The Skaggs Institute
for Chemical Biology

Chemical Synthesis and Chemical Biology

K.C. Nicolaou, I. Andrews, S. Arseniyadis, W. Brenzovich, P. Bulgar, G. Carenzi, J. Chen, A. Converso, A. Corbu, J. Crawford, P. Dagneau, K. Dellios, R. Denton, D. Edmonds, A. Estrada, R. Faraoni, T. Francis, M. Frederick, M. Freestone, R. Harbach, D. Harris, S. Harrison, V. Jeso, D. Kim, T. Koftis, S. Lee, A. Lenzen, Y. Lim, T. Ling, D. Lizos, E. Loizidou, N. Mainolfi, S. Mandal, C. Mathison, R. Milburn, R. Mogul, A. Nold, R. de Noronha, A. Ortiz, C. Papageorgiou, L. Pasunoori, G. Petrovic, J. Piper, B. Pratt, D. Sarlah, P. Sasmal, C. Schindler, D. Schlawe, C. Stathakis,C. Solorio-Alvarado, X. Sun, W. Tang, C. Turner, J. Wang, H. Xu, M. Zak

During the past year, we made considerable progress toward the synthesis and investigation of several biologically active molecules. Thus, in 2 communications, we described our work on azadirachtin, the potent antifeedant agent (Fig. 1).

Fig. 1. Selected target molecules.

In subsequent publications, we described our new synthetic methods for constructing important structural motifs of (1) hyperforin, a molecule associated with St. John’s Wort and Alzheimer’s disease, and (2) nocathiacin, a newly discovered antibiotic. We also discovered and reported new synthetic technologies for preparing important building blocks such as carboxylic acids, nitriles, imides, N-acyl vinylogous carbamates and ureas, and enantiomerically enriched compounds. Our full accounts of the diazonamide project and several reviews describing and critically analyzing the impact of a number of important reactions in total synthesis have also been published. In addition, we completed the total synthesis of halipeptins A and D, 2 marine-derived anti-inflammatory agents, and investigated their structure-activity relationships.

Chemical synthesis and chemical biology are among the most active frontiers in chemistry today. Indeed, these disciplines provide unique opportunities for discovery and invention of new science and technology and a vigorous platform for training young chemists and biologists. Often guided by architecturally intriguing and biologically active natural products, investigations in these areas lead to new knowledge that strengthens the foundation on which drug discovery and development rely. The stories of many miracle drugs of our times are associated with chemical synthesis and its creative power, which play pivotal roles either in the discovery or the manufacture of the drugs, and often in both. Advances in the field, therefore, enhance the ability of researchers to discover and develop new medicines for humans. It is within these areas, chemical synthesis and chemical biology, that we endeavor to discover new science, useful biological tools, and potential new drug candidates.

Publications

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., Bulger, P.G., Sarlah, D. Metathesis reactions in total synthesis. Angew. Chem. Int. Ed. 44:4490, 2005.

Nicolaou, K.C., Bulger, P.G., Sarlah, D. Palladium-catalyzed cross-coupling reactions in total synthesis. Angew. Chem. Int. Ed. 44:4442, 2005.

Nicolaou, K.C., Carenzi, G.E.A., Jeso, V. Construction of highly functionalized medium-sized rings: synthesis of hyperforin and perforatumone model systems. Angew. Chem. Int. Ed. 44:3895, 2005.

Nicolaou, K.C., Estrada, A.A., Zak, M., Lee, S.H., Safina, B.S. A mild and selective method for the hydrolysis of esters employing trimethyltin hydroxide. Angew. Chem. Int. Ed. 44:1378, 2005.

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., Lee, S.H., Estrada, A.A., Zak, M. Construction of substituted
N-hydroxyindoles: synthesis of a nocathiacin I model system. Angew. Chem. Int. Ed. 44:3736, 2005.

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

Nicolaou, K.C., Montagnon, T., Vassilikogiannakis, G., Mathison, C.J.N. The total synthesis of coleophomones B, C, and D. J. Am. Chem. Soc. 127:8872, 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., 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, 1: retrosynthetic analysis and construction of key building blocks. J. Am. Chem. Soc. 127:11159, 2005.

Nicolaou, K.C., Sasmal, P.K., Koftis, T.V., Converso, A., Loizidou, E., Kaiser, F., Roecker, A.J., Dellios, K., Sun, X.-W., Petrovic, G. Studies toward the synthesis of azadirachtin, 2: construction of fully functionalized ABCD ring frameworks and unusual intramolecular reactions induced by close-proximity effects. Angew. Chem. Int. Ed. 44:3447, 2005.

Nicolaou, K.C., Sasmal, P.K., Roecker, A.J., Sun, X.-W., Mandal, S., Converso, A. Studies toward the synthesis of azadirachtin, 1: total synthesis of a fully functionalized ABC ring framework and coupling with a norbornene domain. Angew. Chem. Int. Ed. 44:3443, 2005.

Nicolaou, K.C., Schlawe, D., Kim, D.W., Longbottom, D.A., de Noronha, R.G., Lizos, D.E., Manam, 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., Snyder, S.A. Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation. Angew. Chem. Int. Ed. 44:1012, 2005.

Nicolaou, K.C., Tang, W., Dagneau, P., Faraoni, R. A catalytic asymmetric three-component 1,4-addition/aldol reaction: enantioselective synthesis of the spirocyclic system of vannusal A. Angew. Chem. Int. Ed. 44:3874, 2005.

Nicolaou, K.C., Xu, H., Wartmann, M. Biomimetic total synthesis of gambogin and rate acceleration of pericyclic reactions in aqueous media. Angew. Chem. Int. Ed. 44:756, 2005.

Nicolaou, K.C., Zak, M., Safina, B.S., Estrada, A.A., Lee, S.H., Nevalainen, M. Total synthesis of thiostrepton, 2: assembly of key building blocks and completion of the synthesis. J. Am. Chem. Soc. 127:11176, 2005.

Tan, C., de Noronha, R.G., Roecker, A.J., Pyrzynska, B., Khwaja, F., Zhang, Z., Zhang, H., Teng, O., Nicholson, A.S., Giannakakou, P., Zhou, W., Olson, J.J., Pereira, M.M., Nicolaou, K.C., Van Meir, E.G. Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res. 65:605, 2005.