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-acet-oxy-2-cyclohexen-l-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(0)OCH3, are similar in size. To improve the enantioselectivity, the methyl ester was replaced by a fert-butyl ester. The acetate group of the tert-butyl ester of lactyl acetate was hydrolyzed with high enantioselectivity (E > 50). Enantiomerically pure (Ä)-(+)-tert-butyl lactate (>98% ee, 6.4 g) was prepared by kinetic resolution. For the second example, low enantioselectivity (E < 3) was observed in the hydrolysis of c£s-l,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 (98% ee) was obtained after removal of the bromines with zinc and oxidation with Cr03/pyridine.