Scientific Report 2006

Chemistry

Total Synthesis, New Synthetic Technologies, and Chemical Biology

K.C. Nicolaou, S. Arseniyadis, W. Brenzovich, P. Bulger, A. Burtoloso, J. Chen, K. Cole, A. Converso, J. Crawford, P. Dagneau, R. Denton, A. Estrada, D. Edmonds, C. Fang, R. Faraoni, M. Frederick, M. Freestone, R. Gibe, S. Harrison, V. Jeso, A. Johnson, D. Kim, A. Kislukhin, A. Lanver, K. Lee, S. Lee, A. Lemire, A. Lenzen, A. Li, H. Li, Y. Lim, T. Lister, D. Lizos, E. Loizidou, N. Mainolfi, C. Mathison, X. Mico-Alvarez, R. Milburn, A. Nold, A. Noncovich, R. de Noronha, A. Ortiz, C. Papageorgiou, D. Pappo, L. Pasunoori, G. Petrovic, J. Piper, D. Polet, G. Pontremoli, B. Pratt, D. Sarlah, D. Shaw, C. Stathakis, C. Solorio-Alvarado, T. Suzuki, G. Tria, C. Turner, T. Umezawa, J. Wang, H. Xu, M. Zak

We focus on the total synthesis of natural products, the discovery and development of new synthetic technologies, and chemical biology. Naturally occurring substances are selected as synthetic targets because of their novel molecular architectures, important biological properties, and interesting mechanisms of action. The projects are designed to optimize the opportunities for discovery and invention in the areas of chemistry, biology, and medicine. The drug paclitaxel(Taxol), the antitumor epothilones, the neurotoxins brevetoxins A and B, the antibiotic vancomycin, the cholesterol-lowering CP-molecules, the antibiotic everninomicin, the TNF α–associated trichodimerol, the tetrahydropyran class of natural products, apoptolidin, diazonamide A, thiostrepton, and the azaspiracids exemplify this philosophy. Current projects include studies of the antibiotics nocathiacin and abyssomicin C, the antifeedant azadirachtin, and the antitumor agents marinomycin and A lomaiviticin B (Fig. 1).

Fig. 1. Selected target molecules.

In addition, we are developing synthetic technologies and strategies for chemical synthesis and chemical biology studies. Our overall aims are to advance the art and science of chemical synthesis and to develop enabling technologies for biology and medicine while maximizing educational opportunities and training of young men and women in chemistry.

Publications

Ito, E., Frederick, M.O., Koftis, T.V., Tang, W., Petrovic, G., Ling, T., Nicolaou, K.C. Structure toxicity relationships of synthetic azaspiracid-1 and analogs in mice. Harmful Algae. 5:586, 2006.

Nicolaou, K.C. Joys of molecules, 1: campaigns in total synthesis. J. Org. Chem. 70:7007, 2005.

Nicolaou, K.C. Joys of molecules, 2: endeavors in chemical biology and medicinal chemistry. J. Med. Chem. 48:5613, 2005.

Nicolaou, K.C., Brenzovich, W.E., Bulger, P.G., Francis, T.M. Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures: initial forays. Org. Biomol. Chem. 4:2119, 2006

Nicolaou, K.C., Bulger, P.G., Brenzovich, W.E. Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures: revised strategy and final stages. Org. Biomol. Chem. 4:2158, 2006.

Nicolaou, K.C., Chen, D.Y.-K., Li, Y., Uesaka, N., Petrovic, G., Koftis, T.V., Bernal, F., Frederick, M.O., Govindasamy, M., Ling, T., Pihko, P.M., Tang, W., Vyskocil, S. Total synthesis and structural elucidation of azaspiracid-1: synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product. J. Am. Chem. Soc. 128:2258, 2006.

Nicolaou, K.C., Denton, R.M., Lenzen, A., Li, A., Edmonds, D.J., Milburn, R.R., Harrison, S.T. Stereocontrolled synthesis of model core systems of lomaiviticins A and B. Angew. Chem. Int. Ed. 45:2076, 2006.

Nicolaou, K.C., Frederick, M.O., Loizidou, E.Z., Petrovic, G., Cole, K.P., Koftis, T.V., Yamada, Y.M.A. Second-generation total synthesis of azaspiracids-1, -2, and -3. Chem. Asian J. 1:245, 2006.

