Combined coinage metal catalysis for the synthesis of bioactive molecules

Journal of Organometallic Chemistry 704 (2012) 1e8

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Review

Combined coinage metal catalysis for the synthesis of bioactive molecules Norbert Krause*, Özge Aksin-Artok, Martta Asikainen, Viola Breker, Carl Deutsch, Jörg Erdsack, Hong-Tao Fan, Birgit Gockel, Stefan Minkler, Manojkumar Poonoth, Yoshinari Sawama, Yuka Sawama, Tao Sun, Frank Volz, Christian Winter Organic Chemistry, Dortmund University of Technology, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany

a r t i c l e i n f o

a b s t r a c t

Article history: Received 13 December 2011 Received in revised form 14 January 2012 Accepted 16 January 2012

The use of the coinage metals copper, silver, and gold enables an efficient and stereoselective assembly of bioactive heterocycles via allenic intermediates. Whereas copper is mediating or catalyzing the synthesis of functionalized allenes by SN20 -substitution or SN20 -reduction, silver and gold are the catalysts of choice for subsequent 5- or 6-endo-cyclizations. Overall, this sequence proceeds with efficient center-to-axis-tocenter chirality transfer. Recent advances of this combined coinage metal catalysis include the synthesis and transformation of substrates containing two adjacent allenic p-systems or heteroatoms, the development of recyclable gold catalysts, and the combination of two catalytic processes in tandem or one-pot reactions. Ó 2012 Elsevier B.V. All rights reserved.

Keywords: Allenes Catalysis Copper Silver Gold Bioactive molecules

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 Copper-catalyzed synthesis of allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Silver- and gold-catalyzed cyclization of functionalized allenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 Improvement of efficiency and sustainability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 Applications in target-oriented synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1. Introduction The coinage metals copper, silver and gold belong to the seven metals of alchemy. They are known to mankind for thousands of years, and gold may have been the first metal ever used by humans [1]. Whereas copper enjoys a rich history in organometallic chemistry and organic synthesis, starting with contributions by Kharasch and Gilman in the 1940s and 1950s [1,2], the usage of silver and gold in transition metal catalysis

* Corresponding author. E-mail address: [email protected] (N. Krause). 0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jorganchem.2012.01.008

commenced much more recently. In our research program, we are particularly interested in combining the (quite different) reactivities of the coinage metals for the stereoselective synthesis of bioactive target molecules [3]. Due to their high reactivity and axial chirality, functionalized allenes are ideal substrates for these transformations [4]. The challenge in using allenes in organic synthesis is twofold: the high energy of these unsaturated systems (enthalpy of formation for H2C]C]CH2: ca. 190 kJ/mol [5]) has to be provided by using suitable energy-

2

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

rich substrates or reagents, and the relative and/or absolute configuration of these chiral molecules has to be controlled. Many classical reaction types of organic chemistry (addition, elimination, substitution, rearrangement) are applicable to the synthesis of allenes. Stereoselective variations of these transformations often take advantage of center-to-axis chirality transfer. The allenes thus formed are highly interesting in their own right, but are also converted frequently into other target molecules, e.g., by (cyclo)addition, cyclization, and rearrangement. Ideally, the chirality of allenes is utilized in these transformations for the controlled formation of stereogenic centers by axis-to-center chirality transfer.

R1

CuCl (3 mol%) IBiox7 • HOTf (3 mol%) NaOt-Bu (10 mol%)

