Asymmetric Synthesis of Octahydroindoles via a Domino Robinson Annulation/5-Endo Intramolecular Aza-Michael Reaction

Abstract

A straightforward, two-step asymmetric synthesis of octahydroindoles has been developed on the basis of two complementary strategies: (i) an organocatalyzed Michael reaction followed by a tandem Robinson−aza-Michael double cyclization catalyzed by PS-BEMP, and (ii) a diastereoselective cyclization, which formally constitutes a remote 1,6 asymmetric induction mediated by PS-BEMP. This allowed the construction of complex octahydroindoles with up to four stereocenters, excellent enantioselectivities (up to 95% ee), and complete diastereoselective control in a single-pot operation. DFT calculations were performed to understand the origin of this effect.

Enantioselective Organocatalytic Michael Addition Reactions Catalyzed by Proline/Prolinol/Supported Proline based Organocatalysts: An Overview

“…Claudio Parra and co‐authors [83] reported an asymmetric, organocatalyzed, single‐pot Michael addition between acyclic β‐keto ester 212 and 213 followed by a tandem Robinson‐aza‐Michael cyclization catalyzed by XII in presence of Lithium acetate and mediated by PS‐BEMP, that affords polyfunctionalized octahydroindoles 214 bearing four stereocenters, with extraordinary enantioselectivities (up to 95 % ee) and high diastereoselectivities [Scheme 53]. They had also carried out DFT calculations to investigate the reason behind the complete diastereoselectivity exercised by the benzyl substituent on the bicycle formation.…”

Two Decades of Progress in the Asymmetric Intramolecular aza‐Michael Reaction

“…However, brief descriptions of the examples reported to date, including the main author, year of publication and type of catalyst employed are specified in Table 1. Strategies involving Mannich/IMAMR, [47][48][49][50][51][52][53][54][55][56][57][58][59] α-aminoxylation/ IMAMR, [60][61][62][63][64] aza-Friedel-Crafts/IMAMR, [65] cross metathesis/ IMAMR, , [18,28] aza-Morita-Baylis-Hillman/IMAMR, [66] Robinson annulation/IMAMR, [67][68][69][70][71] oxa-Mannich/IMAMR, [72] aza-Henry/IMAMR, [73] peptide coupling/IMAMR, [38] aza-Rahuhut-Currier/IMAMR, [74] Betti/IMAMR, [75] enamine formation/IMAMR [76] and carbene insertion/IMAMR [77] are collected in this table.…”

The endo-aza-Michael addition in the synthesis of piperidines and pyrrolidines

“…A piperidinone synthesis that may involve a Mannich-Michael sequence An exo-activated endo-aza-Michael is a component of a rather complex tandem process leading to octahydroindoles 100 and 101 (Scheme 25). 50 The sequence involves a Michael addition of a -ketoester, 99, to an unsaturated aldehdye, followed by an intramolecular Aldol process. This generates an intermediate 102 which then undergoes an exo-activated endo-aza-Michael addition.…”