Understanding and developing PikC as a tool in organic synthesis. Part I: Total synthesis of methymycin and neomethymycin featuring a catalytic nickel ynal cyclization and a biocatalytic PikC carbon-hydrogen oxidation. Part II: Regiodivergent nickel catalyzed macrocyclizations

Abstract

Organic synthesis has been revolutionized by the widespread adoption of organometallic chemistry. Laboratories lacking specialized expertise in transition metals routinely carry out transformations once deemed impossible or impractical. Enzymes hold similar promise to revolutionize synthetic methods; however significant hurdles exist, including a lack of fundamental understanding. The pikromycin biosynthetic pathway uniquely contains enzymes with native substrate promiscuity. We envision harnessing this catalytic prowess and developing a platform for chemoenzymatic synthesis of macrolide antibiotics and un-natural macrocyclic molecules. These studies provide the groundwork towards a fundamental understanding of PikC, a cytochrome P450 enzyme found within the pikromycin pathway by providing access to substrates to study PikC catalyzed reactions. A total synthesis of methymycin and neomethymycin was developed merging catalytic nickel ynal cyclizations and biocatalytic PikC oxidations. In addition, recently developed methodology from the Montgomery laboratory on regiochemistry reversal was applied to a macrocyclization reaction.