R2 OH

H

O

HO 4

O

R1-R2 = (CH2)5: 60%

O N

R1 = Me, R2 = Cyclopropyl: 72% R1 = Me, R2 = CF3: 50%

N + _

Me

TfO PMHS = Me3SiO IBiox7 • HOTf

One of the most prolific methods for the synthesis of allenes is the SN20 -substitution of propargyl electrophiles with organometallic reagents [6]. Organocopper compounds are the nucleophiles of choice for these transformations, and propargyl oxiranes 1 (or carbonates) are among the most useful electrophiles, not only because the substitution usually takes place with high SN20 -regioselectivity and anti-stereoselectivity (i.e., with center-to-axis chirality transfer), but also because the a-hydroxyallenes 2 formed are highly suitable for subsequent modifications (Scheme 1). The magnesium cuprates used in these transformations are formed in situ from a Grignard reagent and a copper(I) salt, and a phosphine or phosphite added to the reaction mixture prevents the epimerization of the allene by the copper reagent. Magnesium cuprates bearing reactive functional groups can also be used [7], and variations catalytic in copper have been described as well [8]. Interestingly, the smallest nucleophile e the hydride ion e has so far only played a minor role in allene synthesis by SN20 -substitution. Recently, we have established a copper-catalyzed SN20 reduction of propargyl oxiranes 3 which provides an efficient route to a-hydroxyallenes of the type 4 (Scheme 2) [9]. Key to success is the stabilization of the catalytically active copper hydride species (formed in situ from CuCl and the stoichiometric hydride source polymethylhydridosiloxane [PMHS]) by an N-heterocyclic carbene (e.g., IBiox7). This transformation proceeds with high anti-stereoselectivity by center-to-axis chirality transfer and is compatible with various functional groups (alcohols, esters, ethers, etc.). Extension to propargyl carbonates [10] has broadened the range of allenes available by the method and offers advantages with respect to stereoselectivity and substrate reactivity. 3. Silver- and gold-catalyzed cyclization of functionalized allenes The activation of the highly reactive double system of an allene by treatment with a Brønsted or Lewis acid enables a nucleophilic attack which leads to the formation of a new CC or Cheteroatom bond. Because of their soft and carbophilic character, silver [11] and gold catalysts [12] are particularly well suited for the selective activation of allenes in the presence of other reactive functionalities

O R1 1

3

2

R MgX

R

CuCN / R3P THF

Scheme 1. Anti-stereoselective SN magnesium cuprates.

20 -substitution

3

R2

•

R

OH 2

of propargyl oxiranes 1 with

Si O SiMe3 H

Scheme 2. Copper-catalyzed SN

20 -reduction

n

of propargyl oxiranes 3.

[3,13]. In the year 2000, we have started a program dedicated to gold-catalyzed endo-selective cycloisomerizations of chiral allenes 5 bearing a nucleophilic substituent in the allylic (a) or homoallylic (b) position to afford chiral five- or six-membered oxygen, nitrogen or sulfur heterocycles (Scheme 3). These transformations take place with perfect atom economy [14]. The prototype of the gold-catalyzed allene cycloisomerizations established by our group is the conversion of a-hydroxyallenes to 2,5-dihydrofurans. This transformation has traditionally been performed by treating the allene with a silver salt; under these conditions, however, the reactivity is so low that often stoichiometric amounts of silver are required to achieve an acceptable reaction rate [15]. In contrast to this, catalytic amounts of gold(I) or gold(III) salts induce a rapid conversion of various a-hydroxyallenes to the corresponding 2,5-dihydrofurans [16]. Many functionalities (e.g., carbonyl groups, free alcohols, acid-sensitive protecting groups) are tolerated under these conditions. Whereas alkylsubstituted allenes react with complete axis-to-center chirality transfer [12a,17], substrates bearing phenyl or electron-rich aryl groups are prone to epimerization when treated with gold salts. This undesired process probably occurs via zwitterionic intermediates and can be prevented by modulating the Lewis acidity of the gold catalyst [18]. The mechanistic model [19] for the gold-catalyzed cycloisomerization of a-hydroxyallenes (Scheme 4) involves coordination of the carbophilic gold catalyst to the allenic double bond distal to the hydroxy group. This affords p-complex A which undergoes a 5-endo-cyclization to the zwitterionic s-vinylgold species B. Protodeauration leads to the dihydrofuran and regenerates the gold catalyst. The cyclization is accelerated in the presence of external proton donors (water, methanol); this suggests that the protodeauration of B is the rate-limiting step. Experimental support for this model was recently gained by Widenhoefer and coworkers [20] through the isolation of a gold p-allene complex which was characterized by X-ray crystallography and variable-temperature NMR spectroscopy. Moreover, the group of Hammond [21] has isolated

