Carlos F. Barbas, III

 

 

 

One of the ultimate goals in organic chemistry is the catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products. As chemists, we often turn to Nature for inspiration concerning stereochemically complex, diverse, and functional molecules. Indeed, the directed asymmetric assembly of simple achiral building blocks into stereochemically complex molecules has long been the purview of Nature’s enzymes.  Our approach to this problem began in 1997 when we embarked upon studies exploring the similarity between proline and a novel class of aldolase antibodies we had developed earlier. Recently, these studies have allowed us to describe a variety of powerful organocatalytic asymmetric ketone and aldehyde additions in aldol, Michael, Mannich, and Diels-Alder reaction manifolds. Significantly, these studies were originally designed for antibody catalysis years before. This lecture will focus on a few contributions from this laboratory concerned with creating and converting enzymatic enamines, and in some cases imines, into a versatile catalytic asymmetric strategy powered by small organic molecules. Other organocatalytic strategies will also be considered. We believe these studies may impact presently held views on prebiotic chemistry and the generation of complex chemical systems. Perhaps life and its founding molecules were synthesized more easily than previously anticipated. Given time, I will also briefly discuss how our original studies founded in antibody-enamine chemistry have been used to create a new class of drugs called Chemically Programmed Antibodies. Four such drugs are currently in clinical trials in the US.

Barbas III, C.F. (2008) Organocatalysis Lost: Modern Chemistry, Ancient Chemistry, and an Unseen Biosynthetic Apparatus. Angew. Chemie. Int. Ed., 47(1):42-47.

 

Wagner, J.; Lerner, R.A.; and Barbas III, C.F.  Efficient Aldolase Catalytic Antibodies that use the Enamine Mechanism of Natural Enzymes.  Science, 1995, 270:1797.

Notz, W.; Tanaka, F.; Barbas III, C.F. Enamine-based organocatalysis with proline and diamines: The development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Acct. Chem. Res., 2004, 37(8):580.

Uehara, H.; Imashiro, R.; Hernández-Torres, G.; Barbas III, C.F. (2010) Organocatalysis Special Feature: Organocatalytic asymmetric assembly reactions for the syntheses of carbohydrate derivatives by intermolecular Michael-Henry reactions.
 Proc. Natl. Acad. Sci. USA, 107(48):20672-20677

Tan, B.; Candeias, N.; Barbas III, C.F. (2011) Core-Structure-Motivated Design of a Phosphine-Catalyzed [3+2] Cycloaddition Reaction: Enantioselective Syntheses of Spirocyclopenteneoxindoles. Journal of the American Chemical Society, 133(13):4672-4675.

 

Rader, C; Sinha, S.C.; Popkov, M.; Lerner, R.A.; Barbas III, C.F. (2003) Chemically programmed monoclonal antibodies for cancer therapy: Adaptor immunotherapy based on a covalent antibody catalyst. Proc. Nat. Acad. Sci., USA, 100(9):5396-5400.