Nickel-Catalyzed Enantioselective Coupling of Acid Chlorides with α-Bromobenzoates: An Asymmetric Acyloin Synthesis

Abstract

The reaction of common acyl-metal species (acyl anion) with aldehydes to furnish acyloins has received much less attention and specifically was restricted to using preformed stoichiometric acyl-metal reagents. Moreover, the (catalytic) enantioselective variants remain unexplored, and the asymmetric synthesis of chiral acyloins has met significant challenges in organic synthesis. Here, we uncover the highly enantioselective coupling of acid chlorides with α-bromobenzoates by nickel catalysis for producing enantioenriched protected α-hydroxy ketones (acyloins, >60 examples) with high enantioselectivities (up to 99% ee). The successful execution of this enantioselective coupling protocol enables the formation of a key ketyl radical from α-bromoalkyl benzoate in situ generated from corresponding aldehyde and acyl bromide, which finally is captured by chiral acyl-Ni species catalytically in situ formed from acyl chlorides, thus avoiding the use of preformed acyl-metal reagents. The synthetic utility of this chemistry is demonstrated in the downstream synthetic elaboration toward a diverse set of synthetically valuable chiral building blocks and biologically active compounds.

Radical acylation: concepts, synthetic applications and directions

“…as reductant to afford a broad range of enantioenriched protected α-hydroxy ketones with up to 99% ee enantioselectivity (Scheme 52). 90 More than 60 examples have been evaluated in terms of aldehydes and acyl chlorides. A radical trapping reaction indicated that this reaction might involve the formation of a ketyl radical.…”

Recent Advances in Nonprecious Metal Catalysis

“…A group from Nanjing Normal University lead by Han and Chen reported a novel protocol for enantioselective XECs of aldehydes with acid chlorides. 81 Advancing methodologies that utilize ketyl radicals as partners in Ni-catalyzed crosscouplings, 82 the researchers established a method for an efficient preparation of chiral acyloins (Scheme 25). In-situ conversion of aldehydes to α-oxy bromides using benzyl bromide provides a seamless access to ketyl radicals under Ni XEC conditions.…”

Ni/Photoredox-Catalyzed Enantioselective Acylation of α-Bromobenzoates with Aldehydes: A Formal Approach to Aldehyde-Aldehyde Cross-Coupling

“…Key to this XAC strategy is the separate independent control over the activation of two similar aldehydes by fine-tuning the reactivity of a nickel catalyst and a photocatalyst, yielding two unique classes of radical species. Specifically, one aldehyde can be converted in situ into an α-oxy bromide and subsequently into the α-oxy radical through a nickel-mediated halogen-atom transfer (XAT) process by reacting with benzoyl bromide. − The other aldehyde is activated through photocatalyzed hydrogen-atom transfer (HAT), leading to the formation of an acyl radical . Unlike the established XEC or reductive coupling strategies that rely on a single catalyst to distinguish between two similar functional groups, − our proposed XAC protocol is mechanistically different, net redox-neutral, and eliminates the need for prefunctionalized substrates or exogenous terminal reductants.…”