| Autor: |
Lambert WD; Department of Chemistry and Biochemistry , University of Delaware , Newark , Delaware 19716 , United States., Fang Y; Department of Chemistry and Biochemistry , University of Delaware , Newark , Delaware 19716 , United States., Mahapatra S; Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States., Huang Z; Pfizer Worldwide Research and Development , 1 Portland Street , Cambridge , Massachusetts 02139 , United States., Am Ende CW; Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States., Fox JM; Department of Chemistry and Biochemistry , University of Delaware , Newark , Delaware 19716 , United States. |
| Abstrakt: |
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. |
