2,2,2-Trifluoroethanol as a solvent to control nucleophilic peptide arylation

Abstract

The SAr arylation of peptides with perfluoroaromatics provides a route by which to install a useful chemical handle that enables both F-NMR analysis and further chemical modification. However, chemo-selective arylation in peptides containing multiple nucleophilic side chains currently presents a challenge to the field. Herein, we demonstrate that employing 2,2,2-trifluoroethanol (TFE) as a solvent in peptide SAr reactions significantly improves nucleophile-selectivity when compared to N,N'-dimethylformamide (DMF).

Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions

“…In addition, our own group has reported the use of PFP as a tagging reagent in peptide chemistry. We observed that PFP could undergo S N Ar reactions with peptides containing nucleophilic side-chains, including tyrosine 15. We have also developed a range of unnatural amino acids using the same chemistry 16…”

An Intramolecular C(sp2)–H Amidation Using N‐Iodosuccinimide

“…The role of the fluorinated solvent, TFE can be rationalized as follows. Kita and coworkers have shown that when hypervalent iodine reagents are mixed with fluorinated solvents like hexafluoroisopropanol (HFIP), radical‐cation intermediates are stabilized due to the high polarity and low nucleophilicity of the solvent.…”

“…Kita and coworkers have shown that when hypervalent iodine reagents are mixed with fluorinated solvents like hexafluoroisopropanol (HFIP), radical‐cation intermediates are stabilized due to the high polarity and low nucleophilicity of the solvent. [40d] Recently, Donohoe and Compton and coworkers also demonstrated the role of HFIP in the activation of the hypervalent iodine reagents . Similarly, trifluoroethanol is also known to be a fluorinated solvent that could stabilize cationic or radical‐cation species generated using iodine regents.…”

“…Similarly, trifluoroethanol is also known to be a fluorinated solvent that could stabilize cationic or radical‐cation species generated using iodine regents. [40b], [40c], [40e] Therefore we believe that TFE promotes the reaction by stabilizing intermediates 4 and 5 (Figure a).…”

Synthesis of complex unnatural fluorine-containing amino acids

“…Due to their highly electron deficient nature, perfluoroaromatics can have significant effects on the electronics of molecular systems [ 60 ]. Perfluoroaromatic moieties have therefore seen use in materials [ 61 ], catalysis [ 62 , 63 ] and organic synthesis [ 64 , 65 ], and have been exploited in peptide [ 66 , 67 ] and peptoid chemistry [ 68 ]. Access to highly fluorinated amino acids is therefore an area of much research, with several reports detailing the synthesis of aromatic perfluorinated amino acids.…”