Scientific Report 2006

Chemistry

Practical Total Synthesis of Natural Products

P.S. Baran, N.Z. Burns, M.P. DeMartino, C.A. Guerrero, B.D. Hafensteiner, P.J. Krawczuk, K. Li, D.W. Lin, T.J. Maimone, M.K.-D. Maue, S. Nguyen, D.P. O’Malley, J.M. Richter, R.A. Shenvi, B. Whitefield

From penicillin to paclitaxel (Taxol), natural products have an unparalleled track record in the betterment of human health. In fact, 9 of the top 20 best-selling drugs were either inspired by or derived from natural products. Even the best-selling drug of all time, atorvastatin (Lipitor), was based on a natural product lead. Total synthesis, the art and science of recreating these entities in the laboratory, invariably leads to fundamental discoveries in chemistry, biology, and medicine.

We focus on solving interesting challenges in the total synthesis of natural products and on bridging gaps in synthetic capabilities by inventing new reactions. Through judicious target selection and creative retrosynthetic analyses, total synthesis becomes an engine for discovery that drives the field of organic chemistry to new levels of sophistication and practicality. Synthetic organic chemistry requires tremendous ingenuity, artistic taste, experimental acumen, persistence, and character. Not surprisingly, drug development relies on the expertise of researchers who have these characteristics. Although we focus entirely on educating students in fundamental chemistry, we also collaborate with expert biologists to explore the medicinal potential of newly synthesized natural products and the products’ analogs.

Recently completed total syntheses (Fig. 1) include the anticancer agents stephacidins A and B and avrainvillamide; the antibacterial agents sceptrin and ageliferin; members of the bioactive fischerindole, hapalindole, and welwitindolinone indole alkaloid family; and the anticancer agent haouamine A. Current natural product targets (Fig. 2) include chartelline C, axinellamine, strictamine, and sarcodonin.

Fig. 1. Recently completed total syntheses.

Fig. 2. Ongoing natural product total syntheses.

Publications

Baran, P.S., Burns, N.Z. Total synthesis of (±)-haouamine A. J. Am. Chem. Soc. 128:3908, 2006.

Baran, P.S., Hafensteiner, B.D., Ambhaikar, N.B., Guerrero, C.A., Gallagher, J.D. Enantioselective total synthesis of avrainvillamide and the stephacidins. J. Am. Chem. Soc. 128:8678, 2006.

Baran, P.S., Li, K., O’Malley, D.P., Mitsos, C. Short, enantioselective total synthesis of sceptrin and ageliferin by programmed oxaquadricyclane fragmentation. Angew. Chem. Int. Ed. 45:249, 2006.

Baran, P.S., Richter, J.M. Enantioselective total syntheses of welwitindolinone A and fischerindoles I and G. J. Am. Chem. Soc. 127:15394, 2005.

Northrop, B.H., O’Malley, D.P., Zografos, A.L., Baran, P.S., Houk, K.N. The mechanism of the vinylcyclobutane rearrangement of sceptrin to ageliferin and nagelamide E. Angew. Chem. Int. Ed. 45:4126, 2006.