Three microbial lipases have been used to deracemize trans-2-fluorocycloalkanols 2 both by hydrolysis of the corresponding acetates 3 or chloroacetates 4 and by esterification of the fluorohydrins 2 using vinyl acetate and vinyl chloroacetate, respectively. Pseudomonas cepacia lipase was the most selective for the six- and the seven-membered-ring compounds, while the lipase from Candida rugosa was most useful for the eight-membered-ring compounds. Both lipases transform the (R)-enantiomers preferentially. In contrast the lipase from Candida antarctica hydrolyzed the esters of trans-2-fluorocyclohexanol 2a and esterified the fluorohydrin itself with very low enantiopreference for the (R)-isomers. The seven- and the eight-membered ring esters and the corresponding fluorohydrins were also transformed with low, but reverse, enantioselectivity.
Earlier investigations showed that cycloalkyl N-phenylcarbamates were hydroxylated by the fungus Beauveria bassiana predominantly in the 4-position relative to the electron-rich substituent. In cases involving fluorinated methylene groups potentially capable of hydroxylation, however, defluorination and formation of a ketone was observed. The formation of the
Biohydroxylation with Beauveria bassiana of racemates and the pure enantiomers of trans-2-fluorocyclohexyl- 3 and trans-2-fluorocycloheptyl N-phenylcarbamates 6 were investigated and compared with results found for the corresponding nonfluorinated parent compounds. In all cases, mixtures of diastereomeric products hydroxylated in the 4-position were isolated, besides products of p-hydroxylation of the aromatic ring and succeeding compounds derived from these primary reaction products. The regioselectivity of hydroxylation by this fungus is not changed by a single fluorine substituent attached closely to the electron-rich anchoring group in the trans-2-position. There is a different influence on the diastereoselectivity of hydroxylation depending on the absolute configuration of the fluorinated substrates. While the transformation of the (S,S)-2-fluorocycloalkyl N-phenylcarbamates is not diastereoselective giving almost 1:1 mixtures of cis- and trans-4-hydroxyl compounds, the corresponding reactions of the (R,R)-isomers led preferentially to the products trans-hydroxylated in the 4-position. The transformation of the racemic fluorinated six-membered N-phenylcarbamate 3 led to products having a very small enantiomeric excess. The fluorine substituent slightly increased the enantioselectivity of transformation of the racemic seven-membered substrate 6 compared to the C(s)()-symmetric nonfluorinated carbamate. Thus, the fluorine substituent in the trans-2-position in these examples did not change the regioselectivity but rather influenced the stereochemistry of biotransformation, depending on the absolute configuration of the substrate and ring size.
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