Total Synthesis Of (-)-Brazilane And (-)-Brazilin

Natural products containing homoisoflavonoids skeleton possessed novel biological activity and played an important role in the pharmaceutical research and application.As an important part of high isoflavone natural products,brazilian family,represented by Brazilin and Brazilane,have been found to have a series of outstanding biological activities,such as anti-cancer,anti-inflammatory and hypoglycemic activities.It has attracted the research interest of many synthetic chemists and medicinal chemists.As we known,for all of the reported researchs on the syntheses of Brazilin and Brazilane at home and abroad,there are many problems,such as long synthetic steps,difficult individual reactions,expensive reagents and high toxicity,and no unified strategy was employed for the synthesis of these two molecules.Therefore,we designed to develop a concise and efficient total synthesis with lower synthetic steps and using common and readily available starting materials.Meanwhile,we tried to design and finish the synthesis of Brazilin and Brazilane using a unified approach based on the chemical structure of Brazilin and Brazilane.Through the synthsis of Brazilin and Brazilane,it would give inspirement to the related molecules with similar structure of synthesis of Brazilin and Brazilane.This thesis takes(-)-Brazilane and(-)-Brazilin as the synthetic goals,and designs a unified synthetic route.The present route uses 3,4-dimethoxybenzyl alcohol as a common starting material.The approach characterized the lipase-catalyzed desymmetrical reaction and the acid-catalyzed intramolecular Prins/Friedel-Crafts tandem reaction.The main contents of this thesis are as follows:(1)The synthesis was implemented from commercially available 3,4-dimethoxy benzyl alcohol.Diol compounds was obtained by a protection reaction,a S_N2 reaction and a reduction using lithium aluminum hydride.Through the selective acetylation of diol and following Mitsunobu reaction,the two aromatic rings fragment could be connected,and then the aldehyde was obtained through two simple convertions.Cis-fused chromane and indane framework of Brazilane could be accessed through the intramolecular Prins/Friedel-Craft tandem reaction from aldehyde.Finally,(±)-Brazilane could arise from its O-methyl ether via the deprotection.(2)Total synthesis of(-)-Brazilane was conducted based on the above synthesis of (±)-Brazilane.The prochiral diol compound underwent a desymmetrical reaction catalyzed by lipase with ethylene acetate as the acetyl donor,and the regioselectivity was analyzed by chiral HPLC with 96%ee value.And the other chial center was controlled by this produced chiral center,and we could accomplished the asymmetric total synthesis of(-)-Brazilane.(3)Based on the asymmetric total synthesis of(-)-Brazilane in Part(2),the diester compound obtained by the nucleophilic substitution reaction underwent an oxidation to give a tertiary hydroxyl at the methylene position,which was subjected to the reduction using lithium aluminum hydride,selective acetylation of diol,S_N2 reaction,intramolecular Prins/Friedel-Crafts tandem reaction and dephenolic hydroxyl methyl deprotection group to finish asymmetric synthesis of(-)-Brazilin.