Synthesis estrone

R B Woodward was one of the leading organic chemists of the middle part of the twenti eth century Known pnmanly for his achievements in the synthesis of complex natural products he was awarded the Nobel Pnze in chemistry in 1965 He entered Massachusetts Institute of Tech nology as a 16 year old freshman in 1933 and four years later was awarded the Ph D While a student there he earned out a synthesis of estrone a female sex hormone The early stages of Woodward s estrone synthesis required the conversion of m methoxybenzaldehyde to m methoxy benzyl cyanide which was accomplished in three steps... 

CYP19 (aromatase) Steroid 19-OHase estrogen and estrone synthesis... 

Testolactone is a synthetic drug related to testosterone. It is used for palliative treatment of advanced breast cancer in postmenopausal women and in women who have had their ovaries removed. The principal action of testolactone is reported to be inhibition of steroid aromatase activity and the reduction in estrone synthesis. The most common adverse effects are nausea, vomiting, and anorexia. An advantage is that it does not cause women to develop male characteristics such as a deep voice or facial hair. 

Scheme 5.43 illustrates three applications of this methodology to total synthesis. The first exeunple is taken from Posner s synthesis of estrone and estradiol [211], the second from Posner s synthesis of methyl jasmonate [212], and the third from Holton s synthesis of aphidicolin [213]. The latter is particularly noteworthy in that two contiguous quaternary centers are created in the asymmetric addition with excellent selectivity. In the estrone synthesis, the chirality sense of the product is consistent with the nonchelate model, but the other two examples adhere to a chelate model. Note that the difference is the degree of substitution at the a-position of the enolate. 

Case Study (+)-Estrone 24. The Dane-style estrone synthesis provides a classic example of stereoselective access to an envisaged target molecule. The Diels-Alder reactions between 14 and 15a or 19a are chirogenic71 reaction steps or, put another way, the enantioselective access to the Diels-Alder adducts can already be set at this stage. This requires, for example, the participation of a nonracemic Lewis acid with the right sense of chirality. In the presence of a Ti-TADDOLate [42], cycloadduct 20a was thus obtained from the Dane diene 14 and the bidentate dienophile 19a and was further transformed via 23 into (+)-estrone 248) [33d]. 

Diels-Alder reaction constituting the key step of the quinkert-dane estrone synthesis, Eur. J. Org. Chem. 2003, 1661, and earlier papers. 

The possibility of utilization of DHEA as a substrate for estrone synthesis has been proposed but not addressed directly. ... 

Figure 10.20. A convergent retrosynthetic analysis of Velluz s estrone synthesis. Total synthesis of estradiol, schematic. The figures between the individual stages indicate the numbers of reaction steps. ( ) denotes optical resolution at that step.

The Sobering group described a route to ( + )-13-p-ethylgon-4-ene-3,17-dione 35 (for conversion to norgestrel), which is clearly adaptable to estrone synthesis. The key step (Scheme 5) ° is a variant of the Mannich reaction involving sulfonylmethylation of 29 with formaldehyde and benzenesulfinic acid in 3 1 triethanolamine.acetic add at 50° to yield unsaturated sulfone 30. Hydrogenation of the latter in ethanol 1% W hydrochloric acid gave crystalline saturated sulfone... 

For estrone synthesis the vinyldiacetylene 121 was required (Scheme 16). It was obtained, as indicated from 2-methylcyclopentenone 1 and 1, S-hexadiyne, as an epimeric mixture at C-4, but with the key cyclopentanone substituents trans. In the alkylation step a 3 1 molar ratio of 120 to 95 was utilized. Cooligomerization of 121 with refluxing bistrimethylsilylacetylene in the presence of five mol percent of CpCo(CO>2 catalyst led to the trans-anti-trans bistrimethyl-silylestratriene 122 in 71% yield. It is noteworthy that five carbon-carbon bonds... 

Based on this methodology, syntheses of ( )-estrone methyl ether and ( )-6P-methylestra-l,3,5(10)-triene-17-one were then developed.In the estrone synthesis (Scheme 20), the aromatic component 149 was obtained in high yield from 3-methyl-4-chlorophenol. The trimethylsilylmethylene moiety was introduced in >90% yield by nickel catalyzed cross-coupling of trimethylsilylmethyl magnesium chloride and aryl chloride 148. 

Because of its historic importance for the development of the convergency principle, we summarize in Scheme 8.11 the estrone synthesis by Velluz [23]. 

Scheme 8.11 Overview of the estrone synthesis by Velluz (left, including functional...

In the left half of Scheme 8.11 the full sequence of the estrone synthesis is given. In the right half merely the construction plan (i.e., the skeletal atoms and connectivities) [22, 24] is shown, highlighting the (partial) convergency [25],... 

The chemo- and regioselectivity problems can be solved by the [2+2+2] cycloaddition of diynes with monoynes, although the accessible products are limited to bicyclic compounds. The [2+2+2] cycloaddition of diynes with monoynes has been applied to the synthesis of biologically active molecules and functional materials. The first application in the natural product synthesis was the dl-estrone synthesis using CpCo(CO)j as a catalyst. The [2+2+2] cycloaddition followed by the benzocyclobutane to ort/jo-quinodimethane rearrangement and intramolecular Diels-Alder reaction afforded a dZ-estrone precursor (Scheme 21.8) [11]. 

Volhardt s tZZ-estrone synthesis was the first application of a transition-metal-catalyzed [2 -1- 2 -I- 2] alkyne cyclotrimerization in natural product synthesis, and the overall beauty of the synthetic sequence is still appealing [4,5]. Undoubtedly, this brilliant synthesis is a classic in its field. Following a D ABCD ring formation approach, the tetracyclic core of estrone was produced in a single reaction step by profiting from a reaction cascade that started with a cobalt-mediated crossed [2 + 2 + 2] alkyne cycloaddifion, which was followed by a benzocyclobutane to o-quinodimethane rearrangement, and was finalized by an intramolecular Diels-Alder reaction (Scheme 7.2). 

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