Ir/Cu Dual Catalysis: Enantio- and Diastereodivergent Access to α,α-Disubstituted α-Amino Acids Bearing Vicinal Stereocenters

Abstract

We describe a fully stereodivergent synthesis of a range of α,α-disubstituted α-amino acids via an Ir/Cu-catalyzed α-allylation of readily available imine esters. The introduction of a Cu-Phox complex-activated imine ester into the chiral iridium-catalyzed allylic allylation process is crucial for its high reactivity and excellent enantio- and diastereoselectivity (up to>99% ee and >20:1 dr). Importantly, the two chiral catalysts allow for full control over the configuration of the stereocenters, affording all stereoisomers of the desired products. The utility of this methodology was demonstrated by synthesizing dipeptides and analogues of bioactive molecules in a stereodivergent manner.

Sequence‐Dependent Stereodivergent Allylic Alkylation/Fluorination of Acyclic Ketones

“…The combination of a chiral Ir catalyst and a chiral amine catalyst allowed full control of the prochiral faces of the allylic electrophiles and nucleophiles, respectively, thus affording the desired products with all four possible stereoisomers. Later on, elegant examples of stereodivergent synthesis through asymmetric allylic substitution reactions with prochiral nucleophiles by dual catalysis were reported by the groups of Jørgensen, Zhang, Hartwig, and Wang . In all these studies, two different chiral catalysts were needed to realize the stereodivergent synthesis.…”

Enantioselective and Diastereodivergent Access to α‐Substituted α‐Amino Acids via Dual Iridium and Copper Catalysis

“…Following our research on cooperative bimetallic catalysis and the asymmetric synthesis of unnatural α‐AAs,,, we aim to provide a universal access to the stereodivergent construction of α‐substituted α‐AAs bearing two adjacent stereogenic centers with identical starting materials and reaction conditions, by using the predominant bimetalic catalysts system (Scheme ). However, several problems must still be overcome to obtain highly enantiopure α‐substituted α‐AAs: (a) the internal contradictions of maintaining the high reactivity of the bimetallic catalysis and lowering the reactivity of the substrates to avoid the formation of disubstituted products, must be addressed; (b) the stereoselectivity of the prochiral nucleophile must be controlled; and (c) the potential enolization of α‐substituted α‐AAs in the presence of a Lewis acid or under basic conditions must be avoided…”

“…[6] Recently, Carreira and co-workers successfully implemented this strategy for the stereodivergent allylation of aldehydes by combining iridium and enamine catalysis. [9] Indeed, several elegant bimetallic catalysts systems have been recently developed for stereodivergent synthesis by the groups of Zhang, [10] Wang, [11] and Hartwig. [9] Indeed, several elegant bimetallic catalysts systems have been recently developed for stereodivergent synthesis by the groups of Zhang, [10] Wang, [11] and Hartwig.…”

Synergistic catalysis for cascade allylation and 2-aza-cope rearrangement of azomethine ylides

“…Previously, we 11 and others 15 have reported Cu/Ir dual catalysis system for the stereodivergent construction 22,23 of α,α-disubstituted α-amino acids by the asymmetric allylation of aldimine esters with full control of the diastereoselectivity and enantioselectivity. The idea for the current approach to the synthesis of chiral homoallylic amines stemmed from the observation that an allyl-azaallyl core structure was imbedded in the branched allylation products.…”

“…Alternatively, various nonproteinogenic chiral α-amino acids can be obtained via catalytic asymmetric Michael additions and allylation reactions, in which metallated azomethine ylides behave as viable nucleophiles (Fig. 1a) 8– 15 . It is well known that the asymmetric attack of carbon-based nucleophiles to various imines (C=N) constitutes one of the most powerful methods for the construction of biologically important chiral amine derivatives 6 .…”