Fundamental Hydrocarbons and their Applications in Alkaloid Natural Product Synthesis

Abstract

The ongoing relevance of organic synthesis is largely owing to its array of potential applications in agriculture, drug discovery, materials science, and related fields. The lessons learned in a total synthesis can also expand our knowledge of chemical reactivity, which in turn can be applied to improving future syntheses. Therefore, methodological advancement and total synthesis go hand in hand, and provide the basis for their applications in other fields and industries. This thesis describes the development of efficient and practical syntheses of both fundamental hydrocarbons and their application in alkaloid total synthesis. Specifically, the synthesis of the substituted family of TVE-TEE hybrids, substituted [5]dendralenes, and the total synthesis of the matrine alkaloids are reported. Chapter Two details the synthesis of the substituted TVE-TEE hybrids. Synthesis of the parent TVE-TEE hybrids was complicated by the volatility and sensitivity of these compounds when stored neat. The synthesis of substituted members of this family demonstrated that these are a more stable family of compounds which enabled further exploration of their properties and reactivity. Alongside the first general synthesis of the substituted TVE-TEE hybrids, their reactivity in pericyclic reaction cascades and in preparation of extended cross-conjugated systems is also reported. The potential applications of these molecules are exemplified through a study of their fluorescence properties. Chapter Three explores the synthesis of the substituted [5]dendralenes. Substituted [3] and [4]dendralenes have been extensively reported and investigation into their applications in total synthesis is underway. However, applications of substituted variants of the higher dendralenes are hindered by lack of synthetic routes to access them. This chapter details progress towards general syntheses of substituted [5]dendralenes. Diels Alder reaction between a 3'-substituted [5]dendralene with N-methylmaleimide is completely regioselective, demonstrating that substituted [5]dendralenes may provide more useful building blocks for synthesis than the parent [5]dendralene which suffers from poor selectivity in Diels Alder reactions. Chapter Four describes the total synthesis of the matrine alkaloids. The keys to our efficient strategy are the use of a substituted [3]dendralene precursor and exploitation of the ability of the matrine alkaloids to isomerise under catalytic hydrogenation conditions. Through a two-fold intramolecular hetero-Diels Alder sequence, an acyclic [3]dendralene precursor constructs all four rings of the matrine framework. This synthesis also provides novel mild conditions for N-acyliminium dienophile generation. Ten members of the matrine alkaloid family are produced by semisynthesis. Show more