Preparation by yeast reduction and determination of the sense of chirality of enantiomerically pure ethyl (−)‐4,4,4‐trichloro‐3‐hydroxy‐ and (+)‐4,4,4‐trifluoro‐3‐hydroxybutanoate

Abstract

(Fig. 2 and 3).Enantiomerically pure 4,4,4-trichloro-and 4,4,4-trifluoro-3-hydroxybutanoic acid derivatives 1 and 2 are highly desirable chiral starting materials for organic synthesis. Thus, the p-lactone of (S)-4,4,4-trichloro-3-hydroxybutanoic acid was shown by Wynberg & Staring [I] to be accessible in 98% enantiomeric excess (ee) by quinidine-catalyzed asymmetric cycloaddition of ketene to chloral, and was hydrolyzed to (S)-malic acid, a source of numerous useful chiral building blocks [2]. In view of the interest in fluorinated analogues of biologically important natural products and drugs, an access to the chiral, non-racemic trifluoroester 2 would be even more important. Furthermore, it was interesting to find out, whether Prelog's rule [3] for the enantioselective hydrogenation of carbonyl compounds by NADH-dependant enzymes of microorganisms (see A-B) would be followed by the trihalomethyl precursors of 1 and 2, as it is for the 3-ketoesters which are reduced by baker's yeast (Saccharomyces cerevisiae) to the hydroxyester 3 [4][5][6], 4 [4], and 5 [7] of more than 90% ee') (ee N optical purity in the present paper).

Efficient NADPH Recycling in Enantioselective Bioreduction of a Ketone with Permeabilized Cells of a Microorganism Containing a Ketoreductase and a Glucose 6‐Phosphate Dehydrogenase

“…[15] This enzyme demonstrated the highest enantioselectivity observed for this bioreduction known thus far. [16] Bioreduction of 1 (20 mM) with resting cells of Bacillus pumilus Phe-C3 (6.7 g cdw/L, cdw ¼ cell dry weight) showed that the addition of 2% glucose increased the initial activity from 2.7 to 12 U/g cdw (U ¼ mmol/min) via the recycling of NADPH inside the cells. However, such cofactor recycling is not efficient, and biotransformation for 5 h yielded (R)-2 in only 42% yield.…”

Quasienantiomers and Quasiracemates: New Tools for Identification, Analysis, Separation, and Synthesis of Enantiomers

“…More generally, the difference in ideality of phase behavior can often be used to assign absolute configuration of a molecule if a close analogue of known configuration is available because the heterofacial (quasienantiomeric) combination of molecules almost always deviates more from ideality than the homofacial combination. [10] In a related method, cocrystallization of a pair of quasienantiomers, one of known absolute configuration and the other of unknown configuration, followed by X-ray crystallographic analysis of the quasiracemate can directly yield the absolute configuration of the unknown component. Again, the method is limited since the pair of compounds must yield suitable crystals.…”

Yeast‐Mediated Stereoselective Synthesis

“…Many β-keto esters possessing one or more heteroatoms containing moieties attached to C-4 have been reduced by baker's yeast, and the yeast-to-substrate ratio was found to be the most important parameter for obtaining good results [193,250,251,256,265,[276][277][278][279][280][281][282]. Yields and stereoselectivity were dropped for β-keto esters carrying an additional stereogenic center [283,284], and the reduction of α-thiosubstituted β-keto esters has been suggested as an alternative to the reduction of unsubstituted β-keto esters to improve yields and selectivity.…”

“…(E)-2-Alkyl-4,4,4-trichloro-2-butenals were regiospecifically converted to the corresponding saturated alcohols with high enantioselectivity, whereas the (Z)-isomers were reduced to afford allyl alcohols [472]. Polyfluorinated β-keto esters were efficiently reduced, and the products were usually obtained in good yields [276,278]. The reduction of 2-fluorocinnamyl alcohols by baker's yeast furnished (S)-2-fluoro-3-aryl-propanols in high yields with up to 92% ee [473].…”