place in the first case, but not in the second example (Scheme 27).114

3.12.3.2

1,4-Addition Reactions

The asymmetric 1,4-addition reaction is one of the most prominent carbon–carbon bond forming reactions, and a number of chiral auxiliary-based approaches have been devised to date for this important addition reaction.115

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

SnBu3

O O

O

MgBr2·Et2O H

OBn

CH2Cl2, −60 °C 95%

O

de 96%

SnBu3

O O

MgBr2·Et2O H

OTIPS

OH O

OBn

159a

O

159b

CH2Cl2, −60 °C 95%

323

O

OH O

OBn de 86%

Scheme 27 The reaction of allyltributyltin with a sugar-derived a-alkoxyaldehydes.

In 1966, Kawana and Emoto116 reported the copper(I)-catalyzed addition of phenylmagnesium bromide to the 1,2:5,6-di-Oisopropylidene-a-D-glucose ester of crotonic acid 160 (equation 23), which was followed by hydrolysis to give the (R)-()-3phenylbutanoic acid 161 with 70% ee Difficulty with reproducing this result has been reported.117 Reactions with similar substrates gave product with ee’s ranging from 10% to 74%.

O

O

O O

(i) PhMgBr, CuCl (catalyst.)

HO

(ii) OH−

O

O O

(iii)

O

ð23Þ Me

Ph

H3O+

161 70% ee

160

In recent years, several new methods for the diastereoselective conjugate addition of organocuprates to the chiral auxiliarybased a,b-unsaturated esters have been developed with the majority utilizing chiral sugars.118 Tadano and coworkers118c,d extensively studied the selectivity of 1,4-additions of cuprates to crotonates attached to various carbohydrate scaffolds. Authors concluded that the crotonic esters 162 and 163 (Scheme 28) provided the best results in terms of both yield and diastereoselectivity due to the different dimensions of the substituents at the 2- and 6-positions of the sugar moiety. With these auxiliaries, the addition products were obtained in excellent yield (80–95%) and with high diastereoselectivity (92–96%). O

R O

O PivO

O

RMgBr (10 equivalent) CuBr·SMe2 (5 equivalent)

PivO OMe

O PivO

THF/Me2S (2:1) −78 °C

O PivO OMe

162

OPiv

OPiv

OBn O

RMgBr (10 equivalent) CuBr·SMe2 (5 equivuivalent)

O O

BnO OMe

THF/Me2S (2:1) −78 °C

163

OBn O

O O

BnO OMe

R

R= Et, vinyl 80−95%; de 92−96% Scheme 28 The 1,4-additions of cuprates to crotonates attached to carbohydrate scaffold.

The stereochemical outcome observed in the 1,4-addition was explained in terms of steric interactions (Figure 6).118d The crotyl ester 163 probably prefers the s-trans-conformation due to the complexation of both the crotyl and pivaloyl carbonyl groups by the magnesium organocuprate or magnesium halide. The cuprate attacked preferentially from the more accessible re-face of the

324

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

double bond whereas the si-face of the double bond is effectively shielded by the bulky 3-O-substituent. Similar transition states were proposed for the chiral auxiliaries derived from glucose and mannose.

MLn O

O BnO

re-face approach of cuprate

O OBn O

PivO R OBn O OMe O

O BnO

OMe

O

MLn

163

Figure 6 The stereochemical outcome observed in the 1,4-addition of cuprates to unsaturated esters bearing the sugar-derived auxiliary.

Kunz and co workers119 showed that, after O-silylation of the N-galactosyl-2-pyridone 164, the addition of Grignard reagents proceeded with high 1,4-regioselectivity and complete diastereoselectivity to furnish 4-substituted 5,6-dehydro-2-piperidones 165 (equation 24). PivO PivO

OPiv O

(i) TMSOTf or TIPSOTf (2.0 equivalent) CH2Cl2, r.t., 1 h

N

PivO

R

OPiv O

N

PivO

OPiv

(ii) RMgBr (1.5 equivalent) 2,6-lutidine (2.0 equivalent) r.t., 1 to 2 h

O

164

OPiv

O

ð24Þ

165

R: Et, n-Pr, c-hexyl, Ph; 54−88%; de>98%

The same group have also found that the carbohydrate-derived oxazolidinones are efficient tools in the 1,4-addition reactions of organoaluminium compounds to the a,b-unsaturated carboxylic derivatives of type 166 (equation 25).120 PivO

PivO

OPiv O

Et2AlCl, −78 °C

PivO

84% O

N

Ph O

OPiv O

PivO

O

ð25Þ

O

O

Et

166

O

N

Ph

(R):(S) 94:4

The oxazolidinones 167 derived from D-glucosamine gave lower selectivities than those prepared from D-galactosamine. However, they proved to be more useful in cascade-type functionalization of the carbon–carbon double bond of Michael acceptors, furnishing products 168 with a high anti-selectivity in the ratio of 92:7:1 (equation 26).121

PivO PivO

OPiv O

(i) Et2AlCl, −40 °C O

N

Ph O 167

O

OPiv O

PivO PivO

(ii) NCS 64%

O Et

N Cl

O O

ð26Þ

Ph 168 dr 92:7:1

3.12.3.3

Alkylation of Enolates

The asymmetric alkylation of ester and amide enolates is one of the most popular applications of chiral auxiliaries in general.122 To obtain the high asymmetric induction in alkylation reactions of auxiliary linked ester or amide enolates, they must be formed

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

325

with a high (E)- or (Z)-selectivity and the stereotopic faces of the enolate double bond must be efficiently differentiated by the auxiliary. Mulzer et al.123 explored a method for the alkylation of ester enolates having 1,2:5,6-di-O-isopropylidene-D-gulofuranose as a chiral auxiliary. On treatment with LiTMP (2 equivalent) ester 169 reacted with methyl iodide effectively and with a high stereoselectivity (equation 27). The authors also found that the reaction yield and stereoselectivity were not influenced by the addition of complexing reagents (i.e., MgBr2) or reagents that reduce complexation (HMPT). (i) LiTMP, −100 °C, THF, 60 min (ii) CH3I, −100 °C to r.t.

O O

O O

O

O O

O

O

O

O

O

89%

O

O

O

O

O

O

(R)

ð27Þ

O

O

O

(S)

169

The benzylation of a propionate group attached to the 3-C-hydroxymethylglucose 170 under two different reaction conditions afforded the complementary benzylated products 171 and 172 with a high diastereoselectivity.124 The newly introduced chirality at the a-carbon was governed by the state of protection at the 3-OH. A significant effect of additives (LiCl, HMPA) on the selectivity of the reaction was also observed (Scheme 29). LDA, LiCl, BnBr, −78 °C R=H

O O

60%

OR O O

O

Sugar Bn

O 171 de 92%

O LDA, HMPA, BnBr, −78 °C R = TMS

O

Sugar Bn

95%

170

O

O O 172 de 91%

Scheme 29 The benzylation of a propionate group attached to the 3-C-hydroxymethylglucose 170.

Recently, Tadano and coworkers125 developed a novel asymmetric synthesis of a key intermediate 176 in the synthesis of 1b-methyl carbapenem (Scheme 30). The Mannich-like reaction of D-glucose-derived 4-O-propionate 173 and azetidin-2-one 174 produced the adduct 175 with a high diastereoselectivity, from which the desired 76 was obtained after removal of the sugar auxiliary. The authors proposed a plausible transition-state model for explanation of the observed diastereoselectivity. As depicted in Scheme 30, the (E)-enolate obtained from 173 attacked preferentially the re-face of N-acylimine derived from 174, the less sterically congested rear side as written, thus leading to 175.

OTBS H

O O MeO

O

OAc

+ NH

MeO OMe 173

0.2 M LiOH/MeOH (1:1),

O

NH

O

Sugar

O

O 175 de 86%

174

OTBS H re-face attack

OTBS H H CO2H

H2O2 82%

OTBS H H

NaHMDS LiCl 42%

O

NH 176

Scheme 30 The asymmetric synthesis of an intermediate 176.

N

O−M+

O E-enolate

O MeO

O MeO OMe

326

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

The acylation of chiral oxazolidin-2-ones, readily available from D-xylose, leads to imides, are substrates for a range of alkylation, acylation, and halogenation reactions.126 The stereochemical outcome observed for the a-alkylation of N-acylated oxazolidinones is dependent on the nature of the acyl substituents. For example, the aliphatic imides 177 formed lithium-chelated (Z)-enolates 178 and the alkylation occurred from the less hindered si-face of the enolate double bond (product 179), whereas the aryl-substituted imide 180 formed (E)-enolate 181, and the product 182 arose from the reaction at the re-face (Scheme 31).

O

O O

O

LDA THF

O N

O O

O

O

Li

O

N O

O

LDA THF

O

O

N O

O

O

(i) CH3I, 4h O

−78 °C, 30 min

O 180

O O

179 dr 7:1

N O

O

(ii) sat. NH4Cl 45%

178

177

O

O

−78 °C, 30 min

O O

O

O (i) CH3I, 4h

N

O O

181

O

O N

(ii) sat. NH4Cl 63%

O

O O

Li

182 dr 12:1 Scheme 31 The acylation of chiral D-xylose-derived oxazolidin-2-ones.

These N-acylated sugar-derived oxazolidinones can also be used in the diastereoselective halogenation reactions via their boron enolates to get a-halogenated products with a diastereomeric ratio of 4:1. Similarly to the above alkylation reactions, an inversion of stereoselectivity was observed during reaction with phenylacetimides.127 Somewhat more selective a-halogenation of aliphatic silyl ketene acetals was achieved by Duhamel and coworkers128 using a diacetone-D-glucose template. Asymmetric induction in the alkylation of enolates may be effected also by introduction of a chiral group on the alkylating agent. The enantioselective methylation of imine enolates of aminoesters 183 using diacetoneglucose methyl sulfate 184 has been carried out by Duhamel.129 After hydrolysis, the nonracemic a-alkyl alanines 185 are obtained with enantiomeric excess up to 76% (equation 28).

OMe R1 R2

O N R3 183

3.12.3.4

O

O

(i) THF-HMPA O

+

Li

O MeO3SO

O 184

(ii) H3O+

Me H2N

R1 COOH

ð28Þ

185 70% ee

Aldol Reaction

Beginning in the early 1980s, the remarkable progress has been achieved in the development of asymmetric aldol reaction of silyl enolates. Early in the development of this process, chiral auxiliary-controlled reactions were extensively studied.130 An initial investigation of asymmetric aldol reactions with chiral carbohydrate auxiliaries was described by Heathcock et al.,131 but only low asymmetric inductions were observed. The chiral N-acylated oxazolidin-2-ones 186 derived from D-glucose have been shown to undergo the diastereoselective aldol reaction via their boron imide enolates to afford the b-hydroxylated products.132 The best results were obtained when isobutyric aldehyde was used (equation 29). The authors explain the selectivity by a chair-like transition state according to Zimmermann–Trexler model.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives PivO PivO

OPiv O

(I) i-Pr2NEt n-Bu2BOTf 0 °C, 30 min

O

(ii) (CH3)2CHCHO −78 °C, 20 min 59%

N O 186

PivO PivO

O

OPiv O

O

327

OH

N

ð29Þ

O O dr 16:1

A carbohydrate auxiliary can also be linked to the electrophilic component of an aldol reaction. Ozaki et al.133 showed that the Mukaiyama aldol reaction of cyclitol pyruvates such as 187 is a reliable method for a highly enantioselective synthesis of functionalized tertiary alcohols 188 (Scheme 32). In the transition state, nucleophilic attack occurs from the sterically less hindered re-face of the five-member chelate, whereas the si-face is shielded by the bulky trialkylsilyl group.

