Asymmetric piperidine synthesis

Abstract

It has been demonstrated that bakers' yeast reduction of 1-tert-butyl-2-methyl 3-oxo-piperidine-1,2-dicarboxylate gives (2R, 3S), 1-tert-butyl-2-methyl 3-hydroxy-piperidine-1,2-dicarboxylate in 80% chemical yield with >99% d.e. and >97% e.e. Also bakers' yeast reduction of 1-tert-butyl-3-ethyl 4-oxo-piperidine-1,3-dicarboxylate gives (3R, 4S), 1-tert-butyl-3-ethyl4-hydroxy-piperidine-1,3-dicarboxylate in 74% chemical yield with >99% d.e. and >93% e.e. The optical purity and absolute configurations of the hydroxy-ester derivatives were determined by conversion into the corresponding chiral bis-tosylate derivatives of 2- and 3-piperidinemethanol respectively. It has also been shown that bakers' yeast reduction of 1-tert-butyl-4-methyl 3-oxo-piperidine-1,4-dicarboxylate gives (3R, 4R)-1-tert-butyl-4-methyl 3-hydroxypiperidine-dicarboxylate in 81% chemical yield with >99% d.e. and 87% e.e. The optical purity and absolute configuration of the hydroxy-ester derivative were determined by utilisation of the compound in the total synthesis of (R)-3-quinuclidinol via chain elongation at C-4 of the piperidine followed by cyclisation to produce the bicyclic structure. Further work is reported on the diastereoselective synthesis of polyhydroxylated indolizidine alkaloids. 1-Acetoxy-2-hydroxy-3-(hydroxymethyl)-indolizidine has been synthesised as a single diastereomer from 2-piperidinemethanol via attack of an amine onto an epoxide functionality thus producing the bicyclic system