Unsaturated Nitriles: New Reactions and Reactivities

Nitriles are extremely important intermediates in pharmaceutical synthesis and as medicines in their own right. Almost 30 commercial pharmaceuticals incorporate the nitrile functionality including the block-buster drug Anastrazole, the drug of choice for treatment of advanced breast cancer; Escitalopram for depression; Primacor for heart failure; Tagamet for peptidic ulcers; and Rilpivirine, potentially "the most potent anti-HIV agent(s) ever discovered." Our research focuses on developing new reactions of nitriles with an emphasis on stereoselective formation of quaternary stereocenters.  The research program has pioneered several nitrile-based conjugate additions, alkylations, and cyclizations that are ideal for assembling complex medical and non-medical targets.

Key to the success of much of this program is an understanding of the fundamental reactivity of metalated nitriles – perhaps the most well studied and yet misunderstood organometallic reagent. Generating metalated nitriles in which the metal is selectively coordinated with carbon or nitrogen which allows stereo- and regioselective alkylations that were previously not possible. Central to this venture has been the selective synthesis of different metalated nitriles which allows control over the geometry of the nucleophilic carbon. Exciting developments continue to reveal a remarkable versatility of nitriles in synthetic ventures and suggest that the chemistry of nitriles will continue to be a practical and profitable for many years to come.

Understanding the unusual reactivity of metalated and unsaturated nitriles has led to many new synthetic methods for selectively generating new stereocenters and has led to several innovative approaches to medicinally important bicyclic carbocycles. Descriptions of this chemistry, the research group and facilities, and current projects are available on our group website.