Deuterated reagents in multicomponent reactions to afford deuterium labeled products.

chemistry Medicinal and pharmaceutical chemistry Nano- and molecular-scale electronics Nano-biomaterials and bioscience Nanomagnetics Nanomaterials, thin films and nanointerfaces Nanomedicine Nanometrology and nanomechanics Nano-optics Nanopatterning, self-assembly and nanofabrication Nanostructures for energy and sensing applications Natural products chemistry Organo main group chemistry Other nanotechnology (unclassified) Other organic chemistry (unclassified) Photochemistry and photovoltaics Physical organic chemistry Supramolecular chemistry The utility of bio-isosteres is broad in drug discovery and methodology herein enables the preparation of deuterium labeled products in the most fundamental of known bio-isosteric replacements. As such we report the use of both D1-aldehydes and D2-isonitriles across 8 multi-component 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.

multi-component reactions • deuterated formamides • deuterated isocyanides • microsomal stability • Leuckart Wallach • kinetic isotope effect • deuterated aldehydes • DHPs | Format: DOCX | Size: 3.8 MB | Download | When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information: Schofield, K.; Maddern, S.; Zhang, Y.; Mastin, G.; Knight, R.; Wang, W.; Galligan, J.; Hulme, C. Beilstein Arch. 2024, 202438. doi:10.3762/bxiv.2024.38.v1 Citation data can be downloaded as file using the "Download" button or used for copy/paste from the text window below. Citation data in RIS format can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Zotero. © 2024 Schofield et al.; licensee Beilstein-Institut. This is an open access work licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-archives.org/xiv/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this work could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.