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Synfacts 2016; 12(06): 0547
DOI: 10.1055/s-0035-1562130
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of an 11-β-HSD-1 Inhibitor via Asymmetric Methallylation

Authors

    Contributor(s):

  • Philip Kocienski

Zhang Y * et al. Boehringer Ingelheim Pharmacueticals, Ridgefield, USA
An Enantioselective Synthesis of an 11-β-HSD-1 Inhibitor via an Asymmetric Methallylation Catalyzed by (S)-3,3′-F2-BINOL.

J. Org. Chem. 2016;
81: 2665-2669
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Further Information

Publication History

Publication Date:
17 May 2016 (online)

 
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Key words

11-β-HSD-1 inhibitor - asymmetric methallylation - organocatalysis

Significance

The target molecule J inhibits 11-β-hydroxysteroid dehydrogenase-1 (11-β-HSD-1), an enzyme that catalyzes the reduction of inactive cortisone to the active glucocorticoid cortisol. An elevated glucocorticoid level correlates to metabolic comorbidities such as obesity, diabetes, dyslipidemia, and atherosclerosis. The key feature of the synthesis depicted is an asymmetric meth­allylation of 3-chloro-1-phenylpropan-1-one (A) catalyzed by (S)-3,3′-F2-BINOL (C) under solvent-free and metal-free conditions.


Comment

The five-step process delivered the target API J in 53% overall yield on a multikilogram scale. Direct hydration of F to H using oxygen and Co(acac)2 as the catalyst in 2-propanol stalled at 62% conversion after 4 h at 75 °C, even in the presence of 40 mol% Co(acac)2. Reductive cleavage of the epoxide G by the use of a catalytic amount of LiBHEt3 (0.1 equiv) in the presence of stoichiometric LiBH4 (0.3 equiv) proceeded in 96% yield after 3 h at 35 °C.





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