O

O

O O

TBS O O

O OSiMe3 + R

O

O

SnCl4 CH2Cl2

187

O O

O O

TBS O OH

O R

O

O

O O

O O

O Si

O

O (Sn)

nucleophile 188a R: t-Bu, 98%, de >98% 188b R: Ph, 97%, de 94%

Scheme 32 The Mukaiyama aldol reaction of cyclitol pyruvates.

3.12.4

Rearrangement Reactions

In the early 1990s, Kakinuma134 demonstrated the Overman rearrangement of allylic trichloroacetimidates based on the Dglucofuranose chiral auxiliary to afford selectively either enantiomer of variety of a-amino acids. For example, the diacetone-Dglucose 189 was used in the stereoselective synthesis of D- or L-alanine (Scheme 33).134 Compound 189 was converted into acetylene 191 in two-step sequence involving oxidation to 3-ulose derivative 190 and addition to the carbonyl group. The subsequent reduction of triple bond in 191, by treatment with LiAlH4, introduced (E)-olefin 192a, whereas a hydrogenation of 191 in the presence of Lindlar catalyst provided (Z)-olefin 192b. The treatment of 192a and 192b with trichloroacetonitrile in the presence of KH gave imidates 193a and 193b, respectively. The (R)-alanine was obtained with 88% de by the thermal [3,3] rearrangement of (E)-allylic imidate 193a, whereas the (Z)-isomer 193b gave the (S)-alanine essentially as a single diastereoisomer. Both amino acids were released oxidatively by the treatment of 194a and 194b with RuCl3/NaIO4. The oxidation step also regenerated the 3-ulose from chiral auxiliary for possible reuse. Based on the kinetic and theoretical studies, the Kakinuma group proposed the transition-state models to explain these highly selective chirality transfers observed in the Overman rearrangements of both 193a and 193b. The same group also explored the stereoselective [2,3]-Wittig rearrangement of alkylated allyloxyacetic acids 189 linked to C-3 of diacetone-D-glucose for the synthesis of (2R,3S)-3-alkylmalic acids 197 in conjunction with the biochemical studies on the thermostable isopropylmalate dehydrogenase (Scheme 34).135 The treatment of 195 with LDA, followed by the esterification of resulting [2,3]-Wittig rearrangement product with CH2N2 provided 196 with a useful level of diastereoselectivity. Diastereomeric excess of the threo-product (major) to the erythro-product (minor) varied in the range of 74–90%. Despite of the size of the R group, each rearrangement proceeded smoothly to provide 196 efficiently. It should be emphasized that the alkyl group and the newly created hydroxyl group in 196 are in an antiperiplanar relationship (threo-configuration) in every case. After protection of the hydroxyl group of 196, the desired stereochemically defined (2R,3S)-3-alkylmalic acids 197 were prepared by cleavage of the carbon–carbon double bond by ozonolysis, followed by the further oxidative work-up with hydrogen peroxide and final deprotection. The D-glucopyranose-derived auxiliary has also induced a high level of diastereoselectivity in the [2,3]-Wittig rearrangements (equation 30).136 When 198a was treated with n-BuLi, rearrangement afforded exclusively the propargylic alcohol 199 in 92% yield. The more substituted olefin 198b gave a 9:1 mixture of diastereomers 200 and 201 (94%), where the configuration of the major alcohol 201 was reversed in respect to that of 199. Authors proposed that the rearrangement proceeded via transition states in which olefins adopted gauche orientations relative to the endocyclic oxygen of the auxiliary. This type of geometry conforms to expectations based on the presumed influence of the exo-anomeric effect. The change in selectivity at the alcohol center was

328

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O O

O

oxidation

O

O

O

O

HO

O

O

O O

addition

O

O

O

OH

190

189

O

O

O

O

O R1

O

O

OH

R2

LiAlH4, 85% 192a R1: Me, R2: H H2, Pd/CaCO3, 78% 192b R1: H, R2: Me

191

KH, CCl3CN 68−76% O

O

O

O

O

COOH 1

R R2

NH2

xylene reflux

O

(i) RuCl3, NaIO4 (ii) 2 M HCl

R1 R2

D-alanine (from 194a) R1: Me, R2: H; L-alanine (from 194b) R1: H, R2: Me;

194a (from 193a)

>96%

NH

R1

CCl3

O

O

O

O O NH

O R2

CCl3

R1

2

R1:

193a Me, R2: H 1 193b R : H, R2: Me

: Me, R : H;

de 88% 194b (from 193b) R1: H, R2: Me; de 98% Scheme 33 The Overman rearrangement of allylic trichloroacetimidates bearing the D-glucofuranose chiral auxiliary.

O O

O

O 189

R O

O O

(i) LDA (ii) CH2N2

O

O

O O

74%

COOH

HO

R

HOOC

R HO

HOOC

197 COOMe

195 R: Me, Et, i-Pr, t-Bu CH2CHMe2, CH2CH2CHMe2

196 de 74−90%

Scheme 34 The stereoselective [2,3]-Wittig rearrangement of alkylated allyloxyacetic acids linked to C-3 of diacetone-D-glucose.

subsequently explained in terms of the different orientation of the silylacetylene chains in the transition states arising from 198a and 198b. These differences arose because of the unfavorable steric interactions when the vinylic substituent was bulkier than the hydrogen atom.

BnO BnO BnO

O R BnO O

198a R: H 198b R: Me

TMS

n-BuLi 92−94%

BnO BnO BnO

O

R

OBn

TMS

BnO BnO + BnO

O

TMS

OBn HO

199 R:H 200 R:Me

HO 201

ð30Þ

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

329

Recently, Tomooka and coworkers137 evaluated the effectiveness of sugar-derived alkoxides (e.g., 202) as chiral promoters for the enantioselective [1,2]-Stevens rearrangement (equation 31). This reaction provided amines, containing a quaternary chiral center, with a moderate enantioselectivity.

Ph

chiral alkoxide 202

Ph

N

Ph

O Ph

N

O

O

O

O Br

ð31Þ

O

LiO yield 91%; 61% ee (S)

O

202

In contrast to the examples presented earlier, carbohydrate-derived auxiliaries have not become the useful asymmetry inductors for Claisen rearrangement of glucosyl allyl vinyl ethers due to the observed low diastereoselectivity of the process.138

3.12.5

Radical Reactions

The radical processes are important class of organic reactions presenting an attractive alternative to ionic processes.139 Numerous chemo- and regioselective methods have been developed. During the past few decades, an increased level of interest in the development of stereoselective radical reactions is evident.140 In some examples, the stereochemistry of radical process was controlled by the sugar-derived chiral auxiliary or by use of the sugar-derived chiral reagent. Garner and coworkers141 developed an effective auxiliary for hydroxyalkyl radicals. The radical precursor 204, obtained from carboxylic acid 203, was decarboxylated under Barton’s conditions to afford the radical 205 which was trapped with methyl acrylate or its derivatives (Scheme 35). The diastereoselectivity of this process was good (dr410:1) with yield ranging from moderate to good. This approach was used in the synthesis of the aldol product 206 and g-butyrolactone 207. Enholm et al.142 reported the diastereoselective cyclization of radicals linked to a carbohydrate scaffold. (þ)-Isosorbide and D-xylose were used as chiral auxiliaries. In the presence of tributyltin hydride and Lewis acid, bromoester 208 underwent cyclization to yield product 209 (Scheme 36). Optimization of reaction conditions revealed that the best results were obtained when ZnCl2 was used and the process was conducted at a low temperature. Under these conditions, the cyclization furnished product 209 in good yield and with an excellent diastereoselectivity. The LiOH mediated cleavage of auxiliary provided (S)-(þ)indan acid 210 with high enantiomeric excess. The excellent enantiomeric purity of (S)-(þ)-indan acid 210 was also achieved in the case of a similar reaction of precursor 211, derived from D-xylose in the presence of TiCl4 as a Lewis acid (Scheme 36). The high yield and stereoselectivity were also observed employing a polymer-supported D-xylose auxiliary.143 The same group also investigated the free-radical allylation of carbohydrate-derived bromo esters. For example, the D-xylosederived ester 212 treated with allyl tributyltin in the presence of ZnCl2 gave ester 213 with a high diastereoselectivity (equation 32).144 Excellent results were also achieved when the same reaction was performed in a solid state with the sugarauxiliary linked to a polymer resin. The approach presented in equation 32 was also effective in the case of asymmetric aldehyde–alkene radical cyclizations.145 BnO

BnO O

O

O

SnBu3

O

ZnCl2 O

O

CH2Cl2/THF −78 °C

O Br 212

O

O

ð32Þ

O 213 yield 83% dr 28:1

Lin et al.146 pointed out that several easily accessed and inexpensive sugar-derived chiral auxiliaries can serve as effective stereodifferentiation agents for the SmI2-induced reductive radical coupling of unsaturated esters with aryl ketones leading to optically active g-butyrolactones possessing high enantiomeric purity (Scheme 37). Roberts and colleagues147 have employed carbohydrate-derived thiols as catalysts for the enantioselective radical-chain reactions. Lactone 214 undergoes the enantioselective hydrosilylation in the presence of triphenylsilane, an initiator and suitable thiol (Scheme 38). The thiol acts both as achiral source of hydrogen atom and the chain-carrier. As the authors demonstrated, the asymmetric induction is controlled by two factors: the configuration at anomeric position (b-anomers are active, whereas the a-anomers give no selectivity) and the configuration at the C-2 atom (b-mannose is far more effective than b-glucose).

330

BnO BnO BnO

R

N

R

BnO BnO BnO

O

O

DCC

R

O

COOH

203a R: H 203b R: Me

204

BnO BnO BnO

hv

O

CH2Cl2 O

R O

−78 °C O N

R

COOMe

O

R:H O

BnO BnO BnO

O O

COOMe SPy

S

205 OCOCF3 COOMe

61% (3 steps) dr 11:1

R: Me

OH

O

COOMe 206 90% (4 steps) dr 10:1 Scheme 35 Sugar-derived auxiliaries for hydroxyalkyl radicals.

hydrolysis

BnO BnO BnO

(i) Ra-Ni, EtOH (ii) PPTS, MeOH 58%

O O

COOMe OTFA SPy

O

207

O

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

HS

R

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

OBn

O

H

H

Br

O

O

O

H

O

n-Bu4SnH, ZnCl2 Et3B, O2

331

COOH

OBn

O O

H

LiOH

CH2Cl2 /THF −78 °C

O 208

209

210

yield 85% dr 100:1 BnO

BnO

O

O

O O

O

O

n-Bu4SnH, TiCl4 CH2Cl2 −78 °C

O

LiOH

O

O O

yield 81% dr 70:1

Br 211

Scheme 36 Diastereoselective cyclization of radicals linked to a carbohydrate scaffold.

