Activators for peptide synthesis

Success in the chemical synthesis of peptides, performed either in solution or via solid-phase techniques, relies heavily upon efficient coupling reagents. HOAt and HATU, the newest coupling reagents sold in bulk by Medpep. They enhance coupling yields, minimize racemization, and reduce the need for multiple couplings.

HOAt 1-HYDROXY-7-AZABENZOTRIAZOLE
HOAt is a coupling additive that can be used in conjuction with active ester (OPfp, ODhbt) and carbodiimide (DCC, DIPCDI, EDC) chemistry. Recent research has shown that HOAt is a superior coupling additive in both solution and solid-phase synthesis when compared to HOBt¹. HOAt enhances coupling yields in solution by 6-32 fold and reduces the loss of chiral integrity by up to 50%.^2,3 The HOAt molecule incorporates both key elements of the 1:1 mixture of HOBt and a tertiary amine; in couplings involving active esters, this results in greater catalytic activity than HOBt alone.¹

HATU (N-[DIMETHYLAMINO)-1H-1,2,3,-TRIAZOLO[4,5-b] PYRIDIN-1-YLMETHYLENE]-N-METHYLMETHANAMINIUM HEXAFLUOROPHOSPHATE N-OXIDE^4,5
HATU, the onium salt of HOAt, is a stand-alone coupling reagent that has been shown to be particularly effective in difficult couplings via both solution and solid-phase techniques. HATU has shown special utility for the synthesis of peptides containing hindered amino acids, N-methyl amino acids, and in segment condensations. ^2,3,6,7

The benefits of HOAt and HATU

• Enhances coupling yields and reduces racemization
• Reduces cycle times
• Allows coupling of hindered amino acids and synthesis of difficult peptides
• Reliability and ease of use
• Compatible with tBOC- and Fmoc-based methods
• Suitable for the assembly of peptide libraries

References:

1. Carpino, L.A 1993. 1-hydroxy-7azabenzotriazole. An efficient peptide coupling additive. J. Amer Chem. 115:4397.
   
2. Carpino, L.A., El-Faham, A., Minor, C., Albericio, F. 1994. Advantageous applications to azabenzotriazole-based coupling reagents to solid-phase peptide synthesis. J. Chem Soc., Chem. Commun. 201.br>

3. Carpino, L.A., El-Faham, A., Albericio, F. 1994. Racemization studies during solid-phase peptide synthesis using azabenzotriazole-based coupling reagents. Tetrahedron Letters 35:2279.
   

4. Abelmoty, I., Albericio, F., Carpino, L.A., Foxman, B.M., Kates, S.A. 1994. Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU. Letters in Peptide Science 1:57.
   

5. Note: The systematic name given here for HATU differs from that previously given in the literature. Recent x-ray structural determinations for this compound as well as HBTU have clarified the crystal structures as guandinium N-oxides rather than uronium salts (refer to reference #3).
   

6. Carpino, L.A., El-Faham, A. 1994. Effect of tertiary bases on O-benzotriazoyl uronium salt-induced peptide segment coupling. J. Org. Chem. 59:695.
   

7. Angell, Y.M., Garcia-Scheverria, C., Rich, D.H. 1994. Comparative studies of the coupling of N-methylated, sterically hindered amino acids during solid-phase peptide synthesis. Tetrahedron Letters. 35:5981.

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