Enantioselective Synthesis of α‐Hydroxy Allyl Ketones via BINAP‐CuH‐Catalyzed Hydroacylation

Abstract Catalytic hydrocupration of unsaturated carbon‐carbon bonds to generate organometallic nucleophiles has recently become an attractive alternative to conventional stoichiometric reagents in the stereoselective synthesis. Herein, we have developed an efficient and economical method to synthesize enantiopure α ‐hydroxy allyl ketones via a copper hydride (CuH)‐catalyzed hydroacylation of alkoxyallenes, a significant advancement given the scarcity of reports on such scaffolds in the literature. DFT calculations reveal that this reaction proceeds through the nucleophilic attack of a kinetically favourable Z ‐selective allyl‐copper intermediate on acid anhydrides via a six‐membered chair‐like transition state, stabilized by strongly attractive non‐covalent interactions that ultimately leads to high level of enantioselectivities using the simple BINAP ligand. This method successfully overcomes the challenges of over‐reduction of carbonyl functionality in the presence of CuH‐complex, olefin isomerization and the presence of a highly enolizable α ‐stereocenter, which can lead to erosion in enantioselectivities, making our strategy highly desirable. The reaction exhibits a wide range of substrate scope including symmetrical as well as carbonic anhydrides with both aromatic, and aliphatic substitutions. In addition, α ‐substituted acid anhydrides provide exclusive syn ‐selective α,α′ ‐disubstituted allyl ketones in excellent enantiomeric ratios, where the nucleophilic allylation occurs on one of the carbonyls containing the matched α‐ stereocenter, confirmed with mechanistic studies.