R1

● 2

R1

R2

OH

3

2. Copper-catalyzed synthesis of allenes

R1

●

PMHS (2 eq.) Toluene, t-BuOH, 0°C Workup: n-Bu4NF • 3 H2O

R

Au(I) or Au(III)

n

HX 5

R3 R4

R1...R4 = Alkyl, Aryl X = O, NR, S n = 0 (α), 1 (β)

n

R1 R2

X 6

R3

R4

Scheme 3. Gold-catalyzed endo-cycloisomerization of a- or b-hetero-functionalized allenes 5.

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

R4 R R1 R2

•

[Au]

R4

R

R3

O

1

R

Me 3

R

[Au]

R1

R4

2

3

R

H

O

R

• R

R3

Me

A

Me AuCl (5 mol%) H

HO 7

NH

CH2Cl2, rt

O 10

OBn

R = H: 72% R = n-Bu: 77%

t-Bu OBn

various stable s-vinylgold compounds (similar to species B) formed from allenic esters and stoichiometric amounts of gold salts. These were characterized by NMR spectroscopy and in one case also by Xray crystallography. In order to broaden the scope of the gold-catalyzed allene cyclization, we have recently applied the method to substrates containing two adjacent allenic p-systems or heteroatoms. Allenic hydroxylamine derivatives proved to be particularly interesting substrates since three different chiral heterocycles can be obtained with high regio- and stereoselectivity, depending on the starting material, the gold catalyst and the protecting group at nitrogen [22]. In all cases, the nitrogen atom acts as the nucleophile and attacks the allene in a 5- or 6-endo-cyclization. Thus, N-hydroxy-aaminoallenes 7 afford N-hydroxypyrrolines 8 with complete axisto-center chirality transfer in the presence of 5 mol% AuCl (Scheme 5). Under these conditions, the allenic hydroxylamine ethers 9 with exchanged positions of the heteroatoms afford mixtures of 4,5-dihydroisoxazoles and 3,6-dihydro-1,2-oxazines. The regioselectivity can be shifted in favor of the isoxazoles 10 by using the cationic gold(I) complexes Ph3PAuBF4 or C (Scheme 6) [22]. In contrast to this, a selective 6-endo-cyclization to the oxazines 11 is possible by treatment of the N-Boc-protected hydroxylamine ethers with gold(I) chloride. Overall, this method is particularly versatile because the precursors 7 and 9 of the three heterocycles 8, 10, and 11 are all obtained in a stereoselective manner by Mitsunobu reaction from the same a-hydroxyallenes. Conjugated bis(a-hydroxyallenes) 12 represent another intriguing substrate class for coinage metal catalysis. Like their “simple” counterparts (e.g., 2), they are accessible be copper-mediated SN20 -substitution of bis(propargyloxiranes) [23]. Interestingly, silver turned out to be superior with regard to gold for

●

N

PG = H

PG = Boc

Scheme 4. Mechanistic model for the gold-catalyzed cycloisomerization of ahydroxyallenes.

R2

R

CH2Cl2, rt

OH

2

R

Me

NHPG

C (5 mol%)

AuCl (5 mol%) CH2Cl2, rt

R4

R1

H B

H

OBn O 9

[Au]

R1

Me

●

OH

2

3

R2 R1

N

H

OH 8 R1 = n-Bu, R2 = CH2OBn: 80% R1 = Ph, R2 = CH2OBn: 73% R1 = n-Bu, R2 = CH2OH: 67%

Scheme 5. Gold-catalyzed cycloisomerization of N-hydroxy-a-aminoallenes 7 to Nhydroxypyrrolines 8.

