Stereospecific Synthesis of 2,3,6-Trisubstituted Piperidines: An Efficient Total Synthesis of (+/-)-Pumiliotoxin C

Article abstract of DOI:10.1021/ja00191a038

The intramolecular cycloaddition of N-(1-alkyl-4-pentenyl)nitrones provides a highly regio- and stereoselective route to all-cis-2,6-disubstituted-3-(hydroxymethyl)piperidines 3 by way of the bicyclic isoxazolidines 2.In demonstration studies, the 2,6-dimethyl analogue was transformed into 2r,3c,6c-trimethylpiperidine (9) and into N-tert-butoxy-2c,6c-dimethylpiperidine-3r-carboxaldehyde (10).Facile and complete epimerization of the latter into the all-equatorial, 2t,3r,6t aldehyde 11 was achieved, thus giving entry into the diastereomeric 2,3,6-trisubstitutedpiperidines.These protocols can give rise to short and efficient syntheses not only of the piperidines but of bicyclic nitrogen heterocycles depending on the nature of the substituents.An additional stereogenic center was introduced into the 3-(1-hydroxyalkyl) side chain by employing trans and cis isomers of N-(1,5-disubstituted-4-pentenyl)nitrones.The methodology was used to rapidly assemble a piperidine containing four stereogenic centers starting from 2-pentanone and methyl phenyl ketone.This intermediate 20 was then easily converted into (+/-)-pumiliotoxin C (12) by way of an intramolecular alkylation with inversion of configuration.The highly convergent total synthesis was accomplished in 14 steps and 14percent overall yield with no attempt at optimization.