Vancomycin remains one of the clinically most effective and important antibiotics for treatment of life-threatening Gram-positive bacterial infections, including methicillin-resistant S. aureus (MRSA). Its complex structure, the three strained macrocyclic ring systems interwoven into a highly functionalized heptapeptide core, the unusual centers of axial or planar chirality (atropisomers), and its glycosylation each present formidable synthetic challenges.
A next-generation total synthesis of vancomycin aglycon 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. Highlights of the approach include an 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 S_NAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from preorganization by the rigid AB ring system.
The streamlined total synthesis of vancomycin served as a framework for a divergent total synthesis of analogues that directly address the underlying mechanism of resistance to vancomycin. This work hinges on the late-stage conversion of fully deprotected and glycosylated [ψ[C(=S)NH]Tpg⁴]-vancomycin to the corresponding aminomethylene and amidine analogues, both of which are active against vancomycin-resistant bacteria. Key features of this next-generation route include a double Sandmeyer chlorination that leverages a deuterium kinetic isotope effect to suppress protodediazoniation, a one-pot enzymatic glycosylation, and thoroughly optimized conditions for the introduction of binding pocket modifications. Most importantly, the overall yield of [ψ[C(=S)NH]Tpg⁴]-vancomycin has been improved 25-fold over previous efforts with a 10 step reduction in LLS, allowing for the preparation of sufficient quantities of pocket-modified analogues for preclinical evaluation.

Dr Dale L Boger

Richard and Alice Cramer Professor of Chemistry, The Scripps Research Institute

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