Acid Halogenation Reagents

The generation of an acid chloride is an obvious way to activate the carboxy group for amide bond formation. However, practical application of acid chlorides in peptide synthesis is restricted, because they are prone to side reactions and racemization. In spite of this disadvantage, acid chlorides are frequently recommended to link extremely hindered or achiral amino acids. 1-Chloro-N,N,2- trimethyl-1-propenylamine, developed by Ghosez, enables the conversion of carboxylic acids into the corresponding chlorides under strictly neutral conditions.¹ This method was successfully applied by Fürstner in the total synthesis of Caloporoside and Roseophilin.²

The most notable advance in acid halogenation has been the introduction of fluoroamidinium salts by Carpino.³ Compared to the chlorides, the acid fluorides show greater stability toward water and a relative lack of conversion to the corresponding oxazolones upon treatment with organic bases. TFFH (fluoro- N,N,N’,N’-tetramethylformamidinium hexafluorophosphate) and BTFFH (fluoro-N,N,N’,N’-bis(tetramethylene)formamidinium hexafluorophosphate) are stable, non-hygroscopic salts. These reagents act in situ as fluorinating reagents and are suitable both for solution syntheses and for solid-phase peptide synthesis (SPPS).

References

1. 1979. a-CHLORO ENAMINES, REACTIVE INTERMEDIATES FOR SYNTHESIS: 1-CHLORO-N,N,2-TRIMETHYLPROPENYLAMINE. Org. Synth.. 5926. https://doi.org/10.15227/orgsyn.059.0026

2. Fürstner A, Konetzki I. 1998. Total Synthesis of Caloporoside. J. Org. Chem.. 63(9):3072-3080. https://doi.org/10.1021/jo9800098

3. Carpino LA, El-Faham A. 1995. Tetramethylfluoroformamidinium Hexafluorophosphate: A Rapid-Acting Peptide Coupling Reagent for Solution and Solid Phase Peptide Synthesis. J. Am. Chem. Soc.. 117(19):5401-5402. https://doi.org/10.1021/ja00124a040