Stereoselective Synthesis and Applications of Pinane-Based Chiral 1,4-Amino Alcohol Derivatives

Abstract

A new library of pinane-based 1,4-amino alcohols was synthesised and utilised as chiral ligands in enantioselective diethylzinc addition to benzaldehyde. Aldol condensation of (+)-nopinone, derived from (–)-β-pinene, with 2-pyridinecarboxaldehyde gave the key intermediate α,β-unsaturated ketone, which was transformed in diastereoselective reduction, followed by hydrogenation, resulting in 1,4-amino alcohols. On the other hand, epoxidation of the α,β-unsaturated ketone, followed by reduction and then hydrogenation of the pyridine ring, afforded a mixture of 4-amino-2,3-epoxy-1-ols. Stereoselective hydride reduction of the epoxy ketone and subsequent condensation of the resulting products with substituted benzyl bromides provided quaternary ammonium salts, which were subjected to hydride reduction and then hydrogenation, affording 4-amino-2,3-epoxy-1-ol derivatives containing an N-benzylpiperidine moiety. The inhibition of nucleophile-initiated opening of the oxirane ring was interpreted by a systematic series­ of comparative Hartree–Fock modelling study using the 6-31+G(d,p) basis set. The antiproliferative activities of 4-amino-2,3-epoxy­-1-ol derivatives were examined, and structure–activity relationships were studied from the aspects of the stereochemistry of the oxirane ring, saturation, and substituent effects on the piperidine ring system.