Highly Enantioselective Synthesis of Substituted Piperidines Using the Chiral Lithium Amide Base Approach

Abstract

The symmetry-breaking enolisation reaction of a mesopiperidine diester using a chiral bis-lithium amide base allows access to alkylated derivatives in highly diastereo-and enantioselective fashion (≥ 98% ee).

A Chiral Base Desymmetrisation-Ring-Closing Metathesis Route to Chiral Azaspirocycles: Synthesis of Core Structures Related to Pinnaic Acid and Halichlorine

“…[4][5][6] Some time ago we described a new type of chiral lithium amide base reaction, which provided chiral polyfunctional piperidines with high levels of stereocontrol. 7 In the present paper we describe how one such piperidine can be usefully transformed into a range of azaspirocyclic systems, with a focus on compounds closely related to the pinnaic acid core structure. 8 The previously described desymmetrisation reaction involves enolisation of the readily available piperidine diester 4 with chiral base 5, and subsequent alkylation to give products such as the allyl derivative 6, Scheme 1.…”

Stoichiometric asymmetric processes

“…103 Simpkins and co-workers have described a novel desymmetrisation reaction mediated by dilithiated chiral base 200. 104 Thus, deprotonation of meso-bis-ester 199 using chiral base 200 and subsequent trapping with methyl iodide afforded enantiomerically pure piperidine 201 (Scheme 55). In addition, this was the only diastereoisomer detected from this reaction.…”

Saturated nitrogen heterocycles

“…Simpkins and co-workers have described the desymmetrizing deprotonation of meso-piperidine diester 164 (readily obtained by hydrogenation of pyridine-2,6-dicarboxylic acid) with a chiral lithium amide base (Scheme 54). 95 Trapping of the resulting organolithium with a range of reactive electrophiles gave piperidines 165 in excellent yields, with near perfect stereocontrol (single diastereomer, у 98% ee).…”