The First Synthesis of ( ± )-3 , 4-Dihydroxy-8 , 9-methylenedioxypterocarpan , an Antitumoral Agent and its Coumestan Derivative

Apresentamos a primeira síntese do (±)-3,4-diidroxi-8,9-metilenodioxipterocarpano, um isoflavonóide natural que apresenta atividade antitumoral. A etapa chave envolveu uma arilação de Heck entre o 7,8-dibenziloxicromeno e o organomercurial derivado do sesamol, seguido de reação de desbenzilação. O aduto de Heck foi também empregado na síntese do correspondente derivado cumestano, utilizando DDQ como agente oxidante.


Introduction
A great number of naturally occurring biologically active flavonoids is described in the literature.In the area of antitumor drug discovery, some flavonoids derivatives ( chalcones, flavones, isoflavones, rotenoids etc. ) were shown to be active in vitro and in vivo. 1 At the present time, cancer claims the lives of more than seven million people worldwide on an annual basis.Thus, the development of new cancer treating drugs is a must. 2 In 1995, Wall et al. isolated three pterocarpans from Petalostemon purpureus (Figure 1). 3 Compound (+)6aS, 11aS -3,4-Dihydroxy-8,9-methylenedioxypterocarpan (1)  was active in a standard in vitro DNA strand-scission assay, and presented cytotoxity toward KB tumor cell line (ED 50 = 0.9 µg mL -1 ).Pterocarpans (2) and maackiain (3) [(+)-6aS,11aS-4-hydroxy-3-methoxy-8,9-methylenedioxypterocarpan] were found to be moderately active for KB cells (ED 50 values of 4.0 µg mL -1 and 5.6 µg mL -1 , respectively), but inactive in the DNA strand-scission assay.Since these compounds have the same pterocarpan skeleton and differ only in the pattern of substitution in ring A, we believe that the cathecol moiety in compound 1 is important for antitumoral activity.The enantiomers of 1 e 2 were also previously isolated from plants, 4 while 3 has been isolated only as a racemate. 5 part of a program aimed at synthesizing biologically active anticancer products, 6,7 we describe the first racemic synthesis of the natural product 3,4-dihydroxy-8,9methylenedioxypterocarpan (1) and its derivative, 3,4dihydroxy-8,9-methylenedioxycoumestan (13).

Results and Discussion
The key step 6,7 in our strategy to prepare compound 1 was the coupling of chromen 8 and the organomercurial 9 derived from sesamol. 8The chromen was synthesized using 2,3-dimethoxybenzaldeyde (4) as starting material.Treatment of 4 with BBr 3 at -78 o C gave the cathecol derivative in an excellent yield. 9This compound was bisprotected with the benzyl group leading to aldeyde 5.The corresponding phenol 6 was prepared by Baeyer-Villiger oxidation using MCPBA.O-alkylation of the resulting phenol was acomplished by using 3-iodopropanal dimethylacetal, furnishing compound 7. Cyclization of 7 in acid medium led to chromen 8 in good yield (Scheme 1).
Compound 8 was allowed to react with 9 in the presence of lithium tetrachloropalladate II and acetone leading to cis-(±)-O-di-benzyl-pterocarpan 10. 10 Finally, natural product 1 was obtained by hydrogenolysis of the benzyl groups using the catalytic amount of Pd-C (10% m/m) and all the spectroscopic data were similar to those observed in the natural product. 3We also observed the clevage of the furan ring when an excess of Pd-C was used, to yield product 11.(Scheme 2).
Oxidation of the 3,4-di-O-benzyl-pterocarpan 10 with DDQ in THF at room temperature for 4 h led to the intermediate 3,4-di-O-benzylated coumestan 12, which precipitated out of the solution, and was collected by filtration.The presence of the conjugated system in 12 was clearly showed by the batochromic shift observed in the UV spectrum. 11The synthesis of coumestan 13 was acomplished by hydrogenolysis of the protecting benzyl groups in 12 ( Scheme 3).
In summary, we have, for the first time, prepared natural pterocarpan 1 and its derivatives 11 and 13 in good overall yields.These compounds will be evaluated as antitumoral agents.

General
Melting points were measured with a Fisher-Johns (Fisher Scientific Co) apparatus.Flash chromatography was performed using Merck silica gel 60, 230-400 mesh and Merck silica 60F 254 sheets. 1 H NMR and 13 C NMR were recorded on a Varian Gemini-200 instrument.

Electronic Supplementary Information
1 H NMR, 13 C NMR and mass spectra for compounds 1 and 13 are available as PDF file at http://jbcs.sbq.org.br.