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

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.

Nitrogen‐Doped TiO2 Nanotubes‐Catalyzed Synthesis of Small D‐π‐A‐Type Knoevenagel Adducts and β‐Enaminones

“…Knoevenagel adducts are utilized as starting materials in the synthesis of fine chemicals, pharmaceutical drugs, natural products, perfumes, agrochemicals, cosmetics, herbicides, insecticides, functional polymers, etc. [24][25][26][27][28][29] Due to their potential utility, various homogeneous and heterogeneous catalysts like amines, [30] alkali salts, [31] ionic liquids, [32] selfassembled solids, [33] polyoxometalates, [34] metal oxides, [35] immobilized mesoporous silica, [36] Al 2 O 3 , [37] polyacrylamide, [38] polyacrylonitrile fiber, [39] mesoporous C 3 N 4 [40] and zeolites [41,42] have been utilized for Knoevenagel condensation. Despite the efficiency of above-mentioned catalysts, still there is a scope for the development of green and sustainable heterogeneous catalytic systems for Knoevenagel and other related condensation reactions.…”

“…The products obtained in these conversions are widely used in the various fields of chemistry. Knoevenagel adducts are utilized as starting materials in the synthesis of fine chemicals, pharmaceutical drugs, natural products, perfumes, agrochemicals, cosmetics, herbicides, insecticides, functional polymers, etc [24–29] . Due to their potential utility, various homogeneous and heterogeneous catalysts like amines, [30] alkali salts, [31] ionic liquids, [32] self‐assembled solids, [33] polyoxometalates, [34] metal oxides, [35] immobilized mesoporous silica, [36] Al 2 O 3 , [37] polyacrylamide, [38] polyacrylonitrile fiber, [39] mesoporous C 3 N 4 [40] and zeolites [41,42] have been utilized for Knoevenagel condensation.…”

Rose bengal photocatalyzed Knoevenagel condensation of aldehydes and ketones in aqueous medium

“…Knoevenagel condensation 6,7 is a powerful and environment-friendly synthetic tool for the formation of CC bonds from carbonyl derivatives and active methylene compounds. Knoevenagal products serve as versatile intermediates for the construction of heterocycles, pharmaceutical drugs, 8 natural products, 9 polymers, 10 and cosmetics (Fig. 1).…”