Organocatalysis: A Bioorganic Approach to Catalytic Asymmetric Synthesis with Small Organic Molecules

In Search of Beautiful Reactions: Organocatalysis

Beautiful Reaction- a reaction facilitated by an environmentally safe catalyst in an environmentally safe solvent. Ideally, multiple reaction components are assembled in a diastereo- and enantiospecific fashion to furnish stereochemically complex products in a single step without by products.

Our interest in organocatalysis was piqued in 1997 when we initiated comparative studies of aldolase antibodies with L-Proline, the well-known catalyst of the intramolecular Hajos-Eder-Sauer-Wiechert reaction, an enantiogroup-differentiating aldol cyclodehydration reaction. Evidence suggested that this intramolecular proline-catalyzed reaction proceeds via an enamine reaction mechanism much like our aldolase antibodies. Mechanistically then, catalysis with antibody aldolases and the simple amino acid proline are very similar. We then demonstrated that our aldolase antibodies were actually better catalysts than proline in the intramolecular Hajos-Eder-Sauer-Wiechert reaction and in fact could catalyze the Michael step as well as the aldol step of this annulation reaction. Empowered by our findings with aldolase antibodies, we screened a wide variety of amino acids and chiral amines with and without additives for catalysis of the U.V. active retro-aldol reaction we developed to facilitate reaction screening with aldolase antibodies under the premise that catalysts better than proline might be readily discovered. In late 1998, after performing several hundreds of assays in order to best the known catalyst proline, the technician assigned to this project, Tommy Bui*, reported that despite his efforts proline and hydroxyproline remained most active catalysts in the aldol reaction and organocatalysis with proline was reborn. Proline provided us with the open active-site catalyst we had been searching for in our promiscuous aldolase antibodies and it allowed us to catalyze reactions that failed with aldolase antibodies due to substrate restrictions.

We have since shown that L-Proline and other chiral amines can be efficient asymmetric catalysts of a variety of significant imine- and enamine-based reactions. Studies from our laboratory and the contributions of others have advanced one of the ultimate goals in organic chemistry, the catalytic asymmetric assembly of simple and readily available precursor molecules into stereochemically complex products under operationally simple and in some cases environmentally friendly experimental protocols. One of the significant findings of these studies is the development of catalysts that allow aldehydes, for the first time, to be used efficiently as nucleophiles in a wide-variety of catalytic asymmetric reactions. Previously, only Nature’s enzymes were thought capable of this chemical feat. With future efforts, small organic catalysts may match some of Nature’s other heretofore unmatched synthetic prowess and in doing so they may help explain the development of complex chemical systems in the prebiotic world and provide hints towards yet to be discovered mechanisms in extant biological systems. We proposed and demonstrated for the first time that amino acids could catalyze the direct synthesis of carbohydrates in optically active form. This theory is now being investigated in laboratories around the world. Furthermore, we believe that there exists a class of yet discovered Diels-Alderase enzymes that utilize enamine and iminium catalysis. Using enamine and imine-based organocatalysis, we have been able to directly synthesize a wide variety of α- and β- amino acids, carbohydrates, amino sugars, Diels-Alder products, and lactams. Stereochemically complex molecules can now be assembled using small molecules in a manner analogous to nature’s enzymes. Indeed, we have now shown that much of the synthetic chemistry of nature’s aldolase enzymes can be mimicked using proline or other amine catalysts.

Organocatalysis is a creative and fast moving field of chemistry. A number of postdoctoral fellows formerly associated with this laboratory and now in their own laboratories have helped advance the field with the development of new reactions and further elaborations of the reactions first developed here: Benjamin List, Guofu Zhong, Shin-ichi Watanabe, Nobuyuki Mase, and Buchi Ramachary Dhevalapally. This chemistry is also moving into the pharmaceutical industry with the considerable contributions of Juan Betancort, Kandasamy Sakthivel, Wolfgang Notz, Derek Steiner, Jeff Suri, Sreenivas Chowdari Naidu, and Rajeswari Thayumanavan from this laboratory.

We believe that Organocatalysis will provide many new and beautiful reactions for some time to come.

For reviews of this area see:
Notz, W.; Tanaka, F.; Barbas III, C.F. (2004) Enamine-based organocatalysis with proline and diamines: The development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Accounts of Chemical Research, 37(8):580-591.

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

*Tommy Bui went on to receive his Ph.D. in Organic Chemistry with Scott Denmark and returned as a postdoctoral fellow in the Barbas Lab.