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.
Key words
β-pinene - 1,4-amino alcohols - diethylzinc - tetrahydropyridine - antiproliferative
