The application of diazoketones to the synthesis of natural and unnatural products

This dissertation details the development and investigation of three independent research projects. While seemingly unrelated, each of these aims makes use of the chemistry of transient rhodium carbenoids for the construction of highly-functionalized heterocyclic rings. The first section proposes an approach to the pyran A ring of bryostatin 1 through a novel [3+2] dipolar cycloaddition/SmI2 fragmentation sequence. During the course of this synthesis, an interesting route to furanone ketals and spiroketals was also developed through the acidic fragmentation of the dioxabicyclo[2.2.1]heptanone cycloadducts. Due to poor chiral induction during the key cycloaddition with β-alkoxy aldehydes, our route did not prove amenable to a stereoselective synthesis of bryostatin 1, although moderate levels of selectivity were seen with α-alkoxy aldehydes. The following section has its foundation upon moderate levels of diastereoselection observed with the use of glyceraldehyde acetonides with cyclic carbonyl ylides. The potential synthons of this novel chemistry were the impetus for an approach to the potent influenza neuraminidase inhibitor, zanamivir. In the key event, poor facial diastereoselectivity was observed in combination with the modified carbonyl ylides. The concluding section details the identification of a novel dihydro-oxazine scaffold for influenza therapeutics bases on zanamivir. Preliminary modeling studies predicted similar binding of our compounds in the active site of influenza neuraminidase in comparison to zanamivir. The syntheses of our simple dihydro-oxazine analogues of known dihydropyran inhibitors make use of an intramolecular cyclization of in situ generated rhodium carbenoids, although the failure of this approach prompted the exploration of an interesting dihydro-oxazine forming reaction, the Boyer-Aubé reaction. Ultimately, a model system of the 2-(t-butoxycarbonyl)-dihydro-oxazine proved that such analogues were susceptible to hydrolysis under neutral conditions, although future directions of this latter project are presented