Stereoselective Synthesis of Highly Substituted Piperidines

Abstract

Enantiopure piperidines 4 may be accessed in very good overall yields and high stereoselectivity from the bifunctional products 2 of the silyloxy Cope rearrangement of chiral aldol products 1 by sequential nucleophilic addition of primary amines and subsequent hydrogenation. The reaction is proposed to proceed by initial imine formation followed by an intramolecular aza‐conjugate addition to the α,β‐unsaturated imide. The stereoselectivity is controlled by A(1.2) strain between the imine N‐alkyl group and the conjugate double bond. In an alternate approach, polyalkyl‐substituted piperidines were prepared by the addition of organozinc reagents to cyanopiperidines readily obtained from the Cope products in the presence of a silver salt.

Saturated nitrogen heterocycles

“…Schneider has described the elaboration of 238 (obtained from a chiral auxiliary-controlled Cope rearrangement) to highly substituted piperidines (Scheme 78). 148 Thus imination of 238 with benzylamine followed by treatment with trimethylsilyl cyanide and silica gel gave the amino nitrile 239. This was cyclized by the action of Triton B in methanol to give 240.…”

A Single Step Approach to Piperidines via Ni-Catalyzed β-Carbon Elimination

“…1 Over the past few years, tremendous progress has been made in accessing substituted piperidines. 2 Specifically, aza-Achmatowicz rearrangement 3 and ring closing metathesis 4 provide access to these motifs in an efficient fashion (Scheme 1). However, synthesizing highly substituted piperidines is still a challenging problem.…”