Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C–O Bond Coupling of Acyl Radicals

Abstract

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemoand stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C−O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters. Partnered by one-or two-step follow-up transformations, this reaction provides a convenient and practical strategy for the rapid preparation of chiral C3 building blocks from readily available alcohols, particularly the industrially relevant glycerol. Mechanistic studies supported the proposed C−O bond coupling of acyl radicals.

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

“…The high compatibility of the catalyst system to substrates bearing various nonionic substituents preluded that non-carbon substituted could be tolerated (Scheme E). Indeed, the remote desymmetrizing Suzuki–Miyaura reaction provides unified access to enantioenriched (86:14–96:4 er) α-tertiary alcohol derivatives ( 40 – 42 ), α-tertiary amide ( 43 ), and α-tertiary fluorine ( 44 ) . Furthermore, a collection of diarylmethanes bearing chiral α-tertiary carbon was synthesized in good enantioselectivity ( 45 – 47 , 46–55% yield, 89.5:10.5–93:7 er) by desymmetrization.…”

Emerging Trends in Copper-Promoted Radical-Involved C–O Bond Formations

“…Recently, Liu et al demonstrated the first highly chemo- and enantioselective desymmetrization C–O coupling of aldehydes ( 201 ) with prochiral and meso diols ( 202 ) using their previously developed copper/chiral sulfonamide ( L25 ) complex in the presence of a stoichiometric amount of an oxidant ( 203 ) (Scheme ). Detailed mechanistic studies suggest that this reaction involves acyl radicals as key intermediates, which are generated from the aldehydes by a tert -butoxy radical-mediated HAT. In this reaction, a chiral Cu­(I)/ L25 complex first functions as a SET reductant and is then oxidized to the Cu­(II) species by the terminal oxidant ( 203 ) during the generation of tert -butoxy radicals.…”

“…Using Togni-II reagent, Yang and Cao developed an efficient method for the copper-catalyzed radical trifluoromethylbenzoxylation of 1,3-enyne derivatives (111) for preparing CF 3substituted allenols (112). (Scheme 7d).…”

Synthesis of a C2-Symmetric Chiral Borinic Acid and Its Application in Catalytic Desymmetrization of 2,2-Disubstituted-1,3-Propanediols

“…Among the reported protocols, desymmetrization is one of the most powerful strategies to achieve this goal . In continuation of our efforts to selectively manipulate alcohols, we aimed at desymmetrization of 2,2-disubstituted-1,3-diols, which are challenging substrates in enantioselective desymmetrization.…”