Enantioselective S_N2 Alkylation of Homoenolates by N‐Heterocyclic Carbene Catalysis

Abstract

The functionalization of the β‐carbon of enals with electrophiles is a signature umpolung reactivity of N‐heterocyclic carbene (NHC) derived homoenolates. However, only a limited number of electrophiles are shown to be compatible, with most of them being π‐electrophiles. In this study, the successful enantioselective β‐alkylation of homoenolates is reported using Csp3 electrophiles through an SN2 strategy. The protocol shows a broad scope regarding alkyl electrophiles, delivering good yields, and excellent enantioselectivities (up to 99% ee). It enables the installation of drug‐like structural motifs in either enals or alkylating agents, demonstrating its potential as a valuable tool for late‐stage modification. Furthermore, a concise synthetic route is presented to chiral pyrroloindoline‐type skeletons. Preliminary mechanistic studies support a direct SN2 mechanism.

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

“…The cascade oxidant-free esterification of enals was achieved via the pathway involving the reaction of NHC-linked homoenolate intermediates with electrophiles [142][143][144][145][146][147][148][149].…”

“…The cascade oxidant-free esterification of enals was achieved via the pathway involving the reaction of NHC-linked homoenolate intermediates with electrophiles [142][143][144][145][146][147][148][149]. In the presence of chiral NHC generated from the precursor A3, the reaction of cinnamaldehyde 5 with (E)-1-nitrobut-1-ene 64 was performed in EtOH at 23 • C to generate δ-nitroester 65 in 70% yield with 93% ee (Scheme 19) [143].…”