Hoque Md Asmaul, Jiang Tianxiao, Poole Darren L, Stahl Shannon S
Department of Chemistry, University of Wisconsin─Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States.
Molecular Modalities Capabilities, GSK Medicines Research Centre, Gunnels Wood Rd., Stevenage SG1 2NY, U.K.
J Am Chem Soc. 2024 Aug 7;146(31):21960-21967. doi: 10.1021/jacs.4c07058. Epub 2024 Jul 23.
Oxygen-atom transfer reactions are a prominent class of synthetic redox reactions that often use high-energy oxygen-atom donor reagents. Electrochemical methods can bypass these reagents by using water as the source of oxygen atoms through pathways involving direct or indirect (mediated) electrolysis. Here, manganese porphyrins and related mediators are shown to be effective molecular electrocatalysts for selective oxidation of thioethers to sulfoxides, without overoxidation to the sulfone. The reactions proceed by proton-coupled oxidation of a Mn-OH species to generate a Mn-OH and Mn═O species. This methodology is compared to direct electrolysis methods initiated by single-electron oxidation of the thioether, and chloride-mediated electrochemical oxidation of thioethers. The Mn-mediated reactions operate at lower applied potential and exhibit improved substrate scope and functional group compatibility relative to direct electrolysis, and the tunability of the Mn-based mediators allows for improved performance relative to chloride-mediated electrolysis. An electrochemical parallel screening platform is developed and applied to a library of pharmaceutically relevant thioethers.
氧原子转移反应是一类重要的合成氧化还原反应，这类反应通常使用高能氧原子供体试剂。电化学方法可以通过涉及直接或间接（介导）电解的途径，以水作为氧原子源，从而绕过这些试剂。在此，锰卟啉及相关介导剂被证明是用于将硫醚选择性氧化为亚砜的有效分子电催化剂，且不会过度氧化为砜。反应通过质子耦合氧化Mn-OH物种以生成Mn-OH和Mn═O物种来进行。该方法与由硫醚的单电子氧化引发的直接电解方法以及硫醚的氯介导电化学氧化进行了比较。相对于直接电解，锰介导的反应在较低的外加电位下运行，并且表现出更宽的底物范围和官能团兼容性，而且基于锰的介导剂的可调性使得其相对于氯介导的电解具有更好的性能。开发了一种电化学平行筛选平台，并将其应用于一系列与药物相关的硫醚。
