Scientific Report 2007

Chemistry

Total Synthesis, New Synthetic Technologies, and Chemical Biology

K.C. Nicolaou, X. Alvarez-Mico, R. Aversa, W. Brenzovich, P. Bulger, A. Burtoloso, J. Chen, K. Cole, J. Crawford, P. Dagneau, R. Denton, D. Edmonds, S. Ellery, A. Estrada, C. Fang, R. Faraoni, M. Frederick, M. Freestone, R. Gibe, S. Harrison, V. Jeso, A. Johnson, A. Kislukhin, A. Lanver, K. Lee, A. Lemire, A. Lenzen, A. Li, H. Li, Y. Lim, T. Lister, N. Mainolfi, C. Mathison, A. Morgan, A. Nold, A. Ortiz, K. Pendri, G. Petrovic, D. Polet, G. Pontremoli, B. Pratt, F. Rivas, A. Sanchez Ruiz, D. Sarlah, D. Shaw, A. Stepan, T. Suzuki, A. Talbot, Y. Tang, V. Trepanier, G. Tria, C. Turner, T. Umezawa, J. Wang, T. Wu, H. Xu, H. Zhang

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 for 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 drugs diazonamide A, thiostrepton, azaspiracid-1–azaspiracid-3, abyssomycin C, the bisanthraquinones, and the marinomycins exemplify this philosophy. Current projects include studies on the antibiotics nocathiacin I and platensimycin, the antifeedant azadirachtin, the antitumor agents lomaiviticin B and unicalamycin, and the anti-HIV agent biyouyanagin (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

Alfonso, A., Vieytes, M.R., Ofuji, K., Satake, M., Nicolaou, K.C., Frederick, M.O., Botana, L.M. Azaspiracids modulate intracellular pH levels in human lymphocytes. Biochem. Biophys. Res. Commun. 346:1091, 2006.

Altmann, K.-H., Pfeiffer, B., Arseniyadis, S., Pratt, B.A., Nicolaou, K.C. The chemistry and biology of epothilones: the wheel keeps turning. ChemMedChem 2:396, 2007.

Hamel, E., Day, B.W., Miller, J.H., Jung, M.K., Northcote, P.T., Ghosh, A.K., Curran, D.P., Cushman, M., Nicolaou, K.C., Paterson, I., Sorensen, E.J. Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly. Mol. Pharmacol. 70:1555, 2006.

Nicolaou, K.C., Edmonds, D.J., Bulger, P.G. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 45:7134, 2006.

Nicolaou, K.C., Edmonds, D.J., Li, A., Tria, G.S. Asymmetric syntheses of platensimycin. Angew. Chem. Int. Ed. 46:3942, 2007.

Nicolaou, K.C., Estrada, A.A., Freestone, G.C., Lee, S.H., Alvarez, X.M. New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems. Tetrahedron 63:6088, 2007.

Nicolaou, K.C., Estrada, A.A., Lee, S.H., Freestone, G.C. Synthesis of highly substituted N-hydroxyindoles through 1,5-addition of carbon nucleophiles to in situ generated unsaturated nitrones. Angew. Chem. Int. Ed. 45:5364, 2006.

Nicolaou, K.C., Frederick, M.O. On the structure of maitotoxin. Angew. Chem. Int. Ed. 46:5278, 2007.

Nicolaou, K.C., Harrison, S.T. Total synthesis of abyssomicin C, atrop-abyssomicin C, and abyssomicin D: implications for natural origins of atrop-abyssomicin C. J. Am. Chem. Soc. 129:429, 2007.

Nicolaou, K.C., Li, A., Edmonds, D.J. Total synthesis of platensimycin. Angew. Chem. Int. Ed. 45:7086, 2006.

Nicolaou, K.C., Lim, Y.H., Piper, J.L., Papageorgiou, C.D. Total synthesis of
2,2′-epi-cytoskyrin A, rugulosin, and the alleged structure of rugulin. J. Am. Chem. Soc. 129:4001, 2007.

Nicolaou, K.C., Lister, T., Denton, R.M., Montero, A., Edmonds, D.J. Adamantaplatensimycin: a bioactive analogue of platensimycin. Angew. Chem. Int. Ed. 46:4712, 2007.

Nicolaou, K.C., Nold, A.L., Milburn, R.R., Schindler, C.S. Total synthesis of marinomycins A-C. Angew. Chem. Int. Ed. 45:6527, 2006.

Nicolaou, K.C., Nold, A.L., Milburn, R.R., Schindler, C.S., Cole, K.P., Yamaguchi, J. Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A. J. Am. Chem. Soc. 129:1760, 2007.

Nicolaou, K.C., Sarlah, D., Shaw, D. Total synthesis and revised structure of
biyouyanagin A. Angew. Chem. Int. Ed. 46:4708, 2007.

Nicolaou, K.C., Tang, Y., Wang, J. Formal synthesis of (±)-platensimycin. Chem. Commun. (Camb.) 1922, 2007, Issue 19.

Nicolaou, K.C., Zhang, H., Chen, J.S., Crawford, J.J., Pasunoori, L. Total synthesis and stereochemistry of uncialamycin. Angew. Chem. Int. Ed. 46:4704, 2007.

Nicolaou, K.C., Zou, B., Dethe, D.H., Li, D.B., Chen, D.Y.-K. Total synthesis of antibiotics GE2270A and GE2270T. Angew. Chem. Int. Ed. 45:7786, 2006.

Vale, C., Nicolaou, K.C., Frederick, M.O., Gomez-Limia, B., Alfonso, A., Vieytes, M.R., Botana, L.M. Effects of azaspiracid-1, a potent cytotoxic agent, in primary neuronal cultures: a structure-activity relationship study. J. Med. Chem. 50:356, 2007.

Vilariño, N., Nicolaou, K.C., Frederick, M.O., Cagide, E., Ares, I.M., Louzao, M.C., Vieytes, M.R., Botana, L.M. Cell growth inhibition and actin cytoskeleton disorganization induced by azaspiracid-1: structure-activity studies. Chem. Res. Toxicol. 19:1459, 2006.