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.