Bioinspired Total Syntheses And Antimicrobial Activity Study Of Nucleotide Antibiotics A201A,A201D And A201E

The A201 family is a class of structurally unique nucleoside antibiotics containing1,2-cis-L-ribofuranose,D-configuration rhamnose and deaminopurinomycin units.1,2-cis-ribofuranoside is the core structure of the A201 family,among which the excellent antibacterial activity of A201 A and the rare L-ribofuranose unit of the extracyclic enzyme methyl ether have attracted the attention of medicinal chemists,synthetic chemists and chemical biologists.In 2014,Yu Biao’s group achieved the first total synthesis of A201 A by a 47-step linear strategy,and in 2017,Ju Jianhua’s group reported the biosynthetic pathway of A201 A.As the A201 family exhibited excellent antibacterial activity against Gram-positive and anaerobic Gram-negative bacteria,while no relevant conformational studies were available,we proposed to investigate the synthesis and antibacterial activity of this family.We first speculated on the potential biogenic relationships of A201 A,A201D and A201 E,and designed and synthesized A201 A,A201D and A201 E based on the hypothesis of biogenic relationships;we also carried out conformational studies around A201 A and A201 E,and initially elucidated the conformational relationships through synthesis and activity characterization,which laid the foundation for the development of antibiotics based on the A201 family.The paper is divided into three chapters as follows The thesis is divided into three chapters as follows:Chapter 1: Hydrogen bond mediated aglycone delivery(HAD)strategy and its application in the synthesis of bioactive molecules(Review)A brief overview of hydrogen bond-mediated glycosylation reactions(HAD)to construct 1,2-cis or 1,2-trans glycosidic bonds is given,while for 2-deoxy glycocyclic construction of α or β glycosidic bonds can also be readily achieved;examples of their application in the synthesis of biologically active molecules and a brief outlook on the prospects for the application of this reaction in the synthesis of biologically active molecules are given.Chapter 2: Exploration of the total synthesis and antibacterial activity of the nucleoside antibiotic A201EIn this chapter,the background of the isolation,structural features,antibacterial activity and the related synthetic background of the nucleoside antibiotic A201 family are firstly presented.The synthetic route was followed by a masonry synthesis strategy and divergent thinking for its total synthesis.The core structure of L-furanogalactose was successfully constructed by using inexpensive and readily available Dgalactopyranose,which was converted to L-galactose through a C1 and C6 head-to-tail oxidation state conversion strategy;subsequently,1-,2-cis-furanoside was constructed by hydrogen bonding orientation using 2-quinolinecarbonyl,and finally The first total synthesis of A201 E was achieved by an amidation reaction.The A201 family showed excellent antibacterial activity against Gram-positive and most anaerobic Gram-negative bacteria.Based on the synthetic route of A201 E,the synthesis and characterization of A201 E analogues were completed,and the conformational relationships of A201 E and its analogues were initially elucidated,which laid the foundation for new antibiotics based on the A201 family backbone.Chapter 3: Biomimetic total synthesis study of nucleoside antibiotics A201 A,A201D and A201EThe synthetic route was developed using a blocky synthetic strategy and a divergent mindset.The core structure of L-furanogalactose was successfully constructed using cheap and readily available D-galactopyranose via C1 and C6 headto-tail oxidation state conversion strategy.After methylesterification and basepromoted glycosylation,regioselective and stereoselective glycosylation of alkyl alcohols was achieved in the aqueous phase,and the conversion from A201 D to A201 A was successfully achieved,providing a synthetic route for later conformational studies.