Deuterated reagents in multicomponent reactions to afford deuterium-labeled products.

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]-aldehydes and [D]-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 limiting metabolic soft-spot via use of [D]-aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of of the new deuterated analogs. We also report the first preparation of [D]-isonitriles from [D]-formamides via a modified Leuckart-Wallach reaction and their use in an MCR to afford products with [D]-benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.