Part A. The syntheses of dillapiol and its 4-thio derivatives. Part B. The synthesis of trichiliasterone B.

Abstract

Part A. This thesis describes a new route for the synthesis of dillapiol, a natural synergist, starting with the commercially available sessamol. It has potential for significant scale-up reactions. A key step in our synthesis is the introduction of an oxygen substituent at the C-4 position via an ortho metallation--DMF sequence on suitably protected sessamol followed by a Baeyer Villiger oxidation. The new route allowed us to prepare the first 4-thio, 4-sulfinyl and 4-sulfonyl derivatives of dillapiol. The 4-thio derivatives have been screened for their ability to synergize the light-activated pesticide, alpha-T. Some of the 4-thio derivatives were more active than dillapiol; the 4-sulfinyl and the 4-sulfonyl compounds showed lower synergism with alpha-T than dillapiol. The ability of these compounds to act as drug sparing agents by inhibiting CYP3A4 has also been briefly investigated. In this case the 4-sulfonyl derivatives were found to be potent in inhibiting CYP3A4 with IC50 values in micro molar range.* Part B. The synthesis of trichiliasterone B was completed starting from an androsterone intermediate (16-ethylenedioxypregnan-3-one) prepared earlier by Hantos. It involved converting the 3-keto functionality of the Hantos intermediate into a 2-keto-3beta-hydroxy arrangement. This was accomplished via preparation and thermolysis of 3beta-acetoxy-2alpha,3alpha-epoxy-16-ethylenedioxypregnane followed by treatment with basic alumina.* Four ester derivatives of 3beta-hydroxyandrost-17(20)-en-16-one were prepared and sent for screening as potential anti-cancer agents based on the concept that the alpha,beta-unsaturated ketone should act as a potential Michael acceptor. Promising activity was found towards in vitro tests against the human leukemia cell line.* *Please refer to dissertation for diagrams.