Coupling in the absence of tertiary amines

Area of Science:

• Organic Chemistry
• Peptide Synthesis
• Medicinal Chemistry

Background:

• Tertiary amines are commonly used as bases in peptide coupling reactions to neutralize acids.
• However, tertiary amines can catalyze undesirable side reactions, complicating synthesis and purification.
• Developing amine-free coupling strategies is crucial for efficient and clean peptide synthesis.

Purpose of the Study:

• To investigate the use of 1-hydroxybenzotriazole (HOBt) as a substitute for tertiary amines in peptide coupling.
• To explore methods for preparing HOBt salts of amino components without amine bases.
• To evaluate the efficiency of acylation reactions using HOBt salts.

Main Methods:

• Acidolysis of acid-labile protecting groups (e.g., Bpoc, Nps, Trt) using HOBt solutions.
• Hydrogenolysis of the Z group and thiolysis of the Nps group in the presence of HOBt.
• Displacement of acetate from acetate salts with HOBt to form HOBt salts.
• Acylation of HOBt salts using symmetrical or mixed anhydrides and active esters.

Main Results:

• HOBt in various solvents (trifluoroethanol, acetic acid, phenol/p-cresol mixtures) effectively cleaved acid-labile protecting groups.
• HOBt facilitated the formation of amino component salts via hydrogenolysis or thiolysis.
• Acylation of HOBt salts proceeded efficiently without the need for tertiary amines, indicating successful amine-free coupling.
• Pentachlorophenol and 2,4-dinitrophenol were less effective than HOBt for protecting group removal.

Conclusions:

• 1-hydroxybenzotriazole (HOBt) serves as a versatile reagent for preparing amino components in peptide synthesis, obviating the need for tertiary amines.
• Amine-free peptide coupling strategies utilizing HOBt can be achieved through various salt formation and acylation methods.
• This approach minimizes base-catalyzed side reactions, leading to cleaner and potentially more efficient peptide synthesis.