Utilization of N,N,N′,N′-Tetramethylfluoroformamidinium Hexafluoro­phosphate (TFFH) in Peptide and Organic Synthesis

Abstract

N,N,N¢,N¢-Tetramethylfluoroformamidinium hexafluorophosphate (TFFH) has been shown to be an excellent peptide-coupling reagent. It is an easily handled, crystalline compound, it has a long shelf life, and it reacts rapidly with carboxylic acids to give the corresponding acid fluorides or mixed anhydrides depending on the reaction conditions. TFFH has been shown to be useful as a peptidecoupling reagent and for the preparation of various carboxylic acid derivatives. Both aspects will be surveyed in this Account.

Isolation and Total Synthesis of Albu­peptins A–D: 11‐Residue Peptaibols from the Fungus Gliocladium album

“…TFFH was used as an in situ reagent to obtain reactive amino acid fluorides. [34] It has been described as a useful coupling reagent for sterically hindered, poorly reactive α,α-dialkyl amino acids such as Aib and Iva. [35,36] It proved to be superior to other coupling reagents, since well-known strategies such as PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) coupling did not lead to noticeable product formation in our preliminary studies.…”

Synthesis of β‐Amino Alcohols Using Ethyl 2‐Cyano‐2‐(2‐nitrobenzenesulfonyloxyimino)acetate (o‐NosylOXY)

“…Low cost, ease of handling and high stability make this reagent more attractive in the laboratory as well as in the industry compared to other reducing agents. Various coupling reagents such as (benzotriazol‐1‐yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), tetramethylfluoroformamidinium hexafluorophosphate (TFFH)/ benzyltriphenylphosphonium dihydrogen trifluoride (PTF), 2,4,6‐trichloro‐1,3,5‐triazine (TCT), cyanuric fluoride, 1,1‐carbonyldiimidazole, sulfonylbenzotriazole derivatives, 1‐propanephosphonic acid cyclic anhydride and 3,4,5‐trifluorophenylboronic acids have been used as acid activators in combination with NaBH 4 to attain the direct reduction of carboxylic acids into the β ‐amino alcohols under mild conditions. However, cost, the requirement of harsh conditions and toxic chemicals in the preparation of these reagents, non‐recyclability, inability in suppressing the racemization satisfactorily and difficulty in removing the by‐products remain as the bottleneck for the convenient use of these reagents.…”

Purification of Peptides in High-Complexity Arrays

“…[33][34] Another major group is the active esters ( constant. [28][29] Using carbodiimides in combination with hydroxylamines such as 1-hydroxybenzotriazol (HOBt, Figure 3, i) and 1-hydroxy-7-azabenzotriazol (HOAt, not shown) has proven to be an excellent activation strategy in SPPS.…”

“…However, acyl fluorides are a useful tool in sterically challenging couplings [29] because they are more stable to moisture than chlorides or bromides and can easily be prepared with cyanuric fluoride. [33] Reagents also exist to form acyl fluorides in situ such as 1,1,3,3-tetramethylfluoroformamidinium hexafluorophosphate (TFFH),…”