A Rule To Predict Which Enantiomer of a Secondary Alcohol Reacts Faster in Reactions Catalyzed by Cholesterol Esterase, Lipase from Pseudomonas cepacia, and Lipase from Candida rugosa

Article abstract of DOI:10.1021/jo00008a016

The enantioselectivity of the title enzymes for more than 130 esters of secondary alcohols is correlated by a rule based on the sizes of the substituents at the stereocenter.This rule predicts which enantiomer of a racemic secondary alcohol reacts faster for 14 of 15 substrates of cholesterol esterase (CE), 63 of 64 substrates of lipase from Pseudomonas cepacia (PCL), and 51 of 55 cyclic substrates of lipase from Candida rugosa (CRL).The enantioselectivity of CRL for acyclic secondary alcohols is not reliably predicted by this rule.This rule implies that the most efficiently resolved substrates are those having substituents which differ significantly in size.This hypothesis was used to design syntheses of two chiral synthons: esters of (R)-lactic acid and (S)-(-)-4-acetoxy-2-cyclohexen-1-one, 70.As predicted, the acetate group of the methyl ester of lactyl acetate was hydrolyzed by PCL with low enantioselectivity because the two substituents, CH3 and C(O)OCH3, are similar in size.To improve enantioselectivity, the methyl ester was replaced by a t-butyl ester.The acetate group of the tert-butyl ester of lactyl acetate was hydrolyzed with high enantioselecticity (E > 50).Enantiomerically pure (R)-(+)-tert-butyl lactate (>98percent ee, 6.4 g) was prepared by kinetic resolution.For the second example, low enantioselectivity (E < 3) was observed in the hydrolysis of cis-1,4-diacetoxycyclohex-2-ene, a meso substrate where the two substituents, CH2CH2 and CH=CH, are similar in size.To improve enantioselectivity, the size of the CH=CH substituent was increased by addition of Br2.The new substrate was hydrolyzed with high enantioselectivity (E > 65) using either CE or CRL.Enantiomerically pure 70 (98percent ee) was obtained after removal of the bromines with zinc and oxidation with CrO3/pyridine.