Haifeng Yang*, Zheng Huang, Dan Lehnherr*, Yu-hong Lam, Sumei Ren, Neil A. Strotman
{"title":"Efficient Aliphatic Hydrogen-Isotope Exchange with Tritium Gas through the Merger of Photoredox and Hydrogenation Catalysts","authors":"Haifeng Yang*, Zheng Huang, Dan Lehnherr*, Yu-hong Lam, Sumei Ren, Neil A. Strotman","doi":"10.1021/jacs.1c13265","DOIUrl":null,"url":null,"abstract":"<p >Employment of a combination of an organophotoredox catalyst with Wilkinson’s catalyst (Rh(PPh<sub>3</sub>)<sub>3</sub>Cl) has given rise to an unprecedented method for hydrogen-isotope exchange (HIE) of aliphatic C(sp<sup>3</sup>)–H bonds of complex pharmaceuticals using T<sub>2</sub> gas directly. Wilkinson’s catalyst, commonly used for catalytic hydrogenations, was exploited as a precatalyst for activation of D<sub>2</sub> or T<sub>2</sub> and hydrogen atom transfer. In this combined methodology and mechanistic study, we demonstrate that by coupling photocatalysis with Rh catalysis, carbon-centered radicals generated via photoredox catalysis can be intercepted by Rh-hydride intermediates to deliver an effective hydrogen atom donor for hydrogen-isotope labeling of complex molecules in one step. By optimizing the ratio of the photocatalyst and Wilkinson’s catalyst to balance the rate of the dual catalytic cycles, we can achieve efficient HIE and high recovery yield. This protocol was readily applied to direct HIE of C(sp<sup>3</sup>)–H bonds in 10 complex drug molecules, showing high isotope incorporation efficiency and exceptionally good functional group tolerance and demonstrating this approach as a practical and attractive labeling method for deuteration and tritiation.</p>","PeriodicalId":49,"journal":{"name":"Journal of the American Chemical Society","volume":null,"pages":null},"PeriodicalIF":14.4000,"publicationDate":"2022-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the American Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/jacs.1c13265","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 2
Abstract
Employment of a combination of an organophotoredox catalyst with Wilkinson’s catalyst (Rh(PPh3)3Cl) has given rise to an unprecedented method for hydrogen-isotope exchange (HIE) of aliphatic C(sp3)–H bonds of complex pharmaceuticals using T2 gas directly. Wilkinson’s catalyst, commonly used for catalytic hydrogenations, was exploited as a precatalyst for activation of D2 or T2 and hydrogen atom transfer. In this combined methodology and mechanistic study, we demonstrate that by coupling photocatalysis with Rh catalysis, carbon-centered radicals generated via photoredox catalysis can be intercepted by Rh-hydride intermediates to deliver an effective hydrogen atom donor for hydrogen-isotope labeling of complex molecules in one step. By optimizing the ratio of the photocatalyst and Wilkinson’s catalyst to balance the rate of the dual catalytic cycles, we can achieve efficient HIE and high recovery yield. This protocol was readily applied to direct HIE of C(sp3)–H bonds in 10 complex drug molecules, showing high isotope incorporation efficiency and exceptionally good functional group tolerance and demonstrating this approach as a practical and attractive labeling method for deuteration and tritiation.
期刊介绍:
The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.