Study On Synthesis Of Ellagic Acid Derivatives

Ellagic acid derivatives including biphenyl structure have wide biological activity, and as chiral ligands in asymmetric synthesis. Therefore, study on the synthesis of its derivatives is significant. The synthesis of compounds(e.g. Dimethyl-4,4′,5,5′,6,6′-hexamethoxy-biphenyl-2,2′-dicarboxylate, 4,4′,5,5′,6,6′- hexamethoxy-2,2′-diphenic acid, diethyl-4,4′,5,5′,6,6′-hexaethoxy-biphenyl-2,2′- dicarboxylate, 3,3′-di-C-benzyl-4,4′,5,5′-Tetra-O-benzylellagic acid, dibenzyl-3,3′-dibenzyl-4,4′,5,5′,6,6′-hexabenzyloxy-diphenyl-2,2′-dicarboxylate, 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′-dihydroxymethyl-biphenyl, camphor sulfonic acid 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′-dihydroxymethyl- biphenyl esters, 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′-diphenic acid) were described in this paper.1)The synthesis of DDB derivativesThrough methylation (ethylation) of hydroxyl groups of ellagic acid protected by, dimethyl-4,4′,5,5′,6,6′-hexamethoxy-biphenyl-2,2′-dicarboxylate(diethyl-4,4′,5, 5′,6,6′-hexaethoxy-biphenyl-2,2′-dicarboxylate) was obtained by one-step process strarting from ellagic acid. The method had some advantages, such as mild reaction conditions, short steps, simple operation, less reagents. 4,4′,5,5′,6,6′-hexamethoxy-2,2′-diphenic acid was synthesized successfully in the mixture solvent of tetrahydrofuran, methanol and water(volume ratio, 1:1:1) from dimethyl-4,4′,5,5′,6,6′-hexamethoxy-biphenyl-2,2′-dicarboxylate and potassium hydroxide. The analysis of IR, 1H-NMR showed that synthetic materials were the target products.2)The synthesis of Biphenyl chiral ligandsAfter protection of hydroxyl, 3,3′-di-C-benzyl-4,4′,5,5′-Tetra-O-benzylellagic acid was synthesized using ellagic acid as raw materials. dibenzyl-3,3′-dibenzyl-4,4′,5,5′,6,6′-hexabenzyloxy-diphenyl-2,2′-dicarboxylate was obtained via lactone opening. 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′- dihydroxymethyl- biphenyl was obtained via diester reducing. 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′- dihydroxymethylbiphenyl reacted with camphor sulfonyl chloride, camphor sulfonic acid gave 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′-dihydroxymethyl-biphenyl esters. With diester hydrolyzing, 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′-diphenic acid was obtained. Through the optical resolution of 3,3′-dibenzyl -4,4′,5,5′,6,6′-hexamethoxy-2,2′-diphenic acid, (R)-3,3′-dibenzyl-4,4′,5,5′,6,6′- hexamethoxy-2,2′-diphenic acid was successfully obtained by using cinchonine. The optical resolution of 3,3′-dibenzyl-4,4′,5,5′,6,6′-hexamethoxy-2,2′- dihydroxymethyl- biphenyl was tried. The analysis of IR, 1H-NMR, 13C-NMR, MS showed that synthetic materials were the target products. Meanwhile, the reaction mechanisms of 3,3′-di-C-benzyl-4,4′,5,5′-Tetra-O-benzylellagic acid and dibenzyl-3,3′-dibenzyl-4,4′,5,5′,6,6′-hexabenzyloxy-diphenyl-2,2′-dicarboxylate were also discussed.Comparing to the other routes, such as route 1 (Ullamnn reaction) or route 2 (Gettermann reaction), our synthetic route of the above products has some advantages, such as short steps, simple operation, less reagents. More importantly, the reaction route was short and it had higher total yield comparing to other synthtic routes.