Acid-Amine Coupling using TBTU

• TBTU is very similar to HBTU with respect to structure except for the nature of salt (BF₄ salt is TBTU and PF₆ salt is HBTU)

• Uronium salts are useful for the coupling of sterically hindered amino acids in peptide synthesis

• When the carboxylic acid contains epimerizable α-stereocenter, 1 eq. of HOAt or HOBt shall be used to suppress epimerization.

Disadvantages of Uronium salts:

• The by-product from these uronium salts, namely N,N,N′,N′-tetramethylurea are cytotoxic

• The presence of high energy moiety (Benzotriazole) makes it less attractive for large-scale reactions – Mild reaction conditions should only be maintained

• As the molecular weight is high, quantities required would be higher, thereby higher cost per mole

Comparison of HATU, HBTU and TBTU from Scale-up perspective:  Refer to the tab "Scale-up & Green Chem"

Commonly used Uronium salts:

• The counterion in the above salts has no influence on the reactivity

Side-product formation while using HBTU or HATU or TBTU:

• Uronium species are also known to be guanidylation agents as well

• The side-product formation shall can be diminished by adding HOBt to the reaction (similar to HOBt in DCC)

• HOBt and HOAt have explosive character, especially in water-free form

• HOBt and HOSu are commonly used additives. HOAt is very expensive

Oxyma Pure® (Ethyl 2-cyano-2-(hydroximino)acetate)

• A recently developed additive and is trademark of Luxembourg Bio Technologies Ltd, Rechovot, Israel
• Oxyma Pure®is a non-explosive alternative to HOBt or HOAt, and allows high coupling rates at low racemization when applied in combination with carbodiimides.