[16357-59-8] · C14H17NO3 · 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline · (MW 247.29)
(activating agent used in peptide synthesis)
Alternate Names: ethyl 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate; EEDQ.
Physical Data: mp 66-67 °C; bp 125-128 °C/0.1 mmHg.
Solubility: sol water, alcohol.
Form Supplied in: white powder; widely available and can be easily prepared.1
In peptide synthesis, peptide bonds are created from the activated carboxylic group of a Na-protected amino acid that is reacted with the nucleophilic free amino group of another amino acid (eq 1).
Activation of the carboxylic acid can be performed according to several strategies, leading mainly to two kinds of intermediates: active esters and acid anhydrides, which can be either symmetrical anhydrides or mixed anhydrides. EEDQ is a reagent used in peptide synthesis for the mixed carbonic anhydride strategy. It allows a slow formation of unsymmetrical anhydrides under very mild conditions (eq 2).2
Faster reaction of the mixed anhydride with nucleophilic species reduces the extent of side reactions that occur with high concentration of the anhydride (eq 3).3
The tendency to racemization is limited to a small extent. Nevertheless, wrong-side attack, leading to the formation of urethane, is not suppressed (eq 4).4
As best results had been obtained with mixed anhydrides of Isobutyl Chloroformate, probably because the isobutyl group decreases the amount of urethane products, IIDQ (1), an analog of EEDQ, has been proposed for use in peptide synthesis.5,6
As another alternative, EEDQ has been linked to a polymeric support, providing a supported coupling reagent in high yield (eq 5).7
Coupling reactions mediated by this reagent occur cleanly in high yield and with a low degree of racemization, comparable with that observed with EEDQ itself.8 Nevertheless, the use of EEDQ in peptide synthesis is rather limited, other coupling reagents being very much more popular. Examples are: the carbodiimides, mainly 1,3-Dicyclohexylcarbodiimide and diisopropylcarbodiimide; the family of BOP reagents such as Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate; uroniums such as O-Benzotriazol-1-yl-N,N,N´,N´-tetramethyluronium Hexafluorophosphate (HBTU), or urethane N-protected carbonic anhydrides (UNCA), and active esters.
Institut Pasteur, Lille, France