The Combination of Lewis Acid with N-Heterocyclic Carbene (NHC) Catalysis

Abstract

In the last ten years, the combination of Lewis acid with N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in a variety of important asymmetric synthesis, due to the ready availability of starting materials, operational simplicity and mild reaction conditions. Recent findings illustrate that Lewis acid could largely enhance the efficiency and enantioselectivity, reverse the diastereoselectivity, and even influence the pathway of the same reaction partners. Herein, this review aims to reveal the recent advances in NHC-Lewis acid synergistically promoted enantioselective reactions for the expeditious assembly of versatile biologically important chiral pharmaceuticals and natural products.

Oxidative N‐Heterocyclic Carbene Catalysis

“…In 2015, this kind of processes were independently reported by the Ye [107] and Studer [108] groups for the enantioselective synthesis of bicyclic δ‐enollactones (iridoid core structures) with three adjacent stereocentres: enals and ϵ‐oxo‐γ,δ‐unsaturated malonates were involved in chiral NHC/Lewis acid cooperative catalysis [76] to obtain almost the same cyclopentane‐ and cyclohexane‐fused δ‐lactones, but as opposite enantiomeric products, as a result of each author using optical antipodes of the same carbene catalyst (Scheme 73).…”

“…The allenolate species 39 that forms passes through an intramolecular proton transfer, and the resulting α,β‐unsaturated acyl azolium 40 turns into the pyrone product by O−C bond formation and NHC undocking. This Michael addition/lactonization strategy is driven by the co‐present Lewis acid, [76] as concurrent coordination of magnesium cation to the ketoenolate and the alkynyl acyl azolium favours the C ‐attack over the O ‐attack in the crucial 1,4‐addition step.…”

Asymmetric organocatalysis involving double activation

“…been achieved with the double and concerted activation system of NHCs and Lewis acids [39]. In 2010, the Scheidt group [40] reported a pioneering work on an asymmetric [3 þ 2] annulation reaction between chalcones 8 and enals 9 under the catalysis of NHC C12/Ti(Oi-Pr) 4 , constructing cis-cyclopentenes 10 in moderate to good yields with excellent stereocontrol (Scheme 9).…”

New Trends in Asymmetric Catalysis

“…Their mode of action involves the generation of intermediates such as acyl anions, homoenolates, enolates and α,β-unsaturated acylazolium equivalents, and their subsequent reaction with electrophiles. Recently, as illustrated in the review by Ren et al [5], Lewis acids, in combination with chiral NHC catalysts, were proved to increase the reaction yields and enantioselectivity of many reactions, as well as decisively affect (often reversing) regio-and diastereoselectivities. The review examines several examples categorized according to the Lewis acid type involved.…”