Coupling reagents PyBOP

The well-known and less-toxic peptide coupling reagent PyBOP (benzotriazol-1-yloxy-tris(pyrrolidino)phosphoirium hexafluorophosphate) has been employed in the selective dehydration of aromatic and aliphatic primary carboxamides to the corresponding nitriles. The reaction conditions are mild, the dehydration being performed at 40 °C reaction times are 5-8 h, and yields are 80-95% [1138]. 

J Coste, D Le-Nguyen, B Castro. PyBOP A new peptide coupling reagent devoid of toxic by-product. Tetrahedron Lett 31, 205, 1990. 

Formation of a peptide bond involves two steps (1) activation of the carboxylic acid, and (2) aminolysis of the activated species. The first step starts with the reaction of the carboxylate ion with the phosphorus atom of the coupling reagent. The resulting acyloxyphosphonium ion 27 (Scheme 10) has only been observed for PyBOP- or PyCloP-mediated activation by using low temperature P NMR experiments and the sterically hindered 2,4,6-tri-methylbenzoic acid.P With N-protected amino acids, the acyloxyphosphonium intermediate reacts to give more stable species, the structure of which depends on the type of the reagent involved (Scheme 11).0 1... 

Gly-NH2 1 = product 2 = del[Arg], Synthetic conditions 20% piperidine in DMF = deprotection PyBOP-HOBt-DlEA 0.9 1 2, x6 excess = coupling, reagent K = cleavage. 

More recently, the use of phosphonium (e.g., benzotriazole-1-yl-oxy-tris-pyrrolidino phosphonium hexafluorophosphate (PyBOP)) and uronium (e.g., 2-(1H- benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU)) coupling reagents have gained wide use in effecting peptide bond formation, particularly in SPPS (Fig. 7.6). The structures of PyBOP and HBTU both incorporate an equivalent of HOBt, and the final reactive Boc or Fmoc amino acid species is the corresponding OBt active ester (13). 

Phosphonium-based reagents PyBOP and PyBroP were found to be very effective in this transformation, affording oxytripyrrolidino-phosphonium intermediates in high yields, with PyBroP being slightly superior to PyBOP. Weak nucleophiles such as iV-methyl benzenesulfonamide, imidazole, indole, diethyl malonate, and phenol were coupled smoothly with oxytripyrrolidino-phosphonium in high yields. Sodium terr-butoxide was found to be an excellent base to ensure a clean and complete reaction. 

---