O

H

N Boc 11

O

P

Au

NCPh SbF6

t-Bu

3

C

R = i-Pr: 75% R = n-Bu: 85% Scheme 6. Gold-catalyzed cycloisomerization of allenic hydroxylamine ethers 9.

the cycloisomerization of these bisallenes. Depending on the steric demand of the substituent R, either mono-cyclization products 13 or bis(2,5-dihydrofurans) 14 were obtained in the presence of 0.25e0.3 eq. of silver nitrate in acetone (Scheme 7). In contrast to this, no conversion whatsoever (or decomposition of the starting material) was observed with gold(I) or gold(III) salts alone. In the presence of stoichiometric amounts of N-iodosuccinimide (NIS), however, a very fast gold-catalyzed cyclization of 13 to the iodinated bis(2,5-dihydrofuran) 15 took place. The accelerating effect of N-iodosuccinimide can be utilized in various gold-catalyzed transformations. For example, the 6-endocycloisomerization of b-hydroxyallenes (e.g., 16) to 5,6-dihydro2H-pyrans of the type 17 (X ¼ H) is usually very slow and may take several days at room temperature for complete conversion (Scheme 8) [24]. However, addition of NIS to the reaction mixture induces a tremendous acceleration, leading to the formation of the corresponding iodinated dihydropyran within 1 min [25]. This effect is probably caused by a very rapid iododeauration of a s-gold intermediate (cf. B in Scheme 4) by NIS which is activated by the gold catalyst (species D) [26]. 4. Improvement of efficiency and sustainability An important task for the future development of preparative chemistry is the improvement of efficiency and sustainability. In transition metal catalysis, this involves decrease of the catalyst loading, recycling of the catalyst, combination of several catalytic processes in one-pot, and use of environmentally friendly reaction media. A serious problem of homogeneous gold catalysis is the (almost inevitable) reduction of the catalyst to metallic gold after the reaction or upon workup, so that the catalyst cannot be reused. This issue can be solved by using ionic liquids as reaction medium. Thus, for the cycloisomerization of a-hydroxyallene 18 to dihydrofuran 19, AuBr3 in the imidazolium-derived medium [BMIM] [PF6] gives the best results (Scheme 9) [27]. This catalyst system is not only stable to water and air, but can also be recycled easily (after extraction of the product with hexane) without loss of efficiency. Interestingly, the reactivity of the catalyst decreases after the first run, but is constant after that. Over five runs, only 0.03% of the original catalyst loading is lost during extraction of the product. This almost negligible leaching makes the method attractive for the synthesis of pharmacologically active target molecules and indicates that the solution of AuBr3 in [BMIM][PF6] is potentially recyclable several thousand times.

4

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

MeO HO

i-Pr

R

●

R

AgNO3 (0.25 eq.) Acetone, rt, 2 h

OH

●

O

R = i-Pr

R = Et

O

OMe

i-Pr 13 (97%) AuBr3 (2 mol%) NIS (1.2 eq.) CH2Cl2, rt, 10 min

AgNO3, (0.30 eq.) Acetone, rt, 1 d OMe

Et

MeO

MeO

OMe

12

OH ●

i-Pr

O O

Et

MeO

14 (59%)

OMe O

i-Pr I

15 (61%)

Scheme 7. Silver- and gold-catalyzed cyclization of conjugated bis(a-hydroxyallenes) 12.

X n-Bu

●

Me

O

AuCl (5 mol%) n-Bu

CH2Cl2, r.t.

HO

Me

16

N

O

17 Additive None NIS

Time

X

Yield (%)

5d

H

50

1 min

I

56

I

O [Au] D

Scheme 8. Accelerating effect of N-iodosuccinimide in the gold-catalyzed cycloisomerization of b-hydroxyallene 16.

