An Optimized Sequential Kinetic Resolution of trans-1,2-Cyclohexanediol

Quantitative analysis of sequential kinetic resolutions (resolutions that proceed via two or more enantioselective steps) indicates that optimal reinforcement of the enantioselectivities occurs when the rates of the two steps are equal. Under these conditions, the reinforcement is multiplicative and the overall enantioselectivity, E_T(max), is given approximately by [1 + (E₁-E₂)]/2. To test these ideas we optimized the resolution of trans-1,2-cyclohexanediol, 1. The first step of the porcine liver esterase (PLE) catalyzed hydrolysis of trans-1,2-diacetoxycyclohexane proceeded 47 times faster than the second step and the resolution yielded 1 with only 58% ee at 44 mol %. Addition of a hexane phase slowed the first step by selectively extracting the fast-reacting 1-diacetate (relative rate = 6) and increased the enantiomeric purity to 94% ee at 34 mol %. The resolution of 1 was further improved using lipase from Pseudomonas cepacia (Amano P, PCL) which showed an E_T(max) of >2000 as compared to an E_T(max) for PLE of 54. Resolution with PCL after equalization of the rates of the two steps gave (R)-1 and recovered (S)-1-diacetate both with >99% ee.