Brief enantioselective total syntheses of nakadomarin A and of guanacastepene have been proposed in which the asymmetric cyclopentannelation is the key step. Nakadomarin A, which has been isolated from an Okinawan Amphimedon sp. sponge in 1997 is biosynthetically related to the manzamines, but is structurally without precedent. It has a fairly complicated bridged system of six heterocyclic and carbocyclic rings. It is cytotoxic in the L1210 assay (IC50 1.3 microg/mL), shows inhibitory activity against cyclin dependent kinase 4 (IC50 = 9.9 microg/mL), and has antibacterial and antifungal activity. Guanacastepene, which was isolated in 2000 from an endophytic fungus from a tree in Costa Rica, also has a unique carbon skeleton. It is active against both methicillin-resistant S. aureus (MRSA) and against vancomycin-resistant Enterococcus faecalis (VREF). The absolute stereochemistry of both compounds is in doubt, so the total synthesis will also constitute a proof of structure. Both natural products are structurally unique, therefore they may exert their respective activities through unusual mechanisms. Cancer and multi-drug-resistant human pathogens are two areas of concern in public health. In parallel with the total syntheses we will work to improve the methodology which was developed during the first funding cycle, and expand its scope. A long-range goal of the work is to determine whether the basic method can be adapted for the enantioselective synthesis of compounds with contiguous quaternary carbon atoms. This is still a difficult problem in synthesis.