Enantioselective C(sp³)–H Functionalization of Oxacycles via Photo-HAT/Nickel Dual Catalysis

Abstract

The selective functionalization of ubiquitous but inert C−H bonds is highly appealing in synthetic chemistry, but the direct transformation of hydrocarbons lacking directing groups into high-value chiral molecules remains a formidable challenge. Herein, we develop an enantioselective C(sp 3 )−H functionalization of undirected oxacycles via photo-HAT/nickel dual catalysis. This protocol provides a practical platform for the rapid construction of high-value and enantiomerically enriched oxacycles directly from simple and abundant hydrocarbon feedstocks. The synthetic utility of this strategy is further demonstrated in the latestage functionalization of natural products and the synthesis of many pharmaceutically relevant molecules. Experimental and density functional theory calculation studies provide detailed insights into the mechanism and the origin of enantioselectivity for the asymmetric C(sp 3 )−H functionalization.

The mechanism of visible light-induced C–C cross-coupling by Csp3–H bond activation

“…Very recently, a similar Ni catalytic cycle has been developed by Wang and Kong to explain the enantioselective arylation of α-oxy-C sp 3 –H bond catalysed by diaryl ketone/Ni II . 100 They proposed that the reaction proceeds via SET-RA-OA-RE sequence, which is consistent with both reports by us 36 and Su. 108 Their calculated energy profile indicates that the oxidative addition is rate-limiting, which is in line with the mechanism proposed by our group.…”

“…99 Recently, Wang and Kong expanded the scope of this protocol through incorporation of a chiral ligand to control the enantioselectivity of the arylation reaction. 100 The first report of α-amino-C sp 3 –H cross coupling using the PC-HAT/TM dual catalysis strategy was recently published by MacMillan using decatungstate W 10 O 32 4− (DT) as the photocatalyst. 101 Using tetrabutylammonium decatungstate (TBADT) as the PC and nickel catalysis based on potassium-tris(3,5-dimethyl-1-pyrazolyl) borate (KTp*) as the source of the Ni ligand, he was able to achieve methylation of α-amino-C sp 3 –H bonds (Scheme 6b).…”

“…Based on steric effect arguments, 109,110 they have explained that enantioselectivity is controlled at the step involving radical addition to LNi I Br. 100…”

“…The calculated results clearly indicated that oxidative addition of PhBr to the Ni I (Alk) 51 is the rate-limiting step, which is consistent with other reports. 29,36,89,100…”

Recent Advances in Carbonyl‐Photoredox/Transition Metal Dual Catalysis

“…PT is excited by irradiation to generate excited species PT*. Abstraction of benzylic CÀ H bond of (3chloropropyl)benzene by PT* yields C-centered radical (34) and [PTÀ H] * , which then reduces the nickel-coordinated N-sulfonylimine (36) to produce intermediate (37) and photocatalyst (PT). Intermediate 38 is formed by the addition of the 34 to 37, followed by an intra-molecular nucleophilic attack to give 39.…”