Stereoselective Construction of Less-Accessible Acyclic α,α-Disubstituted β-Ketiminonitriles via Electrophilic Cyanation of β,β-Disubstituted Enesulfinamides

Abstract

The metalloenamines, formed by NH-deprotonation of β,β-disubstituted enesulfinamides, can undergo reactions with commercially available electrophilic cyanating reagents such as tosyl cyanide (TsCN) or 3-oxo-1,2-benziodoxole-1(3H)carbonitrile (CBX). Through the utilization of appropriate stereoisomers of enesulfinamides, this method enables the selective synthesis of any of the four stereoisomers of α,α-disubstituted βsulfinylimino nitriles, which feature acyclic quaternary stereocenters and are typically more challenging to synthesize. These compounds can then undergo stereoselective nucleophilic addition, leading to the creation of valuable enantioenriched multisubstituted β-amino carbonyl surrogates with a high degree of structural diversity.

Asymmetric Construction of Ethenyl-Substituted Acyclic Quaternary Stereocenters at the α-Position of Carbonyl Surrogates via Stereoselective Sulfonylvinylation–Reductive Desulfonylation

“…Recently, we have developed three approaches to stereoselectively access the β,β-disubstituted aza-enolates and also explored their applications in stereoselective construction of the less-accessible quaternary or tetrasubstituted stereocenters at the α-position of the aza-analogs of ketones, namely N - tert -butanesulfinyl ( N - t BS) ketimines . For example, persubstituted metalloenamines, generated from deprotonation of the NH in the β-methyl, β-ethyl-substituted enesulfinamides, underwent conjugate addition–elimination cascade with β-nitro α,β-unsaturated ketones or β-tosyl acrylonitrile to afford α-alkenylated ketimines with high stereocontrol (Scheme A) .…”

Stereoselective Electrophilic Sulfenylation of β,β-Disubstituted Enesulfinamides: Asymmetric Construction of Less Accessible Acyclic α,α-Disubstituted α-Sulfenylated Ketimines

“…To address the challenges associated with controlling the geometry of enamine intermediates formed from challenging acyclic α,α-disubstituted carbonyls in enamine- and iminium ion-mediated asymmetric synthesis (Scheme A­(iv), X = chiral NR 2 ), we have recently developed methods for the precise formation of either Z or E isomers of alternative chiral enamines, namely enesulfinamides (Scheme A­(iv), X = NH- t BS, where t BS refers to the tert -butanesulfinyl group). These methods involve the α-deprotonation of enantioenriched α-branched N - tert -butanesulfinyl ( N - t BS) ketimines (not shown), as well as the conjugate addition (not shown) or conjugate reduction (Scheme C) of α,β-unsaturated ketimines. Our hypothesis was that sulfenylation of the enesulfinamides using suitable sulfur-based electrophiles would enable stereoselective synthesis of α-sulfenylated carbonyl surrogates with acyclic tetrasubstituted α-stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl; Scheme D).…”