A Novel Family of Onium Salts Based Upon Isonitroso Meldrum's Acid Proves Useful as Peptide Coupling Reagents

Abstract

A new family of uronium salts (HTMU, HMMU, and HDmPyMU) based on isonitroso Meldrum's acid (HONM) are reported as stand-alone coupling reagents. Amide bond formation with the use of these reagents occurred more quickly than that with other uronium salts as a result of the presence of a neighboring group effect with a cyclic structure. Thus, these novel onium salts were often more effective in the acylation of poor nucleophiles and in the control of optical purity

TOMBU and COMBU as Novel Uronium-Type Peptide Coupling Reagents Derived from Oxyma-B

“…In order to examine the configuration retention induced by the new coupling reagents, the novel uronium coupling reagents were tested and compared with HBTU (4), HATU (5), and COMU (11) using the previously studied peptide models, namely the stepwise coupling of Z-Phg-Pro-NH2(24) and segment coupling of Z-Phe-Val-Pro-NH2(25) [20,21,25].In the first model (24), the α-phenyl moiety in Phg ensured high sensitivity toward racemization because of the high stability of the counter anion. Oxyma-B-based uronium salts 17 and 18 showed better performance in reducing racemization than HBTU (4) and HATU(5) and similar performance to COMU (11).…”

“…The second model was the segment coupling (2+1) of dipeptide Z-Phe-Val-OH onto H-Pro-NH2 to afford Z-Phe-Val-Pro-NH2 (25). This model is known to give higher racemization levels than the previous stepwise coupling model because oxazolone formation during the activation of dipeptide is promoted as a result of the electron-donating effect of the N-aminoacyl substitution [6].…”

“…This model is known to give higher racemization levels than the previous stepwise coupling model because oxazolone formation during the activation of dipeptide is promoted as a result of the electron-donating effect of the N-aminoacyl substitution [6]. In the segment coupling model (25), the best results were obtained with HATU (5), which gave the highest yield and the lowest racemization. However, TOMBU (17) and COMBU (18) showed better performance in reducing the racemization than HBTU (4).…”

“…In addition, they had a lower risk of explosion than that of benzotriazole derivatives [20][21][22][23][24]. More recently, in 2010, a new family of uronium salts [HTMU (13), HMMU (14), and HDmPyMU (15)] based on isonitroso Meldrum's acid (HONM, 12) was reported as stand-alone coupling reagents [25] (Figure 2). HONM (12) shows structural similarities to OxymaPure (10), except that it has a special orientation of the carbonyl moiety and can therefore play an assisted basic catalytic role during the coupling reaction.…”

“…HONM (12) shows structural similarities to OxymaPure (10), except that it has a special orientation of the carbonyl moiety and can therefore play an assisted basic catalytic role during the coupling reaction. While HONM (12)cannot be used as an additive for the carbodiimide, because it reacts with this functional group to form a nonreactive intermediate [25], its uronium salts 13-15 showed increased reactivity when compared with classical coupling reagents, especially during acylation of non-hindered poor nucleophiles, such as p-chloroaniline [25]. More recently, we have reported 5-(hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Oxyma-B, 16) as an excellent additive for the suppression of racemization during peptide synthesis [26].…”