Chemoenzymatic approach to enantiopure piperidine-based β-amino esters in organic solvents

This research concentrates on the enantioselectivities of lipase-catalysed reactions with methyl esters of 2-piperidylacetic acid and 3-piperidinecarboxylic acid derivatives. N-Acetylated 2-piperidylacetic acid methyl ester displayed good enantioselectivity (E = 66) in a 1:1 mixture of diisopropyl ether and butyl butanoate in the presence of lipase PS-C II from Burkholderia cepacia. The reaction is known as interesterification with butyl butanoate rather than alcoholysis with the butanol, because butyl butanoate has to be first hydrolysed or go through alcoholysis with MeOH in order to release butanol. Other N-protective groups (Boc, Ns, Fmoc and Bzn) gave excellent enantioselectivity (E >200) under the same conditions, and a gram-scale resolution was performed with N-Boc-2-piperidylacetic acid methyl ester. Reaction with a 3-piperidylcarboxylic acid derivative took place with disappointingly low enantioselectivity (E = 4), with Candida antarctica lipase B being the best of the lipases screened.

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N-tert-Butoxycarbonyl-(R)-2-piperidylacetic acid methyl esterC13H23NO4Ee = 94%[α]D20=+9.9 (c 4.54, CHCl3)Source of chirality: enzymatic resolution by lipase PS-C II from Burkholderia cepaciaAbsolute configuration: (R)

N-tert-Butoxycarbonyl-(S)-2-piperidylacetic acid butyl esterC16H29NO4Ee = 99%[α]D20=-5.4 (c 1, CHCl3)Source of chirality: Enzymatic resolution by lipase PS-C II from Burkholderia cepaciaAbsolute configuration: (S)