Investigations into Polyketide Biosynthesis through the Use of Oxetanes as Carbonyl Isosteres & Studies in the Total Synthesis of Marine-Derived Isocyanoterpenoid Natural Products

The research contained herein describes the use of organic synthesis to answer fundamental questions in both chemistry and biology. Chapter 1 begins by giving a brief overview of the current understanding of polyketide synthase (PKS) enzymes, as well as some of the many tools utilized to study them. Chapter 2 describes our contribution to the field of PKS enzymology—namely, through the synthesis of a new class of PKS substrate mimetics. The first report of an acyl–enzyme intermediate for a Type II PKS is described, and validates the use of oxetanes as carbonyl isosteres. The Chapter ends by detailing some of the many strategies we’ve investigated towards the modular synthesis of higher-order poly-beta-ketone mimics. Chapter 3 moves away from the aforementioned PKS studies, and instead described the history, relevance, and a selection of the previous syntheses of marine-derived isocyanoterpenoid (ICT) natural products. Chapter 4 details our strategy that led to a concise synthesis of the flagship member of the ICTs—7,20-diisocyanoadociane (DICA). Key contributions include a unique epoxidation/cyclodehydration sequence, as well as a solution to the problem of axial methylation of substituted cyclohexanones. Chapter 5 continues the theme of ICT total syntheses, and describes the ongoing efforts towards one of the most unique members of the diterpenoid ICT family—neoamphilectane. Details regarding substrate synthesis as well as attempts at our proposed key step are described