Decoupling strategy-enabled radical generality via an asymmetric SH2 path

12 February 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Reaction generality is essential for evaluating the value and impact of a synthetic method. However, asymmetric catalysis, particularly that involving highly reactive species such as radicals, typically prioritizes enantioselectivity at the expense of generality. Selectivity and reactivity often conflict because the bond-forming step is usually also stereodetermining. If these two steps were separated, the reaction selectivity and generality issues could then be addressed independently. Herein we report a catalytic asymmetric radical coupling with great generality by merging the copper-catalyzed enantioselective S(IV) center formation and copper-mediated enantiospecific SH2 radical coupling. This decoupling strategy has enabled the successful coupling of over 30 different carbon-, nitrogen-, and oxygen-based radicals having a broad range of reactivity with N-acyl sulfenamides, leading to diverse S-chiral compounds with exceptional enantioselectivity. Thus, it offers a holistic approach to accessing a rich portfolio of S(IV) and S(VI) chiral centers, which is anticipated to have a transformative impact on the synthesis of S-chiral compounds and benefit medicinal chemistry and other related fields. Furthermore, this decoupling strategy via SH2 processes has promising potential to enable a comprehensive single-electron methodology for forging other chiral centers with heteroatoms such as phosphorous(III) and silicon(IV), and eventually also carbon atoms.


Copper catalysis
Asymmetric intermolecular homolytic substitution
Radical cross-coupling
S-Chiral compounds
Asymmetric catalysis


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