Peptide Coupling in the Presence of Highly Hindered Tertiary Amines

Abstract

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.

Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries

“…The Fmoc-protecting group of the coumarin 3 is removed by brief treatment with 20% piperidine in DMF to provide support-bound coumarin 4. Because of the very poor nucleophilicity of the coumarin amine, modified coupling conditions of Carpino et al (19) are used to provide P1-substituted ACC-resin 5 in good yields (57-Ͼ95%) ʈ . For amino acids that typically provide lower coupling yields, such as Pro (63%), a second coupling provides increased substitution levels (70%).…”

Development of Efficient Methods for Accomplishing Cysteine‐Free Peptide and Glycopeptide Coupling

“…The sterically hindered base, 2,5-di-tert-butyl-N,N-dimethylaminopyridine (DBDMAP, pK a % 9), provided the most promising results, although coupling rates and yields dropped slightly in comparison with DIEA (Table 2, entries 4 and 5). [16] Racemization of Ala (16) decreased from 12-15 % to 7-9 % and racemization of Phe (18) decreased from 40-45 % to 20-25 %. Thus, although some improvements with this method have been realized, complete suppression of the racemization at non-Gly or Pro sites remains an elusive goal.…”

Synthesis and characterization of biotin derivatives as multifunctional oligosaccharide tags

“…This was attributed to lower nucleophilicity of the amino group due to resonance with the aromatic ring. However, coupling promoted by N- [34][35][36][37] gave 5 (202 mg, 0.59 mmol, 72%). Subsequent reaction of 5 with 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine gave 5a (73 mg, 0.13 mmol, 56%) in moderate yield.…”