Catalytic Reactions

One major focus of our work is centered on catalytic asymmetric [2,3]-rearrangements of reactive zwitterions, which are synthetically versatile molecules implicated in a diverse range of chemical transformations (Fig. 1). These reactive substrates were traditionally thought to be incompatible with enantioselective catalysis, because of their propensity to undergo facile thermal [2,3]-rearrangements in the absence of a catalyst. Our group has challenged this assumption held widely in our field for decades.

We have developed a palladium-catalyzed enantioselective [2,3]-rearrangement of allylic amine N-oxides, which serves as a general platform for catalytic [2,3]-rearrangements of reactive zwitterions. We have also uncovered a new research program of tandem reactions that are initiated by allylic aminations with tertiary amines, which generate reactive intermediates for [2,3]-rearrangements. We plan to exploit this new chemical reactivity for the synthesis of complex chiral products, including unnatural amino acids and polycyclic alkaloids.

Most recently, we have been exploring enantioselective rearrangements for the functionalization of inert C–H bonds. As a first step towards this goal, we recently developed a [2,3]-rearrangement that has enabled the first catalytic enantioselective allylic amination of unactivated olefins for the synthesis of chiral amines in high enantiomeric excess (Fig. 2). In this transformation, a C–H bond adjacent to the double bond of an unsaturated hydrocarbon is converted stereoselectively into a C–N bond.

Prior to our work, the most promising strategy for allylic amination of terminal olefins was based on the metal-catalyzed activation of inert C–H bonds via organometallic intermediates (Fig. 2, path a). Despite some success, this approach has not produced general methods for the catalytic enantioselective intermolecular allylic amination of unactivated terminal olefins. We have successfully implemented a conceptually distinct allylic amination strategy that is based on a metal-catalyzed enantioselective [2,3]-rearrangement of a reactive zwitterion (Fig. 2, path b).