Scientific Report 2007

Chemistry

Practical Total Synthesis of Natural Products

P.S. Baran, M.B. Biskup, N.Z. Burns, K. Chen, M.P. DeMartino, K.J. Eastman, S.N. Georgiades, C.A. Guerrero, B.D. Hafensteiner, P.J. Krawczuk, C. Li, K. Li, D.W. Lin, J.W. Lockner, T.J. Maimone, M.K.-D. Maue, T.R. Newhouse, D.P. O'Malley, J.M. Richter, I.B. Seiple, R.A. Shenvi, J. Shi, S. Su, B. Whitefield, J. Yamaguchi

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 (1) the anticancer agents stephacidin A and B and avrainvillamide; (2) the antibacterial agents sceptrin and ageliferin; (3) members of the bioactive fischerindole, hapalindole, and welwitindolinone indole alkaloid family; (4) the anticancer agent haouamine A; and (5) the structurally exotic marine alkaloid chartelline C. Current natural product targets (Fig. 2) include stylissadine A and sarcodonin.

Fig. 1. Recently completed total syntheses.

Fig. 2. Recent natural product targets.

PUBLICATIONS

Baran, P.S., DeMartino, M.P. Intermolecular oxidative enolate heterocoupling. Angew. Chem. Int. Ed. 45:7083, 2006.

Baran, P.S., Maimone, T.J., Richter, J.M. Total synthesis of marine natural products without using protecting groups. Nature 446:404, 2007.

Baran, P.S., Shenvi, R.A. Total synthesis of (±)-chartelline C. J. Am. Chem. Soc. 128:14028, 2006.

Baran, P.S., Shenvi, R.A., Nguyen, S.A. One-step synthesis of 4,5-disubstituted pyrimidines using commercially available and inexpensive reagents. Heterocycles 70:581, 2006.

Maimone, T.J., Baran, P.S. Modern synthetic efforts toward biologically active terpenes. Nat. Chem. Biol. 3:396, 2007.

O'Malley, D.P., Li, K., Maue, M., Zografos, A.L., Baran, P.S. Total synthesis of dimeric pyrrole-imidazole alkaloids: sceptrin, ageliferin, nagelamide E, oxysceptrin, nakamuric acid, and the axinellamine carbon skeleton [published correction appears in J. Am. Chem. Soc. 129:7702, 2007]. J. Am. Chem. Soc. 129:4762, 2007.