Solid-phase peptide synthesis coupling agents used

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

The formation of deletion sequences in solid-phase peptide synthesis either occurs as a result of incomplete coupling or incomplete N-terminal deprotection.P l The former is less common nowadays due to the extremely efficient coupling agents used and this problem is now... 

Figure 2.2 Modern solid phase peptide synthesis. Process begins with a-N terminal Fmoc deprotection of resin bound C-terminal amino acid residue with piperidine (mechanism illustrated). Peptide link formation follows (typical solvent Al-methylpyrrolidone [NMP]) by carboxyl group activation with dicyclohexylcarbodiimide (DCC) (mechanism illustrated) in presence of hydroxybenzotriazole (HOBt). HOBt probably replaces DCC as an activated leaving group helping to reduce a-racemization during peptide link formation. Other effective coupling agents used in place of DCC/HOBt are HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate Py-BOP benzotriazole-l-yl-oxy-tns-pyrrolidino-phosphonium hexafluorophosphate. The Process of a-N deprotection, and peptide link formation, continues for as many times as required (n-times), prior to global deprotection and resin removal.

The salt 138, formed from 2-chloro-4,6-di-methoxy[l,3,5]triazine and A -methylmorpholine (DMTMM), is also an effective coupling agent for solid-phase peptide synthesis that can be used as economical alternative to PyBop (Scheme 65) <2000SL275>. 

Esterification, Amide Bond Formation, and Peptide Synthesis. In the presence of NMI, MSNT can be used as a coupling agent for amide bond formation both in solution and in solid-phase peptide synthesis. The dipeptide Phe-Ala is formed very rapidly in 84.3% yield with virtually no racemization using MSNT as the coupling agent in the presence of NMI (eq 8). The combination of MSNT and NMI can also be used for peptide formation on sohd supports. ... 

Use of diphenyl phosphorazidate and diethyl phosphorocyanidate as coupling agents for solid-phase peptide synthesis. 

A-Acetylimidazole was found to be a very efficient terminating (capping) agent in the solid-phase synthesis of peptides.t40],[41] A terminating agent is used to block any N-terminal amino groups that have not reacted in the coupling steps.[40]... 

A new peptide synthesis with adducts of phosphorous compounds and tetrahalomethanes has been reported N-(Chlorophosphoryl)pyri-dinium betaines are remarkably reactive acylating agents for the preparation of esters, amides, and peptides. They can easily be prepared from phosphorous acid or its esters, pyridine, and mercuric chloride Peptides have also been prepared through polymeric N-acoxydicar-boxylic acid imides with markedly reduced coupling times at elevated temperature (70°). The solid-phase method, first used in the synthesis of peptides, gains wider application. Recently a solid-phase Wit-tig synthesis of olefins has been published . 

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