Total synthesis of -estrone

Along the road from photoenolization as a reaction principle [117] to photoenolization as a key reaction in the total syntheses of (+)-estrone [118] and (-)-norgestrel [119], some questions have been put, and answers found, from which emerges the prospect of deliberately plaimed application of photochemical reactions in sophisticated syntheses of target compoimds. No more talk of photochemistry shrouded in mystery (see Sect. 1.1). 

The alkylation of cyclic 1,3-diketones with allyl bromides of the type of (356) takes place with low yields. Moreover, it has been shown to be inapplicable to allyl bromides containing an aromatic ring A or a bond since the yields are too low or the reaction does not take place at all [452,453]. However, in 1959 Nazarov et al. [452] showed that a vinyl car-binol with an aromatic ring A or a A ( )-bond can be condensed directly with 1,3-diketones under the action of alkaline catalysts, giving high yields of the corresponding diketones,t This reaction has been the basis of a large number of total syntheses of estrone, D-homoestrone, and many of their derivatives (Schemes 35-39). 

Easily available copper(II) tartrate has also been used for an enantioselective cyclopropanation. From 3-methoxystyrene and 4-bromo-l-diazo-2-butanone, the cyclopropanes cis/trans-204 were obtained the mainly formed frans-isomer displayed an enantiomeric excess of 46% i99>. This reaction constituted the opening step of asymmetric total syntheses of equilenin and estrone. 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

The chemical syntheses of ( )-estrone and related steroids have attracted the attention of many organic chemists because of their promising biological activities. In this context, a variety of elegant cascade reactions have been developed during the last century. In 2004, the group of Pattenden reported a total synthesis of estrone based on a novel radical-mediated macrocyclization/transannulation cascade reaction (Scheme 13.12) [14]. 

Two new total syntheses of dl-estrone utilize the blcycllc aldehyde 5. and the vlnylketone as key intermediates. These are condensed respectively with m-methoxybenzyltriphenylphosphon1 urn chloride and 2-methylcyciopentanedione to give the appropriate intermediates for ring closure. 

The contents of the second section (syntheses of the AB - CD type) include the condensation of vinylbicyclenes with cyclic dienophiles. Among these, the successful total synthesis of estrone (Scheme 19) and the synthesis of nonaromatic D-homosteroids (Scheme 22) deserve to be mentioned. ... 

Several total syntheses of estrogenic hormones and, in the first place, of derivatives of equilenin have been carried out by this route. The principles of the approach to total steroid synthesis considered in this chapter generally come up against serious obstacles even in their application to estrone derivatives. Moreover, their application to the synthesis of nonaromatic steroids has generally been unsuccessful. 

A similar sequence has been utilized for an elegant assembly of the estrone derivative 68. " Under modified Heck conditions, the dibromomethoxystyrene 66 was coupled with the enantiomerically pure hexahydroindene derivative 67, prepared from an established C,D-ring building block of previously developed steroid total syntheses, under... 

Several applications in total syntheses exemplify the value of this methodology 11-oxoequiienin methyl ether (101 Scheme 38),105 107 (+)-a-cuparenone,109 (-)-podorhizon,112 (-)-methyl jasmonate (102 Scheme 39),114 (+)-estrone methyl ether,116 and the so called (+)-A-factor (103 Scheme 40)117 were all prepared in high enantiomeric purity. Other applications constitute preparations of 2-alkylchro-man-4-ones,118 and of 3-vinylcyclopentanones, highly valuable intermediates for steroid total synthesis.106,107... 

The driving force behind the development of total syntheses for estrane and to some extent gonanes described in Chapters 2 and 3 lay in the then scarce and hence expensive steroid starting materials. The schemes that were developed made possible the elaboration of derivatives not accessible from estrone, such as gonanes with an additional carbon on the angular methyl at C13. Both androstene-17-dione and testosterone have been prepared by total synthesis. The schemes by which that was accomplished, however, were lengthy and complex. Those syntheses mainly represented a tour deforce for chemical synthesis since they were not competitive with sources of androstanes from pregnenolone or by fermentation. 

In the first of them, the ascending" type of synthesis with the subsequent addition of rings C and D to the initial AB fragment is considered. In this section, the syntheses of equilenin by Bachmann (Scheme 2) and Johnson (Scheme 4), which have not lost their importance, and also the synthesis of an isomer of estrone by Bachmann (Scheme 11), the first total synthesis of natural estrone by Anner and Miescher (Scheme 12), and the synthesis of 19-norpregnanes by Nagata (Scheme 13) are of interest. 

---