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Synfacts 2014; 10(7): 0665
DOI: 10.1055/s-0034-1378238
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of an Estrogen Receptor Beta Agonist

Contributor(s):
Philip Kocienski
Maddess ML, * Scott JP. * et al. Merck & Co., Inc., Rahway, USA and Merck Sharp & Dohme Research Laboratories, Hoddesdon, UK
Enantioselective Synthesis of a Highly Substituted Tetrahydrofluorene Derivative as a Potent and Selective Estrogen Receptor Beta Agonist.

Org. Process Res. Dev. 2014;
18: 528-538
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Publication History

Publication Date:
16 June 2014 (online)

 
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Key words

estrogen receptor β agonist - quaternary center - diastereoselective enolate alkylation - trifluoromethylation - tetrahydrofluorenes

Significance

The target tetrahydrofluorene is an estrogen receptor β agonist that is of interest for the treatment of symptoms associated with reduced estrogen levels in post-menopausal women. The large-scale synthesis depicted features a chiral auxiliary mediated dialkylation to construct the quaternary center in G with excellent stereocontrol. Note the intramolecular enolate alkylation F → G in which phenoxide ion is the leaving group.


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Comment

This route delivered more than 30 kg of drug candidate in 21% overall yield through a longest linear sequence of 13 steps and with >99% ee. For syntheses of related tetrahydrofluorenes, see: M. A. Huffman et al. Tetrahedron 2007, 63, 4459; J. P. Scott et al. Org. Process Res. Dev. 2008, 12, 723; D. J. Wallace, R. A. Reamer Tetrahedron Lett. 2013, 54, 4425.


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