Estrone, racemic

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... 

The in situ-generated o-quinodimethane 51 underwent Diels-Alder reaction giving rise to the formation of both B- and C-rings with the correct relative stereochemistry in one step. Racemic estrone was then obtained in two steps in very good yield. A one-pot access to the ABCD-rings of diter-penes has also been described by ourselves [49]. In the following example, the -acetylenic- -ketoester 53 furnished through a diastereoselective one-pot sequence [ene type]/[2 + 2 + 2]/[4 + 2] the phyllocladane framework 56 in 42% yield (Scheme 26). 

Based on the use of 4-methoxybenzocyclobutene-1-carboxylic acid, racemic homoestrone has been synthesised (ref. 124). A strategy based on boron annulation led not directly to estrone but to a synthesis of norpregnenolone which was then degraded by standard procedures to afford estradiol derivatives (ref. 125). 

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. 

A photochemical route to racemic estrone commencing with 2-bromo-5-methoxytoluene depended upon the generation of a quinodimethane intermediate incorporating an enolic component (ref. 129). Subsequently the method was adapted to furnish an asymmetric synthesis of (+)-estrone as described in the ensuing section. The cyclopentanone component was derived by the reaction of dimethyl malonate with E-1,4-dibromobut-2-ene to give racemic dimethyl 2-vinylcyclopropane-1,1-dicarboxylate which was then transformed by reaction with dimetyl methylmalonate followed by hydrolysis into racerruc 2-methyl-3-vinylcyclopentanone. 

An ingenious approach to racemic estrone has used two reactions in a combined tandem Cope-Claisen rearrangement (ref. 130). 1-Bromomethyi-3,4-dihydro-6-methoxynaphthalene is used to alkylate 1-methoxycarbonyl-2-methylcyclopent-2-ene and the ester group in the product converted to a vinyloxymethyl substituent. Thermolysis afforded a mixture of diastereoisomeric aldehydes (2 1) containing a majority of the trans compound. Ozonolysis and epimerisation at the 8-position succeeded by McMurry coupling gave the required tetracyclic structure from which racemic estrone methyl ether was obtained. 

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 total synthesis of equilenin also completed the advances achieved in the thirties. The following decade, after the interruption in the work caused by the war, was marked by the total synthesis of estrone (3). The synthesis of estrone was an incomparably more difficult task because of the presence in estrone of two more centers of asymmetry than in equilenin. The attempts of Bachmann et al. (Scheme 11) to obtain estrone by a method analogous to that which they used in the synthesis of equilenin led only to a stereoisomer of low activity. Only in 1948 did Anner and Mies-cher (Scheme 12) succeed in performing the synthesis of natural estrone, and also five of its racemates (of the eight theoretically possible), using the tricyclic intermediates that had been obtained in the thirties. 

According to the linear scheme (Fig. 2a), a substance undergoes reaction which possesses a basic structure approximating more and more to the end product during the synthetic process. This method of synthesis, as an example of which may be taken the production of estrone by Anner and Miescher (Schemes 8 and 12), presents the maximum difficulties, since there is a progressive decrease in the yields of the key intermediates of the synthesis. Consequently, the production in high yield of optically active steroids in particular, by total synthesis, requires the earliest possible resolution of racemates. ... 

The estrapentaenone (400) with a free hydroxy group also reacts in a similar manner to its methoxy analog (395). The exhaustive hydrogenation of its diene system led to 8-isoestrone (yield 35%) [468, 482, 483,489], and selective hydrogenation, isomerization with hydrochloric acid to the derivative, and hydrogenation of the latter gave racemic estrone (yield 11%) [463, 484, 500]. 

On being heated with pyridine hydrochloride, the methyl ethers (33)-(38) were demethylated to the corresponding isomers of estrone [83, 84]. The constants of all eight theoretically possible racemates of estrone obtained by this and other methods of synthesis and also the arbitrary designations given to them by various authors are shown in Table 8. The racemates of the isomeric estrones are arbitrarily shown in this table by the formulas of the corresponding -enantiomers. 

The synthesis of an analog of (403) with a methyl group at Cjo has also been described [Z. G. Hajos, D. R. Parrish, and E. P. Oliveto, Tetrahedron Letters, 1966 6495]. By the method of constructing ring A with l,3-dichloro-2-butene, compound (403) was converted into 4,9-estra-diene 3,17 dione, the acid isomerization of which led to the methyl ether of racemic estrone [O. I. Fedorova, G. S. Grinenko, and V. I. Maksimov, Dokl. Akad. Nauk SSSR, 171 880 (1966)]. 

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