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Beilstein Arch. 2024, 202438. https://doi.org/10.3762/bxiv.2024.38.v1
Published 10 Jun 2024
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.
Keywords: multi-component reactions • deuterated formamides • deuterated isocyanides • microsomal stability • Leuckart Wallach • kinetic isotope effect • deuterated aldehydes • DHPs
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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
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