Chiral Nucleophilic Carbenes for use in Organic Synthesis

Bench-stable nucleophilic carbenes have found increased use as catalysts and ligands in organic synthesis. Since 2000, our ongoing interest in this field has led us to develop chiral versions of these catalysts, and apply them to problems in organic synthesis. Our efforts are focused on the use of the carbenes as catalysts for organic transformations, a branch of the emerging field of organocatalysis, as well as the use of these carbenes as modifying ligands for transition metal catalyzed reactions.

Carbenes as catalysts

Our family of triazolinylidene carbenes catalyze the asymetric Stetter reaction, an umpolung addition of an aldehyde to a Michael acceptor. The reaction has proven tolerant of many michael acceptors and is able to form quaternary stereocentrs as well as contiguous stereocenters in an enantio-and diastereoselective fashion( JACS 2002,10298; JACS 2005, 6284; JACS 2006, 2552). Current efforts are focused on expanding the scope of this transformation, and applying it to the synthesis of complex molecules (vide infra).

The potential of nucleophilic carbenes as catalysts lies far beyond their use in generaing acyl anion equivalents. The attraction of new reagents is their potential to help identify new reaction pathways. To date, we have identified one such reaction: treatment of alpha-halo aldehydes with a catalytic amoun of nucleophilic carbene in the presence of a stoichiometric amount of nucleophile leads to an intriguing redox process wherein the halide is displaced and the aldehyde oxidized. The use of chiral carbenes as catalysts alows the conversion of dihloroaldehydes into chloroesters is high enantioselectivity and goog yield (JACS 2004, 9518; JACS 2005, 16406).

We are currently engaged in discovering other novel reaction pathways using these catalysts including asymmetric C-C and C-N bond forming reactions. Ultimately, the Stetter reaction is the coupling of one electrophile (aldehyde) with a second (Michael acceptor). A more fundamental question thus arises: what other electrophiles can be induced to couple?

Carbenes as ligands

Nucleophilic carbenes are also useful ligands for transition metals. The most spectacular example of their impact on synthesis is as a ligand on Ru in the second generation Grubbs catalyst. We are engaged in identifying other catalyzed reactions amenable to the unique benefits afforded by carbenes as ligands.