Total Synthesis of Tetrachlorovancomycin

Key words

vancomycin - antibiotics - total synthesis - atropisomerism - S_NAr reaction - Sandmeyer chlorination - symmetrization

Significance

Vancomycin has been the subject of significant synthetic efforts for decades, due to its potent antimicrobial properties. Its structure, harboring three elements of atropisomerism, poses a tremendous synthetic challenge. Removal of two elements of atropisomerism by addition of two aryl chlorides at rings C and E significantly reduced synthetic complexity and yielded the stereochemically simplified tetrachlorovancomycin (E), which retains significant antimicrobial activity. Peripherally modified derivatives further showed high potencies against vancomycin-resistant bacterial strains. This work is an important contribution to the development of new synthetic glycopeptide antibiotics to tackle the challenge of rising antibiotic resistances.

Comment

Building on their 2020 vancomycin synthesis, the Boger group prepared intermediate A, carrying additional chloro substituents at rings C and E. The macrocyclic proportion of A was constructed via atroposelective Suzuki–Miyaura coupling and macrolactamization. The vancomycin core structure B was generated by two-fold S_NAr macrocyclization after desilylation, yielding a mixture of four atropisomers. The mixture was converted into symmetrical tetrachloro intermediate C via nitro group reduction and Sandmeyer chlorination. TFA-mediated nitrile hydration and global deprotection afforded aglycon D in over 50% yield over five steps starting from A. Enzymatic glycosylation concluded the total synthesis of E with an exceptional yield of 15% over 15 steps.

Publikationsverlauf

Artikel online veröffentlicht:
15. November 2023