Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

Even though there are dozens of biologically active 2‐substituted and 2,6‐disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich‐type additions to nitrones, one using β‐ketoacids under catalyst‐free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2‐substituted materials, as well as other ring variants, in the form of β‐N‐hydroxy‐aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8‐step total syntheses of the 2,6‐disubstituted piperidine alkaloids (−)‐lobeline and (−)‐sedinone. Just Mannich enough: Despite their prevalence, 2‐ and 2,6‐disubstituted piperidines are challenging to prepare enantioselectively, particularly when they possess β‐functionalization. Two new approaches based on the use of cyclic nitrones provide the means to readily fashion an array of such materials, one of which proceeds with high enantioselectivity (up to 98 % ee) using a chiral thiourea promoter. Their sequential use has enabled 8‐step total syntheses of both (−)‐lobeline and (−)‐sedinone from a common intermediate.