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Synfacts 2014; 10(11): 1119
DOI: 10.1055/s-0034-1379222
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a CETP Inhibitor

Contributor(s):
Philip Kocienski
Han ZS * et al. Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA; Boehringer Ingelheim Pharma Gmbh, Biberach/Riss and Ingelheim, Germany
Facile Entry to an Efficient and Practical Enantioselective Synthesis of a Polycyclic Cholesteryl Ester Transfer Protein Inhibitor.

Org. Lett. 2014;
16: 4142-4145
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Publication History

Publication Date:
20 October 2014 (online)

 
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Key words

CETP inhibitors - Hantzsch pyridine synthesis - asymmetric ketone reduction - diastereoselective lactol hydrogenation

Significance

The target molecule is a cholesteryl ester transfer protein (CETP) inhibitor that is of interest for the treatment of atherosclerosis. Key steps in the synthesis depicted are (1) a highly efficient Hantzsch reaction leading to pyridine I, (2) an enantioselective reduction of the highly hindered ketone F using (1R,2S)-1-amino-2-indanol as a chiral chaperone and (3) a diastereoselective hydrogenation of the lactol K.


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Comment

The asymmetric hydrogenation of ketone F using 0.01 mol% of the proprietary catalyst RuCl2(MeO-BIBOP)–(Ampy) (S. Rodríguez et al. Adv. Synth. Catal. 2014, 356, 301) in isopropanol under 300 psi H2 afforded H in 90% yield and with er > 99:1. The scale of the reaction is not specified nor is a detailed experimental procedure provided, whereas scale and experimental details are provided for the borane reduction depicted.


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