Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

Abstract

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 [D1]-aldehydes and [D2]-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 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

• deuterated aldehydes
• deuterated formamides
• deuterated isocyanides
• dhps
• kinetic isotope effect
• leuckart–wallach
• microsomal stability
• multicomponent reactions