Combretastatin Analogs via Hydration of Stilbene Derivatives

Abstract

Hydration of the double bond of some stilbene congeners of Picea abies bark by TiC14 . NaBH4 reagent is described. Five racemic 1,2-diphenylethanol derivatives (9-13), structurally related to (R)-(-)-combretastatin [(R)-11, have been obtained and characterized mainly by 13C-and 'H-NMR as well as mass spectrometry. The antileukemic activity of each compound has preliminarily been tested by the mouse leukemia L1210 system. Compound 10 has been synthesized by Friedel-Crafts acylation.Combretastatins and their synthetic analogs, having a few structural features resembling those of colchicine, also display similar modes of action. Several naturally occurring combretastatins and their derivatives have been isolated or synthesized. (R)-( -)-Cornbretastatin, an antineoplastic and antimitotic agent originally isolated from Combreturn caffrum, consists structurally of two substituted benzene rings linked together by a saturated, hydroxysubstituted two-carbon bridge"]. Such a structure can easily be prepared from stilbene by a direct hydration of the skeleton double bond.In connection with our studies of the bark constituents of Piceu ubies we have made some progress in the improvement of the biological activity by modifying the structures of the isolated stilbene derivatives by methylation of the aromatic hydroxy groups and hydrogenation of the stilbene double b~n d [~,~] .One highly active, one active and several somewhat active compounds have been obtained from these reactions when provided by mouse leukemia model L1210 treatmentr3x4]. In the present paper we report on the results obtained by modifying the structures by hydration of the stilbene double bond in order to prepare racemic compounds structur-The NaBH4 . TiC14 reagent has been selected from several direct double bond hydration methods mainly because in the selected method the use of strong acids or alkalis is not needed, and the possible dehydration of the expected reaction product is avoidedr5]. However, some limitations to this method are observed. Unsubstituted (E)-stilbene (2) as a model compound can easily be hydrated to (?)-1,2-diphenylethanol (3). (E)-3,3',4,5'-tetramethoxystilbene (4) and (E)-3,4',5-trimethoxystilbene (5) react in a very similar way to afford a mixture of the isomers 9 and 10 from 4 as well as of 11 and 12 from 5, respectively, in a ratio of 3:2. A strong regioselectivity is observed in the hydration reaction of 3,4,5'-trimethoxystilben-3'-01 (6), as (?)-1-(3-hydroxy-5-methoxypheny1)-2-(3,4-dimethoxypheny1)ethanol (13) is the only product that can be isolated and characterized. The application of the NaBH4 . TiC14 method has proven to be unsuccessful when the stilbene bears several aromatic hydroxy substituents or contains a glucosidic bond, for example natural (E)-3-methoxystilbene-3',4,5'-tri01[~1 and its 3'-0-p-D-glucopyranosiderz1. The separation of the compounds 9 and 10 with a standard adsorption chromatographic equipment gives almost pure 9, but only enriched 10. A small amount of 10, needed for recording a IH-NMR spectrum and ...

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