Synthesis of a Coumarin-Based Analogue of Schweinfurthin F

Abstract

The natural schweinfurthins are stilbenes with significant antiproliferative activity and an uncertain mechanism of action. To obtain a fluorescent analogue with minimal deviation from the natural structure, a coumarin ring system was annulated to the D-ring, creating a new analogue of schweinfurthin F. This stilbene was prepared through a convergent synthesis, with a Horner–Wadsworth–Emmons condensation employed to form the central stilbene olefin. After preparation of a tricyclic phosphonate via a recent and more efficient modification of the classic Arbuzov reaction, condensation was attempted with an appropriately substituted bicyclic aldehyde but the coumarin system did not survive the reaction conditions. When olefin formation preceded generation of the coumarin, the stilbene formation proceeded smoothly and ultimately allowed access to the targeted coumarin-based schweinfurthin analogue. This analogue displayed the desired fluorescence properties along with significant biological activity in the National Cancer Institute’s 60-cell line bioassay, and the pattern of this biological activity mirrored that of the natural product schweinfurthin F. This approach gives facile access to new fluorescent analogues of the natural schweinfurthins and should be applicable to other natural stilbenes as well.

Total Syntheses, Absolute Configurations, and Cytotoxicity Evaluation of Ugonstilbenes A, B, and C from the Rhizomes of Helminthostachys zeylanica

“…The starting 4-bromo-3,5-dihydroxybenzioic acid was esterified with MeOH in the presence of 3 N HCl under reflux to afford methyl ester 6 , which was converted to 7 by protection of the hydroxy groups with MOMCl . Reduction of 7 with LiAlH 4 in THF gave benzyl alcohol 8 , which was then treated with 60% sodium hydride (NaH) and MeI to produce methyl ether 9 in quantitative yield . The aryllithium generated in situ by treatment of 9 with n -butyllithium ( n -BuLi) in THF at −10 °C was allowed to react with ( R )- 5 and ( S )- 5 at −10 °C, providing a good yield of the coupling products 10a and 10b , respectively.…”

“…The starting 3-bromo-4-hydroxybenzaldehyde was reacted with MOMCl to give 14, followed by reduction with NaBH 4 in MeOH to provide benzyl alcohol 15, which was converted to methyl ether 16 by treatment with 60% NaH and MeI in good yield. 21 The aryllithium generated in situ by treatment of 16 with n-BuLi in THF at −10 °C was able to react with (R)-5 and (S)-5 at −10 °C, providing a good yield of the coupling products 17a and 17b, respectively. Compounds 17a and 17b existed as diastereomeric mixtures and could not be separated.…”

“…20 Reduction of 7 with LiAlH 4 in THF gave benzyl alcohol 8, which was then treated with 60% sodium hydride (NaH) and MeI to produce methyl ether 9 in quantitative yield. 21 The aryllithium generated in situ by treatment of 9 with n-butyllithium (n-BuLi) in THF at −10 °C was allowed to react with (R)-5 and (S)-5 at −10 °C, providing a good yield of the coupling products 10a and 10b, respectively. Compounds 10a and 10b existed as diastereomeric mixtures and could not be separated.…”

Plant Growth Suppressive Activity of (R)-3-(7′-Aryl-9′-hydroxyprop-8′-yl)coumarin, Structural Isomer of Z-2-Hydroxybenzylidene-γ-butyrolactone-type Lignan

“…Lignans and related compounds, which are biosynthesized by the coupling of two phenylpropanoid (C6-C3) units, have been isolated from many kinds of plants containing dietary plants. − The isolation and pharmaceutical, synthetic, and chemical research of coumarino-lignans − and phenylalkylcoumarin-lignan-related compounds − have been reported. We decided to promote the agrochemical and phytochemical study of these compounds.…”