Synthesis of polycyclic compounds

Abstract

The thesis entitled “Synthesis of Polycyclic Compounds” is divided into two sections, A and B.

Section A comprises two chapters.

Chapter I is a review of the benzhydrindane approach for the total synthesis of steroids.

Chapter II deals with investigations on the extension of the Ensminger method of ring annelation with vinyl methyl ketone to ?,??unsaturated ketones. A model study with octalin?2?one led to the formation of the desired 2?keto?2,3,4,5,6,7,8,8a,9,10?decahydrophenanthrene, the structure of which was firmly established by conversion to phenanthrene and 2?methoxyphenanthrene. Application of the same reaction sequence to 1?,3??(3??2?carbomethoxycyclopentano)?2?methyl?6?keto?1?,2,3,4,6,7,8,8a?octahydronaphthalene (2b), prepared stereospecifically from m?hydroxybenzaldehyde by the method of Banerjee and Johnson and coworkers, resulted in a mixture of 1?,2??(3???carbomethoxycyclopentano)?2?methyl?5?(3??oxobutyl)?6?keto?1?,2,3,4,5,6,7,8?octahydronaphthalene and methyl oestr?4,9?diene?3?one?17??carboxylate. The latter was not obtainable in pure form. However, aromatisation of the crude dienone ester led to methyl 3?methoxy?oestra?1,3,5(10)?triene?17??carboxylate.

Section B consists of two chapters.

Chapter I presents a brief review of the different syntheses of 19?norprogesterone.

Chapter II describes two different lines of investigation on the synthesis of this hormone from the tricyclic acid (1).

Elaboration of ring?A on the tricyclic unsaturated keto?acid (2a) through reductive alkylation with 1,3?dichloro?2?butene followed by hydrolytic cyclisation furnished oestr?4?ene?3?one?17??carboxylic acid in very poor yields. The second approach involved the initial conversion of acid (1) to 20?hydroxy?desA?19?norpregn?9?ene?5?one (2c) as a mixture of epimers, and development of ring?A on this compound as described before. The chloro?keto?alcohol (3a) could not be obtained in pure form. A wide variety of conditions for hydrolysis of the vinyl chloride group in the impure (5a) and closure of ring?A were studied, culminating in the synthesis of 19?norprogesterone, identified in the form of its bis?2,4?DNP derivative.

By a modified approach, acid (1) could be converted to crystalline 20??hydroxy?desA?19?norpregn?9?ene?5?one (2d). Reductive alkylation studies on this unsaturated keto?alcohol with both dichlorobutene and vinyl methyl ketone did not yield encouraging results. A major side reaction in all these reductive alkylation experiments was the formation of tricyclic saturated ketones by simple reduction of the ethylenic linkage.

Later, a totally different approach for ring?A development on the unsaturated keto?alcohol (2d) was studied. Catalytic hydrogenation of 2d resulted in a mixture of the saturated hydroxy?ketone (3b) and its 9??epimer. Blocking of the reactive C9?methylene group in 3b, followed by formylation at C11 and ring annelation with vinyl methyl ketone, afforded 19?norpregn?4?ene?3?one?20??ol.