Novel Access to Methyl Substituted Polyketide Structural Units Through 1,5-Hydride Shift and Ether Transfer: Application to the Syntheses of Diospongins A and B and Towards Lyngbyaloside C

This dissertation comprises three major components that sequentially describe the development of three methodologies for the formation of novel methyl substituted polyketide structural units and their application in complex molecule synthesis.

This research dissertation commences with a literature review pertinent to the development of an ether transfer protocol, enabling a novel access to the formation of 1,3-syn-diol mono- or diethers through electrophilic activation of homoallylic alkoxymethyl ethers. Starting from 1,1-disubstituted alkenes, this transformation enabled us to stereoselectively access tertiary ethers. The use of iodine monochloride proved critical for a selective process, but other reagents such as IDSI and BDSB have shown to be as efficient. Additional advancements have led to the discovery of 2-naphthylmethyl ether which proceeded smoothly through ether transfer and was easily cleaved by DDQ oxidation. This new method to access structural units containing tertiary ethers was applied in the synthesis of the C9-C19 fragment of lyngbyaloside B and C.

In several cases, we observed the failure of the ether transfer methodology to provide the desired reactivity. This was particularly true when sp^{2-hybridized substituents were adjacent to the reacting alkoxymethyl ether, resulting in the formation of dihalogenated byproducts upon activation with iodine monochloride. We therefore developed a second generation of activating conditions, using N-iodosuccinimide in wet nitromethane, to resolve this lack of selectivity. This new, stereoselective route to access 1,3-syn-diol mono- or diethers was successfully applied to the syntheses of diospongins A and B.}

The final section describes a method that enabled sp³ C-H bond functionalization by means of a hydride shift. We discovered that protonation of an alkene with a strong Br?nsted acid initiated a 1,5-hydride shift through reduction of a tertiary carbocation by an appropriately positioned benzyl ether. Modifications to the starting material or to the activating conditions allowed the formation of a variety of synthetically useful motifs that could be potentially employed in the synthesis of complex natural products.