Thesis(M.S.)--Auburn University, 2006. / Abstract. Vita. Includes bibliographic references (p.45-47).

The ozonization of 7-ketocholesteryl acetate has yielded 5-keto-5, 7-seco-6-nor-3-cholesten-7-oic acid, an intermediate useful in the preparation of 6-azacholestane. Catalytic hydrogenation converted this intermediate to 5-keto-5,7-seco-6-norcholestan-7-oic acid which, upon treatment with benzyl amine, gave N-benzyl-6-aza-4-cholesten-7-one. Catalytic reduction of this enol-lactam yielded N-benzyl-6-azacholestan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azacholestane. The generality of this route was shown when it was applied to compounds of the androstane series. Ozonization of 3β,17β-dihydroxy-5-androsten-7-one diacetate gave 17β-hydroxy-5-keto-5,7-seco-6-nor-3-androsten-7-oic acid which was hydrogenated catalytically to 17β-hydroxy-5-keto-5,7-seco-6-norandrostan-7-oic acid. This saturated acid ring—closed with benzyl amine to yield 17β-hydroxy-N-benzyl-6-aza-4-androsten-7-one. Catalytic hydrogenation of this enol-lactam gave 17β-hydroxy~N-benzyl-6-azandrostan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azaandrostan-17β-ol. A mild chromic acid oxidation converted the alcohol to the keto compound, N-benzyl-6-azaandrostan-17-one. / Science, Faculty of / Chemistry, Department of / Graduate

Steroids are one of the essential classes of bioactive compounds and are involved in many biological functions which include their role as signaling compounds, the alteration of membrane fluidity and the regulation of a variety of metabolic processes. In order to identify novel compounds with beneficial pharmacological action, the synthesis of modified steroids is gaining much attention in recent years. Among those analogs, azasteroids are one of the most important classes which display a variety of biological activities, often free from undesirable side effects. The challenges in the synthesis of steroids, particularly azasteroids, and the potential of azasteroids as novel drugs has prompted numerous investigations in this field. The synthetic methods leading to steroidal derivatives (azasteroids) with one or more nitrogen atoms are very limited. Generally, oxidative cleavage of the steroidal rings is needed to introduce nitrogen atom(s) in order to synthesize azasteroids. In the first part of this dissertation, explorations into the synthetic methods needed for making a new steroidal A-ring or seco A-ring on a tricyclic benz[e]indenedione (a dimer compound obtained in connection with continued work on the study of anhydrobases of the isoxazole series) were pursued. In this process, a series of three tricyclic hydrazone compounds have been designed and synthesized to mimic the tetracyclic rigid core structure of azasteroids. We are eager to ascertain if these compounds possesses any interesting biological properties. In continued research on the synthesis of azulenyl and pseudoazulenyl nitrones, (to target ROS generation at the site of mitochondria), the second part of this research was aimed at the synthesis of cationic pseudoazulenyl nitrones with mitochondriotropic properties. Several pseudoazulenyl nitrone derivatives were synthesized using the natural compound valtrate, obtained from the roots of Centranthus ruber. Unfortunately, the attempts made to convert these compounds into the corresponding cationic pseudoazulenyl nitrones failed. However, an interesting pseudoazulenyl dinitrone molecule bearing an imidazole group was prepared. Also, a pseudoazulenyl mono nitrone compound with an electron donating group was synthesized by leaving a highly reactive aldehyde functionality intact for further use in synthetic study.

Au cours de ces travaux de thèse, une voie de synthèse de différentes cyclopropylamines a été développée. Leur fonctionnalisation a ensuite été mise en œuvre à l’aide de réactions de métallation ou de couplages croisés catalysés au palladium. Les cyclopropylamines ainsi fonctionnalisées furent alors soumises à des conditions de cyclisation dans le but d’obtenir tout ou partie d’une structure 14-azastéroïde. Si notre modèle, dont la synthèse s'est construite autour d’une aniline, nous a permis d'obtenir la structure des cycles B, C et D d'un 14-azastéroïde, nous n'avons pas été en mesure d'obtenir la structure dans sa totalité en partant d'une naphtylamine. Nous avons cependant dans ce cas obtenu un arrangement original pentacyclique comportant un motif cyclobutane. Nous avons enfin réalisés des travaux sur des réactions de type condensation, principalement entre divers dérivés d'aniline et le pyruvate d'éthyle. Lors des résultats préliminaires, nous avons cette fois encore majoritairement obtenu des structures comportant un motif cyclobutane et non celles se rapprochant des azastéroïdes. / In the course of this thesis, a method to synthesize new cyclopropylamines was developed. Their functionalization was then implemented using metallation reactions or palladium catalysed cross-coupling reactions. The functionalized cyclopropylamines were then subjected to cyclization conditions in order to obtain all or part of a 14-azasteroid structure. Our synthetic model, which was built around an aniline moiety, allowed us to obtain the structure of the B, C, and D rings of a 14-azasteroid. Unfortunately, when this strategy was applied to synthesize the complete tetracyclic backbone of the 14-azasteroid from a naphthylamine, the reaction failed to give the same results. We have however in this case reached an original pentacyclic framework containing a cyclobutane motif. Finally, we studied condensation-type reactions between various derivatives of aniline and ethyl pyruvate toward synthesis of the desired structure. Preliminary results show formation of structures with a cyclobutane motif.