International Research Fellowship Program: Enantioselective Synthesis of Spiro[Pyrrolidine and- Pyrrolidinone-Oxindoles and Indolines: The Total Synthesis of - Pauciflorine A

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0502009WaltmanThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Andrew W. Waltman to work with Dr. Erick M. Carreira at the Swiss Federal Institute of Technology (ETH), in Zurich, Switzerland.Traditionally, many drug candidates are organic compounds derived from, or inspired by compounds obtained from, natural sources. The complexity and challenge of these natural products has driven the discovery of new methods of constructing them. Such endeavors are further complicated by the fact that most advanced organic compounds are chiral, meaning that they have two mirror-image orientations of atoms in space, called enantiomers. Often, the synthesis of safe and effective drugs requires that organic compounds are made as only one of these mirror images. Unfortunately, it is not often easy to selectively form only one of two potential enantiomers. A major component of modern synthetic organic research is the development of reactions that are enantioselective, meaning that they selectively form only a single enantiomer (enantiomers). One very large class of organic compounds, the indole alkaloids, offers especially promising targets for synthesis. Among the indole alkaloids, there is a large class of compounds that feature a molecular architecture called a spiro[pyrrolidine] unit, which is particularly difficult to form. Recently, an efficient approach to these molecules has been developed in the host laboratory. Using this technique, several non-enantioselective syntheses of very complicated organic molecules have been achieved. This project will involve the modification of the previously discovered reaction to render it enantioselective. Once this goal has been met, the second task will be to apply this approach in the enantioselective synthesis of a complicated organic molecule, Pauciflorine A. Pauciflorine A, or compounds related to it, may one day serve as skin cancer therapies, since it has been observed to inhibit melanin biosynthesis in melanoma cells. Beyond this, the enantioselective formation of the spiro[pyrrolidine] unit may aid in the synthesis of a large number of indole alkaloids, thereby expanding the scope of compounds attainable by organic chemists. Many of these may possess novel medicinal value of their own. The laboratory of Prof. Carreira is at the forefront of synthetic organic research.