O +

R*

SmI2 proton source

O

Ar

O

R*: O

O O

O

trans

O

yield 60−75% cis /trans >96 : <4 ee (cis) 85−98% ee (trans) 0 −70%

O

O

cis

Ar: 2-naphtyl, p-MeOC6H4, p-Br-C6H4 3,4-methylenedioxy-phenyl

O

Ar

+

O

O

THF

Ar

O

yield 53−89% cis/trans 30:70 ee (cis) 30−66% ee (trans) 90−92%

O

R*: O

O O

Scheme 37 Sugar-derived chiral auxiliaries as effective stereodifferentiation agents for the SmI2-induced reductive radical coupling of unsaturated esters with aryl ketones.

TBHN, Ph3SiH O

thiol

O

214

Ph3Si

O

TBHN: di-t-butyl hyponitrite

RO

RO

RO

O RO

O SH

RO

O

OR

34% ee

RO

O SH

RO

OR

71% ee

RO

SH

RO

OR

5% ee

Scheme 38 The carbohydrate-derived thiols as catalysts for the enantioselective radical-chain reactions.

3.12.6 3.12.6.1

Oxidation Reactions Epoxidation Reactions

The oxirane ring is one of the fundamental functional groups in organic chemistry.148 Its formation can be accomplished using a set of simple strategies. Even so, a large number of methods and reagent systems have been developed for its formation. Among

332

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

them, the asymmetric epoxidation of olefins is an effective approach for the synthesis of enantiomerically enriched epoxides.149 Various methods have been developed, including Sharpless epoxidation of allylic alcohols,150 metal-catalyzed epoxidation of unfunctionalized olefins,151 and nucleophilic epoxidation of electron-deficient olefins.152 For more details about asymmetric epoxidation of olefins see Chapters 6.19, 6.23 and 6.24. Numerous stereocontrolled protocols involving carbohydrate moiety as a chiral auxiliary either in classical way,153 with sugar unit attached to olefin reactant, or by applying a sugar-derived epoxidation reagent have been developed.

3.12.6.1.1

Epoxidation of olefins bearing carbohydrate-derived chiral auxiliary

Chiappe and coworkers154 investigated the stereocontrolled epoxidation of b-D-glucose-derived allyl ether 215a with anhydrous m-chloroperbenzoic acid in aprotic solvents of moderate polarity (1,2-dichloroethane, dichloromethane, chloroform and toluene) at  18 1C (Table 3, entry 1). The highest efficiency (conversion and diastereoselection) for this process was observed when reactions were carried out in dichloromethane. Owing to the poor reactivity of the allyl derivative 215a, lower temperatures, which, in principle, should promote higher diastereoselection, could not be used. The (R) configuration of resulting epoxide was determined on the basis of absolute configuration of the product arising from the regiospecific oxirane ring opening. The epoxidation of corresponding 2-O-acetyl derivative of 215a (215b) was slower and practically nondiastereoselective154 demonstrating that, in agreement with the bromination of allyl glycosides155 and with the epoxidation of 1-O-(E)-2-butenyl3,4,5-tri-O-benzyl-b-D-glucopyranose,156 the presence of the free hydroxyl at C-2 position is necessary for viable enantiofacial selection. Based on these observations and the absolute configuration of major product, authors proposed that the formation of hydrogen bond between the OH group and the peroxyacid preferentially stabilizes the transition state for electrophilic addition to the re-face of the double bond. Iglesias-Guerra’s group157 studied epoxidation of anomeric allyl ethers 216, 217 and 218 derived from the N-acetyl-D-glucosamine (Table 3, entries 2–4). The investigation of reactions carried out under different conditions revealed that the de of oxidation reactions was higher when the reaction temperature was lowered. However, at the same time the reaction time increased dramatically. The diastereomeric excesses obtained for the peracetylated derivatives 216 are lower than those found for the corresponding benzylidene derivatives 217 with the same aglycone measured at the same temperature, probably because of the greater rigidity of the latter compounds. The diastereomeric excesses obtained for the alkenyl glycosides 218 with protected O-3 hydroxyl group were again lower than those for the corresponding compounds of 217 with the same aglycone measured at the same temperature. This effect was marked for the oxidation of 219, a compound which lacks free hydroxyl group at the position 3 of the sugar and also does not have the N–H bond as a result of the formation of oxazolidine bridge between these two positions. This observation supported the previously proposed idea154 that the formation of a hydrogen bond between the XH group at C-2 position of the sugar unit (in this case NH group) and the peroxyacid is preferentially stabilizing the transition state leading to the electrophilic addition from the re-face of the double bond. Moreover, the comparison of results obtained for reactions of 217 and 219 suggested the additional stabilization of this transition state, probably by the formation of a hydrogen bridge between the free hydroxyl group at a position 3 and the acetamido group. Ph

O O O

O

O

NAc 219

Recently, the same group demonstrated that the b-D-galactopyranose-derived chiral auxiliaries 220a–c (Table 3, entry 5), used in the asymmetric cyclopropanation (see Section 3.12.2, Table 1, entry 5), are also effective chiral auxiliaries for stereocontrolled epoxidation.5 As in previously described examples, the diastereoselectivity of epoxidation reaction (similarly to the cyclopropanation process) depends on the presence of unprotected hydroxyl group at the position 2 of sugar unit, which determines the selective transfer of the reagent to one face to the double bond. Iglesias-Guerra’s group also investigated the synthesis of 2,3-epoxyamide derivatives of 2-amino-2-deoxy-D-allose 221 and 222 (Table 3, entries 6 and 7).158 However, the allose moiety provided only a moderate asymmetric induction in the oxidation process (only in few cases did the de exceed 75%). Epoxidation of the corresponding a,b-unsaturated amides with m-CPBA took place with a better stereoselectivity when an oxazolidine ring was fused to the 2,3-positions of the sugar molecule. Several sugar-based auxiliaries were utilized for the stereoselective epoxidation of alkenylidene acetals – Table 4. The epoxidation of corresponding N-acetyl-D-glucosamine- and D-glucose-derived alkenylidene acetals159 using m-CPBA took place with a varying stereoselectivity, depending on the substitution of the unsaturated system, the presence of protecting groups on the hydroxyl group at C-3 of the sugar moiety, and its configuration (Table 4, entries 1–4). With regard to the degree of substitution of the double bond, higher diastereoselectivity was observed for methyl substituted double bonds. Within the series of compounds with gluco configuration (223–225) investigated, olefins with the free hydroxyl group at position 3 of sugar unit gave significantly higher diastereoselectivity than the corresponding compounds with a protected 3-OH group. Once again, this effect indicates that the formation of hydrogen bond between 3-OH group and peracid in the transition state for electrophilic addition to the double bond controls the stereochemical course of the reaction, similarly to the previously described oxidation of the allyl glycosides. As mentioned before, protection the 3-OH group by its transformation into an oxazolidine derivative (e.g., 226) resulted in a complete loss of stereoselectivity.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Table 3

Carbohydrate-based auxiliaries for asymmetric epoxidation of allyl ethers

Entry

Chiral auxiliary

1

BnO BnO BnO

O

O

OR

215a R: H 215b R: Ac 2

AcO AcO AcO

R1

O

R2

O

NHAc

3

O O HO

Ph

R1

O

R2

O

NHAc

R3

217

O O RO

Ph

R1

O

R2

O

NHAc

Conditions

Yield (de)

m-CPBA CH2Cl2  18 1C 4 days

80% (80%) for 215a

m-CPBA CH2Cl2

69–75% (35–78%) at 10 1C 42–67% (50–80%) at  15 1C

 15 1C, 55–90 days or 10 1C, 1–6 days

R3

216

4

R3

m-CPBA CH2Cl2  15 1C, 24–90 days or 10 1C, 1–6 days

m-CPBA CH2Cl2  15 1C, 14–60 days

69–81% (66–93%) at 10 1C 48–66% (75–100%) at  15 1C

for 220a 63–90% (76–100%) 47–85% (64–74%)

Configuration of major isomer

Reference

O

O

R1 O

O

155

158b

R2

R3

R1 O

O

158a,b

R2

R3

R1 O

O

158a,b

R2

R3

218 R: Me, Ac, Bn, TBS

5

Ph

m-CPBA

O

O

CHCl3

R1 O

R2O

R2

O

OR1

for 220b 72–90% (0–23%)

 15 1C

for 220c 61–98% (73–88%)

m-CPBA

70–95% (0–40%)

R1 O

O

5

R2

R3

R3

R1=R2=H

220a 220b R1=R2=Bn 220c R1=H, R2=Bn

6

Ph

O O

O

OBn R

HN OH

Ph

H N

CH2Cl2 r.t.

O

R

5

R

158

O

O

221

7

333

O O

O O R1

OBn

N R1O

222 R1: H, Me

R

m-CPBA CH2Cl2 r.t.

75–94% (44–94%)

H N

O O

334

Table 4

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Carbohydrate-based auxiliaries for asymmetric epoxidation of allyl acetals

Entry

Chiral auxiliary

1

Ph

O O HO

R

O

223 R: H, Me

2

OH OMe

O O HO

Ph R2

O

OR1

NHAc

Conditions

Yield (de)

m-CPBA CHCl3  15 1C

77–78% (R¼H 46%) (R¼Me 72%)

m-CPBA CHCl3  15 1C

58–84% (34–74%)

m-CPBA CHCl3  15 1C

65–89% (12–36%)

Configuration of major isomer

O Ph

Reference

O O

160a

O O

160a

O O

160a,b

O O

160a,b

R2

O Ph R2

224 R1: c-C6H11, Bn, n-C12H25 R2: H, Me 3

O O R2 R3O

Ph

O

OR1

NHAc

O Ph R2

225 R1: c-C6H11, Bn, n-C12H25 R2; H, Me R3: Bn, 5-dibenzylsuburyl, COOBn, Me, NHAc

4

O O

Ph R2

O OR1

On-C12H25

NHAc

O

m-CPBA CHCl3  15 1C

72–83% (R¼H 68–72%) (RaH 20–28%)

Ph

m-CPBA CHCl3  15 1C

62–67% (R: H 26%) (R: Me, 74%)

Ph

m-CPBA CHCl3 r.t.

