Asymmetric Synthesis Research Of Danshensu And The Derivatives

Chirality is a fundamental property of nature. Almost all the largebiological molecules are chiral. They consist the complicated chiral environmentin human body. When the chiral drug enter into human body, the differentconfigurations of drug usually have different pharmacological effects evenopposite results at times. Therefore, it is very important to get single enantiomerof drug when we research them.Danshensu which is named3,4-dihydroxyphenyl lactic acid is a highlywater-soluble and active compound of Danshen (Salvia miltiorrhiza) root extract.The research indicates Danshensu has the special effects on cardiovascular andcerebrovascular diseases. The diversity of the potential of Danshensu also findexpression in attenuating microcirculatory disturbance, including antioxidation,inhibition of expression of adhesion molecules and so on. However, Danshencontains few Danshensu and the purification of the active compound is difficultand the costs of developing are expensive. Therefore, to get a single enantiomer of Danshensu through asymmetric synthesis for researching its pharmacologicaleffects has an improtant sense.In addition, Danshensu is a highly water-souble compound which hasphenolic hydroxyl and carboxyl in chemical structure. It rarely enter the cellmembrane lipid bilayer and the absolute bioavailability is low by oralmedication administration at same time the half-time is very short in vivo, forthe carboxyl is combined with glucuronic acid and excreted in the urine. Theapplication of Danshensu is restricted in clinical. Therefore, modification ofchemical structure for Danshensu is a successful way to obtain prodrugs whichhave excellent pharmacokinetic properties and stable spatial configuration. It isbenefit for Danshensu to widely use in clinical.Based on the above purposes, we have studied one method to asymmetricsynthesis the single enantiomer of natural Danshensu for the first time.Meanwhile, two kinds of derivatives of Danshensu are studied by asymmetricsynthesis in this thesis.The article recommends the method to asymmetric synthesis naturalDanshensu in part one. The steps are as follows: taking Piperonal as rawmaterial, following the reactions of Knoevenagel condensation, hydrolysis andreduction by the chiral catalyst (-)-DIP-Cl to attain high optical purity ofR-(+)-3-(3,4-methylenedioxyphenyl)-2-hydroxy propionic acid and to obtain thesingle enantiomer of (R)-Danshensu1through the reaction of opening-ring. Thedesired product was obtained in99%ee and65%chemiscal yield. In our work group, we make a lot of efforts to research metabolites ofDanshen after oral administration of the compound Danshen Dripping pills. Wefound isopropanol β-(3,4-dihydroxyphenyl)-α-hydroxypropanoate is the mainmetabolite of Danshen Dripping pills and set up a feasible way of asymmetricsynthesis to gain the high enantionmeric excesses of Danshensu isopropanolester2. However, the operation was complicated and PH was uneasilycontrolled in selective deoxidation of this route. The product was easilyracemization and qulity of product was inferior in repeatability for large scalesynthesis. Therefore, this article improves the old route and the new route hasbeen established. The new route had the merits of highly selectivity, goodoptical purity and convenient operation to get over those disadvantages and theoptical purity of product had been improved from97.8%ee to nearly100%ee.β-(3,4-dihydroxyphenyl)-α-hydroxypropanoate borneol ester3(Danshensuborneol ester) was obtained under the theory of Chinese traditional medicine andthe guidance of pharmaco-principle of hybridization. Danshensu borneol esterwhich is a candidate compound of treating cerebrovascular disease had beenapplied for the China’s Patent (ZL200610042787.3) and International Patent(PCT/CN2007/0011550). In this paper, we have studied a asymmetric synthesisway to obtain two diastereoisomers of Danshensu borneol ester. This route is asfollows: taking3,4-dihydroxy benzaldehyde as raw material, following thereactions of protection by benzyl chloride, Knoevenagel condensation, esterification and Sharpless asymmetric dihydroxylation to construct chiralcenter and to attain Danshensu borneol ester3upto99.9%ee by selectivedeoxidation and deprotection. The route has been applied to China’s patent.Using1H NMR,13C NMR, HRMS methods we characterized the productsand intermediates. The enantionmeric excesses of products has been analysed bythe chiral HPLC columns. Asymmetric synthesis methods of Danshensu andderivatives of Danshensu contain the merits of easy manipulation and highenantioselectivity.