We are developing efficient strategies for the synthesis of natural products with important biological activity. Targets include the microsclerodermin family of antifungal cyclic peptides. These marine natural products hold promise for the treatment of drug resistant pathogenic fungal infections that are a major problem for the growing number of AIDS and organ transplant patients who have compromised immune systems. Work to date has secured access to several of the unusual amino-acid building blocks required for the synthesis. Future work will explore strategies to unify these units and complete the synthesis. We are also pursuing an approach based on alkene-alkyne metathesis for the synthesis of the pyrrolo[2,1-c][1,4]benzodiazepine family of natural products typified by porothramycin A. Members of this family display potent in vitro and in vivo cytotoxicity, and have been observed to disrupt endonuclease activity and inhibit DNA transcription. We are also targeting non-natural analogues of the alkaloid methyllycaconitine, a neuronal nicotinic acetylcholine receptor antagonist, to elucidate their mode of action at nicotinic receptors. The development of the reactive modifications of these ligands can be used in combination with cysteine mutagenesis to help identify where these ligands bind in the receptor to exert their biological activity.