Synthetic approaches to steroidal bisquaternary ammonium compounds

This thesis is divided into four sections with the addition of two appendices. The first section gives a brief summary of the theoretical Justifications for undertaking the research and includes an account of the role of acetylcholine at the neuromuscular synapse and an account of the receptor theory of neuromuscular blockade. The classification of neuromuscular blocking agents is then discussed and a survey given of the two point, multi-point and one point attachment theories. These considerations are followed by a discussion of rigid bisquaternary molecules leading to an outline of the factors influencing the choice of the compounds whose syntheses were to be attempted and an account of the synthetic routes proposed. The second section of the thesis is a report of the preparation and reduction of a number of methanesulphonates derived from hydroxy 5beta-5alpha-cholanes. These studies were deemed necessary in view of the poor yields of p-toluene-sulphonates which were encountered in certain instances and indeed it was found that utilisation of methanesulphonyl chloride rather than the more commonly employed p-toluenesulphonyl chloride afforded superior yields of sulphonate esters. In the course of this work it was shown that the material previously reported as 3alpha, 12alpha-dihydroxy-5beta-cholane was in fact a mixture of this compound with 12alpha,24-dihydroxy-5beta-cholane. Selectivity of sulphonation of the hydroxyl groups at positions 3,7,12 and 24 of the cholane skeleton is discussed. Lithium aluminium hydride reduction of the sulphonate esters was shown to hydrogenolyse the sulphonyloxy group when it is in the equatorial configuration and to generate the parent alcohol when the sulphonyloxy group has the axial ccnfiguration. Gas liquid chromatographic analyses of certain complex mixtures of steroidal hydrocarbons are reported. The third section of the thesis reports the results of a study of the reductions under a variety of conditions, of 12-oximino-5beta-Cholane and 12-oximino-5alpha-cholane. In all instances only the 12a-amino compound was obtained and the assignments of configuration are rigorously proved. All attempts to obtain 12p-amino compounds by nucleophilic displacement reactions were unsuccessful. The fourth section of the thesis records attempts to synthesise various steroidal bisquatemary ammonium compounds. Appendix I consists of the reprints of a review article entitled, 'Biological Activity in Steroids Possessing Nitrogen Atoms', published in two parts and prepared as a general background with which to place the present work in perspective. An addendum indicates progress in the field since the review was published and points out several errata in the review. Appendix II describes an attempt to isolate acovenoside A, which would have served as a suitable material for the preparation of 1-amino steroids, from the trunk wood of Acocanthera longiflora Stapf. However although present in the seeds and bark of this tree, acovenoside A was not present in the wood. Another hitherto unreported cardenolide glycoside was shown to be present but its constitution was not established