Integrating Diverse Methodologies and Strategies for the Total Synthesis of Certain Alkaloids and Terpenoids

Abstract

The body of this thesis is comprised of five scientific articles and is preceded by an overview that contextualizes all of this published/submitted/to be submitted work.

The first major part of this thesis is comprised of publication 1. This is a review concerned with the application of Raney-cobalt in organic synthesis. The author's work described in publications 2 and 3 featured Raney-cobalt mediated reductive cyclization reactions as key steps in the construction of the framework of various uleine alkaloids and certain of these are highlighted in this review.

Publication 2 comprises the second major part of this thesis. This article details the total syntheses of some key members of uleine alkaloid family (specifically uleine, noruleine, dasycarpidone, nordasycarpidone) by using, as key steps, a palladium-catalysed Ullmann cross-coupling reaction to generate key coupling product and the immediate reductive cyclization of this so as to assemble the uleine alkaloid framework.

The third major part of this thesis is comprised of publication 3. This article describes the total synthesis of uleine alkaloid gilbertine. The key intermediate embodying the framework of uleine-type alkaloids was assembled by the Raney-cobalt mediated reductive cyclization of an nitrile compound which was itself constructed via a reaction sequence including a palladium-catalysed Ullmann cross-coupling process. The end-game associated with the synthesis involved a cationic (and possibly biomimetic) cyclisation reaction that established the final, tetrahydropyran ring of gilbertine.

The fourth major part of this thesis is comprised of publication 4. This details the total synthesis of a marine-derived sesquiterpene (+)-viridianol. The target molecule was derived from a key intermediate cyclobutone through various functional group manipulations. This cyclobutone was prepared through a photochemically-promoted 1,3-acyl migration reaction involving the cyclopentannulated bicyclo[2.2.2]-octenone, itself constructed from the homochiral compound cis-1,2-dihydrocatechol using Negishi cross-coupling and intramolecular Diels-Alder (IMDA) cycloaddition reactions as key steps. The starting material, a cis-1,2-dihydrocatechol, was obtained through the whole-cell biotransformation of p-iodotoluene using a genetically engineered micro-organism over-expressing the enzyme toluene dioxygenase.

The fifth major part of this thesis is comprised of publication 5. This article details a model study relevant to the total synthesis of the marine-derived sesquiterpene (+)-viridianol. Specifically, two structurally related ring-fused cyclopropanes were subjected to the same hydrogenolytic conditions. However, they showed dramatically divergent behavior.