71–84% (R: H 56%) (R: Me, 60%)

Ph

m-CPBA CHCl3  15 1C

84–89% (R: H 22%) (R: Me, 30%)

Ph

227 R1: H, Ac, Bn R2: H, Me

5

Ph R

O

R O

O O

160b

O O

OMe

HO OH 229 R: H, Me

6

O

R

O

O

O Ph

HO 230 R: H, Me

R

7

Ph

O

O O

H 231 R: H, Me

R O

O O

160b

O

O O

R O

O O

160b

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O O O

Ph

O

Ph

Oc-C6H11

R

NAc

335

OEt O

O O

OMe

OH

226

228

Similarly, for allo series of compounds 227,159 the alkenylidenes with an unprotected hydroxyl group at C-3 provided a higher diastereofacial selectivity of addition to the double bond (Table 4, entry 4). Moderate diastereoselectivity was observed for alkenylidene acetals derived from carbohydrates with D-altro (228), D-galacto (229), D-gluco (230), and D-xylo (231) configurations (Table 4, entries 5–7).159 In this series of compounds, a slightly better stereoselectivity of epoxidation reactions was observed for the (E)-a-methyl-cinnamaldehyde derivatives.

3.12.6.1.2

Epoxidation with carbohydrate-derived oxidants

Another way to perform stereocontrolled oxidation of olefins to epoxides is to employ a chiral oxidatizing agent. The commonly used approaches are: (1) metal-catalyzed epoxidation, (2) epoxidation with chiral dioxiranes, and (3) oxidation with chiral hydroperoxides. For more details on asymmetric epoxidations see Chapter 6.4. Among different metal-catalyzed oxidation processes, the most important one is the enantioselective Jacobsen–Katsuki epoxidation151 of (Z)-olefins using a chiral Mn–salen catalysts and a stoichiometric oxidant (e.g., bleach). In comparison with the Sharpless reaction,150 the Jacobsen–Katsuki epoxidation allows a broader scope of substrates for the transformation; good substrates are conjugated (Z)-olefins R1-CH ¼ CH-R2 (R1: aryl, alkenyl, alkynyl; R2: alkyl) or alkyl-substituted (Z)-olefins bearing one bulky group. Several carbohydrates have been utilized as the chiral scaffold in salen complexes. Ruffo and coworkers160 described the synthesis of Mn(III) complexes with D-mannopyranose- and D-glucopyranose-derived salenes (232 and 233, respectively), which were useful in the asymmetric epoxidation of styrenes (Scheme 39). The oxidation of styrene resulted in a good conversion of initial olefin. The highest enantiomeric excess was obtained for the glucose-derived Mn(III)–salen complexes. The corresponding mannose-derived complexes were less selective. Furthermore, the mannose ligands induced the opposite selectivity to that observed for the corresponding glucose ligands. With regard to the epoxidation of (Z)-1-phenylpropene, the glucose-derived complexes led to the cis-epoxide as a major product, with a high conversion (up to 99%) and good ee’s (up to 86%) (Scheme 39). However, the use of the mannose-based Mn(III)–salen complexes as a catalysts led to the lower conversion rate, a reduced cis/trans ratio, and a poor enantioselectivity. As discussed above, in this case as well, mannose ligands provided opposite enantiostereoselectivity. The different behavior of the two sugar-derived complexes was explained by the differences in the geometry of the respective Mn–salen complexes Scheme 39.160

O

O O

O

O N

N

OH HO

t-Bu

O

OMe

N t-Bu

t-Bu

t-Bu

Mn(III)-salen m-CPBA, NMMO

N

OH HO

R

R

t-Bu

t-Bu

232

R

OBn

233a R: H 233b R: t-Bu

(S)

O

(R)

R CH2Cl2, −78 °C R: H

gluco-salen: conversion 99%; ee 45−54% (1S) manno-salen: conversion 99%; ee 30−32% (1R)

R: Me

gluco-salen: conversion 84−99%; cis /trans 95/5; ee 86% (1S, 2R) manno-salen: conversion 36−59%; cis /trans 80/20; ee 0−50% (1R, 2S)

Scheme 39 Epoxidation of styrenes by mannose-derived salen complexes.

336

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Although Jacobsen–Katsuki epoxidation has proved to be highly useful process, it often results in a poor outcome for (E)-disubstituted and terminal alkenes. Organocatalytic alkene epoxidation offers highly complementary alternatives.161 The most efficient protocols involve Oxones as a stoichiometric oxidant and a chiral ketone as an organocatalyst. The idea of using chiral ketones as catalysts for the asymmetric epoxidation of olefins was first proposed by Curci et al. in the mid 1980s.162 As shown in Scheme 40, the chiral ketone is oxidized by KHSO5 to afford chiral dioxirane, which reacts with olefin to provide the enantioenriched epoxide. Several types of chiral ketones, which were applied in the oxone-mediated epoxidation, are depicted below (234–239).161–165 Among them, a few carbohydrate-based C2-symmetric ketones, like D-mannitol-derived compound 239,165a can be found.

O

O

Ph Ph O

O

O O

O Ph

234

R X

H

X R

235

O

O

O F

OH

O

O

O

O

O O

237

**

O

O

Ph Ph

236

R1

O

238

239

R2 O

R3 R1

HSO5

R2

R2

R1 R3

SO3 O O

O

R1

O

HO

R2

R1

R2

SO3 O

SO42

O R1

OH

O R2

Scheme 40 Catalytic cycle of the asymmetric epoxidation of olefins with chiral ketones as catalysts.

Ketones such as 234–239 require rather expensive starting materials and their preparation takes several synthetic steps. Consequently, the relatively high catalyst loading (typically not less than 10 mol% relative to the olefin) is regarded as disadvantageous for a broad application of this method. This problem was solved by Shi in 1996.166 He described an asymmetric epoxidation in the presence of ketone 240 which can be prepared from the inexpensive and readily available D-fructose in two simple steps (equation 33).167 The other enantiomer can be prepared in five steps from L-sorbose.168 A brief discussion of Shi epoxidation will be provided below. For more details about organocatalytic epoxidations, see Chapters 6.23 and 6.24.

O

OH

HO

OH OH

OH D-fructose

(i) acetone, H (ii) PCC

O

O O O

O

ð33Þ

O 240

Ketone 240 is usually employed in a buffered solution (pH 10–10.5, by adding K2CO3 or KOH) at c. 20–30 mol% loading and it mediates the asymmetric epoxidation of various nonfunctionalized olefins with 490% ee (Scheme 41).166 In the same way as already discussed ketones 234–239, the epoxidation works particularly well with the (E)-1,2-disubstituted or nonconjugated

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O

O

Ph

Ph

O

Ph

98% ee

O

Ph

95% ee

O

OTBS

OTBS

94% ee

C6H13

94% ee

C6H13

O

Ph

95% ee

337

COOMe

92% ee

(a) (E)-alkens O

O Ph

Ph

COOMe

Ph

O

O

O

O C10H21

O 95% ee

94% ee

98% ee

97% ee

86% ee

(b) Trisubstituted olefins O Ph

O

TMS

Ph

O

O

TMS Ph

94% ee

93% ee

Ph

TBDPSO

90% ee

92% ee

(c) Vinyl silanes O

Ph

O

Ph

OH

OH

Ph

94% ee

Ph

91% ee

OH

O O

OH

94% ee

94% ee

O

O Ph

OH

Et

74% ee

OH

90% ee

(d) Hydroxy alkenes O

O

O 96% ee

TMS

94% ee

95% ee TMS

O

Ph 96% ee

COOEt

COOEt

COOEt

Ph

97% ee

O

O

O

Ph

Ph

89% ee

92% ee TMS

O

O

93% ee

TMS

O 93% ee

95% ee

(e) Conjugated dienes and enynes

BzO

BzO O

BzO O

O

BzO

O

AcO

O

Ph 80% ee

93% ee

95% ee

88% ee

91% ee

(f) Enol esters Scheme 41 Scope of Shi’s epoxidation.

olefins (Scheme 41a) which are not suitable substrates for the Jacobsen–Katsuki epoxidation. Trisubstituted alkenes, dienes, and enynes can be epoxidized with 490% ee (Scheme 41b).169 The epoxidation conditions are also compatible with various functional groups such as ethers, ketals, esters, etc. A variety of 2,2-disubstituted vinyl silanes can also be enantioselectively epoxidized (Scheme 41c).170 Desilylation of the resulting epoxysilanes with tetrabutylammonium fluoride provides an easy access to optically active 1,1-disubstituted terminal epoxides. The epoxidation can also be extended to the allylic and homoallylic or bis-homoallylic alcohols (Scheme 41(d)).171 This modification is noteworthy, especially in the case of latter compounds, which normally are not favorable substrates for the Sharpless epoxidation.150 Conjugated dienes can be regioselectively epoxidized to provide vinyl epoxides with high ees (Scheme 41(e)).169a Monoepoxides are produced preferentially if a proper amount of catalyst is used, since epoxidation of the remaining olefin is deactivated by the first epoxide introduced. The regioselectivity for the epoxidation of unsymmetrical dienes can be adjusted using steric or

338

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

electronic effects or both. For conjugated enynes, the olefin can be chemo- and enantioselectively epoxidized to produce the optically active propargyl epoxides (Scheme 41(e)).169c Enol silyl ethers can be also epoxidized to give the enantiomerically enriched a-hydroxyketones, usually with only a moderate enantioselectivity.172,173 However, the enol esters have been found to be more effective substrates for such an epoxidation (Scheme 41(f)).174 Detailed studies of the mechanism of chiral ketone-mediated epoxidation can be found in several recent review articles.161 To understand the structural requirements for ketone catalysis in this process, several variations of the basic structure 240 have been explored (241–247).161 O

O O O

O

O

Cl

O

O O

O

O

OH

O O

R

O

O

O O O

O

O

O

O

O

O

O

242

RN

244

O

O

O

O

243

NBoc

O

O

245

O

AcO

O

O 241

O

O O

OAc

246

247

These extended studies allowed development of ketones that are able to catalyze the epoxidation of (Z)-olefins and terminal olefins (e.g., ketone 246, Scheme 42).175–178 Some of them, like ketone 247 (Scheme 43), are able to catalyze the epoxidation of electron-deficient olefins.179 The latter case is particularly noteworthy because ketone 240 is usually ineffective due to its low reaction rate which allows certain competitive processes, such as decomposition of the catalyst or the oxone cooxidant to compete with epoxidation. O

246/Oxone

R1

R1 R2

R2

O

O

NC

O

O

O

91% ee

91% ee

97% ee*

85% ee

*absolute configuration unknown Scheme 42 The Shi’s epoxidation of (Z)-olefins and terminal olefins.

Ti(Oi-Pr)4 sugar hydroperoxide OH

O OH

CH2Cl2, −20 °C

(R)

253 28% ee (R) 254 44% ee (R) -252 52% ee (R) -252 44% ee (S) 251b 50% ee (R) Ti(Oi-Pr)4 sugar hydroperoxide Ph

O

O

Ph

O 91% ee

O

OH

CH2Cl2, −20 °C

O Ph

OH

253 10% ee 256 18% ee 251b 12% ee Scheme 43 Epoxidation of electron-deficient olefins.

