Study On Total Synthesis Of Krisynomycin

As a commonly used anti-infective drug,antibiotics have saved the lives of countless infected patients and are closely related to people's health.However,due to the abuse of antibiotics and the bacterial resistance resulting from their own evolution,clinical doctors in the face of drug-resistant bacteria infection often face a no cure,so the research and development of new antibiotics is urgent.Krisynomycin,a macrocyclic depsipeptide natural product,is a new antibiotic that targets type I bacterial signal peptidase(SPase I),but because of its extremely low natural abundance,limits its potential for further clinical practice.Therefore,developing a simple and efficient strategy for synthesizing Krisynomycin and its derivatives is of great significance for the pharmaceutical chemistry research of Krisynomycin.This thesis mainly studying on the total synthesis of Krisynomycin,including the following contents:Firstly,the research background of antibiotics and their targets,bacterial signal peptidase I and its inhibitors,the synthesis of tryptophan derivatives and solid phase peptide synthesis were introduced.Secondly,the specific research work is introduced in two aspects:(1)The synthesis of two tryptophan derivatives was studied by multiple routes.Among them,L-tryptophan was used as the starting material,through a strategy of C7-selective boronation,substitution reaction and other steps,the tryptophan derivative 1 has been synthesized in 7 steps with an over yield of 24.4%.(2)The strategy of using solid phase synthesis of macrocyclic ester peptide was studied.Firstly,the side chain of serine is attached to 2-chlorotriphenyl chloride(2-CTC)resin.Secondly,the other amino acids were connected in turn.Then through condensation in the molecule,deprotection and oxidation of the side chain,macrocyclic ester peptides molecule 3.18 was cleavaged from the 2-CTC resin.Finally,the research summary and perspective.In this paper,the synthesis of tryptophan derivative 1 was completed,and the synthesis of tryptophan derivative 2 was attempted,and the solid phase synthesis of macrocyclic ester peptides was studied,which provided a basis for the synthesis of Krisynomycin.The total synthesis of Krisynomycin would not only develop a new class of antibiotics,but also provide an important synthesis idea for the synthesis of these natural ester peptides macromolecules.