Investigations towards the total synthesis of natural and modified steroids

Abstract

Thesis Entitled: “Investigations Towards the Total Synthesis of Natural and Modified Steroids”

The thesis is presented in four chapters.

Chapter 1 describes the synthesis of a novel synthon, 2,6,7,7a-tetrahydro-1-tert-butoxy-4-formyl-7a-methylindene (1), for the total synthesis of steroids. It is divided into three sections:

Section A begins with a brief introduction to the total synthesis of steroids, with emphasis on recent approaches involving CD-intermediates, followed by a discussion of the present synthetic strategy for achieving an enantioselective total synthesis of natural and modified steroids.

Section B presents a new method for preparing the key synthon (1) starting from the known 3-ketoester (2), in both racemic and optically active (> 99% ee) forms. Alternate routes explored for the synthesis of the known 3-ketoester (2) are also discussed.

Section C deals with investigations towards developing an alternative route to synthon (1) via intermediate (3). While the desired compound (3) could not be prepared by the proposed route, interesting pathways leading to two novel products (4 and 5) were encountered during an attempted annelation reaction of ketone (6) with dione (7). Trapping of an intermediate in this reaction led to the formulation of a reasonable mechanism.

Chapter 2 is concerned with the elaboration of the dione aldehyde (8) to the tricyclic skeleton (BCD) and functional modifications of the product. Annelation of aldehyde (8) with methyl acetoacetate yielded the tricyclic dienone (9), which was converted to an isomeric dienone ester (10) by hydrogenation of the ?,?-double bond followed by introduction of a new double bond using selenium methodology. Condensation with methyl vinyl ketone afforded the desired alkylated product (11).

Chapter 3 records experiments designed to prepare a new synthetically significant synthon (12) with the trans CD-ring junction already built in. This compound was prepared from ester (2) in seven steps, both as a racemic mixture and in enantiomerically enriched form (> 99% ee).

Chapter 4 is an account of synthetic studies in the field of modified steroids, specifically B-seco-steroids. A variety of seco-steroids (13a–e) with a 13-ethyl group were synthesized following Torgov’s route, starting from appropriately substituted acetophenones (14a–e) in six steps.