Peptide coupling reagents
Peptide coupling reagents
Peptide coupling reagents are more than fancy dehydrating reagents , and there is a wide range of costs. Some commercially available reagents shown in Table 4.5 are ranked by the cost per mol relative to thionyl chloride, along with some exemplary references. (Thionyl chloride was selected as the least expensive reagent, for the formation of acid chlorides. Acid chlorides are rarely used for amide couplings of amino acids, and acid fluorides have some advantages over acid chlorides .) HBTU and HATU highly active and may be used for more difficult amide bond formations, as with resins or hindered carboxylic acids . Byproducts from HBTU and BOP-Cl are water-soluble. An amine and a carboxylic acid can be mixed with either carbodiimides or T3P for coupling without prior activation of the carboxylic acid. The urea byproduct from the water-soluble carbodiimides can be readily removed by extractions, due to the basic amine functionality. Dicyclohexylurea will crystallize from DMF and can be removed by filtration. The phenolic byproduct from CDMT couplings can be removed by extractions into a basic aqueous phase. SAFETY precautions should be taken with all these reagents, as they can be severe irritants.
TABLE 4.5. Relative Costs of Peptide Coupling Reagents
|O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU)||1048||(1)|
|Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl)||273|
|2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)||250||(2, 3)|
|(Chloromethylene)dimethyliminium chloride (Vilsmeier reagent)||82||(4)|
|N-(Dimethylaminopropyl)-N′-ethyl-carbodiimide (as the liquid free base or solid hydrochloride: EDAC, EDC, WSC)||70||(5)|
|Carbonyl diimidazole (CDI)||53||(See text)|
|Propylphosphonic anhydride (cyclic trimer, T3P)||44||(6)|
|Diethyl chlorophosphate||19||(7, 8)|
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- Garrett, C. E.; Jiang, X.; Prasad, K.; Repic, O. Tetrahedron Lett. 2002, 43, 4161.
- For use of trichlorotriazine for coupling: Rayle, H. L.; Fellmeth, L. Org. Process Res. Dev. 1999, 3, 172.
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