Ketone Tamoxifen

Another example is tamoxifen (89). Its synthesis begins with Grignard addition of reagent to aryl ketone giving carbinol Dehydration leads to the readily separable and... 

Tamoxifen is a drug used in the treatment of breast cancer. How would you prepare tamoxifen from benzene, the following ketone, and any other reagents needed ... 

Highly arylated ketones have been prepared successfully. For example, arylation of the enolate of the deoxybenzoin 4 gives 1,1,2-triarylethanones that are related to substances such as tamoxifen.176... 

A variant on the sequence in which the third aromatic ring is introduced by reaction of the ketone in chloroethyl ether (9-4) with the hthio reagent from 1-4-di-iodobenzene leads in several steps to iodoxifene (9-5) [10]. 4-Hydroxy-tamoxifen, in which a hydroxyl group has been introduced on one of the benzene rings, comprises one of the principal metabolites of the drug. The unnatural meta isomer of... 

Tamoxifen, the chapter-opening molecule, is a potent anticancer drug that has been used to treat certain forms of breast cancer for many years. One step in the synthesis of tamoxifen involves the treatment of ketone A with NaH as base to form an enolate. Alkylation of this enolate with CH3CH2I forms B in high yield. B is converted to tamoxifen in several steps, some of which are reactions you have already learned. 

Treatment of ketone A with LDA followed by CH3CH2I did not form the desired alkylation product B. What product was formed instead Devise a muitistep method to convert A to B, a synthetic intermediate used to prepare the anticancer drug tamoxifen (Section 23.8C and the chapter-opening moiecule). 

The arylation of benzyl ketones has been applied to the synthesis of analogs of tamoxifen, which is a medicinal agent for breast cancer (Eq. 10) [52,53]. 

The initial idea in the preparation of complex 25 was to use tamoxifen as a vector for the potentially cytotoxic Cp2TiCl2 2 (section 2, this book). Preparation of complex 25, in which the aromatic p ring of tamoxifen is substituted by a Cp2TiCl2 entity, required development of a novel synthesis (Scheme 3.10) [72]. This synthesis starts with a McMurry coupling reaction between propionyl cyclopentadienyl manganese tricarbonyl 21 and the ketone 22, permitting preparation of the complex diphenyl-ethylene 23. This is converted to a cyclopentadienyl 24 via photochemical decomplexation, and immediately recomplexed in the presence of CpTiClj to give 25, which is isolated as the chloride. 

Potter, G. A. McCague, R. 1990. Highly stereoselective access to an (E)-vinyl bromide from an aryl ketone leads to short syntheses of (2)-tamoxifen and important substituted derivatives. J. Org. Chem. 55 6184-6187. 

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