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Synfacts 2010(10): 1095-1095  
DOI: 10.1055/s-0030-1258073
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Prostaglandin D2 Receptor Antagonist

Contributor(s):Philip Kocienski
M. Tudge*, C. G. Savarin, K. DiFelice, P. Maligres, G. Humphrey, B. Reamer, D. M. Tellers, D. Hughes
Merck & Co., Rahway, USA
Development of a Kilogram-Scale Asymmetric Synthesis of a Potent DP Receptor Antagonist
Org. Process Res. Dev.  2010,  14:  787-798  
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Publication History

Publication Date:
22 September 2010 (online)

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Key words

prostaglandin D2 receptor antagonists - pyridine annulation - azaindoles - sulfenylation - asymmetric hydrogenation

Significance

An efficient kilogram-scale synthesis of the target prostaglandin D2 receptor antagonist features a Friedel-Crafts cyclization of an i­minopyrrole to generate the azaindole core in D. Key steps are (1) a very efficient asymmetric hydrogenation to install the single stereogenic center (G → H) and (2) a mild sulfenylation using the shelf-stable N-arylthiophthalimide I.

Comment

The high er of the hydrogenation was surprisingly insensitive to solvent, but it was sensitive to the E/Z ratio. Thus, batches of G that contained 9% of the Z-isomer afforded H in only 81% ee, whereas batches of G containing 1% of the Z-isomer gave H in 96% ee. The E/Z ratio of the ­Horner-Wadsworth-Emmons reaction (14:1) could be upgraded to 1000:1 by crystallizing the phosphate salt of G.

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