Molecules 2012-01-01

Total synthesis of flocoumafen via knoevenagel condensation and intramolecular ring cyclization: general access to natural products.

Jae-Chul Jung, Eunyoung Lim, Yongnam Lee, Dongguk Min, Jeremy Ricci, Oe-Sook Park, Mankil Jung

Index: Molecules 17(2) , 2091-102, (2012)

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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.