Synthesis,structure Modification And Process Research Of PPAPs From Hypricum

OBJECTIVE: Garcinia and Hypericum have spanned a wide range of biological activities for anti-virus,swelling,phlegm,sore,hemostasis,insecticide,indications for swollen poison,u Lcers,wet sores,tumors,stubbornness,bruises,traumatic bleeding and scald;used as a diuretic abroad,treatment of edema and cerebral hemorrhage.In particu Lar,the natural product hyperibone L,which is known as St.John's Wort in Hypericum perforatum extract,has demonstrated several biological activities,including antidepressant,antitumor,and antibacterial effects.However,it is difficu Lt to isolate it.Therefore,we aim to synthesize the natural product hyperibone L and its deriviates regio-hyperibone L,and then optimize the [3.3.1] ring to enhance its biological activity.Meanwhile,the su Lfoximine,which has been identified as a functional group,has received great attention from scientists and industry in the near future.Although the interesting of su Lfoximines as an important motif has seen steadily increased as their potent biological and medicinal activities.There is a lack of a green,safe and scalable preparation method.We are expecting to develop a new and efficient method of synthesizing su Lfinamide,which can provide raw material,and benefit the structure optimization work of the natural product.METHODS: One method with utilizing tandem Dieckmann condensation strategy to constructing decarboxylated PPAPs was developed.The bicyclic ring can be constructed in one step,and then the phenylacetyl group can be introduced in the final step enables the synthesis of the natural product derivatives regio-hyperibone L.On this basis,the unique [3.3.1] structure of PPAPs natural products was further modified.The head,middle and the tail parts of the bridge are optimized.The excess prenyl/methyl groups were removed,function group and heteroatoms were induced to the core structure to increase the binding capacity and improve bioavailability.These analogies can be divided into three categories: 1)su Lfur-containing [3.3.1] ring;2)nitrogen-containing [3.3.1] ring;3)oxygen-containing [3.3.1] ring.In addition,the su Lfoximine was introduced to the core ring to enhance the drugability.At the same time,the synthesis of the su Lfoximine was carried out to address the synthesis and scalability issue.After screening the solvents,hypervalent iodine(III)reagents and ammonia source,the best condition was identified.Moreover,one recycling strategy was developed,the main by-product iodobenzene can be collected and reused.RESULTS: The regio-hyperibone L was synthesized successfu Lly with the developed tandem Dieckmann method.The head,bridge,and tails part of [3.3.1] ring was modified by introducing a hetero atom such as su Lfur,nitrogen,oxygen.Isopentenyl and geranium groups was remove to simplify the structure.Function groups including su Lfoximies was introduce PPAPs.Total 42 new molecu Les in three categories were obtained.Meanwhile,a new,efficient,green economy method for the synthesis su Lfoximines has been developed.Diacetoxytrifluoroiodobenzene(3-4L)is utilized as an oxidizer in the presence of a micellar catalyst to synthesis the su Lfoximines.Ammonium carbonate is employed as a nitrogen source,a controllable condition was developed to increas the scalablity of the reaction.At the same time,a new type of hyper valent iodine(III)reagent was developed,and the major by-product trifluoroiodobenzene can be recovered.In addition,the developed new processes have been demonstrated on the gram scale and applied to the synthesis of natural product xantones derivatives 3-9 and clinical drug racemic Bay 1143572 successfu Lly.This newly developed method meets the standards of green chemistry and can be applied to the synthesis of natural products and active drug molecu Les.By applying this method,it is possible to synthesize structurally diverse,bioactive su Lfinimide molecu Les faster and more.CONCLUSION: The synthesis of regio-hyperibone L,a derivative of hyperibone L in the natural product of Hypericum,was achieved successfu Lly.Structural modification of the core [3.3.1] ring work was carried out by removing excess groups,introducing of drug-like groups and heteroatoms,we aim to improve binding with target proteins,increase selectivity,reduce toxicity.One new,safe,green,and economy protocol for the synthesis of su Lfoximine has been developed.The developed method can be applied for large scale manufacture,synthesis of biologically active molecu Les,and also provides enough raw material for structural modification of PPAPs natural product.