Investigations on the total synthesis of oxasteroids

Abstract

The thesis is divided into three parts:

Part I: Review

A review of the chemistry of known oxasteroids with particular emphasis on:

Total synthesis Physiological activity

Part II: Introduction

Outlines the objectives and planning of the present investigations.

Part III: Experimental Work This part is divided into four sections:

Section 1: Alternative Total Synthesis of 6-Oxaestra-1,5,5,8,14-Pentaen-17-one-3-Methyl Ether (J)

Reaction of 2-(m-methoxyphenoxy)-ethyl bromide with sodium acetylide in liquid ammonia ? 4-(m-methoxyphenoxy)-but-1-yne Converted to Mannich base: 1-diethylamino-5-(m-methoxyphenoxy)-but-2-yne (2) Hydration of acetylene amine (2) followed by condensation with 2-methylcyclopentane-1,3-dione (3) ? triketone (4) and hydroxy diketone (5) By-product tentatively assigned as 1-(m-methoxyphenoxy)-pentan-4-one Cyclodehydration of (4) and (5) with p-toluenesulphonic acid furnished 6-oxaestrapentaenone (J)

Section 2: Attempted Synthesis of Des-A-11-Oxasteroid Intermediate (6)

7-Methoxychroman-4-one converted to isoxazole (7) via hydroxymethylene derivative Isomerization of isoxazole (7) with potassium t-butoxide in t-butanol followed by methylation ? cyano methyl ketone (8) and several by-products (10, 11, 12) Modified conditions gave mainly cyano methyl ketone (8) and a by-product Stobbe condensation of (8) with dimethyl succinate failed

Section 3: Synthesis of 2',4'-Dimethoxy-3-Alkoxypropiophenones (15)

Required as starting materials for ring B oxasteroids (see Section 4) Acylation of m-dimethoxybenzene with 3-alkoxy- or 3-halopropionic acid in polyphosphoric acid gave unexpected ketones (16 and 17) These were prepared by unambiguous syntheses; mechanism discussed Required alkoxypropiophenones (15) prepared by reaction of corresponding alcohols with 3-chloropropiophenone derivative

Section 4: Attempted Synthesis of B-Seco Steroid Derivative (18)

Grignard reaction of vinyl magnesium bromide with methoxypropiophenone ? vinyl carbinol Condensation with dione (3) ? diketone (19) Attempts at cyclodehydration of (19) to pentaenone (18) unsuccessful Treatment of (19) with ethanolic hydrochloric acid ? mixture of products; none was expected pentaenone (18) One product (~20%) identified as novel tricyclodecane derivative (20)

Appendix: Published Papers

“Studies in Oxasteroids-I. Synthesis of 5-cyano-3-methyl-7-methoxychroman-4-one and the Structure of an ‘Abnormal’ Product” T.R. Kasturi and K.M. Damodaran, Tetrahedron, 1027 (1966)

“Structure of Abnormal Products Isolated from the Isomerization of 7-Methoxychromano[3,4-d]isoxazole” T.R. Kasturi, K.M. Damodaran, G. Subrahmanyam, P. Brown and G.R. Pettit, Chem. Comm. (London), 794 (1968)

“Acylation and Alkylation of 1,3-Dimethoxybenzene in Polyphosphoric Acid” T.R. Kasturi and K.M. Damodaran, Can. J. Chem., 47, 1529 (1969).