We have chosen to pursue our goal of contributing to scientific discovery and understanding through the vehicle of natural product synthesis. Our objective is to find simple solutions to complex synthetic problems. Frequently this leads to the discovery of new strategies, reagents, and reactions, and it potentially can be of great benefit to society.
Our group is engaged in synthesis of molecules which challenge the state of the synthetic art, and these frequently also have interesting biological activity. Three specific examples are taxol, lonomycin A, and brevitoxin B.
Of these, taxol has recently occupied most of our attention and effort. Isolated from the bark of the relatively rare and slow-growing pacific yew tree over twenty years ago, taxol is the most promising new antitumor agent for the treatment of ovarian and breast cancers. It has a unique mechanism of action, blocking cell division by binding and stabilizing microtubules, structures which comprise the cytoskeleton and the mitotic spindle. A few years ago, our group developed an efficient semisynthesis of taxol which will provide the commercial supply, and this has made it unnecessary to destroy the environment through the harvest of yew trees. More recently, we have completed the first total synthesis of taxol, which, while not commercially viable at this time, provides molecules which can be used to explore the details of taxol s biology, and are potentially more effective antitumor agents than taxol. We are currently looking for simpler methods for the synthesis of taxol and taxol-like molecules while attempting to understand more precisely their interaction with microtubules.
"First Total Synthesis of Taxol," Holton, R. A.; Somoza, C.; Kim, H. B.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J. Am. Chem. Soc., 1994, 116, 1597-1599.
"Total Synthesis of Taxusin: An Initial Step Toward Taxol Synthesis," Holton, R. A. Strategies and Tactics in Organic Synthesis, vol. III, 1991 T. Lindberg, Ed., Academic Press.
"Palladium Mediated Biomimetic Synthesis of Narwedine," Holton, R. A.; Sibi, M. P.; Murphy, W. S. J. Am. Chem. Soc., 1988, 110, 314.
"An Enantioselective Total Synthesis of Aphidicolin," Holton, R. A.; Kim, H. B.; Kennedy, R. M.; Krafft, M. E. J. Am. Chem. Soc., 1987, 109, 1597.
"Synthesis of the Taxane Ring System," Holton, R. A. J. Am. Chem. Soc., 1984, 106, 5731.
"Prostaglandin Synthesis via Carbopalladation," Holton, R. A. J. Am. Chem. Soc., 1977, 99, 8083.