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

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

doi:10.3390/molecules17022091

Jae-Chul Jung, Eunyoung Lim + Show 5 more

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https://doi.org/10.3390/molecules17022091

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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.

Highlights

The physiological potential of naturally occurring coumarins has attracted considerable attention
We developed a method for multi-step synthesis of 4-hydroxycoumarin derivatives using Friedel-Crafts, Refortmasky, and ring cyclization and reported the biological activities of various derivatives [13]
The retrosynthetic analysis shown in Scheme 1 provides a strategy for easy access to flocoumafen (1) through a reaction sequence involving Knoevenagel condensation of p-methoxybenzaldehyde (7) with ethyl cyanoacetate, a Michael

Summary

Introduction

The physiological potential of naturally occurring coumarins has attracted considerable attention. 4-hydroxycoumarin anticoagulant agents, widely used as rodenticides, are of interest for cell growth stimulation, bacteriostatic activity, and the treatment of thrombotic diseases [1]. Many of these compounds have side effects, including the warfarin-related “purple toes” syndrome and inhibition of vitamin K epoxide reductase [2]. Have been developed to control rodents with low toxicity [9] and can be used in low concentrations for the treatment of human circulatory diseases [10]. Flocoumafen (FCF, 1) is a potent, effective anticoagulant agent in the 4-hydroxycoumarin class Warfarin has been tentatively used to control rodents, it is a direct hazard to domestic animals and wild mammals.

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