转自：康龙化成

Carbonyl-to-sulfur Swap Enabled by Sequential Double Carbon-carbon Bond Activation

Zining Zhang and Guangbin Dong*

Department of Chemistry, University of Chicago, Chicago, IL, USA

—Science. 2025, doi: 10.1126/science.adx2723

Recommended by Depei Meng_MC4

KEY WORDS:skeletal edit, carbonyl-to-sulfur swap (反应类型),C(sp3)–S (成键), ketones (原料), thiol ether, sulfur-containing scaffolds(产物), N′-alkyl-hydrazonamide(NAHA) reagent,Ts-S-Ts (Ts, p-toluenesulfonyl),double carbon-carbon bond activation(其他)

ABSTRACT:In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively prepared by de novo synthesis; the existing approach to swap carbon with sulfur is inefficient and involves stoichiometric mercury reagents. In this study, we report a two-step carbonyl-to-sulfur (CO-to-S) atom swap approach, enabled by a rationally designed N′-alkyl-hydrazonamide (NAHA)reagent that promotes forming pre-aromatic intermediates twice sequentially by different mechanisms, thereby achieving homolytic cleavage of both α-C−C bonds of the ketone substrates. A Ts-S-Ts (Ts, p-toluenesulfonyl)reagent mediates this process through successive intermolecular and intramolecular alkyl radical trapping by the central sulfur. This method shows a broad substrate scope and excellent chemoselectivity, providing a streamlined route to sulfur-containing scaffolds from readily available ketones.

Design principle for the NAHA reagent.(A) Enabling the second C–C bond cleavage through intramolecular aryl radical addition. (B) A model study on the second activation shows a strong Thorpe−Ingold effect on the linker design.Substrate scope

Substrate scope to the late-stage functionalization of complex bioactive compounds for analog synthesis (selected)

Zining Zhang and Prof. Guangbin Donghave developed a two-step CO-to-S atom swap strategythat enables streamlined conversion of ketones into the corresponding thioethers. The rationally designed bifunctional N′-alkyl-hydrazonamide (NAHA) reagentsallow for two-stage C−C bond activations, permitting sequential functionalization of both carbon terminus. The broad substrate scope and mild redox-neutral reaction conditions, along with the high efficiency and chemoselectivity of these radical-mediated processes, make this strategy suitable for late-stage modification of structurally complex bioactive compounds. It is anticipated that the unique activation mode enabled by this class of NAHA reagents should serve as a versatile platform for diverse skeletal modification of sp3-rich organic molecules in the future.

芝加哥大学董广彬课题组开发出一种两步法实现羰基交换为硫原子的转化策略，可实现酮类化合物向对应硫醚的高效转化。该策略采用合理设计的的双功能N′-烷基腙酰胺(NAHA)试剂，通过连续两步C−C键活化实现双碳末端的连续官能团化。该策略不仅底物适用性广，其温和的氧化还原中性条件，以及自由基介导过程带来的高效性与化学选择性，使该策略适用于结构复杂生物活性分子的后期修饰。该类NAHA试剂独特的活化模式，未来将成为富sp3碳分子多样化骨架修饰的普适性平台。

（转自：康龙化成）