Open AccessInstallation of Minimal Tetrazines through Silver-Mediated Liebeskind–Srogl Coupling with Arylboronic Acids
Author(s) -
William D. Lambert,
Yinzhi Fang,
Subham Mahapatra,
Zhen Huang,
Christopher W. am Ende,
Joseph M. Fox
Publication year - 2019
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b08677
Subject(s) - tetrazine , chemistry , bioorthogonal chemistry , conjugate , combinatorial chemistry , reagent , aryl , hydrazine (antidepressant) , organic chemistry , alkyl , click chemistry , mathematical analysis , mathematics , chromatography
Described is a general method for the installation of a minimal 6-methyltetrazin-3-yl group via the first example of a Ag-mediated Liebeskind-Srogl cross-coupling. The attachment of bioorthogonal tetrazines on complex molecules typically relies on linkers that can negatively impact the physiochemical properties of conjugates. Cross-coupling with arylboronic acids and a new reagent, 3-(( p -biphenyl-4-ylmethyl)thio)-6-methyltetrazine (b-Tz), proceeds under mild, PdCl 2 (dppf)-catalyzed conditions to introduce minimal, linker-free tetrazine functionality. Safety considerations guided our design of b-Tz which can be prepared on decagram scale without handling hydrazine and without forming volatile, high-nitrogen tetrazine byproducts. Replacing conventional Cu(I) salts used in Liebeskind-Srogl cross-coupling with a Ag 2 O mediator resulted in higher yields across a broad library of aryl and heteroaryl boronic acids and provides improved access to a fluorogenic tetrazine-BODIPY conjugate. A covalent probe for MAGL incorporating 6-methyltetrazinyl functionality was synthesized in high yield and labeled endogenous MAGL in live cells. This new Ag-mediated cross-coupling method using b-Tz is anticipated to find additional applications for directly introducing the tetrazine subunit to complex substrates.