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Synfacts 2010(4): 0375-0375  
DOI: 10.1055/s-0029-1219492
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of (E)- and (Z)-Tamoxifen

Contributor(s):Philip Kocienski
N. Ishida, Y. Shimamoto, M. Murakami*
Kyoto University, Japan
Stereoselective Synthesis of (E)-(Trisubstituted Alkenyl)borinic Esters: Stereochemistry Reversed by Ligand in the Palladium-Catalyzed Reaction of Alkynylborates with Aryl Halides
Org. Lett.  2009,  11:  5434-5437  
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Publication History

Publication Date:
22 March 2010 (online)

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Key words

tamoxifen - carbopalladation - Suzuki-Miyaura coupling - borinic esters - alkynyl borates - palladium

Significance

(Z)-Tamoxifen is used for the treatment of estrogen receptor positive breast cancer. The synthesis depicted features a syn-carbopalladation of alkynyl borate B followed by a 1,2-aryl migration (C → D) to generate a trisubstituted ­alkenylborane in high yield and stereoselectivity. Oxidation of the alkenylbornane D with Me3NO afforded the alkenylborinic ester E that participated in an efficient Suzuki-Miyaura coupling to give (Z)-tamoxifen.

Comment

The fate of the syn-carbopalladation product C depended on the ligand. When the ligand was small [(2-Tol)3P], a 1,3-aryl migration took place (C → G) to generate the alkenylborane H after reductive elimination. Alkenylborane H was converted into (E)-tamoxifen as shown. The borate derived from B is stable towards air and moisture. A further 14 examples of the synthesis of ­alkenylborinic esters via the 1,2-aryl migration pathway are presented.

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