One-pot multiple reactions: asymmetric synthesis of 2,6-cis-disubstituted piperidine alkaloids from chiral aziridine

Abstract

A divergent, new, and highly stereoselective synthesis of cis-2,6-disubstituted piperidine natural products including isosolenopsins, deoxocassine, and spectaline was achieved from chiral aziridine decorated with appropriate alkyl chains for isosolenopsins or alkynyl groups for deoxocassine and spectaline at C2. The characteristic feature of this synthesis is one-pot sequential reactions under atmospheric hydrogen including the reduction of alkyne (for deoxocassine and spectaline), reductive ring-opening of aziridine, debenzylation, and intramolecular reductive amination in high yields. The prerequisite aziridines were elaborated from commercially available (2S)-hydroxymethylaziridine through oxidation, Wittig olefination, and the Grignard reaction for isosolenopsins or substrate-controlled lithium alkynylate addition for deoxocassine and spectaline.

From synthetic control to natural products: a focus on N‐heterocycles

“…Numerous pharmaceuticals and lead compounds, either synthesized or naturally occurring, contain one or more piperidine units and different patterns of substitution on the heterocycle ring. These alkaloids have been subjected to synthetic studies that have led to the development of new chemosynthetic and biomimetic synthetic methods . In recent years, research groups have developed synthetic methodologies for substituted pyrrolidine and piperidine alkaloids (including non‐proteinogenic amino acids) with a high level of stereo‐control.…”

“…These alkaloids have been subjected to synthetic studies that have led to the development of new chemosynthetic and biomimetic synthetic methods. [4][5][6][7][8][9] In recent years, research groups have developed synthetic methodologies for substituted pyrrolidine and piperidine alkaloids (including non-proteinogenic amino acids) with a high level of stereo-control. These methodologies have allowed us to synthetically access natural products and their analogues in which the substituted 5-or 6-membered N-heterocycle is a structural motif.…”

Alkylative Ring-Opening of Bicyclic Aziridinium Ion and Its Application for Alkaloid Synthesis

“…This chemistry has been used for efficient synthesis of alkaloids such as conine and epiquinamide as representative examples (Graphical Abstract). Efficient and stereoselective construction of aza-heterocycles have always been a challenge for synthetic organic chemists because they played a very important role in the field of pharmaceutical industry (Bailey et al, 1998; Husson and Royer, 1999; Passarella et al, 2002; Carry et al, 2013; Yadav et al, 2016). Among them piperidines as a six-membered aza-heterocycles are present in large number of biologically active natural products especially in the class of alkaloids.…”

Convergent Synthesis of <i>trans</i>-2,6-Disubstituted Piperidine Alkaloid, (−)-<i>iso</i>-6-Spectaline by Palladium-Catalyzed Cyclization

“…Synthetic studies of the iso-6-spectaline-containing trans-2,6-disubstituted piperidin-3-ol scaffold have not been reported to date. In contrast, several early synthetic studies of (+)-spectaline with a cis-2, 6-disubstituted piperidine scaffold were achieved stereoselectively [8][9][10] although some refinement regarding the reaction steps and/or the convergence is required to proceed with the structure-activity studies. A recent synthesis of (+)-spectaline from a chiral aziridine was achieved based on a linear synthetic scheme.…”