Asymmetric three-component olefin dicarbofunctionalization enabled by photoredox and copper dual catalysis

The intermolecular three-component alkene vicinal dicarbofunctionalization (DCF) reaction allows installation of two different carbon fragments. Despite extensive investigation into its ionic chemistry, the enantioseletive radical-mediated versions of DCF reactions remain largely unexplored. Herein, we report an intermolecular, enantioselective three-component radical vicinal dicarbofunctionalization reaction of olefins enabled by merger of radical addition and cross-coupling using photoredox and copper dual catalysis. Key to the success of this protocol relies on chemoselective addition of acyl and cyanoalkyl radicals, generated in situ from the redox-active oxime esters by a photocatalytic N-centered iminyl radical-triggered C-C bond cleavage event, onto the alkenes to form new carbon radicals. Single electron metalation of such newly formed carbon radicals to TMSCN-derived L1Cu(II)(CN)2 complex leads to asymmetric cross-coupling. This three-component process proceeds under mild conditions, and tolerates a diverse range of functionalities and synthetic handles, leading to valuable optically active β–cyano ketones and alkyldinitriles, respectively, in a highly enantioselective manner (>60 examples, up to 97% ee).

Xiao, Chen and coauthors describe in this manuscript a novel catalytic protocol for the asymmetric dicarbofunctionalization of aryl alkenes. The reactions are enabled by the combination of radical addition with copper-mediated stereoselective radical-CN coupling, which is orchestrated in a highly efficient way. Visible light photocatalysis is employed to engender the acyl radicals and cyano radicals from oxime esters, and its catalytic cycle is merged nicely into recycling of the active copper species. This method allows a variety of β-cyano ketones and alkyldinitriles to be accessed in good yield and high eantioselectivity. It is impressive that only a tiny amount of catalysts is needed to guarantee a good result. The strategy revealed herein has general applicability for the construction of structurally useful optically active molecules from olefins. I think this work is worthy of publication in Nature Communications. Other comments In this study, purple LEDs were used as the light source to excite fac-Ir(ppy)3 to its excited state. Had the authors tested other light sources such as blue LEDs and CFL lamps? Does the wavelength of the light have any notable effect on the result? If so, it should be commented in the manuscript.
Reviewer #2 (Remarks to the Author): The manuscript reports an intermolecular enantioselective three-component radical dicarbofunctionalisation of alkenes using oxime esters as radical precursors and TMSCN. The chemistry requires the use of dual photoredox and copper catalysis. This is an interesting process, which however relies on established reactivity concepts. The chemistry relies on the chemoselective addition of acyl and cyanoalkyl radicals, generated from the redox-active oxime esters by a photocatalytic N-centered iminyl radical-triggered C-C bond cleavage event, onto the alkenes to form new carbon radicals. Then the copper chiral catalyst intercepts the radical and trigger the formation of a new stereogenic centre with TMSCN. The feasibility of these two individual steps has been already demonstrated. The authors, and others, have used an external photocatalyst to activate redox-active oxime derivatives and generate iminyl radicals, which further triggered the formation of cyanoalkyl and acyl radicals via a C-C bond cleavage process (Refs 44-54). The stereoselective step is based instead on the nice copper-catalyzed radical relay strategy extensively developed by Guosheng Liu. Specifically, the same chiral ligand/copper combination used here was used by Liu to develop an enantioselective intermolecular cyano-trifluoromethylation of alkenes via a radical dicarbo-functionalisation process (see J. Am. Chem. Soc. 2016, 138, 48, 15547). Here the same asymmetric system has been combined with a different radical generation strategy, but the stereoselective step is essentially the same. Although interesting, this approach is therefore conceptually incremental over previous studies. From a synthetic perspective, the chiral products in Figures 2 and 3 can be obtained by catalytic enantioselective conjugate addition strategies of cyanide to enones, as for example reported by Shibasaki (see J. Am. Chem. Soc. 2008, 130, 19, 6072 among other systems). Overall, the present study is interesting but lacks the marks of originality, general advances and broad synthetic interest required for publication on a general chemistry journal. This study seems better suited for a more specialized, synthetically-oriented audience.
Reviewer #3 (Remarks to the Author): Chen and Xiao reported a cooperative photocatalysis and copper catalysis for the development of asymmetric difunctionalization of styrenes under mild conditions. The reaction reported an exciting approach to generate acyl radical to collaborate with copper catalyzed asymmetric cyanation, where the reaction was initiated by a photocatalyzed N-O bond cleavage to give a imino-radical, and followed by a C-C bond cleavage. The generated acyl radical added to styrene rapidly to generate benzylic radical, which was enantioselectively trapped by Box/Cu(II) cyanide. As described in manuscript, the reaction exhibited good substrate scope, where heterocycles could be well tolerated. Various of enantiomeric-enriched nitrile products were obtained with good to excellent ee values. Overall, this is a nice study on the asymmetric radical cyanations, and this referee recommends to publication in Nature Communication with minor revisions.

Comments:
(1) For the acyl radical precursor, how about the reactivity of substrates derived from cyclic diketones?
(2) During the optimization reaction conditions, the observation undesired side products should be given the yields, which can provide more information to get insight on the reaction mechanism.