Estrone, racemic synthesis from

A. Carbocyclic - A few new methods are available to prepare the steroidal skeleton. For tne most part, these involve variations of the previously reported methods for the total synthesis of steroids. Racemic equilenin is prepared stereo-specifically starting with 2-bromo-6-methoxynaphthalene and the i "butyl enol ether of 2-methyl-l,3-cyclopentanedione. Estrone was prepared from the cheap natural product eugenol the key intermediate m-methoxyallylbenzene. Progress toward the total synthesis of terpenes, specifically the pentacyclic triterpene alnusenone, is reported. The synthesis of B-nor, B-nor-D-homo, or normal steroids by the use ot an electrophilic reagent on a bicyclic enamine is recorded. In addition, a bicyclic intermediate can be converted into a D-homo-8g-methyl-B-norestrane. ... 

The homology of the tricyclic products in Scheme 6 to the ABC-ring portion of the steroid nucleus is obvious. In fact, the facility with which these tricyclic materials can be constructed from simple building blocks provided the impetus for the development of an exceedingly efficient synthesis of the female sex hormone, estrone (1). This important biomolecule has stimulated the development of numerous synthetic strategies and these have been amply reviewed.16 The remainder of this chapter is devoted to the brilliant synthesis of racemic estrone by K. P. C. Vollhardt et al.i2 17... 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

Soon after returning to the Shionogi Research Laboratories from the University of Basel, he became Section Manager to pursue the total synthesis of steroids. This work led to total or partial synthesis of the racemic form of many steroids and steroidal alkaloids, such as estrone 3-methyl ether, 3a-acetoxy-5/3-pregna-9(ll), 16-dien-20-one, aldosterone, latifoline, and cones-sine (1961-1963). With extensive support and encouragement from the late... 

Quinodimethanes have been employed in a stereoselective synthesis (ref. 128) of estrone. A silicon-stabilised benzylic carbanion was obtained, avoiding lithiation of the methoxy-substituted ring, from the intermediate [2-[(trimethylsilyl)methyl]-5-methoxybenzyl]dimethylamine and after alkylation with the requisite cyclopentano component, generation of the quinodimethane structure with CsF afforded racemic estrone methyl ether. 

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