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 in the most fundamental of known bio-isosteric replacements. As such we report the use of both D1-aldehydes and D 2 -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 D 1 -aldehydes. Surrogate pharmacokinetic analyses of microsomal stability confirm prolongation of T1/2 of the new deuterated analogs. We also report the first preparation of D 2 -isonitriles from D 3 -formamides via a modified Leuckart-Wallach reaction and their use in an MCR to afford products with D 2 -benzylic positions and likely significantly enhanced metabolic stability, a key parameter for property-based design efforts.