Previously, 2,4,6-trimethylpyridine (collidine), due to steric
shielding around the N-atom, was found
to be an efficient base for effecting peptide segment coupling via
azabenzotriazole-based onium-style coupling reagents. A number of even more highly hindered
bases, including 2,3,5,6-tetramethylpyridine,
2,6-di-tert-butyl-4-(dimethylamino)pyridine,
triisopropylamine, and N-tert-butylmorpholine, have been compared with collidine in such reactions.
Some of the newer bases
showed advantages in terms of convenience in handling and maintenance
of configuration during
segment coupling processes, although dramatic differences based on
steric effects were not observed.
On the basis of results with a number of test peptides and many
base-coupling reagent combinations,
it was noted that most efficient results are obtained if 1 equiv of
HOAt is present as an additive
during the coupling process. For rapid activation of onium-style
coupling reagents during stepwise
solid-phase coupling reactions, the stronger base
2,6-di-tert-butyl-4-(dimethylamino)pyridine
was
more effective than collidine.