Synfacts 2020; 16(12): 1475
DOI: 10.1055/s-0040-1719567
Chemistry in Medicine and Biology

Next Generation Vancomycin Total Synthesis

Contributor(s):
Dirk Trauner
,
Klaus-Peter Ruehmann
Moore MJ, Qu S, Tan C, Cai Y, Mogi Y, Keith DJ, Boger DL. * The Scripps Research Institute, La Jolla, USA
Next-Generation Total Synthesis of Vancomycin.

J. Am. Chem. Soc. 2020;
142: 16039-16050
DOI: 10.1021/jacs.0c07433.
 

Significance

The glycopeptide vancomycin has been used successfully to treat various infections of Gram-positive bacteria for more than 60 years. Vancomycin resistant bacteria have developed a clever alternative peptidoglycan assembly strategy that resulted in significant reduction in binding affinity of the antibiotic. Successful SAR-studies established analogues with high potencies against these resistant strains (J. Am. Chem. Soc. 2015, 137, 3693). However, a lengthy and low yielding synthesis hampered further clinical investigations of these promising candidates. The authors now describe a scalable, practical, and modular synthetic approach, containing 19 linear steps with high yields and atroposelectivities.


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Comment

The first key step of their synthetic approach is a one-pot, atroposelective Miyaura borylation/Suzuki cross-coupling sequence. After macrolactamization and coupling with the central D-ring fragment, an SNAr afforded the ABCD-ring system with excellent diastereoselectivity. Amide coupling with the next building block was followed by yet another highly atroposelective SNAr. Further functional group manipulations afforded the aglycon of vancomycin. Its conversion into the natural product via enzymatic glycosylation has been previously reported (Org. Lett. 2014, 16, 3572).


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Publication History

Publication Date:
17 November 2020 (online)

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