Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6‐Disubstituted Tetrazines from Carboxylic Ester Precursors
2020
As tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3-monosubstituted tetrazines. Described here is a general, one-pot method for converting (3-methyloxetan-3-yl)methyl carboxylic esters into 3-thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pd-catalyzed cross-coupling and in the first example of catalytic thioether reduction to access monosubstituted tetrazines. The method enables the development of new tetrazines possessing a favorable combination of kinetics, small size and hydrophilicity. The chemistry was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied in labeling of endogenous MAGL in live cells.
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