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

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 (-)-beta-pinene, with 2-pyridinecarboxaldehyde gave the key intermediate alpha,beta-unsaturated ketone, which was transformed in diastereoselective reduction, followed by hydrogenation, resulting in 1,4-aminoalcohols. On the other hand, epoxidation of the alpha,beta-unsaturated ketone, followed by reduction and then hydrogenation of the pyridinering, 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 derivativescontaining 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-olderivatives 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.