Total Synthesis Of Natural Product Carolacton And Synthesis Of Chiral Fragments Of Diabetes Treatment Drug Omariglipti

Biofilm bacteria such as Streptococcus mutans cause various diseases such as dental caries and endocarditis.The inherent drug resistance caused by the biofilm makes this type of bacteria difficult tobe completely eliminated.The recently isolated natural product Carolactoncan inhibit the growth of biofilm bacteria with higher activity.Carolacton can inhibit the synthesis of bacterial biofilm by interfering with PknB.Carolacton can also acts on FolD,which exerts its antibacterial effect by inhibiting C1 metabolism of bacteria.Studies also demenstreted that Carolacton can produce anti-cancer effects by inhibiting MTHFD2(ortholog of FolD)in mitochondria;The latest reports show that Carolacton can inhibit a variety of RNA viruses including the COVID-19 with higher activity,making it a lead of broad-spectrum antiviral drugs.Three articles have successfully achieved the complete synthesis of the compound,and there are many synthesis research reports.In addition,some structural modifications have been obtained through synthetic methods,preliminary clarifying the structure-activity relationship(SAR).The main synthesis strategies involved NHK reaction,Aldol reaction,asymmetric crotonyl reactionand RCM reaction.This paper explored an easy-to-implement total synthesis route,and obtained 100 mg level Carolacton and its C15-C16 cis-isomer.In this study,commercial sources of propylene glycol,Roche ester,and D-ribose were used as starting materials.The key building blocks are the five stuctures shown above.Selectively epoxyring-open,Evans-Aldol reaction,reductive deoxygenation reaction,and RCM are the key steps.Finally,the target molecule Carolacton(100 mg level)and its C15-C16 cis-isomer were obtained with 23linear steps,with a total yield of 9.2%.This research makes a foundation for furtherSAR research.Omarigliptin is a long-actingDPP-4inhibitor developed by Merck,which only needs to be taken orally once a week.The existing synthetic routes of key fragment 161 mostly use heavy metal catalysts and complex ligands,and involve several column chromatography steps.This article developed a new synthetic route for Fragment 161 that does not involve heavy metals and complex ligands.The strategies are as follows:Taking Claisen rearrangement,Evans-Aldol reaction,OTf-mediated cyclization reaction and Curitis rearrangement reaction as the key steps,after 11 steps of reaction,the target fragment was obtained with a total yield of 27%.