71% ee*

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives ketone 247 (20−30 mol%) Oxone (5 equivalent)

R1 COOEt

R2

R1

NaHCO3, Bu4HSO4(catalyst) MeCN/aqueous Na2(EDTA) 24 h, 0 °C to r.t.

O

R2

339

COOEt

ð34Þ R1=H, R2=Ph, 96% ee R1=Me, R2=Ph, 96% ee R1=Ph, R2=H, 44% ee R1=Me, R2=Me, 82% ee

In 2009, Iglesias-Guerra and coworkers180 reported new type sugar-derived ketone (248) for an asymmetric epoxidation of olefins (equation 35). In comparison to ketones 234–239, this new reagent is easily synthesized from a commercially available carbohydrate precursor and affords moderate-to-good enantiomeric excesses (57–74%). Very recently, it was demonstrated that further modification of the structure of 248 may increase the level of the sterocontrol. For example, galactose-derived ketone 249 showed enantioselectivity in the range of 53–100%. O

keton/Oxone

R1

Ph

Ph

R1

R2

R2

for 248 yield 38−74%; 55−80% ee for 249 yield 60−75%; 53−100% ee

R1: Me, Ph R2: Me, Ph

ð35Þ O

O Ph

OMe O

O

O

O Ph

OR O

O

O

O O

O

248

249

The nonracemic hydroperoxides can be employed as an alternative chiral oxidant for the asymmetric epoxidation of olefins. For example, Zhang and coworkers181 utilized the, closely related to sugars, TADDOL-derived hydroperoxides TADOOH (250a) and Me-TADOOH (250b) for vanadium(V)- and polyoxometalates-catalyzed epoxidations of allylic alcohols to afford corresponding epoxides in good yield but only with moderate enantioselectivity. Ph Ph O

Ph Ph O

OOH OH

O

OOH OMe

O

Ph Ph

Ph Ph

250a

250b

Chmielewski and coworkers182,183 reported synthesis of carbohydrate-derived anomeric hydroperoxides 251–256. These compounds are relatively stable, can be separated into pure anomers by column chromatography, and stored in the refrigerator without visible decomposition. RO

BnO O

RO

OOH

BnO

OOH

252

OOH BnO

OOH BnO

BnO

BnO 253

RO O

O

O

BnO 251a R: Ac 251b R: Bn

BnO

BnO

BnO O

254

O OOH RO

BnO 255

OOH

RO 256a R: Ac 25b R: Bn

Titanium-catalyzed epoxidation of allylic alcohols with the above anomeric hydroperoxides proceeded with poor to reasonable enantioselectivities (Scheme 43).182–184 Additionally, the observed opposite stereoselectivity for different anomers indicated that anomeric purity of the hydroperoxides is essential achieving enantioselectivity in the reaction (compare Scheme 43, results for a-252 and b-252). Moderate enantioselectivities were also found for molybdenum-mediated epoxidations (equation 36).185

340

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

O O N

Mo

N

ð36Þ

O O O

251−256 CH2Cl2, r.t.

ee up to 53%

Epoxidation of carbon–carbon double bonds usually requires electrophilic oxygen donors such as dioxiranes or oxaziridinium ions. The oxidants typically used for the enone epoxidation are, however, nucleophilic by nature.152 A prominent example is the well-known Weitz–Scheffer epoxidation186 using alkaline hydrogen peroxide or hydroperoxides in the presence of base. Asymmetric epoxidation of enones and enoates has been achieved with both metal-containing catalysts187–189 and with metal-free systems.190 As it was described before, one of the ways to conduct a metal-free epoxidation of electron-deficient olefins is to employ chiral dioxiranes.179 Alternatively, chiral hydroperoxides can be utilized. The 2,3-unsaturated hydroperoxides related to compounds 251 and 252 (i.e., 251c and 257) have been used by Taylor and coworkers191 for the base-catalyzed enantioselective epoxidation of 2-substituted 1,4-naphthoquinones to provide the corresponding epoxide with ee up to 82% (Scheme 44). O

O

hydroperoxide DBU

R

R O

PhMe, r.t. O

O R

PivO O

O OOH

PivO

AcO

251c

OOH

257 257

251c

Yield (%)

Me Ph Me Ph

ee (%)

71 80 32 47

45 82 −78 −37

Scheme 44 The base-catalyzed enantioselective epoxidation of 2-substituted 1,4-naphthoquinones.

For the epoxidation of 2-methyl-1,4-naphtoquinone, Chmielewski et al.192 applied the previously described saturated hydroperoxides 255 and 256, as well as the 2-deoxysugar-derived compounds 258 and 259 (Scheme 45). Replacement of DBU by an inorganic base, such as NaOH or KOH, gave a similar level of enantioselectivity.193 O R

O

hydroperoxide DBU

(S)

PhMe, r.t. O BnO

O

O BnO BnO 258

OOH

RO

O (R)

O

OOH

RO 259a R: Bn 259b R: Ac 259c R: Piv

O BnO BnO -259a

Yield (%) OOH

256b 255 258 259a -259a

89 83 90 76 73

ee (%) 42 45 47 30 −47

(2S,3R ) (2S,3R ) (2S,3R ) (2S,3R ) (2R,3S)

Scheme 45 The epoxidation of 2-methyl-1,4-naphtoquinone by 2-deoxysugar derived hydroperoxides.

Comparable enantioselectivity for the same olefin has also been achieved by Adam et al.194 using 1-phenyl-ethyl-hydroperoxide, and by Lattanzi et al.195 during the asymmetric epoxidation using hydroperoxides derived from (þ)-norcamphor derivatives.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

341

Adam and coworkers196 investigated the epoxidation of simple enones in the presence of chiral hydroperoxide oxidants. The reactions, mediated by the sugar-derived compound 256b, provided the corresponding epoxide with a reasonable selectivity (Scheme 46). The key role of base in these reactions was observed. Depending on the base used, KOH or DBU, a different sense of the asymmetric induction was observed. The authors speculated that the sense and degree of enantioselectivity are determined by the steric interactions between the base-derived, templating K þ and DBUH þ agents, the chiral peroxide anion oxygen donor, and the prochiral enone substrate.

O

O

256b, base

Ph

(R )

Ph

R

(S )

R

O

R

Base

Yield (%)

ee (%)

Ph Ph Me Me

KOH DBU KOH DBU

91 92 92 91

14 (2S,3R) 43 (2R,3S) 31 (2S,3R) 31 (2R,3S)

Scheme 46 The epoxidation of simple enones in the presence of chiral hydroperoxide oxidants.

Chmielewski et al.193 pointed out that for the simple enones, the enantioselectivity of epoxidation process with anomeric hydroperoxides in the presence of an inorganic base strongly depends on the base counter ion (Scheme 47). A particularly high enantioselectivity was obtained when NaOH was utilized. The remarkable effect of sodium ion suggested that the coordination of counterion occurs in the transition state of epoxidation process by both the hydroperoxide and enone. The latter explanation, initially advanced only as an experiment-derived presumption, was later confirmed by the theoretical studies of reaction mechanism at the DFT B3LYP/6-31 G level of theory.193,197

Ph

Ph

PhMe, r.t.

Ph

base:

O

256b, base

O

O

(R)

Ph

(S)

KOH·H2O NaOH LiOH·H2O CsOH·H2O DBU Me4NOH·5H2O

ee [%]:

11

90

20

39

Ph

13

O

256b, base

O Ph

32

Ph

PhMe, r.t.

O

(S)

Ph

(S)

O base: ee (%):

Ph

12

O

256b, base

O

KOH·H2O NaOH DBU

PhMe, r.t.

78

O (S)

base: ee (%):

6

(R)

Ph

KOH·H2O NaOH DBU 10

85

-

Scheme 47 An effect of inorganic base on epoxidation enones with anomeric hydroperoxides.

Phase-transfer catalysis has been widely used for the asymmetric epoxidation of enones.198 This catalytic reaction was pioneered by Wynberg et al.,199 who used mainly chiral and ‘pseudo-enantiomeric’ quaternary ammonium salts derived from the cinchona alkaloids quinine and quinidine, respectively.

342

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

In 2004, Bako´ et al.200 described the asymmetric epoxidation of chalcone in the presence of glucose- and mannose-derived lariat ether catalysts 260 and 261, respectively. The crown ether 260 f proved to be an effective catalyst under phase-transfer conditions, as shown in equation 36. Interestingly, the yield and the enantioselectivity of this process were significantly affected by the N-substituents. For example, the lowest ee values (c. 8–11% ee) were achieved in the case of catalysts 260b, 260c, and 260i containing either n-butyl or the diphenylphosphinobutyl as the N-substituent. The catalysts 260f and 260d showed the best results with up to 92% ee and 82% ee, but only 41% ee was detected using derivative 260h. Such results led to the conclusion that the length of the chain connecting hydroxyl group to the nitrogen atom plays an important role in the asymmetric induction, and the optimal chain length was three carbon atoms as in the case of 260f. The crown ethers 261 containing a mannopyranose side unit could also be used in the above reaction, however, with only moderate enantioselectivity. Poor asymmetric induction was observed during epoxidation of chalcones when the corresponding galactose-,201 mannitol-,201 and altrose-derived202 monoaza 15-crown-5 lariat ethers were employed as catalysts. 260a 260b 260c 260d 260e 260f 260g 260h 260i

OMe O

O

N R O

O

O

O

O Ph

R:H R: Bu R: Ph R: (CH2)2OH R: (CH2)2OMe R: (CH2)3OH R: (CH2)3OMe R: (CH2)4OH R: (CH2)4P(=O)Ph2

OMe O

O

N R O

O

O

O

O

261a R: H 261b R: (CH2)2OH 261c R: (CH2)3OH 261d R: (CH2)3OMe 261e R: Ts

Ph

It was shown that the absolute configuration of carbon atoms of the monosaccharides at the positions of fusion to the crownring had a great impact on the experimental enantioselectivity (equation 37). The observed asymmetric induction was explained by considering possible mechanistic pathways. Molecular modeling and subsequent DFT calculations – in accordance with the experimental results – indicated that the use of glucopyranoside-based catalyst 260 and that of mannopyranoside-based crown ether 261 results in the preferred formation of the opposite antipodes (2R,3S and 2S,3R, respectively) of the corresponding epoxyketone.202

catalyst, t-BuOOH 20% NaOH

O Ph

Ph

PhMe, 5 °C

O Ph

O (R)

(S)

Ph

260a yield 47%, 28% ee (2R,3S) 260c yield 33%, 8% ee (2R,3S) 260d yield 65%, 82% ee (2R,3S) 260f yield 82%, 94% ee (2R,3S) 260g yield 61%, 41% ee (2R,3S) 261b yield 70%, 72% ee (2S,3R) 261c yield 67%, 82% ee (2S,3R)

ð37Þ

Further studies revealed that the crown ether 260f provides good enantioselectivity not only for chalcone but also for its derivatives and analogous enones.203

3.12.6.2

Asymmetric Oxidation of Sulfides

Enantiopure sulfoxides are important auxiliaries in asymmetric synthesis and some examples also show the useful biological properties. A number of methods for the synthesis of enantiopure sulfoxides were developed, including catalytic oxidation mediated by chiral metal complexes or metal-free methods based on the chiral organic oxidants.204 Several of these methods utilize carbohydrates as a chiral auxiliary. The carbohydrate-derived Schiff base ligands, 262205 and 263,206 were applied as asymmetry inductors for the vanadiumcatalyzed enantioselective oxidation of sulfides. The oxidation of thioanisole provided corresponding sulfoxide with a very good chemoselectivity and with a moderate (18–60% ee for 262) to poor (16–26% ee for 263) enantioselectivity.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

343

R

O O OBn

O HO

R

N

N OH HO

O OMe

R2

HO

MeO

OMe

R1 262

263

Chmielewski and coworkers183,184 utilized hydroperoxides 251–255 as chiral oxidants for the enantioselective synthesis of sulfoxides. However, the observed enantioselectivity was only moderate (12–40% ee). Moderate yields and low enantioselectivities (2–25% ee) were also observed when Shi’s reagent (240/Oxones) was utilized as the oxidant.207 However, Fernandez et al.208 reported that the Shi organocatalytic system using carbohydrate-derived ketone 240 with oxone is superior to the vanadium-catalyzed oxidations205,206,209 in terms of both the chemical yield and enantioselectivity. Although the former systems afforded mostly racemic thiosulfinates in a low to moderate yields, the latter one afforded thiosulfinates with up to 96% ee (equation 38).