Nicolaou, K.C., Frederick, M.O., Petrovic, G., Cole, K.P., Loizidou, E. Total synthesis and confirmation of the revised structures of azaspiracid-2 and azaspiracid-3. Angew. Chem. Int. Ed. 45:2609, 2006.

Nicolaou, K.C., Harrison, S.T. Total synthesis of abyssomicin C and atrop-abyssomicin C. Angew. Chem. Int. Ed. 45:3256, 2006.

Nicolaou, K.C., Kim, D.W., Schlawe, D., Lizos, D.E., de Noronha, R.G., Longbottom, D.A. Total synthesis of halipeptins A and D and analogues. Angew. Chem. Int. Ed. 44:4925, 2005.

Nicolaou, K.C., Koftis, T.V., Vyskocil, S., Petrovic, G., Tang, W., Frederick, M.O., Chen, D.Y.-K., Li, Y., Ling, T., Yamada, Y.M.A. Total synthesis and structural elucidation of azaspiracid-1: final assignment and total synthesis of the correct structure of azaspiracid-1. J. Am. Chem. Soc. 128:2859, 2006.

Nicolaou, K.C., Lim, Y.H., Papageorgiou, C.D., Piper, J.L. Total synthesis of (+)-rugulosin and (+)-2,2′-epi-cytoskyrin A through cascade reactions. Angew. Chem. Int. Ed. 44:7917, 2005.

Nicolaou, K.C., Lizos, D.E., Kim, D.W., Schlawe, D., de Noronha, R.G., Longbottom, D.A., Rodriquez, M., Bucci, M., Cirino, G. Total synthesis and biological evaluation of halipeptins A and D and analogues. J. Am. Chem. Soc. 128:4460, 2006.

Nicolaou, K.C., Mathison, C.J.N. Synthesis of imides, N-acyl vinylogous carbamates and ureas, and nitriles with Dess-Martin periodinane. Angew. Chem. Int. Ed. 44:5992, 2005.

Nicolaou, K.C., Papageorgiou, C.D., Piper, J.L., Chadha, R.K. The cytoskyrin cascade: a facile entry into cytoskyrin A, deoxyrubroskyrin, rugulin, skyrin and flavoskyrin model systems. Angew. Chem. Int. Ed. 44:5846, 2005.

Nicolaou, K.C., Pihko, P.M., Bernal, F., Frederick, M.O., Qian, W., Uesaka, N., Diedrichs, N., Hinrichs, J., Koftis, T.V., Loizidou, E., Petrovic, G., Rodriquez, M., Sarlah, D., Zou, N. Total synthesis and structural elucidation of azaspiracid-1: construction of key building blocks for originally proposed structure. J. Am. Chem. Soc. 128:2244, 2006.

Nicolaou, K.C., Pratt, B.A., Arseniyadis, S., Wartmann, M., O’Brate, A., Giannakakou, P. Molecular design and chemical synthesis of a highly potent epothilone. Chemmedchem 1:41, 2006.

Nicolaou, K.C., Safina, B.S., Zak, M., Lee, S.H., Nevalainen, M., Bella, M., Estrada, A.A., Funke, C., Zécri, F., Bulat, S. Total synthesis of thiostrepton: retrosynthetic analysis and construction of key building blocks. J. Am. Chem. Soc. 127:11159, 2005.

Nicolaou, K.C., Schlawe, D., Kim, D.W., Longbottom, D.A., de Noronha, R.G., Lizos, D.E., Manan, R.R., Faulkner, D.J. Total synthesis of halipeptins: isolation of halipeptin D and synthesis of oxazoline halipeptin analogues. Chemistry 11:6197, 2005.

Nicolaou, K.C., Xu, H. Total synthesis of floresolide B and Δ^6,7-Z-floresolide B. Chem. Commun. (Camb.) 600, 2006, Issue 6.

Nicolaou, K.C., Zak, M., Rahimipour, S., Estrada, A.A., Lee, S.H., O’Brate, A., Giannankakou, P., Ghadiri, M.R. Discovery of a biologically active thiostrepton fragment. J. Am. Chem. Soc. 127:15042, 2005.

Nicolaou, K.C., Zak, M., Safina, B.S., Estrada, A.A., Lee, S.H., Nevalainen, M. Total synthesis of thiostrepton: assembly of key building blocks and completion of the synthesis. J. Am. Chem. Soc. 127:11176, 2005.