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Dr. Little received his Ph.D. in 1974 from the University of Wisconsin, and was a postdoctoral fellow at Yale before joining the faculty at UC Santa Barbara in 1975. He is the recipient of an A. P. Sloan Foundation Fellowship and the H. J. Plous Award at UCSB. Dr. Little has been a visiting professor at the University of British Columbia, served on the Medicinal Chemistry Study Section of the NIH, and is currently Chair of the Chemistry Department. Phone: (805) 893-3693     Email: little@chem.ucsb.edu Our research focuses on the investigation and development of novel methodologies targeted for the production of biologically important molecules. Highlighted below are ongoing projects which involve the use of electroorganic synthesis and trimethylene methane (TMM) diradical chemistry. A Novel Ring Fragmentation with Application to the Taxol¨ Skeleton The ring fragmentation/recombination, illustrated below, is a new pathway to the bicyclic system 3, common to many biologically active molecules. The TMM diradical 1 is generated via thermal loss of N2 from a [2.2.1] diazo precursor. We have pioneered this form of TMM diyl chemistry and it is further described in our most recent publications.1,2 Elaboration of the substrate tether (emboldened in 4), has garnered us access to the [5.3.1] skeleton 6, the substructure prevalent in taxanes. This method is our current strategy in the syntheses of Taxol¨ analogs. Electroreductive Cyclization; a Route to Phorbol Analogs Phorbol is a naturally occurring compound isolated from a family of plants, Croton Tilium L., and exhibits strong tumor promoting capabilities.3 By producing simplified systems for structure-activity studies, we hope to aid in the understanding of tumor cell proliferation. One of our target molecules (below) was designed to incorporate important features for biological activity. The synthetic route shown is efficient and highlights two electroreductive cyclizations (ERC) resulting in tricyclic skeleton 5. This pathway allows for several avenues from which phorbol derivatives can be generated. Cyclization experiments of model substrates have provided valuable insight towards the route we are now pursing.4 The ERC of both 1a and 1b routinely generate 2a and 2b (respectively) in 85-90%. Appendage of the cyclopentanone moiety was accomplished via intermolecular reductive coupling with SmI2. The stereochemistry of 3a was confirmed by x-ray crystallography. Investigation of the ERC reaction of substrate 4 is anticipated in the near future. Atom Transfer of a TMM Diyl en route to Rudmollin The intramolecular atom transfer reaction of TMM diyls was initially investigated by Little and Billera.5 The efficient assembly of a functionalized perhydroazulene skeleton, as shown below, encouraged us to extend this process towards a total synthesis.6 Rudmollin (1), our target of choice, is the major constituent of Rudbeckia mollis Ell., the common coneflower. This pseudoguaianolide exhibits in vivo activity against P-388 lymphoid leukemia.6 The structure and stereochemistry of 1 are well established,7 and only one total synthesis has been reported.8 Our approach is outlined in the retro-synthetic scheme, below. To date, we have successfully set five of the six stereocenters; cf 1, and recently completed the synthsis of 4. Sterochemistry of 4 was confirmed by x-ray diffraction analysis. Literature precedent suggests that correction of the stereochemistry at C-1 may be accomplished from the intermediate ketone 5.9 Efforts to do so are in progress. 1 Carroll, G. L.; Little, R. D.; Tetrahedron Lett. 1998, 39, 1893 2 Carroll, G. L.; Allan, A.; Little, R. D. Eur. J. Org. Chem. 1998, 1, 1 3 I. Blerenblum in Risk Factors and Multiple Cancer;B. Stoll, Ed.; John Wiley and Sons: New York, 1984. 4 Carroll, G. L.; Lozano J. I.; Little R. D. In Novel Trends in Electoorganic Synthesis; Torii, S.,Ed.; Springer-Verlag Tokyo: Tokyo, Japan, 1997; p 221. 5 Billera, C. F.; Little, R. D.; J. Am. Chem. Soc. 1994, 116, 5487 6 Unpuplished results from the dissertation of Dr. Michael K. Schwaebe, UCSB, 1996 7 Herz, W. et al; J. Org. Chem. 1981, 46, 1356 8 Fisher, K.; Wender, P. A.; Tetrahedron Lett. 1986, 27, 1857 9 Vanderwalle, M.; De Clercq, P.; J. Org. Chem. 1977, 21, 3447

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