Synthesis of 2,4-Disubstituted Piperidines via Radical Cyclization: Unexpected Enhancement in Diastereoselectivity with Tris(trimethylsilyl)silane

A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of
7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines
with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement
in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade
process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the
translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower
trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts
for the occurrence of the rearrangement cascade in the former case.