The Synthesis Of Neuraminidase Inhibitors— Pterocarpin,and Its Structural Modification

Influenza caused by influenza virus is an acute respiratory infectious disease. It takes the first place among all kinds of infectious diseases which enormously destruct human health and economy. According to different action mechanism, the anti-flu drug can be generally classified into four classes:inhibitor of Hemagglutinin (HA), inhibitor of Inosine mono phosphate dehydrogenase (IMPDH), inhibitor of RNA polymerase or Endonuclease inhibitors and Neuraminidase (NA). NA is a membrane protein located on the surface of influenza virus, and able to cleave the glycosidic bonds of sialic acids to release new born virus away from infected cells and assist the movement of virus through the mucus. Because 30% amino acids of the sequences of NA are conservative and might participate in binding of ligands, inhibitors of NA have been clinically used as broad-spectrum drugs to combat both flu A and flu B.Pterocarpans are a class of plant secondary metabolites with the skeleton of isoflavanone, and composed of chromane and dihydrobenzofuran at positions of C-6a and C-11a. In 2008, Park’s group isolated pterocarpin (la) from the extraction of Sophora flavescens. Further studies indicated that la exerts favorable enzymatic inhibitory activity against NA with the value of IC50=1.4±0.36 μM. More importantly, molecular docking model revealed that la occupies different binding sites from those of traditional NA inhibitors. Consequently, we explored the synthesis of la and its structural modification.This thesis has accomplished the synthesis of la as well as its analogues 1b and lc utilizing a C6+C3+C6 strategy. The process starts with protection of sesamol (C6 synthon). After the screenings of different protecting groups including methyl, benzyl and t-butyldimethylsilyl, mesyl stands out to be the protecting group of the choice because of its tolanrance with subsenquent reactions. Then, the sesamol mesylate is iodinated, followed by copper(I)-catalyzed Hurtley reaction with the diethyl malonate 34 (C3 synthon) to furnish 2-aryl substituted malonate is obtained (C6+C3 synthon). Reduction of 2-aryl substituted malonate to the correspondingl,3-diol 39a followed by selective monoacetylation of diol with n-Bu4NOAc-mediated acetylation and Mitsunobu reaction with 3-methoxyphenol 30a (the second C6 synthon) promoted by ADDP and PBu3 to produce the key intermediate 67a with C6+C3+C6 skeleton.67a is converted into isoflavanone 87a by a four-step reaction sequence involving IBX-mediated oxidation of alcohol to aldehyde, Pinnick oxication of aldehyde, formation of acyl chloride, intramolecular Friedel-Crafts acylation. Sequential reduction of ketone in 87a to alcohol, remove of mesyl group and cyclization under acidic conditions to deliver racemic pterocarpin 1a. Thus, (±)-1a is achieved in a total 11% yield through 16-step reaction from sesamol. In addition, adopting the similar reaction sequences, replacement of 30a with 30b and 30c resulted in synthesis of 5-thia-or 5-aza-pterocarpin 1b or 1c in 3.4% or 4.4% yield over 16 or 17 steps from sesamol, respectively.The enantioselective synthesis of pterocarpin la is also explored on the basis of accomplishment of racemic la. Pig Pancreatic Lipase (PPL) is applied in desymmetric acetylation of 1,3-diol followed by recrystallization to give monoacetylated 95 in 80% yield with 95% ee. According to the same reaction sequence as synthesis of (±)-1a,95 was transformed into (-)-1a in 27% yield with 21% ee.In summary, pterocarpin 1a,5-thia-pterocarpin 1b and 5-thia-pterocarpin 1c have been accomplished by means of a C6+C3+C6 strategy involving key reactions of copper(I)-catalyzed Hurtley reaction and Mitsunobu reaction. Our works provide a new approach to synthesis of isoflavanones and the related natural products. Additionally, PPL mediated desymmetric acetylation of 1,3-diol as high as 95% ee provide a value chiral building block for enantioselective synthesis of natural products.