α-Chymotrypsin and l-acylase aided synthesis of 5-hydroxypipecolic acid via Jacobsen's hydrolytic kinetic resolution of epoxy amino acids

Abstract

Diethyl malonate derivatives were used to synthesize racemic 2-amino-5-hexenoic acid. These racemic 2-amino-5-hexenoic acid (homoallylyglycine) derivatives were efficiently resolved aided by α-chymotrypsin or L-acylase, giving rise to L- and D-enantiomers. These isolated enantiomerically pure amino acids with tert-butoxycarbonyl (Boc) protection were oxidised with 3-chloroperbenzoic acid. The oxidation gave rise to inseparable diastereomeric epoxides due to a newly generated chiral center at the C⁵ carbon. The isolation of one of the diastereomeric epoxides was possible by selectively converting the remaining diastereomer into a dihydroxyl compound catalysed by Jacobsen's hydrolytic kinetic resolution (HKR). The isolated epoxide was regioselectively attacked by LiBr to give vicinal halohydrin, with bromide attacking the terminal C⁶ carbon. Boc deprotection of the halohydrin led to intramolecular cyclization by attack of free amine at the C⁶ carbon, generating a single isomer of 5-hydroxypipecolic acid which was effortlessly recovered in good yield after re-protection of the amine with the Boc group. Similarly the dihydroxyl compound isolated earlier was converted to a halohydrin with iodine at the C⁶ carbon. This was feasible by efficient regioselective mono-tosylation with catalytic Bu₂SnO followed by iodine substitution. This was utilized to synthesize the 5-hydroxypipecolic acid derivative in the same described sequence consisting of Boc removal by acid treatment, cyclization, reprotection and purification. Finally the same sequence was repeated with the D-isomer and two diastereomers were isolated.