Aminium coupling reagents

There are many different types of peptide coupling reagents (e.g., carbodiimides, aminium/uranium salts, and phosphonium salts). The choice of meth-od(s) and reagent(s) depend on a variety of factors, including the specific sequence of peptide to be synthesized, the preferred method of deprotection, the preferred solvents, and the type of active intermediate desired. 

There has been an evolution in the development of new coupling reagents and their application to solid-phase methodology. The formerly predominant carbodiimide reagents are being replaced by onium (phosphonium and aminium) salts. As discussed later, depending on the conditions, the activation step with onium salts occurs faster than with carbodiimides and usually leads to less perishable intermediates. 

Figure 2. The Fmoc strategy illustrated for the synthesis of a dipeptide. A variety of coupling reagents (carbodiimides, pentafluorophenyl esters, aminium salts) may be used.

N-oxide salts (HBTU and TBTU, respectively) [39], or from l-hydroxy-7-azabenzotriazole (HOAt) such as N-[(dimethylamino)-lH-l,2,3-triazolo[4,5-fe] pyridino-l-y]methylene]-N-methy]methanaminium tetrafluoroborate N-oxide (HATU) [40], are well established reagents. They are especially devoted to peptide coupling reactions due to their efficiency and the low degree of undesirable race-mization produced in the final peptide compared to the use of classical carbodi-imide-coupling methods. Therefore, as the polystyrene-supported HOBt is an often used polymeric reagent (Section 7.6.3) [41], its transformation in a supported HOBt and tetramethylurea-derived aminium salt analog to HBTU and TBTU resulted directly. Thus, the reaction of polystyrene-2% divinylbenzene copolymer resin P-HOBt (20) with tetramethylchloroformamidinium tetrafluoroborate (21) (4 equivalents) in the presence of triethylamine gave polymeric N-[(lH-benzotriazol-l-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (P-TBTU, 22) (Scheme 7.6) [42],... 

Phosphonium salts are more unstable than aminium or uronium derivatives in the absence of a base. In the presence of a base, the phosphonium reagents are slightly more stable, indicating that aminium or uronium salts are more reactive in coupling conditions. 

In recent years, aminium- (until recently referred to as uronium) and phosphonium-based derivatives have become the preferred tools for in situ carboxyl activation. The most popular reagents PyBOP 15 (23), TBTU 16 (24), and HBTU 21 (24, 33) smoothly convert Fmoc-amino acids, in the presence of a tertiary base, to their corresponding OBt esters Figure 6). Recently, analogous derivatives HATU 17 (25) and PyAOP 22 (34) which generate OAt esters have become commercially available. These are used in an identical manner but have been shown to give superior results in terms of both coupling efficiency and suppression of enantiomerization (34-37). 

---