Modular synthesis of bis-α-chiral amines using Ellman sulfinamide for consecutive S-to- C chirality induction/transfer

Abstract

Amines are ubiquitous components in pharmaceuticals. Increasing saturated substitutions (sp³-hybridized carbon) at the amino center and the number of chiral centers can enrich the molecular diversity and chemical space, ultimately enhancing the success of drug development. However, the synthesis of such advanced amines is challenging due to a higher level of structural complexity and stereo-control. Here, we report a modular protocol for short de novo synthesis of bis-α-chiral amines. This protocol uses commercially available Ellman sulfinamide, tert-butanesulfinamide (^tBS), as the exclusive chiral source to selectively produce all possible stereoisomers. Sequential formation of contiguous α-amino chiral carbons is achieved by chirality induction and transfer mechanisms that are both enabled by ^tBS, the stereoselective imine functionalization and alkyne-participated rearrangement reaction. The second step we developed is crucial for high diastereoselectivity, which is problematic in previous methods. The other coupling partners used in this protocol are abundant feedstocks, providing desirable chemical diversity in the products.

Fig. 1.. Unsymmetric secondary amines bearing two α-chiral carbons and our synthetic strategy.

(A) functional molecules of chiral amines. (B) limitations of previous synthetic approaches. (C) our proposed protocol.

Fig. 2.. The stereochemistry and scope of the Ellman sulfinamide enabled [2,3]-rearrangement reaction.

(A) Study of the diastereoselectivity in the rearrangement reaction. (B) Scope of the asymmetric rearrangement reaction. (C) Density functional theory calculations.

Fig. 3.. Stereodivergent synthesis of bis-α-chiral amines through consecutive S-to-C chirality induction and transfer strategy (grouped by the first chirality induction reactions involving imine intermediates).

2k: R³ = [CH₂]₃CN, 2l: R³ = CH₂CH[CH₃]₂.

Fig. 4.. Modular synthesis of all four stereoisomers of unsymmetric bis-α-chiral secondary amines (2a: R³ = [CH₂]₃CH₃; 2k: R³ = [CH₂]₃CN).

Fig. 5.. Demonstration of the synthetic utility of the consecutive S-to-C chirality induction/transfer protocol.

(A) Green synthesis using optimized process. (B) Synthetic transformations. (C) Preparation of bioactive molecules. RT, room temperature; MS, molecular sieves; TFA, trifluoroacetic acid; THF, tetrahydrofuran; DCM, dichloromethane; DMAP, 4-dimethylaminopyridine.