Kevin Schofield, Shayna Maddern, Yueteng Zhang, Grace E. Mastin, Rachel Knight, Wei Wang, James Galligan, Christopher Hulme
{"title":"Deuterated reagents in multicomponent reactions to afford deuterium-labeled products","authors":"Kevin Schofield, Shayna Maddern, Yueteng Zhang, Grace E. Mastin, Rachel Knight, Wei Wang, James Galligan, Christopher Hulme","doi":"10.3762/bjoc.20.195","DOIUrl":null,"url":null,"abstract":"<p><font size='+1'><b>Abstract</b></font></p>\n<p>The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium-labeled products is the most fundamental of known bio-isosteric replacements. As such we report the use of both [D<sub>1</sub>]-aldehydes and [D<sub>2</sub>]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a <i>t</i><sub>1/2</sub> limiting metabolic soft-spot via use of [D<sub>1</sub>]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of <i>t</i><sub>1/2</sub> of the new deuterated analogs. We also report the first preparation of [D<sub>2</sub>]-isonitriles from [D<sub>3</sub>]-formamides via a modified Leuckart–Wallach reaction and their use in an MCR to afford products with [D<sub>2</sub>]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.</p>\n<p align='center'><img src='https://www.beilstein-journals.org/bjoc/content/figures/1860-5397-20-195-graphical-abstract.png?max-width=550' border='0'/></p>\n<p><i>Beilstein J. Org. Chem.</i> <b>2024,</b> <i>20,</i> 2270–2279. doi:10.3762/bjoc.20.195</p>","PeriodicalId":8756,"journal":{"name":"Beilstein Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Beilstein Journal of Organic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.3762/bjoc.20.195","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0
Abstract
The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium-labeled products is the most fundamental of known bio-isosteric replacements. As such we report the use of both [D1]-aldehydes and [D2]-isonitriles across 8 multicomponent reactions (MCRs) to give diverse arrays of deuterated products. A highlight is the synthesis of several FDA-approved calcium channel blockers, selectively deuterated at a t1/2 limiting metabolic soft-spot via use of [D1]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of t1/2 of the new deuterated analogs. We also report the first preparation of [D2]-isonitriles from [D3]-formamides via a modified Leuckart–Wallach reaction and their use in an MCR to afford products with [D2]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.
Beilstein J. Org. Chem.2024,20, 2270–2279. doi:10.3762/bjoc.20.195
期刊介绍：
The Beilstein Journal of Organic Chemistry is an international, peer-reviewed, Open Access journal. It provides a unique platform for rapid publication without any charges (free for author and reader) – Platinum Open Access. The content is freely accessible 365 days a year to any user worldwide. Articles are available online immediately upon publication and are publicly archived in all major repositories. In addition, it provides a platform for publishing thematic issues (theme-based collections of articles) on topical issues in organic chemistry.
The journal publishes high quality research and reviews in all areas of organic chemistry, including organic synthesis, organic reactions, natural product chemistry, structural investigations, supramolecular chemistry and chemical biology.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
