Moore MJ,
Qin P,
Yamasaki N,
Zeng X,
Keith DJ,
Jung S,
Fukazawa T,
Graham-O’Regan K,
Wu Z.-C,
Chatterjee S,
Boger DL.
*
The Scripps Research Institute, La Jolla, USA
Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.
J. Am. Chem. Soc. 2023;
145: 21132-21141
DOI:
10.1021/jacs.3c08358
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 SNAr 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.
