| Immunosuppressive drugs have an inhibitory effect on the body’s immune response. It can inhibit the proliferation and function of the immune cells (T cells and B cells etc. macrophages), reduce the antibody immune response. Immunosuppressive drugs was primarily used for organ transplant anti-rejection and autoimmune disease. Treating a variety of serious disease which is harm to human health with immunosuppressive drugs has a significance and is attentted by scholars on domestic and abroad.Due to the adverse events, the application of common clinical immunosuppressive drugs (such as cyclosporine, tacrolimus, rapamycin) has a great limition. In recent years, novel small molecule immunosuppressive drugs in clinical shows good therapeutic effect. The discovery of many immune-related new targets provide new ideas for efficient specificity immune suppression drug developing.Find novel or unique pharmacological effects of bioactive substances from natural products, and use this as one of the lead compounds for development of new drugs by the method of structural modification is already recognized as an important means of research and development of new drugs.The natural product (-)-Ligustiphenol which have a new sesquiterpenoid structure, was isolated from the alcohol extract Ligusticum sinence oliv, and it shows significant immunosuppressive and anti-inflammatory activities. Due to the high oxidation state of molecule and sensitive functional groups in the skeleton,(-)-Ligustiphenol has a less complicated structure, but the synthesis of (-)-Ligustiphenol has a great challenge. It’s necessary to do deep research no matter in chemistry or in biology. On the basis of the total synthesis of racemic Ligustiphenol in early research, we firstly acheived asymmetric total synthesis of (-)-Ligustiphenol.In this thesis, the first asymmetric total synthesis of (-)-Ligustiphenol was completed under asymmetric addition reaction, protection and remove of hydroxyl, ester addition, Aldol condensation etc. six steps from commercially available starting materials. The spectroscopic data (1H-NMR,13C-NMR, HRMS and ORD) of the synthetic product were identical with those of the natural product. The synthesis key steps of (-)-Ligustiphenol as follow.The key step1:According to the retrosynthetic analysis, the chiral center of the quaternary carbon was constructed under the Lewis acid catalyzed asymmetric addition reaction of m-methyl phenol with propionic Acid (-)-Menthyl Ester with induction of (-)-menthol.The key step2:a-hydorxy ester firstly achieve to a-hydroxy methylketone via steric hindrance effect to control the adduct in an addition reaction of the ester with MeLi.The key step3:After the steric hindrance was increased on a position of carbonyl with MOM protection group, Aldol condensation can not react. Under HCl/MeOH, MOM group on a position of carbonyl was selectively removed, the skeleton of (-)-Ligustiphenol was constructed successfully.On the total synthesis of (-)-Ligustiphenol, desing and synthesis a series of analogues of (-)-Ligustiphenol. The activity of the intermediates and the analogues was evaluated. It lay the foundation for studying the pharmacophore and structure-activity realationship.On the total synthesis of (-)-Ligustiphenol, futher application the steric effect to improve the addition reaction from a-hydroxy ester to a-hydroxy methylketone. MEM, SEM, TBS, TIPS etc. groups was investigated. Finally, the phenol hydroxyl was protected with MOM group and the alcoholic hydroxyl was protected with TIPS. The yield of addition reaction of ester carbonyl with MeLi was improved from50%to94%. The total yield of (-)-Ligustiphenol was24.3%.During the total synthesis of (-)-Ligustiphenol, a novel methods for synthesis3-hydroxy benzufuran was discovered, and the reaction mechanism was studied.The activity of (-)-Ligustiphenol, analogues and intermediates are testing in progress. |
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