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Divergent Synthesis of Monosubstituted and Unsymmetrical 3,6- Disubstituted Tetrazines from Carboxylic Ester Precursors

preprint
submitted on 16.04.2020 and posted on 29.04.2020 by Yixin Xie, Yinzhi Fang, Zhen Huang, Amanda Tallon, Christopher W. am Ende, Joseph Fox
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 (3methyloxetan-3-yl)methyl carboxylic esters into 3thiomethyltetrazines. These versatile intermediates were applied as a platform for the synthesis of unsymmetrical tetrazines via Pdcatalyzed 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

Funding

This work was supported by NIH GM132460 and Pfizer. Instrumentation was supported by NIH awards P20GM104316, P30GM110758, S10RR026962, and S10OD016267 and NSF awards CHE-0840401, CHE-1229234, and CHE-1048367.

History

Email Address of Submitting Author

jmfox@udel.edu

Institution

University of Delaware

Country

USA

ORCID For Submitting Author

0000-0002-8258-1640

Declaration of Conflict of Interest

no conflict of interest

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