Synthetic studies on the carpaine alkaloids
This thesis describes synthetic work directed towards the synthesis of the piperidine alkaloids carpamic (1) and pseudocarpamic (100) acids. The introductory chapter reviews the occurrence, structural determination, pharmacological properties and biosynthesis of 2,3,6-trisubstituted piperidines and discusses previous synthetic work. In Chapter Two a synthetic strategy via the 2-azabicyclo [2.2.2]octan-5-ones (156) and (157) is proposed and the use of the imino-Diels-Alder reaction to produce these compounds is described. Chapter Three details the reactions used to convert the ester functionality in (156) and (157) into the methyl group present at C-2 in (100) and (1). In the first section transformations of the bicyclic systems are described. The second section describes the intramolecular Michael reaction of enones (183) and (184), formed as by-products in the imino-Diels-Alder reaction described in Chapter Two, to the ethylene acetals (200) and (204). In the third section unsuccessful attempts to open the bicyclic systems by double Baeyer-Villiger oxidation of dimethyl (217) and diethyl (223) acetals are described. The fourth section contains an NBS-induced rearrangement of benzylidene acetal (160) to benzoate (228) and further transformations of (228) to give (241), which has the required C-2 methyl substituent. Chapter Four describes Baeyer-Villiger oxidations of 2-azabicyclo[2.2.2]octan-5-ones and discusses the factors which may influence the relative proportions of bridgehead and methylene-migrated lactones. In Chapter Five the carpamic and pseudocarpamic acid C-6 side-chains are introduced via Wittig reactions on aldehydes (293) and (284) and methyl N-tosylcarpamate (295) and methyl N-tosylpseudocarpamate (291) are prepared.