8GJV

Chemical synthesis of maxamycins: Intermediate compound 10

Summary for 8GJV

• Entry DOI: 10.2210/pdb8gjv/pdb
• Related PRD ID: PRD_002527
• Descriptor: Intermediate compound 10 for maxamycins synthesis, METHANOL (3 entities in total)
• Functional Keywords: vancomycin multi-drug resistance, antibiotic
• Biological source: synthetic construct
• Total number of polymer chains: 4
• Total formula weight: 8134.05

Authors

Stanfield, R.L.,Moore, M.J.,Boger, D.L. (deposition date: 2023-03-16, release date: 2023-06-21, Last modification date: 2024-09-11)

Primary citation

Moore, M.J.,Qin, P.,Keith, D.J.,Wu, Z.C.,Jung, S.,Chatterjee, S.,Tan, C.,Qu, S.,Cai, Y.,Stanfield, R.L.,Boger, D.L.
Divergent Total Synthesis and Characterization of Maxamycins.
J.Am.Chem.Soc., 145:12837-12852, 2023

PubMed Abstract: A new streamlined and scaled divergent total synthesis of pocket-modified vancomycin analogs is detailed that provides a common late-stage intermediate [Ψ[C(═S)NH]Tpg]vancomycin (LLS = 18 steps, 12% overall yield, >5 g prepared) to access both existing and future pocket modifications. Highlights of the approach include an atroposelective synthesis of [Ψ[C(═S)NH]Tpg]vancomycin aglycon (), a one-pot enzymatic glycosylation for direct conversion to [Ψ[C(═S)NH]Tpg]vancomycin (), and new powerful methods for the late-stage conversion of the embedded thioamide to amidine/aminomethylene pocket modifications. Incorporation of two peripheral modifications provides a scalable total synthesis of the maxamycins, all prepared from aglycon without use of protecting groups. Thus, both existing and presently unexplored pocket-modified analogues paired with a range of peripheral modifications are accessible from this common thioamide intermediate. In addition to providing an improved synthesis of the initial member of the maxamycins, this is illustrated herein with the first synthesis and examination of maxamycins that contain the most effective of the pocket modifications (amidine) described to date combined with two additional peripheral modifications. These new amidine-based maxamycins proved to be potent, durable, and efficacious antimicrobial agents that display equipotent activity against vancomycin-sensitive and vancomycin-resistant Gram-positive organisms and act by three independent synergistic mechanisms of action. In the first such study conducted to date, one new maxamycin (, MX-4) exhibited efficacious activity against a feared and especially challenging multidrug-resistant (MRSA) and vancomycin-resistant (VRSA) bacterial strain (VanA VRS-2) for which vancomycin is inactive.

PubMed: 37278486
DOI: 10.1021/jacs.3c03710

Experimental method

X-RAY DIFFRACTION (0.9 Å)