Studies toward the Total Synthesis of Biselides & Radical Fluorination of Aliphatic Compounds

Modern pharmaceuticals originate predominately either from natural products or totally synthetic compounds. The rich variety of marine life found in the Earth’s oceans have especially allowed our access to increasingly more and intriguing biologically active marine natural products, such as haterumalides and biselides. The lack of materialistic return associated with natural product isolation from marine organisms has prompted the need for practical laboratory synthesis. The same demand holds true for synthetic drugs, as more novel synthetic methods are required to complement the increasingly target- and diversity-oriented approach to synthetic drug discovery. Biselides, isolated from the Okinawan ascidian Didemnidae sp., are marine macrolides which have demonstrated potent cytotoxicity towards a variety of human cancer cell lines while being non-toxic towards brine shrimp. They contain a 2,5-disubstituted-3-oxygenated tetrahydrofuran functionality and a (Z,Z)-1,4-diene as part of a 14-membered macrocyclic molecular skeleton. A proposed total synthesis of biselide A involves the cyclization of chloropolyols to form the substituted tetrahydrofuran and metathesis for construction of the (Z,Z)-1,4-diene. Specifically, direct ring-closing metathesis (RCM), relay ring-closing metathesis (RRCM), and cross metathesis (CM) strategies were examined, with only the CM strategy allowing us to construct the 1,4-diene with desired geometry. The second part of this thesis describes the development of a novel methodology for the direct conversion of C(sp3)-H bonds to C(sp3)-F bonds. This radical-based, photocatalytic process yielded monofluorinated products from various small molecule aliphatic substrates, and has showed further potential with other chemical systems. Improvement and expansion of this methodology could hold positive future implications with regards to fluoropharmaceuticals.