5-Azido-1,1,1-trifluoropentan-2-one

This azidoalkyl trifluoromethyl ketone introduces a highly electrophilic trifluoromethyl ketone functionality by click chemistry.

Trifluoromethyl ketones can be used for multiple purposes:

 

1. They may be used per se as a part of a drug candidate and act as an electrophilic warhead, reversibly forming adducts with various nucleophiles, such as water, oxygen-, nitrogen- and sulfur-centered nucleophiles derived from amino acid side chains. Trifluoromethyl ketones can be used for design of new serine protease inhibitors^1-3 (through hemiacetal forming interference with oxyanion hole), kinase inhibitors,⁴ SARS-CoV 3CL protease⁵ or act as a "molecular glue".
2. As the trifluoromethyl ketone is highly hydrated, the gem-diol may act as a zinc-binding group and be used as an integral part of metalloenzyme inhibitors, such as histone-deacetylase.^6,7
3. They can be transformed to a variety of different derivatives, for example they can be easily reduced to secondary trifluoromethylated alcohols, undergo Friedel-Crafts reaction with electron rich aromatics such as indoles, participate in tandem imine formation followed by hydride reduction to afford α-trifluoromethylated amines or add carbon-centered nucleophiles such as acetylenes.

 

When attached to an alkynylated biomolecule (protein, peptide, nucleic acid, glycan, etc.) or advanced material, the 3 magnetically equivalent fluorines can act as ¹⁹F NMR sensor of its surroundings, for example to detect the local degree of hydration or reversibly form adducts with neighbouring amino acid side chains.

References:

1) Med. Chem. Commun., 2018, 9, 1011-1016.

2) Molecules, 2020, 25 (17), 4031.

3) BMC Mol and Cell Biol, 2020, 21, 38. 

4) Bioorg. Med. Chem., 2021, 50, 116457.

5) Bioorg. Med. Chem., 2008, 16, 4652-4660.

6) Med. Chem. Commun., 2016, 7, 464-470.

7) Synthesis, 2018, 50 (20), 4037-4046.

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