Enzymatic enantioselective

Cychc alcohols are excellent targets for enantioselective enzymatic acylations. For example, acylation of (65) with vinyl acetate catalyzed by Hpase SAM-II gives the (R),(3)-ester with 95% ee (81). Similarly (66), which is a precursor for seratonin uptake inhibitor, is resolved in a high yield and selectivity with Amano Hpase P (82). The prostaglandin synthon (67) is resolved by the same method into the optically pure alcohol in 35% yield (83). 

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

Enantioselective enzymatic desymmetrization is the transformation of a substrate that results in the loss of a symmetry element that precludes chirality (plane of... 

Enantioselective Enzymatic Transformations of Alcohols 153 - y NHCbz Lipase, VA AcO>> - " y< NHCbz... 

Deussen, H.-J., Zundel, M., Valdois, M. et al. (2003) Process Development on the Enantioselective Enzymatic Hydrolysis of S-Ethyl 2-Ethoxy-3-(4-hydroxyphenyl)Propanoate. Organic Process Research Development, 7, 82-87. 

Zhu, D. and Hua, L. (2006) Enantioselective enzymatic reductions of sterically bulky aryl alkyl ketones catalyzed by a NADPH-dependent carbonyl reductase. The Journal of Organic Chemistry, 71 (25), 9484—9486. 

After some early examples of bio-chemo combinations in the 1980s, there was then over a decade of silence , followed by clearly increasing interest from the mid-1990s in the field of dynamic kinetic resolution processes (i.e., chemocata-lyzed racemization combined with enantioselective enzymatic conversion, giving, in principle, 100% yield of an optically pure compound). 

Garcia-Urdiales, E., Alfonso, I. and Gotor, V., Enantioselective enzymatic desymmetrizations in organic synthesis. Chem. Rev., 2005, 105, 313-354. 

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

Scheme 13 Synthesis of a chiral block copolymer by combining ATRP and enantioselective enzymatic ROP of 4-MeCL [27]...

Scheme 14 Tuning of polymer properties by enantioselective enzymatic transesteiification of chiral polymers [107]...

Table 10.3 Effect of deviations of the standard enantioselective enzymatic conversion on the enantiomeric excess. The standard conversion is a single irreversible batch reaction in a homogeneous solution starting form racemic or prochiral substrate. (+)=positive effect, (-)=negative effect, (o)=no effect.

Enantioselective (enzymatic) cyclization of 1 could lead to either enantiomer 2 a or 3 a, depending on which face of the internal double bond is attacked at C-6 by the cation derived from the allylic pyrophosphate unit. Re- or Si-face cyclization (see the detailed discussion in Section 4.3.4.1.2.1., p 442 of 1 b would, however, lead to the diastereomers 2b and 3b. respectively. A thorough analysis of the NMR spectrum of the cyclization product of 1 b definitely showed that 2b was formed thus proving the absolute configuration of (-)-fl-irans-berga-motene to be 2a185. 

Substituted 1,3-diols are valuable intermediates in the synthesis of drugs and natural products [18]. Starting from the regio- and enantioselective enzymatic reduction of diketo esters described above, various methods to obtain enantio-merically pure 3,5-dihydroxy esters were developed. 

Scheme 2.2.7.11 Chiral building blocks evolved from diketo ester la via regio- and enantioselective enzymatic reduction.

Scheme 2.2.7.19 Chiral building blocks evolved from enantioselective enzymatic reduction of propargylic ketones D.

When this reasoning is applied to enantioselective enzymatic reactions, it follows that the ratio of specificity constants should not be affected by a change of medium that leads to different (but of course identical for the two enantiomers) values for the substrate activity coefficients. Indeed, solvent effects were not observed for,... 

Scheme 15)62. After terminating the reaction at a conversion of 38% (relative to total amount of substrate rac-78), the product (S)-43 was separated from the nonreacted substrate by column chromatography on silica gel and isolated on a preparative scale in 71% yield (relative to total amount of converted rac-78) with an enantiomeric purity of 95% ee. Recrystallization led to an improvement of the enantiomeric purity by up to >98% ee. The biotransformation product (S)-43 is the antipode of compound (/ )-43 which was obtained by enantioselective microbial reduction of the acylsilane 42 (see Scheme 8)53. The nonreacted substrate (/ )-78 was isolated in 81% yield (relative to total amount of nonconverted rac-78) with an enantiomeric purity of 57% ee. For further enantioselective enzymatic hydrolyses of racemic organosilicon esters, with the carbon atom as the center of chirality, see References 63 and 64. 

Enantioselective enzymatic ester hydrolyses have also been used for the preparation of optically active silicon compounds with the silicon atom as the center of chirality. An example of this is the kinetic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-(SiR,CR/SiS,CS)-79 with porcine liver esterase (PLE E.C. 3.1.1.1) (Scheme 16)65. Under preparative conditions, the optically active l-silacyclohexan-2-ol (SiS,CS)-80 was obtained as an almost enantiomerically pure product (enantiomeric purity >96% ee) in ca 60% yield [relative to (SiS,CS )-79 in the racemic substrate]. The biotransformation product could be easily separated from the nonhydrolyzed substrate by column chromatography on silica gel. 

Enantioselective enzymatic ester hydrolyses of prochiral trimethylsilyl-substituted diesters of the malonate type have been applied for the synthesis of the related optically active monoesters68. As an example of this particular type of biotransformation, the enantioselective conversion of the diester 82 is illustrated in Scheme 17. Hydrolysis of compound 82 in phosphate buffer, catalyzed by porcine liver esterase (PLE E.C. 3.1.1.1) or horse liver acetonic powder (HLAP), gave the optically active monoester 83 (absolute configuration not reported) in 86% and 49% yield, respectively. The enantiomeric purities... 

