Total Synthesis Of Complex Peptidyl Nucleoside Antibiotics Miharamycin B And Its Biosynthetic Precursor

Miharamycins（MIHs）and amipurimycin（APM）are two peptidyl nucleoside antibiotics with similar structures,which were isolated from the fermentation products of Streptomyces novoguineensis and Streptomyces miharaensis,respectively,by Japanese scientists in the 1970s.In view of the excellent antifungal activity of this class of compounds,especially the outstanding therapeutic effect on rice blast and the novel nine-carbon sugar backbone,it has attracted the interest of many synthetic groups.Among them,Yu Biao’s group completed the first total synthesis of amipurimycin in 2019,and Tang Gongli and Liu Hongwen’s groups reported the biosynthetic pathways of miharamycins and amipurimycin,respectively,from 2019 to2021.In view of the outstanding biological activities and novel scaffolds of such molecules,our group’s research interest in their synthesis has been aroused.This paper firstly provides an overview of Achmatowicz rearrangements and their synthetic applications in bioactive small molecules,followed by a detailed introduction to the total synthesis of miharamycins and their biosynthetic precursors.The thesis consists of the following two chapters:Chapter 1:Achmatowicz rearrangement and its application in the synthesis of bioactive molecules（review）The Achmatowicz rearrangement can convert furfuryl alcohols into dihydropyranone acetals（also known as pyranuloses）.This chapter briefly summarizes the Achmatowicz rearrangement reaction and its mechanism,and enumerates the application examples of this reaction in the synthesis of biologically active molecules.Finally,the application prospect of this reaction in the synthesis of biologically active molecules has been briefly prospected.Chapter 2:Asymmetric synthesis of peptidyl nucleoside antibiotic miharamycin B and its biosynthetic precursorFirstly,the isolation,identification and synthesis background of miharamycins and amipurimycin were introduced in detail,and then the asymmetric synthesis of miharamycin B and its biosynthetic precursor was introduced in detail.This synthetic route adopts the strategy of de novo synthesis of sugars and cleverly utilizes the Achmatowicz rearrangement to successfully construct 3’-branched sugars.Subsequently,by selecting 2-amino-6-chloropurine derivatives as nucleophiles,stereo-and regioselective N-glycosylation was achieved under palladium catalysis.The tetrahydrofuran ring skeleton in natural products was constructed by stereoselective bishydroxylation and regioselective intramolecular S_N2 reaction.Finally,the first total synthesis of miharamycin B and its biosynthetic precursor was achieved in 20 and 18 steps,respectively.The research work of this thesis has made a useful exploration of the synthesis of complex peptidyl nucleoside antibiotics miharamycins family and the application of Achmatowicz rearrangement reaction in the synthesis of biologically active molecules.