R2 R2 R1O

S

240/Oxone S R2 R2

OR1

MeCN/CH2(OMe)2

R2 R2 R1O

S O

S

OR1

R2 R2

R1=H; R2=Et; yield 80%; 72% ee R1=Ac; R2=Et; yield 89%; 89% ee R1=Ac; R2=C5H10; yield 57%; 96% ee R1=PMB; R2=Et; yield 20%; 90% ee R1=Bz; R2= Et; yield 89%; 93% ee

3.12.6.3

ð38Þ

Miscellaneous Oxidation

The C–H oxidation of unactivated alkanes is the most direct method of introducing oxygen functional groups into alkanes. Such oxyfunctionalization, especially when enantioselective, plays an important role in biological systems in which oxidizing enzymes (monooxygenases and dioxygenases) catalyze the C–H insertion directly with molecular oxygen.210 Dioxiranes are currently the only readily available nonmetallic organic oxidants capable of directly oxyfunctionalizing sp3-hybridized C–H bonds. Several methods are available for the preparation of optically active a-hydroxy ketones, which are valuable building blocks in synthetic chemistry.211 For example, Adam et al.212 reported a metal-free method in which silyl enol ethers have been oxidized to optically active a-hydroxy ketones by the in situ generated dioxirane from the fructose-derived ketone 240. Furthermore, it is known that vic-diols may be readily oxidized by dioxiranes to yield the corresponding a-hydroxy ketones. Enantioselective C–H insertion still remains a largely unexplored area in dioxirane chemistry, but its feasibility has been demonstrated in the kinetic resolution of racemic 1,2-diols (e.g., 264) and in the desymmetrization of meso-1,2-diols and their acetals (e.g., 266) to afford enantiomerically enriched alcohols (e.g., 265).213 A moderately good enantioselectivity has been achieved by using the Shi’s ketone 240 as a precursor of chiral dioxirane (Scheme 48). Higher ee values were observed when ketone 246 were utilized.214

3.12.6.4

Dihydroxylation of Olefins

Tatano and coworkers215 examined the dihydroxylations of some a,b-unsaturated esters, i.e., typical examples of activated olefins, linked to sugar templates. All dihydroxylations of olefins 267–269 proceeded cleanly under the standard conditions, affording the vicinal diol derivatives 270–272 in greater than a 90% yield (equation 39). Unfortunately, the diastereomeric excess observed in all cases was approximately 78% de or less and was far from satisfactory compared to the existing asymmetric dihydroxylation methods, such as the Sharpless dihydroxylation.

344

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Ph

OH

Ketone/Oxone

Ph

OH

Ph

OH

buffer (pH 10.5) MeCN

Ph

O

rac-264

(S)-265 Ketone 240: yield 51%, 65% ee Ketone 246: yield 48%, 87% ee

Ph

OH

Ketone/Oxone

Ph

OH

Ph

OH

buffer (pH 10.5) MeCN

Ph

O

meso-266

(R)-265 Ketone 240: yield 89%, 45% ee Ketone 246: yield 80%, 87% ee

Scheme 48 The kinetic resolution of racemic 1,2-diols and the desymmetrization of meso-1,2-diols.

O R1

R2 O

O TBSO

TBSO OMe

t-BuOH/DMF (1:1) 0 °C

269 R1: Me, R2: OBn 268 R1: Me, R2: H 269 R1: H, R2: H

3.12.7

Reduction Reactions

3.12.7.1

Reduction of Olefins

OH

OsO4, NMO

O

R1

O Sug OH

ð39Þ

270 R1: Me, R2: OBn; yield 91%, 74% de 271 R1: Me, R2: H; yield 95%, 78% de 272 R1: H, R2: H; yield 93%, 76% de

The direct metal-catalyzed hydrogenation is a common way to reduce the carbon–carbon double bonds. The reduction of 1,1-disubstituted double bonds in the presence of stereodifferentiating agent may provide enantioenriched products. The classical chiral auxiliary approach in the asymmetric hydrogenation enables only a moderate facial differentiation of double bonds. For example, the heterogeneous hydrogenation of vinyl D-glucoside 273 gives ester 274 in a good yield but with 5.7:1 diastereoselectivity (equation 40).216 The comparable selectivity was observed by other groups using soluble RhCl(PPh3)4 to reduce vinyl D-mannosides and L-rhamnosides.217,218

AcO

O

O

AcO

OAc

COOMe H2, Pd/C

SugO

COOMe

ð40Þ

OAc 273

274 dr 5.7:1

The alternative and more effective approach recommends the application of chiral ligands in the metal-catalyzed hydrogenation. Numerous sugar-derived N,N-, N,P-, P,P-, N,S-, and P,S-ligands have been developed and utilized in the asymmetric hydrogenation. A detailed description of this research can be found in a few recent review articles.219 Herein only a few selected examples will be presented. RajanBabu group explored the Rh(I)-catalyzed asymmetric hydrogenation of variety of dehydroamino acids, that is, b-arylated a-acetamido-acrylic acid esters or acrylic acids (275, Table 5), using the sugar diphosphinite-based ligands, to prepare L- or 220 D-amino acids 276 (Table 5, entries 1 and 2). Sugar phosphinites, such as 277 and 278, served as excellent stereocontrolling elements to produce either functionalized (S)- or (R)-phenylalanine derivatives with high-to-excellent enantioselectivity.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Table 5

Catalytic asymmetric hydrogenation of dehydroamino acids

R

H2, Met/L*

AcHN

COOR

Entry

Ligand

227

RO RO O P

O

R

R + AcHN COOR S-276 (S)-L-amino acid

275 R: H, Me

1

345

AcHN COOR R-276 (R)-D-amino acid

Catalyst

Yiels (ee)

Absolute configuration

Reference

Rh(COD)SbF6

100% (91–99%)

(S)

222

Rh(COD)SbF6

100% (89–97%)

(R)

222

Rh(COD)BF4

100% (98.9–99%)

(R)

223

Rh(COD)BF4

100% (84–88%)

(S)

223

Rh(COD)BF4

100% (97–98%)

(S)

223

Rd(COD)BF4

100% (75%) for 282a

(R)

224

OR

O P

P: diarylophosphino-

2

278

OR

O RO

O P

3

279

OR O P

O O

t-Bu O

t-Bu

O O P O

P

t-Bu

t-Bu 4

280

O O

t-Bu O

t-Bu

O O P O

P

t-Bu

t-Bu 5

281

O OTMS

O TMS

O O P O

O O P O TMS

TMS

6

282a: (S)-BINOL 282b: (R)-BINOL

O P O

O O

O

O O O (Continued )

346

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

Table 5 Entry

Continued Ligand

7

O 283a: (S)-BINOL 283b: (R)-BINOL O

O

Ph

8

284a: (S)-BINOL 284b: (R)-BINOL

O Ph

O

Absolute configuration

Reference

Rh(COD)BF4

100% (80–89%) for 283b

(S)

224

Rh(COD)BF4

100% (96–98%) for 284b

(S)

224

O

O O

Yiels (ee)

O O P O

O

Catalyst

OMe O O P O

Interestingly, the sense of chirality (R or S) of the resulting phenylalanine derivatives was dependent on the relative juxtaposition of the vicinal diphosphinites on the sugar backbone. Thus, the hydrogenation (H2 under 30–40 psi) of 275 in the presence of a catalytic amount of Rh(COD)SbF6 complex with the 2,3-bis-O-[(diphenyl)phosphino]- D-glucopyranoside-type ligand 277 produced predominantly the (S)- L-phenylalanine derivatives (S)-276. Importantly, the electronic tuning of ligand system resulted in an enhancement of enantioselectivity. However, the 3,4-bis-O-[(diphenyl)phosphino]- D-glucopyranoside-type ligand 278 produced corresponding (R)- D-amino acid (R)-276 with an excellent enantioselection. Therefore, these sugar phosphinites, 277 and 278, are in a pseudo-enantiomeric relationship as chiral ligands for the Rh(I)-catalyzed hydrogenation of dihydroamino acids. Furthermore, the disaccharide phosphinites were also used as the water-soluble catalysts for the Rh(I)-catalyzed hydrogenation of dehydroamino acids; however, the observed enantioselectivity was unremarkable.221 Die´guez–Ruiz–Claver group222 prepared several sugar phosphine-phosphite and diphosphite-type ligands, i.e., compounds 279–280 (Table 5, entries 3–5), and applied them to the Rh(I)-catalyzed hydrogenation of some N-acetyldehydroamino acid esters 275. Using the catalyst consisting of the ligand 279 and [Rh(COD)2]BF4, the N-acetylated (R)-alanine methyl ester or N-acetylated (R)-phenylalanine methyl ester (R)-276 were obtained quantitatively with an excellent enantiomeric excess. In contrast, the (S)-enantiomers of these amino acids (S)-276 were obtained in a highly enantioenriched form by switching the chiral ligand 279 to that derived from a sterically less congested sugar phosphine-phosphite or 1,2-O-isopropylidenea-D-glucofuranose-derived diphosphite, i.e., 280 or 281, respectively. Chen and coworkers223 reported the synthesis and application of several sugar monophosphites, such as 282–283, as chiral ligands. These sugar-based ligands served as excellent stereocontrolling elements for the Rh-catalyzed asymmetric hydrogenation of b-substituted or unsubstituted a-dehydroamino acids 275. The results achieved using the Rh complex are shown in Table 5 (entries 6–8). Ligand 282a produced (R)-276 with a moderate enantioselectivity, whereas both 283b and 283b produced (S)-276 with moderate-to-excellent enantioselectivity. These ligands also provided a high level of enantioselectivity during hydrogenation of dimethyl itaconate 285 and 1,1-disubstituted a-arenylamides 286 (Scheme 49).223

