Next-Generation Total Synthesis of Vancomycin

A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2020-09, Vol.142 (37), p.16039-16050
Main Authors: Moore, Maxwell J, Qu, Shiwei, Tan, Ceheng, Cai, Yu, Mogi, Yuzo, Jamin Keith, D, Boger, Dale L
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Crystallography, X-Ray
Models, Molecular
Molecular Structure
Stereoisomerism
Vancomycin - chemical synthesis
Vancomycin - chemistry
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Summary:A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation–Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room-temperature atroposelective intramolecular SNAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large-scale synthetic preparation of pocket-modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.0c07433