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• Jung, J
• Lim, E
• Lee, Y
• Min, D
• Ricci, J
• Park, O
• Jung, M
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• Jung, J
• Lim, E
• Lee, Y
• Min, D
• Ricci, J
• Park, O
• Jung, M
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• Jung, J
• Lim, E
• Lee, Y
• Min, D
• Ricci, J
• Park, O
• Jung, M

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Molecules 2012, 17(2), 2091-2102; doi:10.3390/molecules17022091

Communication

Total Synthesis of Flocoumafen via Knoevenagel Condensation and Intramolecular Ring Cyclization: General Access to Natural Products

Jae-Chul Jung ^1,† , Eunyoung Lim ^2,† , Yongnam Lee ² , Dongguk Min ² , Jeremy Ricci ² , Oee-Sook Park ^3,*  and Mankil Jung ^2,*

¹ Department of Neuroscience and Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea ² Department of Chemistry, Yonsei University, Seoul 120-749, Korea ³ Department of Chemistry, Institute for Basic Sciences, College of Natural Sciences, Chungbuk National University, Cheongju 361-763, Chungbuk, Korea ^† These authors contributed equally to this work.

* Authors to whom correspondence should be addressed.

Received: 4 January 2012; in revised form: 9 February 2012 / Accepted: 14 February 2012 / Published: 21 February 2012

(This article belongs to the Section Organic Synthesis)

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Abstract: The total synthesis and structure determination of cis- and trans-flocoumafen was described. The key synthetic steps involve Knoevenagel condensation with p-methoxybenzaldehyde, in situ decarboxylation and intramolecular ring cyclization to construct the tetralone skeleton. Stereospecific reduction of the O-alkylated ketone 13 afforded good yield of precusor alcohol 5. Final coupling of alcohol 5 with 4-hydroxy-coumarin yielded flocoumafen (1). Separation and structure determination of cis- and trans-flocoumafen through 2D NMR analyses-assisted computer simulation techniques for the evaluation of anticoagulant activities are reported for the first time. This method is useful for generating the core tetralone skeleton of 4-hydroxycoumarin derivatives and provides a generalized access to various warfarin type anticoagulants.

Keywords: flocoumafen; Knoevenagel condensation; tetralone; 2D NMR analysis; computer simulation

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