Scientific Report 2007

Chemistry

Synthesis of Natural Products, Development of Synthetic Methods, and Medicinal Chemistry

W.R. Roush, R. Bates, D. Bykowski, Y.-T. Chen, E. Darout, A. DeBaillie, J. Dunetz, G. Halvorsen, M. Handa, J. Hicks, T. Hopkins, C.-W. Huh, F. Li, R. Lira, C. Nguyen, M. Ober, R. Pragani, J. Roth, T. Ryba, M. Tortosa, P. Va, A. Williams, S. Winbush

Our research has 2 major themes. One is the synthesis of structurally complex, biologically active natural products such as those shown in Figure 1. These efforts in total synthesis are pursued in parallel with reaction design, stereochemical studies, and the development of new synthetic methods. We have been particularly interested in stereochemical aspects of intramolecular and transannular Diels-Alder reactions, in the development of methods for the diastereoselective and enantioselective reactions of allylmetal compounds with carbonyl compounds.

Fig. 1. Structures of recently synthesized natural products.

Recently, we have focused on the Diels-Alder reactions of siloxacyclopentene-constrained trienes, development of new versions of the double allylboration reactions of aldehydes with γ-boryl–substituted allylboranes for stereocontrolled synthesis of 1,5-endiols, synthesis of highly substituted tetrahydrofurans via [3 + 2]-annulation reactions of highly functionalized allylsilanes, and development of phosphine-mediated organocatalytic reactions.

Natural products of current interest to us include amphidinolides C and F, amphidinol 3, angelmicin B, annonaceous acetogenin analogs, durhamycin A and analogs, integramicin, lomaiviticin A, peloruside A, quartromicin D1, reidispongiolide A, spinosyn A biosynthetic intermediates, scytophycin C, superstolide A, tedanolide, and tetrafibricin. We selected these molecules as targets because of their biological properties and their interesting and complex structures. We place a significant emphasis on the discovery, development, and/or illustration of new reactions and synthetic methods for achieving high levels of stereochemical control in each of these synthesis efforts.

Our second area of major interest involves problems in bioorganic chemistry and medicinal chemistry. One long-term project is the design and synthesis of inhibitors of cysteine proteases isolated from tropical parasites, such as Trypanosoma cruzi, the causative agent of Chagas disease, and Plasmodium falciparum, the most virulent of the malaria parasites. This research is performed in collaboration with colleagues at the University of California, San Francisco. In collaboration with S. Reed, University of California, San Diego, we recently developed a cysteine protease inhibitor with remarkable ability to prevent Entamoeba histolytica from invading human intestinal tissue. New projects at Scripps Florida involve discovery of small molecules that affect cancer and other targets, studies of the structure-activity relationship of certain natural products, and optimization of the pharmacologic profile of certain natural products.

Publications

Goetz, D.H., Choe, T., Hansell, E., Chen, Y.T., McDowell, M., Jonsson, C.B., Roush, W.R., McKerrow, J., Craik, C.S. Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus. Biochemistry 46:8744, 2007.

Halvorsen, G.T., Roush, W.R. Intramolecular Diels-Alder reactions of siloxacyclopentene constrained trienes. Org. Lett. 9:2243, 2007.

Lira, R., Roush, W.R. Stereoselective synthesis of the C(1)-C(19) fragment of tetrafibricin. Org. Lett. 9:533, 2007.

Meléndez-López, S.G., Herdman, S., Hirata, K., Choi, M.-H., Choe, Y., Craik, C., Caffrey, C.R., Chávez-Munguìa, B., Chen, Y.T., Roush, W.R., McKerrow, J., Eckmann, L., Guo, J., Stanley, S.L., Jr., Reed, S.L. Use of recombinant Entamoeba histolytica cysteine proteinase 1 to identify a potent inhibitor of amebic invasion in a human colonic model. Eucaryot. Cell 6:1130, 2007.

Qi, J., Roush, W.R. Synthesis of precursors of the agalacto (exo) fragment of the quartromicins via an auxiliary-controlled exo-selective Diels-Alder reaction. Org. Lett. 8:2795, 2006.

Trullinger, T.K., Qi, J., Roush, W.R. Studies on the synthesis of quartromicins A₃ and D₃: synthesis of the vertical and horizontal bis-spirotetronate fragments. J. Org. Chem. 71:6915, 2006.

Va, P., Roush, W.R. Synthesis of 2-epi-amphidinolide E: an unexpected and highly selective C(2) inversion during an esterification reaction. Org. Lett. 9:307, 2007.

Va, P., Roush, W.R. Total synthesis of amphidinolide E. J. Am. Chem. Soc. 128:15960, 2006.

Va, P., Roush, W.R. Total synthesis of amphidinolide E and amphidinolide E stereoisomers. Tetrahedron 63:5768, 2007.