Asymmetric Synthesis of Pyrrolidine‐Containing Chemical Scaffolds via Tsuji–Trost Allylation of N‐tert‐Butanesulfinyl Imines

Abstract

A simple and efficient asymmetric synthesis of novel sp3-rich pyrrolidine chemical scaffolds over five steps starting from simple ketones is described. Key steps involve the use of tert-butanesulfinamide as a chiral auxiliary to perform an asymmetric Tsuji-Trost allylation, with subsequent cross-metathesis with an acrylate ester and reduction of the sulfinimine/cyclisation of the resulting amine giving the pyrrolidine scaffolds in high yields and diastereoselectivites. By removing the chiral auxiliary and functionalising the ester group, the resulting scaffold core can be further derivatised. Introduction Compounds containing a pyrrolidine ring usually possess a wide range of biological activities such as, anticancer, antitumor and anti-biotic activity.[1] Specifically, chiral pyrrolidines constitute a large group of heterocyclic organic compounds which are useful building blocks of pharmaceuticals, [2,3] vitamins, dyes, drug candidates, hormones, agrochemicals [4] and alkaloid natural products. [5,6] Furthermore, these compounds have been used as ligands for transition metals, organocatalysts, [7][8][9] and effective chiral controllers in asymmetric synthesis. [10][11][12] It has been observed that there is a significant interest in the stereoselective synthesis of chiral pyrrolidines, using N-tert-butanesulfinyl imines as a chiral auxiliary. In particular, by the addition of Grignard reagents [13] or hydride[14] to γ-chlorinated N-tert-butanesulfinyl imines followed by cyclisation, or via Wacker-type oxidation cyclisation of alkenes with tertbutanesulfinamide nucleophiles [15] or iodocyclisation of homoallylic sulfonamides. [16] Recently, the diastereoselective α-allylation of a variety chiral α-N-tert-butanesulfinyl imines using Tsuji-Trost reaction has been reported by Stockman and co-workers.[17] In particular, under mild reaction conditions, compounds bearing an allyl group at the α-position of chiral N-tert-butanesulfinyl imines were obtained in high yields, with good diastereoselectivity and substrate tolerance. In a following report, the α-allylation of chiral N-tert-butanesulfinyl imines derived from symmetric cyclic ketones was reported.[18] Hence, we envisioned taking advantage of the Tsuji-Trost allylation of N-tert-butanesulfinyl imines to access, in five steps, pyrrolidine-based chemical scaffolds as outlined in Scheme 1. We aimed to achieve this through cross metathesis of the allylated N-tert-butanesulfinyl imines, followed by reduction and finally ring cyclisation, using an intramolecular Michael addition. Scheme 1. Outline of the asymmetric synthesis of pyrrolidine chemical scaffolds 5. Results and Discussion