Recently, we have established the first example of gold catalysis in micellar systems using the vitamin-E derived amphiphiles polyoxyethanyl a-tocopheryl sebacate (PTS) or D-a-tocopherol-polyethylenglycol-750-succinate monomethylether (TPGS-750-M) [28]. With gold(III) bromide, these afford air-stable aqueous gold catalyst solutions with excellent reactivity and recyclability which allow the smooth and efficient cycloisomerization of various a-functionalized allenes (Scheme 10). For example, treatment of a-hydroxyallene 20 with 5 mol% AuBr3 in a 2% aqueous PTS solution afforded dihydrofuran 21 with 80% yield after 45 min reaction time at room temperature. In the absence of the amphiphile, the cycloisomerization of a-functionalized allenes is much slower or does not occur at all. Addition of NaCl to the reaction mixture affords larger micelles and therefore induces faster reactions. The average diameter of PTS-derived micelles is increased from ca. 10 nm in

Me ●

Me

OTBS OH

H

Me

Me AuBr3 (1 mol%)

Me

[BMIM][PF6], rt H

18

N

N

n-Bu

[BMIM][PF6]

PF6

OTBS O

H 19

Run

Time

Yield (%)

1

10 min

84

2

3h

74

3

3h

81

4

3h

84

5

3h

84

Scheme 9. Gold-catalyzed cycloisomerization of a-hydroxyallene 18 in an ionic liquid.

“sweet” water to ca. 100 nm with 3 M NaCl [28,29]. Accordingly, the time required for complete conversion of allenol 20 to 2,5dihydrofuran 21 is decreased to just 10 min with 3 M NaCl. Even with lower catalyst loadings of 2 or 1 mol% AuBr3, the reaction is still faster than in the absence of salt, and high yields (80e88%) were obtained in all cases. Recycling of the catalyst solution is possible by extraction of the product with hexane with a loss of only 0.29% of the original catalyst loading over four runs. The cycloisomerization of certain a-hydroxyallenes can also be carried out in water with tetrachloroauric acid as catalyst [30]. We have utilized this system for the first example of a tandem lipase/ gold-catalyzed transformation. The one-pot kinetic resolution/ cycloisomerization of racemic allenic acetates ()-22 with Burkholderia cepacia lipase (PS Amano SD) and HAuCl4 afforded 2,5dihydrofurans (R)-23, as well as unreacted starting material (S)22, with 28e50% isolated yield and 86e98% ee (Scheme 11) [31]. The mutual tolerance of the Lewis-acidic gold catalyst with the Lewis-basic lipase is maintained as long as low amounts of the former are used. a-Hydroxyallenes cannot only be prepared by copper- [6] but also by rhodium-catalyzed SN20 -substitution of propargyl oxiranes or carbonates [32]. The latter reaction can be combined with the gold-catalyzed cycloisomerization to 2,5-dihydrofurans in a onepot process which enables an efficient and sustainable access to these heterocycles. Thus, treatment of propargyl oxirane 24 with various arylboronic acids in the presence of KOH and catalytic amounts of [RhCl(nbd)]2, followed by addition of the AuBr3 catalyst, afforded dihydrofurans 25 with good to excellent yield (Scheme 12) [33]. The process tolerates both electron-donating and -withdrawing substituents in the arylboronic acid. Key to the success of this one-pot transformation is the use of the optimal amount of the

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

Me

H

Me

OTBS AuBr3 (cat.)

•

Ph

5

H

Ph

2% PTS/H2O

OH

OTBS

H

H

O

20

21 AuBr3 (mol%)

NaCl

Time (min)

Yield (%)

5

0M

45

80

5

1M

30

88

5

2M

20

86

5

3M

10

88

2

3M

20

88

1

3M

30

84

O O

O 13

H

O 4

O

O PTS

Scheme 10. Gold-catalyzed cycloisomerization of a-hydroxyallene 20 in PTS-derived micelles.

