Our research group is currently engaged in two general fields of interest: the development of new synthetic methods and the total synthesis of biologically interesting natural products. In particular, we are actively pursuing the total synthesis of several tumor-inhibitory or antiviral compounds: normal, 2'-deoxy, and 2',3'-dideoxy modified N-nucleosides (e.g., 2',3'-dideoxycytidine and analogues, AZT and analogues, carbovir), oxetanocin A and its analogues, cyclobut-A and -G, cyclophellitol, the bouvardins, tedanolide and 13-deoxytedanolide, discodermide, dysidiolide, and sclerophytin A. In addition, several co-workers are developing routes for the facile synthesis of L-carbohydrates and their corresponding modified nucleosides, e.g., L-5-F-ddC, which have shown strong antiviral activity. As possible reagents for antisense oligonucleotide therapy, both L-DNA and L-RNA are being prepared. Much of our effort is now being directed toward the synthesis of several polyhalogenated terpenes which show great promise as antitumor agents, e.g., dichlorolissoclimide, the aplysiapyranoids, halomon, isohalomon, and their naturally occurring alkene derivatives. Several students are currently investigating the synthesis of several alkaloid classes: the novel dimeric bis-amino acid isodityrosine, the antifungal agent piperazinomycin, the ACE inhibitor K-13, and the platelet aggregation inhibitor herquline. The use of epoxide rearrangements in synthesis, e.g., the non-aldol aldol process, among others, is also under investigation, especially as a method for the efficient synthesis of polypropionates such as erythromycin and oleandomycin and their respective analogues. We are also studying the use of internal cyclization reactions (e.g., Diels-Alder reactions, radical rearrangements and cyclizations, internal epoxide openings, etc.) for the synthesis of biologically active molecules, e.g., discodermide and cylindramide A, the antiinflammatory agent pseudopterosin A, and the unusual ketosterols xestobergsterol and contignasterol, which are inhibitors of histamine release. We are developing new processes for the efficient synthesis of various cardioactive compounds, e.g., ouabain and several naturally occurring natriuretic agents, e.g., LLU-a. Our current research also includes several collaborative programs with medical schools and institutes to prepare modified peptides as potential inhibitors of carboxy methyl transferases, to develop a new method of delivering antibacterial agents to resistant bacterial strains, and to determine the structures and mechanism of action of several naturally occurring natriuretic agents. And, last but not least, we are investigating the synthetic potential of substituent effects (gem-dialkyl, -dialkoxy, -dithioalkoxy, -dicarboalkoxy, etc.) and polar solvent effects on cyclizations.