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

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

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 / Revised: 9 February 2012 / Accepted: 14 February 2012 / Published: 21 February 2012
(This article belongs to the Section Organic Chemistry)
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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 flocoumafen; Knoevenagel condensation; tetralone; 2D NMR analysis; computer simulation
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Jung, J.-C.; Lim, E.; Lee, Y.; Min, D.; Ricci, J.; Park, O.-S.; Jung, M. Total Synthesis of Flocoumafen via Knoevenagel Condensation and Intramolecular Ring Cyclization: General Access to Natural Products. Molecules 2012, 17, 2091-2102.

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