PS Amano SD

R1

R1 R1

HAuCl4 (0.5 mol%)

● R1

R2 AcO

Phosphate buffer/

H 1

R

THF (150:1), r.t., 48h

O

R

(R)-23 R2

●

R2

R1 AcO

(R)-23

(±)-22

R1

+

2

H

(S)-22

(S)-22

Yield (%)

ee (%)

Yield (%)

ee (%)

-(CH2)5-

Me

28

86

31

93

-(CH2)5-

n-Pr

45

95

40

>95

-(CH2)4-

n-Pr

38

88

33

>95

Me

n-C8H17

50

98

36

95

Scheme 11. Tandem lipase/gold-catalysis.

Me O 24

ArB(OH)2 (1.5 eq.) [RhCl(nbd)]2 (2.5 mol%) KOH (0.4 eq.) THF/H2O (100:1), r.t., 2-5 h then AuBr3 (5-6 mol%) r.t., 2-5 h Ar Ph 4-MeC6H4

Me O

Ar

H 25

Yield (%) 80

base KOH which is essential for the rhodium-catalyzed SN20 substitution, but is also inhibiting the gold catalyst. The dihydrofurans were obtained as a single diastereomer, indicating a high syn-selectivity in the rhodium-catalyzed SN20 -substitution and complete chirality transfer in the gold-catalyzed cycloisomerization. Overall, the transformation of propargyl oxiranes 24 to dihydrofurans 25 is an example for efficient center-to-axis-tocenter chirality transfer. 5. Applications in target-oriented synthesis

84

2-MeC6H4

63

4-CF3C6H4

79

4-MeCOC6H4

90

3-OHCC6H4

77

Scheme 12. One-pot synthesis of 2,5-dihydrofurans 25 from propargyl oxirane 24.

Several examples for the combined use of the coinage metals in the synthesis of bioactive target molecules, taking advantage of an efficient center-to-axis-to-center chirality transfer, have been reported in recent years [34]. Natural products comprising a 2,5dihydrofuran ring are rather rare, one example being the antibiotic amino acid furanomycin (31). We have used Garner’s aldehyde

6

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

AuCl3 (1 mol%)

NBoc O

● H

NBoc

H NBoc HO

THF, r.t. OH

H n-Bu

89%

n-Bu

O

27

O

28

CHO H

AuCl3 (1 mol%)

NBoc

26

NBoc

O

O n-Bu

● H

O

H

O

R

29

CO2H H

OH

THF, 0°C

30

n-Bu R

R = Me: 86% t-Bu: 34%

NH2

(+)-Furanomycin (31) Scheme 13. Synthesis of furanomycin analogs.

AcO

O O

•

MeMgCl CuI, LiBr

O

OTBS OTBS

33 (78%)

O

32 (>98% ee/ds) 1. n-Bu4NF (98%) 2. Ph3PAuCl/AgBF4 (5 mol%)

OH

O O

O

O

(R,R,R)-Bejarol (35) >98% ee/ds

34 (85%)

Scheme 14. Synthesis of (R,R,R)-bejarol (35).

26 as precursor of propargylic oxiranes which were converted into a-hydroxyallenes 27 and 29 by copper-promoted SN20 -substitution. Subsequent cycloisomerization in the presence of 1 mol% of gold(III) chloride in THF afforded the 2,5-dihydrofurans 28 and 30 (Scheme 13) [35]. In case of allene 27, the cyclization was accompanied by acetal cleavage which is apparently linked to the higher reaction temperature (r.t. instead of 0  C). Subsequent removal of the protecting groups and oxidation afforded analogs of furanomycin (31). In the first total synthesis of the naturally occurring sesquiterpenoid (R,R,R)-bejarol (35) and its (3R,5S,9R)-isomer, the diastereomerically and enantiomerically pure propargyl acetate 32 was subjected to an SN20 -substitution with a methylmagnesium cuprate which afforded the desired allene 33 as a mixture of diastereomers with regard to the allenic chirality axis (Scheme 14) [36]. Deprotection of the silyl ether set the stage for the goldcatalyzed cycloisomerization to the dihydropyran 34 which could be converted easily into the target molecule 35. We have also reported the first total synthesis of the b-carboline alkaloids ()-isocyclocapitelline (38) and ()-isochrysotricine (39) by PicteteSpengler reaction of a chiral tetrahydrofuran with

