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.
This Account summarizes efforts in our group toward synthesis of heterocycles in the past decade. Selected examples of transannulative heterocyclizations, intermediate construction of reactive compounds en route to these important motifs, and newer developments of a radical approach are outlined.
1 Introduction
2 Transannulative Heterocyclization
2.1 Rhodium-Catalyzed Transannulative Heterocyclization
2.2 Copper-Catalyzed Transannulative Heterocyclization
3 Synthesis of Heterocycles from Reactive Precursors
3.1 Synthesis of Heterocycles from Diazo Compounds
3.2 Synthesis of Heterocycles from Alkynones
4 Radical Heterocyclization
4.1 Light-Induced Radical Heterocyclization
4.2 Light-Free Radical Heterocyclization
7 Conclusion
more » « less- Award ID(s):
- 1955663
- NSF-PAR ID:
- 10473948
- Publisher / Repository:
- Thieme
- Date Published:
- Journal Name:
- Synlett
- Volume:
- 34
- Issue:
- 13
- ISSN:
- 0936-5214
- Page Range / eLocation ID:
- 1554 to 1562
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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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.
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1055/s-0042-1751429
