Enantioselective Construction of Quaternary Stereocenters via Cooperative Photoredox/Fe/Chiral Primary Amine Triple Catalysis

Abstract

The catalytic and enantioselective construction of quaternary (all-carbon substituents) stereocenters poses a formidable challenge in organic synthesis due to the hindrance caused by steric factors. One conceptually viable and potentially versatile approach is the coupling of a C−C bond through an outer-sphere mechanism, accompanied by the realization of enantiocontrol through cooperative catalysis; however, examples of such processes are yet to be identified. Herein, we present such a method for creating different compounds with quaternary stereocenters by photoredox/Fe/chiral primary amine triple catalysis. This approach facilitates the connection of an unactivated alkyl source with a tertiary alkyl moiety, which is also rare. The scalable process exhibits mild conditions, does not necessitate the use of a base, and possesses a good functional-group tolerance. Preliminary investigations into the underlying mechanisms have provided valuable insights into the reaction pathway.

Enantioselective Decarboxylative C(sp3)-C(sp3) Cross-Coupling of Aliphatic Acids with gem-Borazirconocene Alkanes

“…In 2023, the Baran's group developed a Ni-electrocatalytic enantioselective doubly decarboxylative cross coupling (dDCC), radicals that are derived from malonate half amide and aliphatic acid were generated via single electron-transfer (SET) from Ni(I) to redox-active aliphatic acid NHPI (Nhydroxyphthalimide) esters (Figure 1A, 1) 24 . Recently, the Yang's group disclosed a cooperative photoredox/Fe/chiral primary amine triple catalysis protocol to construct quaternary stereocenters by decarboxylative cross-coupling of 1,3-dicarbonyl compounds with primary alkyl radical, which was generated from the reduction of aliphatic acid NHPI esters (Figure 1A, 2) by an iridium photocatalyst 25 .…”

“…Compared to α-heteroatom and α-carbonyl stabilized radicals, the enantioconvergent C(sp 3 )-C(sp 3 ) cross-coupling of primary radicals via decarboxylation of unactivated primary aliphatic acids remains underexploited 7,25 . Additionally, the selection of organometallic partners in asymmetric decarboxylative cross-coupling is largely confined to alkylzinc reagents, which typically involve tedious synthesis procedures such as oxidative insertion into alkyl halides by zinc or transmetalation using zinc salts.…”