James Frederich, Florida State University

14-3-3 proteins are eukaryotic adapter molecules that regulate hundreds of client proteins by forming transient protein complexes. Certain of these PPIs play a direct role in the pathobiology of cancer and neurological disorders. Thus, there is strong interest in designing chemical tools to interrogate the role(s) of individual 14-3-3•client protein interactions in disease-relevant biochemical pathways. In this regard, the fungal phytotoxin fusicoccin A (FC) harbors special potential because it targets 14-3-3 functions in vivo. FC engages a select group of 14-3-3•client protein contacts and enhances these PPIs via simultaneous interactions with both proteins. This unique biological activity has stimulated efforts to develop non-natural variants of FC with tailored pharmacological profiles; however, synthetic entry to highly oxidized and architecturally complex diterpene framework of FC has emerged as a key limitation. Herein, we describe a modular approach to this motif that leverages a UV- light promoted oxidative cycloisomerization reaction. This chemistry provides stereocontrolled access to the fused 5-8-5 carbocylic ring system of FC in a single step and, importantly, enables the first fully synthetic entry point to this terpene natural product.