Person:

Lee, Amy S

Lomaiviticin A (1) and B (2) are natural products with remarkably complex C2-symmetric structures and potent antiproliferative properties. Achieving total syntheses of 1 and 2 has been a long-standing project in the Shair group and part one of this thesis describes our first successful synthesis of the C4-epi-lomaiviticin A and B core structures. A key stereoselective oxidative enolate dimerization of an oxanorbornanone system was employed to establish the highly hindered C2-C2' bond. Crucial to our completion of the lomaiviticin core structures was the discovery of subtle yet far-reaching stereoelectronic effects imparted by the C4/C4'-stereocenters. The Lycopodium alkaloids are a family of complex polycyclic alkaloid natural products that have long served as popular targets for developing synthetic chemistry. More recently, select members have been reported to exhibit neurological effects. Part two of this thesis presents the development of a biomimetic, unified strategy for the synthesis of 7-membered ring-containing Lycopodium alkaloids and its successful application toward the first total syntheses of the proposed structure of (-)-himeradine A (38), (-)-lycopecurine (39), and (-)-dehydrolycopecurine (199), and the syntheses of (+)-lyconadin A (31) and (-)-lyconadin B (32). A biosynthetically inspired one-pot cascade reaction sequence was developed to construct the strained polycyclic core structure shared amongst these alkaloids. Additionally, the syntheses of 38, 39, and 199 featured a biomimetic intramolecular Mannich reaction to furnish the tetracyclic ring system. The successful application of our unifying strategy toward the synthesis of a diverse set of alkaloids lends support to our biosynthetic hypothesis that 7-membered ring-containing Lycopodium alkaloids arise from a common precursor. Our synthetic approach can potentially provide access to all such natural products.

An efficient synthesis of the C4-epi-lomaiviticin B core is reported. The synthesis features a diastereoselective anionic formal furan Diels-Alder reaction and a stereoselective oxidative enolate dimerization. During the investigation, subtle yet critical stereoelectronic effects imparted by the C4-stereocenter were observed.