Enantioselective electroreductive alkyne-aldehyde coupling

Introduction

Allylic alcohols are integral subunits of numerous biologically significant natural products, as well as versatile building blocks for a range of synthetic applications^1,2, including π-allyl chemistry³, S_N2’ displacements⁴, cationic cyclizations⁵, Claisen rearrangements⁶, and related sigmatropic processes⁶. Traditionally, the enantioselective preparation of allylic alcohols involves the generation of alkenylmetal intermediates from alkynes in the presence of stoichiometric amounts of R₂Zn or RMgX and further reaction with aldehydes via asymmetric addition^{7, 8–9}. These methods are limited by synthetic inefficiencies, chemical waste issues, and low sustainability. Asymmetric reductive coupling of alkynes and aldehydes has thus emerged as a straightforward strategy for obtaining these important substructures, and substantial progress has been made in recent decades (Fig. 1a). However, these transformations require excess reducing agent, e.g., explosive H₂^10,11, pyrophoric Et₃B/Me₂Zn^{12, 13, 14, 15, 16–17}, mass-intensive silane^{18, 19, 20–21}, or Hantzsch ester (HE)^{22, 23–24}, which may lead to serious safety issues, high costs, low functional group tolerance, and low atom economy. Therefore, it is desirable to develop new strategy for highly regio- and enantioselective alkyne-aldehyde coupling using an inexpensive, safe, and easily manipulated reductant.

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Fig. 1

Introduction.

a Metal-catalyzed asymmetric alkyne-aldehyde coupling. b Enantioselective electroreductive alkyne-aldehyde coupling (this work).

Electrosynthesis offers an approach for sustainably mitigating the aforementioned challenges because it uses electrons as inherently safe redox reagents, thereby avoiding the need for stoichiometric and reactive (sometimes dangerous) oxidants/reductants^{25, 26, 27, 28, 29, 30, 31, 32–33}. To date, there are few examples of electroreductive coupling of two π-components^{34, 35, 36, 37, 38–39}. Mechanistic insights from the successful reports indicate that active radical species are generated in situ via direct cathodic reduction of π-components and serve as the key intermediates. These inherently energetic and reactive radical species make it difficult to ensure enantioselective control. Despite progress in asymmetric electrosynthesis^{25,27, 28–29,31}, electrocatalytic methods that enable asymmetric reductive coupling of two π-components with full regio-, stereo-, and enantioselectivity control are, to our knowledge, absent from the literature.

Herein, we propose an electroreductive alkyne-aldehyde coupling reaction using protons, electrons, earth-abundant cobalt, and QuinoxP*