Phosphonium Salts

By: Matthias Junkers, ChemFiles 2007, 7.2, 8.

ChemFiles 2007, 7.2, 8.

Phosphonium salts are powerful and easy-to-use peptide coupling reagents that allow in situ generation of active esters. After the recognition of chlorotris(dimethylamino)phosphonium as the activating species in the tris(dimethylamino)phosphine/CCl4 system and the importance of HOBt as an additive in peptide coupling, Castro proposed BOP (benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate) as a suitable coupling reagent. Thereafter, various groups proved the efficiency of BOP and it has become widely used.1,2 Since the utilization of BOP involves the handling of the toxic and carcinogenic HMPA, the viable alternative PyBOP has been developed where the dimethylamino groups are replaced by pyrrolidine substituents. PyBOP shows comparable performance to BOP, in some cases even better.3 Numerous other variations of BOP have been reported among which the HOAt analogue to PyBOP, PyAOP, excels especially in the coupling of sterically hindered amino acids.4 The halophosphonium compounds BroP or PyCloP are efficient reagents when coupling N-methylamino acids or a,a-disubstituted amino acids.5 Recently, Goodman reported the new DEPBT (3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) with superior performance as coupling reagent. It proved to be especially suitable for PNA synthesis, where it yielded significantly better results than even HATU.6,7

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  1. Hudson, D. J. Org. Chem. 1988, 53, 617.
  2. Rivaille, P.; Gautron, J. P.; Castro, B.; Milhaud, G. Tetrahedron 1980, 36, 3413.
  3. Coste, J.; Le Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205.
  4. Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc., Chem. Commun. 1988, 201.
  5. Coste, J.; Frérot, E.; Jouin, P. J. Org. Chem. 1994, 59, 2437.
  6. Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. Organic Lett. 1999, 1, 91.
  7. Tedeschi, T.; Corradini, R.; Marchelli, R.; Pushl, A.; Nielsen, P. E. Tetrahedron: Asymm. 2002, 13, 1629.

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