Divergent Synthesis of Monosubstituted and Unsymmetrical 3, 6‐Disubstituted Tetrazines from Carboxylic Ester Precursors. (7th August 2020)

• Record Type: Journal Article
• Authors: Xie, Yixin; Fang, Yinzhi; Huang, Zhen; Tallon, Amanda M.; am Ende, Christopher W.; Fox, Joseph M.
• Is Part Of: Angewandte Chemie. Volume 132:Number 39(2020)
• Page Start: 17115
• Page End: 17121
• Publication Date: 2020-08-07
• Subjects: activity-based probes -- bioorthogonal chemistry -- divergent synthesis -- orthoesters -- tetrazines; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202005569
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Since 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 to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It 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 to the labeling of endogenous MAGL in live cells. Abstract : Divergent tetrazine synthesis : Described is a new strategy for the one‐pot synthesis of 3‐thiomethyltetrazines from carboxylic ester precursors, which provides a platform for the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and the first catalytic thioether reduction to access monosubstituted tetrazines.