Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

IF 2.2 4区化学 Q2 CHEMISTRY, ORGANIC

Beilstein Journal of Organic Chemistry Pub Date : 2024-09-06 DOI:10.3762/bjoc.20.195

Kevin Schofield, Shayna Maddern, Yueteng Zhang, Grace E. Mastin, Rachel Knight, Wei Wang, James Galligan, Christopher Hulme

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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 t_1/2 limiting metabolic soft-spot via use of [D₁]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of t_1/2 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.

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Beilstein J. Org. Chem. 2024, 20, 2270–2279. doi:10.3762/bjoc.20.195

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在多组分反应中使用氘化试剂，生成氘标记产品

摘要生物异构体在药物发现中的应用非常广泛，而本文所介绍的制备氘标记产物的方法是已知生物异构替代物中最基本的方法。因此，我们报告了在 8 个多组分反应 (MCR) 中使用[D1]-醛和[D2]-异腈制备各种氘代产品的情况。其中一个亮点是通过使用[D1]-醛，在 t1/2 极限代谢软点选择性地氚化合成了几种 FDA 批准的钙通道阻滞剂。对微粒体稳定性的替代药代动力学分析证实，新的氚代类似物的 t1/2 延长了。我们还报告了首次通过改良的 Leuckart–Wallach 反应从 [D3]- 甲酰胺制备 [D2]- 异腈，并将其用于 MCR，得到了具有 [D2]- 苄基位置的产物，其代谢稳定性可能显著增强，而代谢稳定性是基于性质的设计工作的关键参数。Chem.2024, 20, 2270–2279. doi:10.3762/bjoc.20.195

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来源期刊

Beilstein Journal of Organic Chemistry 化学-有机化学

CiteScore

4.90

自引率

3.70%

发文量

167

审稿时长

1.4 months

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.