Development of Lewis Acid Catalyzed Methods for Carbonyl-Olefin Metathesis, Enantiodivergent Total Synthesis of Lingzhiol and Studies Towards the Divergent Synthesis of ent-Kaurenes

Abstract

The development of new methods for forming carbon-carbon bonds is an important area of research in synthetic organic chemistry. Accomplishing the direct formation of new C-C bonds between a carbonyl and olefin starting material is a powerful transformation, enabling the synthesis of new olefin-containing molecules, especially for molecules containing small rings. Recently, the Schindler group has developed an operationally simple, mild, and environmentally benign strategy for carbonyl-olefin metathesis reactions relying on iron(III) as a Lewis acid. Rather than relying on stoichiometric alkylidenes as reagents, the Lewis acid catalyst induces oxetane formation and subsequent fragmentation, enabling catalyst turnover and producing acetone or aromatic aldehydes as waste products. This dissertation describes the application and extension of this method to a variety of new systems. Polycyclic aromatic hydrocarbons, important in material science and polymer chemistry, have been prepared under these conditions. Alkyl ketones, previously found to be problematic substrates, can undergo the carbonyl-olefin metathesis reaction in systems when iron(III) is able to form singly bridged homo-dimers that lead to much greater carbonyl activation than their monomeric counterparts. Finally, carbonyl-olefin metathesis is demonstrated in transannular systems. Ten membered rings derived from biologically important steroid molecules are shown to undergo divergent reactivity when treated with different Lewis acid catalysts. Total synthesis of terpene natural products is also an important and active area of research in synthesis as means of delivering useful quantities of biologically important, naturally occurring molecules as well as a driving force for the discovery and development of new methods. The tetracyclic meroterpenoid lingzhiol has potential reno-protective biologically activity and is a small but synthetically interesting natural product. This dissertation describes the completion of an enantioselective total synthesis of this compound. In the course of these studies, a metal-mediated reversal of enantioselectivity was discovered. This enables the enantioselective synthesis of both enantiomers. Finally, ent-kaurene diterpenoid natural products are a large class of complex natural products that are found in various traditional East Asian medicines. Over 600 compounds of this class are known and their biological activity has made them targets for synthetic chemistry over the last 60 years. Most of the existing synthetic strategies enable preparation of only one to three ent-kaurene compounds. Here is described studies toward a divergent synthetic strategy relying on synthesis of a common intermediate, which can be elaborated to numerous ent-kaurenes.