Fluorosulfuryl isocyanate (FSI, FSO2NCO) is established as a reliable bis‐electrophilic linker for stepwise attachment of an alcohol bearing module to an amine bearing module and thence a new module RO‐C(=O)‐NH‐SO2‐NR′R′′ is created. FSI's isocyanate motif fuses directly and quickly with alcohols and phenols, affording fluorosulfuryl carbamates in nearly quantitative yield. A new reagent and process to deliver the FSI‐derived fluorosulfuryl carbamate fragment to amines are also developed. The resulting SVI−F motifs from step‐1 are remarkably stable, given the great structural complexities in diverse products. In the step‐2 reaction with amines, the best yield of the S−N linked products arise with water alone. This “on water” interfacial reactivity phenomenon is crucial, revealing the latent reactivity of SVI−F probe for potential covalent capture of proteins in vivo which is important in today's drug discovery. The scope of the SuFEx chemistry is largely expanded thereby and the facile entry to these phosphate‐like connections should prove useful to click chemistry across diverse fields.
We report catalytic Phosphorus Fluoride Exchange (PFEx) as the latest advance in connective click-reaction technology. Emulating Nature, PFEx reaches into the biological world and creates stable tetrahedral P(V)- connections through efficient phosphorus-fluoride exchange chemistry. We showcase PFEx through the coupling of P(V)-F hubs with aryl alcohols, alkyl alcohols, and amines, delivering stable, multidimensional P(V)-O and P(V)- N connected products. The reactivity profile of P-F hubs surpasses that of their P-Cl counterparts, both in reaction performance, rate, and outcome, qualifying PFEx as a true click reaction. The rate of PFEx transformations is significantly enhanced by Lewis amine base catalysis [e.g., 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)]. When using substrates comprising multiple P-F bonds, selective, serial exchange reactions are realized through judicious catalyst selection. Synthesis of the final products (in up to 4 steps) allows controlled projections to be deliberately installed along 3 of the 4 tetrahedral axes departing the P(V) central hub. The unique reactivity window of PFEx allows for selective, modular click-reactions to be performed in series (e.g., SuFEx-PFEx-CuAAC) to rapidly generate complex multidimensional molecules, rendering PFEX a perfect addition to the click chemistry toolbox.
The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant
Enterococcus
(VRE), methicillin-resistant
Staphylococcus aureus
(MRSA), as well as vancomycin-resistant
S. aureus
(VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding
d
-Ala-
d
-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
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