A Ag-mediated Pd-catalyzed cross-coupling method for 3-bromo-1,2,4,5-tetrazine with boronic acids is presented. Electronic modification of the 1,1′-bis(diphenylphosphine)ferrocene (dppf) ligand was found to be crucial for good turnover. Using this fast method, a variety of alkyl-, heteroatom-, and halide-substituted aryland heteroaryl-tetrazines were prepared (29 examples, up to 87% yield).
<div><div><div><p>A fast and mild method for the Pd-catalyzed cross-coupling reaction of monosubstituted 3-bromo-1,2,4,5-tetrazine is presented. Investigation of silver-based additives revealed that Ag2CO3 is the optimal mediator, enabling the process without the need for strong bases or high temperatures. Electronic modification of the classical 1,1′- bis(diphenylphosphine)ferrocene (dppf) ligand proved to be a powerful strategy in tailoring the catalytic system to the requirements set by the process. Under the optimized conditions a scope comprising a variety of alkyl-, heteroatom-, and halide substituted aryl- and heteroaryl-tetrazines were prepared in good to excellent yields (29 examples, up to 87% yield). This method constitutes the first example of a direct cross-coupling reaction of monosubstituted tetrazines.</p></div></div></div>
The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different 'caged' antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 29213, S. aureus ATCC 43300 (MRSA), Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.
In this synthetic procedure, a seven‐step protocol for the preparation of monosubstituted 3‐bromo‐1,2,4,5‐tetrazine is presented. The procedure features efficient transformations and purification methods starting from commercially readily available starting materials and affords the title compound on a gram scale with 13 % overall yield in reliable purity (>97 %). Detailed experimental procedures, supported by images and additional notes, allow the preparation of a valuable advanced building block, enabling further applications in bioconjugation, protein labelling, bio‐orthogonal chemistry, heterocycle syntheses, high energy materials, and drug release, among others.
<p>The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different ‘caged’ antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against <i>Bacillus subtilis</i> ATCC 6633, <i>Staphylococcus aureus</i> ATCC 29213, <i>S. aureus</i> ATCC 43300 (MRSA), <i>Escherichia coli</i> ATCC 25922, and <i>Pseudomonas aeruginosa</i> ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.</p>
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