Design And Synthetic Reaction Studies Of Marine Natural Products---Bromophenol Derivatives

With the improvement of living standards, the morbidity of type2diabetes mellitus (T2DM) is rising sharply year by year, which has seriously threatened the health of human being. Protein tyrosine phosphatase IB (PTP1B) has been implicated as a new drug target for the treatment of T2DM in recent year. PTP1B can dephosphorylate the phosphotyrosine and has been shown to be one of the key negative regulators of insulin and leptin signal transduction pathways. PTP1B gene knock-out mice or mice that given antisense oligonucleotide (ASO) treatment in order to inhibit the expression of PTP1B and mRNA, have identified that they are sensitive to insulin and protected against weight gain, even placed on a high-fat diet. These evidences have made small molecule PTP IB inhibitors a hot issue in the search of insulin sensitizing agent.With the widely used of High through put screening (HTS) and the reserch of in-depth, great varieties of PTP1B inhibitors have been discovered, of which phosphotyrosine (pTyr) mimetics are the most widely explored. There are numerous chemical structural classes associated with pTyr mimetics, such as difluoromethylene phosphonates,2-Carbomethoxybenzoic acids,2-oxalyaminobenzoic acids, benzofuran and benzothiophene-Phenoxyacetic acids, thiadiazolidinones and isothiazolidinones, and so on. Although many PTP1B inhibitors are potent in vitro, they still have to overcome many shortcomings, such as low selectivity, poor cell permeability and low oral bioavailability. So it is still a long way for PTP1B inhibitors to be oral antidiabetic agents.Recent studies have shown that bromophenols isolated from marine algae showed moderate activity against PTP1B. For example,5’-Hydroxyisoavrain-villeol is a natural product isolated from red algae Polysiphonia urceola, IC50=4.9μM. The aim of this research is to estabilish a simple, economic route for the synthesis of bromophenols based on the retrosynthesis analysis. Then the reactions and reaction conditions of every synthetic route were discussed. Based on the retrosynthesis analysis, chemical reagents and reaction conditions, we designed three synthetic routes. Route1chose protocatechuic acid as the starting material and prepared the target compound via methoxy substitution, nitration, reduction, diazonium bromination, reduction, esterification and Friedel Crafts reaction. Route2used veratric acid as the starting material and prepared the target compound via esterification, bromination, reduction and Friedel Crafts reaction. Route3used vanillin as the starting material and prepared the target compound by bromination, methylation, reduction and Friedel Crafts reaction.The experimental results demonstrated that route1was tedious. Route1chose the expensive protocatechuic acid and a mass of highly toxic dimethyl sulfate as the starting material. Becouse3,4-dimethoxy methybenzoate that contained a lot of impurities was obtained, the follow-up separation and purification was very tedious. Route2simplified route1. Route2used cheaper veratric acid as the starting material to prepare3,4-dimethoxy methybenzoate. And the follow-up separation and purification was very simple and safe. Besides, it only need one step to finish bromination. Route3was the simplication of route2, using cheaper vanillin instead of veratric acid as the starting material. Bromination was operated in lower temperature with a higher yield. In the follow-up reduction of aldehyde, only cheaper sodium borohydride was used, which was more economic and practical. Although using different synthetic routes and reaction conditions in the last step of preparing target compoud, we obtained the same special product which has never been reported before, whose molecular structure was determined as [5-Bromo-3,4-dimethoxy-phenyl]methyl-3,4-dimethoxy-5-bromobenzene. Route3also obtained [5-Bromo-3,4-dimethoxy-phenylmethoxy]methyl-3,4-dimethoxy-5-bromobenzene in dilute sulphuric acid.In summary, through different synthetic routes and reaction conditions, we obtained the special products which have never been reported before,[5-Bromo-3,4-dimethoxy-phenyl]methyl-3,4-dimethoxy-5-bromobenzene and [5-Bromo-3,4-dimethoxy-phenylmethoxy]methyl-3,4-dimethoxy-5-bromobenzene. Both of their structures were confirmed via ESI-MS,1H-NMR,13C-NMR and IR. What we have done will lay a solid experimental foundation for the synthesis of bromophenols and their derivatives with symmetrical structures.