•

Me

AuCl3 (0.05 mol%)

OH

BnO

H O

BnO

THF

OH

Me 2

HO 37 97% (96% de, >98% ee)

2

36

N Me

N

Me

N

1. MeI 2. NaOH

O HO 39 (-)-Isochrysotricine

H

Me

N H O HO

H

38 (-)-Isocyclocapitelline

Scheme 15. Synthesis of b-carboline alkaloids ()-isocyclocapitelline (38) and ()-isochrysotricine (39).

N. Krause et al. / Journal of Organometallic Chemistry 704 (2012) 1e8

AuCl3 (2 mol%)

• TBSO

OH HO O

O

41 70% (> 98% ee/ds)

40

CHO

OTBS

THF

OH

7

42 (+)-Citreoviral

Scheme 16. Synthesis of (þ)-citreoviral (42).

tryptamine (Scheme 15) [37]. Key intermediate 37 was obtained from the corresponding a,b-dihydroxyallene 36 with complete axis-to-center chirality transfer by treatment with gold(III) chloride in THF. With a catalyst loading of only 0.05 mol%, this reaction belongs to the most efficient transformations reported so far in homogeneous gold catalysis. Moreover, the gold-catalyzed cycloisomerization of allenic diol 36 is not only stereoselective, but also highly chemo-/regioselective, since no product resulting from nucleophilic attack of the b-hydroxy group was observed. Hydrogenation of the double bond with concomitant removal of the benzyl protecting group, followed by oxidation and carbolin formation, afforded the enantiomerically pure natural products. An analogous gold-catalyzed cycloisomerization of an a,b-dihydroxyallene was also employed by Kocienski and coworkers [38] in their synthesis of the ionomycinecalcium complex. The double bond of the 2,5-dihydrofuran formed by allene cycloisomerization can also be used for oxidative functionalization. We have taken advantage of this possibility in a stereoselective synthesis of (þ)-citreoviral (42), a building block and metabolite of the mycotoxin citreoviridin. Thus, treatment of the diastereo- and enantiomerically pure hydroxyallene 40 with 2 mol% gold(III) chloride in THF afforded the dihydrofuran 41 with complete chirality transfer (Scheme 16) [3a]. Subsequent Sharpless dihydroxylation, followed by inversion of the secondary alcohol, afforded the desired dihydrofuran with the correct relative and absolute configuration at all four contiguous stereogenic centers. The stereoselective synthesis of the cytostatic natural product (þ)-varitriol (46) and several analogs is another recent example for the prolific use of combined coinage metal catalysis in targetoriented synthesis. Here, the propargyl oxirane 43 was submitted to a copper hydride-catalyzed SN20 -reduction using the protocol established before by our group [9] (Scheme 17). The a-hydroxyallene 44 thus obtained was converted into the 2,5-dihydrofuran 45 by treatment with 1 mol% of gold(III) chloride in THF. The subsequent transformation of 45 into the target molecule 46 was accomplished by Sharpless dihydroxylation of the double bond and coupling of the aromatic side chain via HornereWadswortheEmmons-olefination [3b].

CuCl (3 mol%) SIMes • HCl (3 mol%) NaOt-Bu (9 mol%)

O OBn 43

HO

PMHS (1.2 eq.) Toluene, t-BuOH, 0°C Workup: n-Bu4NF • 3 H2O

OH

H

•

OBn OH 44 (78%) AuCl3 (1 mol%) THF, 0°C

OH OMe

O

OBn O 45 (82%)

(+)-Varitriol (46)

Scheme 17. Copper- and gold-catalyzed synthesis of (þ)-varitriol (46); SIMes/HCl ¼ N,N0 -bis(2,4,6-trimethylphenyl)imidazolinium chloride.

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