Aminium salts peptides

In peptide coupling chemistry, tetramethylurea-derived aminium salts from 1-hydroxybenzotriazole (H O B t), such as the N-[( 1 H-benzotriazol-1 -yl) (dimethylamino) methylene]-N-methylmethanaminium hexafluorophosphate and tetrafluoroborate... 

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],... 

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. 

It has recently become appreciated that cysteine derivatives can undergo substantial levels of racemization specifically at the step where they are incorporated (58-60). For example, standard protocols for coupling mediated by the recently popularized phosphonium and aminium (uroniuni) salts (BOP, PyAOP, HBTU, HATU) (61) typically involve 5-min pre-activation times and are conducted in the presence of suitable additives, such as FIOBt or HOAt, plus a tertiary amine base, such as DIPEA or NMM. Under such conditions, the levels of racemization in a model peptide were in the range 5-33% (60). However, these levels were in general reduced by a factor of six-or sevenfold by avoiding the pre-activation step (60). Additional strategics to... 

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