3.12.7.2

Reduction of Carbonyl Group

A few carbohydrate-derived auxiliaries have been applied to the stereocontrolled reduction of ketones. Ozaki and coworkers224 found that the reduction of a-keto esters derived from (1-L)-1,2,5,6-biscyclohexylidene-3-tert-butyldimethysilyl-chiro-inositol (e.g., 287) with K-Selectrides proceeded with a high diastereoselectivity to afford the corresponding (S)-a-hydroxy esters. Addition of 18-crown-6 led to the dramatic changeover of the diastereofacial selectivity to provide (R)-enantiomer (Scheme 50). Ozaki proposed that the auxiliary provided a rigid chiral environment, and that the switch in observed selectivity resulted from two conformers of the ketoester. The syn arrangement of the carbonyls (presenting the ketone’s re-face to the approach of the reagent) was presumably favored by K þ ion chelation, whereas the anti conformer predominated when the cation was sequestered by 18-crown-6.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

COOMe

MeOOC

Rh(COD)2BF4 L*, H2

282b 99.4% ee 283b 92.9% ee 284b 98.8% ee

Rh(COD)2BF4 L*, H2

282a 90.3% ee 283a 96.9% ee

Rh(COD)2BF4

R

Ar

AcHN

R: H, R: Ph 282a 95% ee 283a 91% ee

COOMe

MeOOC

285

R AcHN

COOMe

MeOOC

Rh(COD)2BF4 L*, H2

347

R

L*, H2 Ar

AcHN

Ar

282b 95−98.5% ee 284b 99−99.9% ee

286

Scheme 49 The enantioselectivity in hydrogenation of dimethyl itaconate 285 and 1,1-disubstituted a-arenylamides 286.

O

O Sug

O Ph

O

54%

OH

OSiMe2t-Bu

K-Selectride

O dr 49:1

O Sug

66%

O

O

K-Selectride 18-crown-6

O

Ph OH

O

dr 24:1

O 287

Scheme 50 Carbohydrate-derived auxiliaries for the stereocontrolled reduction of ketones.

The stereocontrolled 1,2-reduction enones is one of the leading methods for preparation of nonracemic allylic alcohols. For example, the reduction of a-D-mannosyl enones 288 (equation 41) with a very bulky hydride reagent led to the (R)-allylic alcohols 289 as a major component of obtained mixtures of diastereomers (dr from 9:1 to 19:1).217 A higher stereoselectivity was observed when the enone contained bulkier R groups. The pseudo-enantiomeric a-L-rhamnosyl enones afforded the (S)-alcohols with a similar level of selectivity. Based on the conformational analysis it was suggested that the relative orientation of enone relative to the sugar auxiliary in 288 may be controlled by the exo-anomeric effect. It would be expected that enone fragment in 288 adopt the s-cis conformation to minimize the A(1,3) strain caused the steric bulk of R group. MeO MeO MeO

OMe O

Li(t-Bu)(i-Bu)2AlH

O O 288

THF R

MeO MeO MeO

OMe O OH O

R

ð41Þ

289 yield 78−89% dr from 9:1 to 19:1

Nair and Prabhakaran225 reported a high level of asymmetric induction in reduction of the g-ketoesters 290 bearing the bicyclic anhydro-D-glucose-derived auxiliary (Scheme 51). Zn(BH4)2 reduced the ketone with up to 28:1 diastereoselectivity. The resulting hydroxyesters 291 were hydrolyzed to afford g-lactones 292 with 72–93% ee. However, d-ketoesters were reduced with poor diastereoselectivity (not higher than 3.5:1). The authors proposed that the chelation of zinc ion was a key factor leading to a high selectivity. To compare, the NaBH4 was essentially nonselective toward either type of ketone. The latter observation was explained by a less effective complexation of the sodium ion. The influence of a strong chelating effect was also observed by Ko and Park during reduction of 2-acyl-1,3-dioxanes derived from D-glucose.226 Attempts to modify reductor, for instance, sodium borohydride, with sugar additives for the asymmetric reduction of ketones have met with only limited success. One example providing good stereoselectivity for some substrates was demonstrated by Brown

348

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

R2

O O

O

H

R2

O O

O R1O

O

OH

H O

ZnCl2 /NaBH4

O

R1O O

O H

H

OH

R2

OH

291 yield >90% dr from 6:1 to 28:1

290 R1: Me, Bn R2: Me, Ph

292 yield 80−82% 72−93% ee

Scheme 51 Asymmetric induction in reduction of the ketoesters bearing the bicyclic anhydro-D-glucose-derived auxiliary.

and coworkers who had employed diacetone glucose in combination with isobutyric acid for stereoselective borohydride reductions of aryl ketones with moderate enantioselectivity.227 The reduction reagent, K-glucoride (293) was obtained from diacetone glucose 189 by treatment with 9-borabicyclo[3.3.1]nonane and potassium hydride (Scheme 52).

O

O

O

O

(i) 9-BBN (ii) KH

O

THF, 96%

O

O

O

O

O O

HO

B

H

K

189 293

R1 R2

R1

293 R2

THF

O

OH

R1

R2

Me

Et

99

3

Me

t-Bu

95

70

Me

C6H13

97

27

Me

Ph

95

78

Et

Ph

93

92

t-Bu

Ph

93

97

Yield (%) ee (%)

Scheme 52 The stereoselective borohydride reductions of aryl ketones.

The stereoselectivity of reductions performed with K-glucoride proved to be strongly dependent on the steric properties of the residues on the ketones. For aliphatic ketones, the stereoselectivity increased notably with the steric bulk of the substituents, whereas aryl alkyl ketones and cyclic ketones with bulky residues generally gave good results (Scheme 52). Despite these positive results, this method did not achieve broad application. Ruffo and coworkers228 investigated the rhodium-catalyzed reduction of acetophenone under hydrogen transfer conditions in the presence of chiral diamine 30 (see Section 3.12.2.1) as an asymmetry inductor and i-propanol as hydrogen source, however, the achieved ees did not exceed 50%. As a surrogate of the hydride reduction of carbonyl compounds, the transition metal-catalyzed hydrosilylation of ketones has been actively investigated in current organic synthesis.229 For example, Dieguez’s group explored the Rh-catalyzed asymmetric hydrosilylation of various ketones in the presence of sugar-based ligands.230 After considerable experimentation, it was found that the specific sugar-based ligand, namely, the D-xylofuranose-type thioether-phosphite 294, worked well as an effective stereocontrolling element for the intended hydrosilylation. In the presence of Rh-294 complex, various acetophenones were converted to the (R)-1-arylated ethanols with a moderate to high enantiomeric excess after the methanolysis of intermediate silyl ethers (equation 42). A bulky group (e.g., t-butyl) on the thioether moiety of ligand was essential for realization of high enantioselectivity.

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives (i) [Rh(µ-Cl)COD]2 293, Ph2SiH2 (ii) NaOH, MeOH

O Ar

t-BuS OH

O O

O P

Ar

72−98%

349

O

ð42Þ 72−90% ee 293

Ar : Ph, 4-F-C6H4, 4-MeO-C6H4,4-CF3-C6H4, 3-MeO-C6H4, 2-MeO-C6H4, 2-naphtyl

3.12.8 3.12.8.1

Miscellaneous Application of Carbohydrate Auxiliaries Displacement Reactions at Sulfur and Phosphorus

As described in Section 3.12.6.2, the sugar-based auxiliaries incorporated within the structure of a chiral oxidant can be used in the asymmetric oxidation of sulfides to sulfoxides. This important class of organosulfur compounds can also be prepared by the displacement of alkoxide moiety from sulfinate ester. Chiral sulfinates are excellent precursors of chiral sulfoxides, and this approach was pioneered by Andersen in 1962, using one diastereomer of menthyl p-tolylsulfinate prepared from ()-menthol.231 Ridley and Smal232 prepared various arenesulfinic esters of dicyclohexyl-D-glucofuranose 295, with a modest diastereoselectivity at sulfur (o3:1) when the esterification was performed in pyridine/ether at  78 1C. Subsequent crystallization led to the formation of one diastereoisomer in low yield. In 1991, Alcudia et al.233 discovered that the diacetone D-glucofuranose 189 (DAG) can be converted stereoselectively in 90% yield into either (S)- or (R)-methanesulfinate starting from methanesulfinyl chloride, according to the nature of the amine used as a base (DAG method). Both diastereoisomeric sulfinates were crystalline and could be easily purified. Further studies on DAG method revealed that the transformation of racemic sulfinyl chloride into chiral sulfinate proceeds through the dynamic kinetic resolution process.234 This methodology was optimized and extended to various 189-derived alkyl- and arylsulfinates (Scheme 53).234 The isolated yield of pure sulfinates 296 and 297 was excellent (R1 ¼ Me, Et, n-Pr, p-Tol), except when R1 ¼ Cy due to the decomposition during the isolation step.234a The tert-butyl sulfinates were also prepared using this approach, however, the de-values were lower (72–84%).234b The mechanistic role of base in the stereochemical outcome of synthesis of sulfinates was described in detail by Maseras et al.235

O

O

O

O

O O

O 295

S

R2

O 298 84−98%

O

R2MgX PhMe

O

O

O O

O 296

S O

R1

56−87% 70−100% de

O HO

HO

R1

O

O

189

R1

O S

O S

Cl

Py THF

−78 °C

189

R1 Cl i-Pr2NEt PhMe

O

O

O

−78 °C

O O

297

O

R2MgX PhMe

R1

S

R2

O S O

R1

299 80−90%

50−90% 92−100% de

Scheme 53 The transformation of racemic sulfinyl chloride into chiral sulfinate through the dynamic kinetic resolution.

Finally, the addition of Grignard reagents to 296 and 297 gave chiral sulfoxides 298 and 299 through the replacement of sugar unit by the alkyl group. In most cases, this step proceeded in very high yield and enantioselectivity through an SN2 mechanism with inversion of the configuration at sulfur atom (Scheme 53). It is worth noting that the replacement of 189 by other chiral alcohols (menthol, cholesterol, borneol, etc.) surprisingly afforded sulfinates with low diastereoselectivity.236

350

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

The DAG method has been successfully used in the synthesis of C2-symmetric bisulfoxides237,238 that have been subsequently applied as chiral ligands in asymmetric synthesis.239 Other compounds with pharmacological and synthetic240 interest have been synthesized using this method as well. An alternative approach to chiral sulfinates utilizes cyclic sulfites, derived from some C2-symmetric alcohols, as their precursors. The two oxygen atoms of such sulfites are diastereotopic and should have different reactivities toward an achiral nucleophilic reagent. Vallee et al.241 found that the cyclic sulfite 300 prepared from mannitol biscyclohexylidene could generate tert-butylsulfinates 301 with substantial stereoselectivity when it was attacked by tert-BuMgCl (Scheme 54). The de-values (prevalent RS configuration) were much improved (up to 96% de) by the addition of 1 equivalent of Et2AlCl, presumably due to the chelation of a magnesium atom by the sulfinyl group. However, the diastereoselectivity was only moderate when i-PrMgCl and BnMgCl were utilized (70 and 78% de, respectively). The sulfite of the bis-acetonide of mannitol was also investigated, but in this case low diastereoselectivity was observed during formation of the sulfinate. Similar formation of enantiomerically enhanced sulfoxides from cyclic 3,5-sulfites derived from 1,2-isopropylidene gluco-furanose has also been reported.242

O HO

OH

O

S

O t-BuMgCl Et2AlCl

O

SOCl2 O

O

O

O

O

O

O

O

THF −40 °C

O

O

O S t-Bu

HO

O

O

300

301

Scheme 54 Synthesis of chiral sulfinates via cyclic sulfites.