Enantioselective enzymatic amide hydrolyses can also be applied for the preparation of optically active organosilicon compounds. The first example of this is the kinetic resolution of the racemic [l-(phenylacetamido)ethyl] silane rac-84 using immobilized penicillin G acylase (PGA E.C. 3.5.1.11) from Escherichia coli as the biocatalyst (Scheme 18)69. (R)-selective hydrolysis of rac-84 yielded the corresponding (l-aminoethyl)silane (R)-85 which was obtained on a preparative scale in 40% yield (relative to rac-84). The enantiomeric purity of the biotransformation product was 92% ee. This method has not yet been used for the synthesis of optically active silicon compounds with the silicon atom as the center of chirality. 

Enantioselective enzymatic transesterifications have been successfully used for the synthesis of optically active silanes with the silicon atom as the center of chirality. As shown in Scheme 20, the prochiral bis(hydroxymethyl)silanes 86 and 88 were transformed into the corresponding chiral dextrorotatory isobutyrates (+)-87 and (+)-89, respectively, using Candida cylindracea lipase (CCL, E.C. 3.1.1.3) as the biocatalyst73. For these bioconversions, methyl isobutyrate was used as solvent and acylation agent. When using acetoxime isobutyrate as the acylation agent and Chromobacterium viscosum lipase (CVL ... 

A similar enantioselective enzymatic transesterification of the prochiral bis(hydroxy-methyl)germane 90 (a germanium analogue of the silane 86) has also been reported74. Transesterification of the germane 90 with vinyl acetate (serving as the acetate source and... 

Enantioselective enzymatic transesterification has also been used for a kinetic racemate resolution75. Starting from the racemic (hydroxymethyl)silane rac-92 (analytical scale), transesterification with vinyl acetate in water-saturated 2,2,4-trimethylpentane, catalyzed by a commercial crude papain preparation (E.C. 3.4.22.2), yielded the corresponding optically active (acetoxymethyl)silane 93 (sign of optical rotation and absolute configuration not reported) (Scheme 21). The enantiomeric purity of the remaining dextrorotatory (hydroxymethyl)silane (+)-92 was moderate (49% ee). 

Enantioselective enzymatic esterifications represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion (kinetic racemate resolution) is illustrated in Scheme 22. Starting from the racemic l-silacyclohexan-2-ol rac-43, the optically active 5-phenylpentanoate (S)-94 was prepared by enantioselective esterification with 5-phenylpentanoic acid using 2-methylheptane as solvent and crude Candida cylin-dracea lipase (CCL E.C. 3.1.1.3) as biocatalyst7. The enantiomeric purity of (S)-94 was ca 65% ee (bioconversion not optimized). 

Enantioselective enzymatic esterifications of trimethylsilyl-substituted alcohols with racemic 2-(4-chlorophenoxy)propanoic acid in water-saturated benzene, catalyzed by the Candida cylindracea lipase OF 360 CCL OF 360 E.C. 3.1.1.3) have been used to prepare (—)-2-(4-chlorophenoxy)propanoic acid76,77. As shown in Scheme 23, the (trimethylsilyl)alkanols 95, 97 and 99 were converted enantioselectively into the corresponding (trimethylsilyl)alkyl (+)-2-(4-chlorophenoxy)propanoates 96, 98 and 100. The enantiomeric purity of the remaining (—)-2-(4-chlorophenoxy)propanoic acid was 95.8% ee (95), 76.1% ee (97) and 77.5% ee (99). 

Analogous results were obtained for the enantioselective enzymatic esterifications of the related t-butyl-substituted alcohols 101 and 103 (carbon analogues of the silanes 95 and 97, respectively). Reaction with racemic 2-(4-chlorophenoxy)propanoic acid in water-saturated benzene yielded the corresponding t-butylalkyl (+)-2-(4-chlorophenoxy)propanoates 102 and 104, respectively76,77. The enantiomeric purity of the remaining (—)-2-(4-chlorophenoxy)propanoic acid was somewhat lower than that observed for the esterification of the analogous silicon compounds [91.1% ee (101), 71.6% ee (103)]. No esterification was observed for the Si/C analogues trimethylsilanol (MesSiOH) and t-butanol (MesCOH). 

ENANTIOSELECTIVE ENZYMATIC REDUCTIVE AMINATION OF 2-(3-HYDROXY-1-ADAMANTYL)-2-OXOETHANOIC ACID... 

In an alternate process, enantioselective enzymatic acylation of racemic a-methyl-l,3-benzodioxole-5-ethanol (55, Fig. 17) was developed using Amano lipase PS-30 (lipase from Pseudomonas cepacia) with vinyl acetate as acylating agent in n-hexane benzene (2 1). This process gave (+)-56 in 54% yield with 80% ee and (-)-57 in 46% yield with 96% ee After separation of alcohol (+)-56 from acetate (-)-57 by methanolysis in the presence of K2CC)3, the acetate was converted to alcohol (-)-56 in 95% yield with 96% ee Mitsunobu inversion of (-)-56 provided (+)-56 in 94% yield with 96% ee The conversion of (.S )-alcohol 56 to (-)-talampanel was carried out in 54% overall yield (Easwar and Argade, 2003). 

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