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Synfacts 2015; 11(5): 0455
DOI: 10.1055/s-0034-1380542
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a FLAP Inhibitor

Contributor(s):
Philip Kocienski
Fandrick KR, * Mulder JA et al.. * Boehringer-Ingelheim Pharmaceuticals, Ridgefield, USA
Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor.

J. Org. Chem. 2015;
80: 1651-1660
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Further Information

Publication History

Publication Date:
17 April 2015 (online)

 
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Key words

FLAP inhibitors - 1,2-metalate rearrangement - quaternary centers - stereoselective metalation

Significance

The target molecule inhibits the 5-lipoxygenase-activating protein (FLAP) that is implicated in the biosynthesis of leukotriene. It is of interest for the treatment of atherosclerosis. The noteworthy feature of this synthesis is the construction of the quaternary center in the aldehyde H using two tandem 1,2-metalate rearrangements.


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Comment

The enantiopure carbamate A was derived from 4-bromoacetophenone using a Noyori asymmetric transfer hydrogenation. Metalation of carbamate A with LDA under noncryogenic conditions in the presence of boronate C gave adduct D with retention of configuration. For an alternative synthesis of H, see: X. Zeng et al. Angew. Chem. Int. Ed. 2014, 53, 12153.


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