Estrone commercial synthesis

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Figure 23.9 This Robinson annulation reaction is used in the commercial synthesis of the steroid hormone estrone. The nucleophilic donor is a /3-diketone.

Since 19-hydroxycholesterol 3-acetate is readily available from cholesterol by the illustrated synthesis, it is possible to predict that this method or one closely allied to it will supplant presently used technology for estrone manufacture to some degree. Estrone, in addition to its uses as a female hormone is a key intermediate for the commercial synthesis of many widely used contraceptive agents. It has been selling for a price in the range of 0.50- 1.00/gram (1965). 

The Danishefsky group reported the use of an organocatalytic intramolecular aldol reaction in the synthesis of a key intermediate, 108, for preparation of optically active estrone and commercially relevant 19-norsteroids [118, 119]. In the presence... 

Commercial facilities constructed include a coal gasification plant for synthesis gas manufacture, raw gas cleanup and separation facilities, a sulfur recovery unit, a coal-fired steam plant, and chemical plants to produce methanol, methyl acetate, acetic acid, and acetic anhydride. In the 1980s, these plants gasified approximately 900 tons of coal/day to produce annually over 500 million lb of acetic anhydride, 150 million lb of acetic acid, 390 million lb of methyl acetate, 365 million lb of methanol, and 15 million lb of sulfur. An expansion in 1991 more than doubled the capacity for methyl acetate, acetic acid, and acetic anhydride. Approximately one billion lb of acetic anhydride, one of Eastman s key raw materials, is used each year in making photographic film base, Tenite cellulosic plastics, Estron acetate for filter tow, textile yarns, and coatings chemicals. 

Estrone is an important intermediate in the production of 19-nor steroids, and is one of the few steroids produced commercially by total synthesis. For a review of the earlier synthetic approaches,see ArtOrg. Synth., 177 (1970). 

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