Chemical and Enzymatic Resolution of (R,S)-N-(tert-Butoxycarbonyl)-3-hydroxymethylpiperidine

摘要

(S)-N-(tert-Butoxycarbonyl)-3-hydroxymethylpiperidine 1 was made from (R,S)-3-hydroxymethylpiperidine 2 via fractional crystallization of the corresponding L(-)-dibenzoyl tartarate slat 3 followed by hydrolysis and acylation. Lipase from Pseudomonas cepacia was found to be the best enzyme for the stereospecific resolution of (R,S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine 4. (S)-N-(tert-Butoxycarbonyl)-3-hydroxymethylpiperidine 1 was obtained in 16% yield and >95% enantiomeric excess (ee) by hydrolysis of (R,S)-acetate 5 by lipase PS from Pseudomonas cepacia. Lipase PS-catalyzed esterification of the (R,S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine 4 with succinic anhydride provided the S-hemisuccinate ester 6, which could be easily separated and hydrolyzed by base to the (S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine 1. The yield and ee could be improved greatly by repetition of the process. Using the repeated esterification procedure (S)-N-(tert-butoxycarbonyl)-3-hydroxymethylpiperidine 1 was obtained in 32% yield (maximum theoretical yield 50%) and 98.9% ee.