The DAG method was successfully applied independently by Kolodiazhnyi243 and Alcudia.244 for diastereoselective preparation of phosphines, phosphine oxides, and phosphinates. Analogously, as in the case of reactions with sulfinyl chlorides, a similar base-dependent reversal of stereoselectivity was observed by both research groups during reactions of asymmetric chlorophosphines with D-glucose derivatives 189. In the presence of DABCO or Et3N, the chlorophosphine 302 reacted with 189 to give almost exclusively (S)-phosphinites 303 (Scheme 55). When pyridine was employed as base, the reverse stereoselectivity was observed, but affording only a moderate excess of the (R)-product. As shown in Scheme 55, the phosphinites 303 were directly transformed into chiral phosphines 304 by treatment with alkyllithium reagents, into phosphinates 305 by oxidation with t-butylhydroperoxide, or into thiophosphinates 306 by treatment with sulfur. The last two processes proceeded with a complete retention of configuration at the phosphorus atom, whereas the first one with a complete inversion of configuration. Again, other noncarbohydrate chiral auxiliaries provided a lower level of diastereoselectivity.243b

Ph

P R

Cl

MeLi

302

racemic 189

R Ph 304

O

DABCO or Et3N PhMe

Me P

R Ph

P OSug*

303

t-BuOOH R Ph S8

P OSug* 305

S R Ph

P OSug* 306

Scheme 55 The diastereoselective preparation of phosphines, phosphine oxides, and phosphinates.

Alcudia and coworkers244 pointed out that the stereochemically defined phospinates (e.g., 305) can be obtained directly by the same method using phosphinyl chloride and glucose derivative (Scheme 56). Thus, racemic phospinyl chloride 307 on reaction with alcohol 189 could be transformed into a single diastereoisomer of 305. The removal of chiral auxiliary by the treatment of 305 with Grignard reagents provided enantiomerically pure phosphine oxides 308 with a complete inversion of configuration at the phosphorus atom (Scheme 56).

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

351

O R P Cl 307 Ph racemic Et3N

189

O R Ph

PhMe

C3H7MgCl

P OSug*

O C3H7 P

R Ph

308

305 Scheme 56 The synthesis of phospinates from phosphinyl chloride and sugar derivative.

3.12.8.2

Sugars as Ligands for Metal-Catalyzed Processes (Selected Examples)

The sugar-derived P,P-ligands 277–284, as well as the sugar-derived P,N-ligands (i.e., 309) have also been utilized as chiral ligands in the asymmetric hydrovinylation of olefins.245 The D-allosamine-derived monophosphinite 309 served as a good chiral ligand for the asymmetric Ni(0)-catalyzed hydrovinylation of styrene derivatives 310 with ethylene as shown in Scheme 57.246 In the presence of ligand 309, the reaction produced (S)-1-(methyl)-allylbenzenes 311 with high enantioselectivity. One of the hydrovinylation products, 1-bromo-4-[(S)-1-methylallyl]benzene, was converted to (R)-ibuprofen, a pharmacologically important 2-arylpropionic acid. (Ni(allyl)Br)2, ligand 309 NaB(3,5−(CF3)2−C6H3)4 ethylene CH2Cl2,−78 °C

R

R

89−99%

310 R: H, i-Bu, Br

OH

R: Br t-Bu 311 ee 74−89%

Ph

O

O O

O

NH Ar2P O OBn Ac

(R)-Ibuprofen

308

Scheme 57 Asymmetric Ni(0)-catalyzed hydrovinylation of styrenes.

The RajanBabu group explored the asymmetric hydrocyanation of vinylarenes for evaluation of the sugar phosphinite-type ligands as effective stereocontrol elements.247 For example, the hydrocyanation of vinylnaphthalenes such as 312 with HCN in the presence of catalytic amount of Ni(0) complex, prepared from D-glucose-derived ligand 313, gave nitrile 314 in a good yield and with a high enantioselectivity (equation 43).247a RajanBabu et al.247b also studied the mechanism of hydrocyanation as well as proposed other sugar phosphinites as ligands for this process.247c In further studies, the hydrocyanation of dienes was also explored.247d

CN

HCN, Ni(COD)2 ligand 313 quantitative

MeO 312

Ph

O O

O

OPh

O O Ar2P Ar 2P

MeO 314 ee 85%

ð43Þ

313 Ar: 3,5-(CF3)2-C6H3

Dieguez–Ruiz–Claver group248 demonstrated the efficiency of sugar-derived ligands as a regio- and stereocontrol elements for the Rh-catalyzed hydroformylation of vinylarenes and dihydrofuranes. With ligand 315, the hydroformylation of styrene with CO/H2 (10 bar) in the presence of Rh(acac)(CO)2 catalyst provided (R)-2-phenylpropanal with 89% ee (Scheme 58). A similar Rh-catalyzed hydroformylation of styrene in the presence of 316 provided (S)-enantiomer with 90% ee (Scheme 58). Olefin metathesis catalysts incorporating carbohydrate-based NHCs 317 and 318 have also been synthesized, and their structural characteristics and reactivity evaluated by Keitz and Grubbs.249 These complexes were characterized by a relatively rigid structure due to the steric bulk of the carbohydrate and, in contrast to many N-alkyl NHCs, showed good stability and reactivity in a variety of olefin metathesis reactions, including ROMP, RCM, CM, and AROCM. Furthermore, they also showed the surprising selectivity in CM compared to other catalysts, supporting earlier observation that the steric bulk plays a large role in influencing olefin geometry. Similarly, observable levels of enantioselectivity due to the chiral nature of the carbohydrate were also noticed.

352

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives

CHO (S)

CO, H2 Rh(acac)(CO)2 ligand 315

CO, H2 Rh(acac)(CO)2 ligand 316

80%

83%

CHO (R)

regio 98% ee 89%

regio 98% ee 90% t-Bu

R O

O

O O

O P O

R:

O

O R

R

OMe

O

t-Bu

O

O R

OMe

315

O

316

Scheme 58 Sugar-derived ligands as regio- and stereocontrol elements for the Rh-catalyzed hydroformylation of vinylarenes and dihydrofuranes.

OAc O

AcO AcO

AcO N

OAc Cl Cl Ru

N Mes

AcO

Ph PCy3

317

3.12.8.3

OAc O

N N Mes OAc Cl Cl Ru Ph PCy3 318

Nazarov Cyclization

The modified Nazarov cyclization developed by Tius and Hoppe250 can be considered a domino process involving the initial in situ preparation of a chiral lithium allenolate, its subsequent conjugate addition to the alkenoylmorpholinide (319), followed by the 4p-electrocyclization process furnishing the enantioenriched 5-alkylidene-2-cyclopentenones (i.e., 322). Various chiral auxiliaries were employed, such as D-glucose- and camphor-derived chiral allenes.250,251 Excellent enantioselectivity was observed particularly in the case of lithium allenolates with sugar auxiliaries bearing bulky protection groups (321, 322) as shown in Scheme 59. Tius and coworkers251 pointed out the key role of conformational aspects of sugar in the stereocontrol of cyclization. The inversion of pyranoid ring is induced by the electrostatic attraction between the developing oxocarbenium ion and the nonbonding electron pair on the axial oxygen atom. Whether or not the inversion of ring takes place during the stereochemistry-determining operation, there is a strong evidence that the pyran ring oxygen atom restricts the conformational mobility of the pentadienyl cation and is necessary for realization of both high enantioselectivity and optimal yields of the cyclic product. A key to the high enantioselectivity is the presence of a large axial or pseudoaxial substituent on the pyran ring that shields one face of the pentadienyl cation. The buttressing effect provided by the axial (or pseudoaxial) substituent predisposes the conrotation to take place only in a single direction.251c

TBSO TBSO

OTBS O

TBSO O

Ph (R)

321

OH

O

C Li

O

TBSO

Ph

OTBS O O 322

Li C

Ph (S)

N

89%

O

93% O

OH

319 320 er 93:7 Scheme 59 Asymmetric Nazarov cyclization of D-glucose-derived chiral allenes.

ent-320 er 96:4

Carbohydrate Derived Auxiliaries: Mono (and Disaccharide) Derivatives 3.12.8.4

353

Photochemical Reactions

Piva and Pete252 investigated the photoenolization of a-alkyl-a,b-unsaturated esters 323, which after protonation of the enolate 324 resulted in the deconjugation leading to a new stereogenic center adjacent to the ester group 325 (Scheme 60). They demonstrated that the diacetone-D-glucose 189 was a highly effective chiral auxiliary for this process. The reaction was completely diastereoselective (497% de, favoring the (R)-configuration in 325), when reaction was performed in hydrocarbon solvents at low temperature in the presence of N,N-dimethyl aminoethanol as a proton source. The 189-mediated asymmetric photodeconjugation has been employed, for instance, during the synthesis of perfume components (2R)-2-methyl-decanol and -undecanol,253a and also during the preparation of terpene (R)-lavandulol.253b An excellent level of stereoselectivity was also observed when the fructose-derived auxiliaries were applied.254

R3

O

R2

OR* R1

H

(E)-323 hv hexane −40 °C

hv

R

3

R2

R1

R

OR* R2

OH R3

N

OH

70−85%

1

324 H

O

R3

R1 OR*

R2 O 325 >97% de

OR*

(Z)-323

R*: 1,2,5,6-di-O-isopropylidene-D-glucofuranose (189)

Scheme 60 The photoenolization of unsaturated esters.

The diacetone-D-glucose 189 has also been shown to be an effective chiral auxiliary in the photo-rearrangement of oxepine diesters into the methanohydroazulenes.255

3.12.9

Conclusions

Asymmetric reactions employing carbohydrates as chiral auxiliaries have experienced a remarkable progress over the past decades. Recent results, presented in this paper, demonstrate that auxiliary-controlled reactions are still essential tools in the construction of complex molecular targets. The ready availability of the starting materials, the facile and versatile cleavage, as well as the applicability and reliability in a variety of stereoselective transformations allows chiral sugar auxiliaries to endure today as excellent synthetic intermediates in asymmetric synthesis.

Acknowledgments Authors are grateful to the European Union (European Regional Development Funds, Project POIG.01.01.02.-14-102/09) for financial support.

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