Synthetic Studies On Serine/Threonine Kinase Inhibitor Torin1 And Centrinones

Serine / threonine(Ser/Thr)protein kinase are a class of enzymes which catalyze a variety of Ser/Thr residues phosphorylation on the substrate proteins.Through the protein phosphorylation and dephosphorylation,the protein kinases can regulate the cell cycles,and cause the growth of tumor cells.Studies have shown that blocking the expression of serine/threonine protein kinase can destroy the signal pathways of tumor cells,so as to achieve the purpose of anti-tumor.The targeted drugs which regard Ser/Thr protein kinases as targets can aim at specific targets,reduce the risks of harming normal cells during the treatment of tumors.Torin1 and natural products Centrinones are serine / threonine protein kinase inhibitors with good inhibitory effects.However,the current reported Torin1 synthesis method has the disadvantages of cumbersome operation and low overall yield,which is not conductive to industrial production.Natural synthesis of Centrinones has not been reported so far.This paper mainly describes the process improvement of serine/threonine protein kinase inhibitors Torin1 and the total synthesis of nature products Centrinones.By consulting the related papers of Torin1,we have made an improvement of the reported synthesis route as following: the key intermediate was synthesized through coupling reaction first,and then cyclization reaction;in the reduction step,Lithium tri-tertbutoxyaluminum hydride was used in methanol-tetrahydrofuran solvent for reduction,simplifying the extraction and purification of product in the oxidative cyclization step,took two steps together to avoid the deterioration of the intermediate aldehydes.Through the optimization of reaction conditions above,several key problems in the original synthesis were solved,which simplified operation steps,increased the total yield,and was easy to synthesize in a large amount.There has been no report on the synthesis of Centrinones so far,in this paper,we first took retrosynthetic analysis of Centrinones,and gave three synthesis routes.After consultation and comparison of the relevant papers,the synthesis route was confirmed and Centrinones was synthesized totally in the end.In this study,the conditions of the key reactions and the synthesis strategies were optimized,and a suitable route for Centrinones synthesis was determined: started from o-fluoroaniline,the intermediate one was synthesized through the substitution,oxidation,protection,coupling,deprotection;started from dimethyl methoxymalonate,the intermediate two was synthesized through the condensation,methylation,chlorination,two-step coupling reaction.Centrinones was obtained by condensation reaction of the two intermediate above in a high yield.The structure of the product was confirmed by spectral analysis,which was consistent with the paper reports.