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 1 ]-aldehydes and [D 2 ]-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 [D 1 ]-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 [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.