Intramolecular reaction aminolysis

Aspartame is relatively unstable in solution, undergoing cyclisation by intramolecular self-aminolysis at pH values in excess of 2.0 [91]. This follows nucleophilic attack of the free base N-terminal amino group on the phenylalanine carboxyl group resulting in the formation of 3-methylenecarboxyl-6-benzyl-2, 5-diketopiperazine (DKP). The DKP further hydrolyses to L-aspartyl-L-phenyl-alanine and to L-phenylalanine-L-aspartate [92]. Grant and co-workers [93] have extensively investigated the solid-state stability of aspartame. At elevated temperatures, dehydration followed by loss of methanol and the resultant cyclisation to DKP were observed. The solid-state reaction mechanism was described as Prout-Tompkins kinetics (via nucleation control mechanism). 

In principle, solid state degradation should also take place slowly in surface moisture films at ambient temperatures and humidities. Similar products are to be expected as for solution degradation, but no studies were found that examined this phenomenon. Given the high concentrations of substrate that are present in surface moisture films, there is also the possibility that intermolecular self-aminolysis and polymerization could occur, in addition to the intramolecular reaction reported under anhydrous conditions by Grant and coworkers. 

Figure 1 Coupling in peptide synthesis. Aminolysis (A) of the activated residue gives the L-L peptide. A competing intramolecular reaction (B) may occur giving the 5(4H)-oxazolone. When R = alkoxy (BzIO, tBuO, or FmO), the oxazolone is aminolyzed (E) giving the L-L peptide. When R = peptidyl (-Xaa-NHCHR ) the oxazolone tautomerizes (F) and is then aminolyzed (E, E ) giving also the D-L peptide.

In an earlier study, we pointed out some important aspects of aminolysis of thioester in our enzyme model. First, the fastest rate for aminolysis of thioester was obtained in the presence of equimolar amounts of acid and base catalysts. Second, the reaction proceeded in aprotic nonpolar solvents such as benzene, ethyl acetate, dichloromethane, and so on [7]. Thus, the peptide syntheses by the enzyme model have been performed in benzene buffered with equimolar amounts of pivalic acid and triethylamine as acid and base catalysts, respectively. Third, the superiority of intramolecular aminolysis over an intermolecular one was clearly demonstrated, despite the large membered cyclic intermediate expected for the intramolecular reaction. The host 10 could achieve the synthesis of the tetrapep-tide derivative (11) by formal turnover of the intra-complex thiolysis and the intramolecular aminolysis, but its efficiency as an enzyme model has remained to be improved [3]. 

Several attempts to measure the maximal rate enhancements that can be achieved through proximity effects alone have been performed. A typical example compares the in-termolecular aminolysis of phenyl acetate by trimethylamine (Eq. 9.3) to the intramolecular cyclization of phenyl 4-(N,N-dimethylamino)butanoate (Eq. 9.4). The intermolecular reaction has a rate constant = 1.3 X 10 M" s , while the intramolecular reaction has ki = 0.17 s k This suggests a rate enhancement of 1200 for the intramolecular reaction. Even in pure trimethylamine, the pseudo-first order rate constant for the intermolecular reaction would be less than the intramolecular rate constant. 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

BF Gisin, RB Merrifield. Carboxyl-catalyzed intramolecular aminolysis. A side reaction in solid-phase peptide synthesis. J Am Chem Soc 94, 3102, 1972. 

FIGURE 7.34 Decomposition of the symmetrical anhydride of A-methoxycarbonyl-valine (R1 = CH3) in basic media.2 (A) The anhydride is in equilibrium with the acid anion and the 2-alkoxy-5(4//)-oxazolone. (B) The anhydride undergoes intramolecular acyl transfer to the urethane nitrogen, producing thelV.AT-fcwmethoxycarbonyldipeptide. (A) and (B) are initiated by proton abstraction. Double insertion of glycine can be explained by aminolysis of the AA -diprotected peptide that is activated by conversion to anhydride Moc-Gly-(Moc)Gly-0-Gly-Moc by reaction with the oxazolone. (C) The A,A -diacylated peptide eventually cyclizes to the IV.AT-disubstituted hydantoin as it ejects methoxy anion or (D) releases methoxycarbonyl from the peptide bond leading to formation of the -substituted dipeptide ester. 

The intramolecular aminolysis reaction was also shown to be involved in the formation of (Gly-Gly) and the biosynthetic pathway of the biologically active cyclic dipeptide cyclo(His-Pro), found throughout the CNS, peripheral tissue, and body fluids. ... 

The kinetics of the aminolysis reactions of the a-effect nucleophiles hydrazine and hydroxyiamine with Y-phenyl X-benzoates (8) have been reported." The results demonstrated that the magnitude of the a-effect decreases with increasing electron-withdrawing ability of the acyl substituents. The authors propose that hydrazine stabilizes the transition state (9) by intramolecular H-bonding. ... 

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminolysis during the coupling step with DCC. 70% of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proEne was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

Cl+ transfer from /V-chlorosuccinimidc (146) to an amine or amino acid to fonn an iV-chloro compound is seen as the key step in the reactions of (146) widi glycine, sarcosine, 2-methylalanine, proline, and pyrrolidine (Scheme 11). The reaction was first order in (146), first order in amine/amino acid and first order in proton.123 The aminolysis of /V-cthoxycarbonylphthalimide (14) was mentioned earher in this review.13 Twelve of the thiadiazoles (147) were prepared by the acid-catalysed intramolecular... 

Both of the examples of intramolecular Diels-Alder reactions of carbene complexes involve the 1,3-diene tethered through the heteroatom ancilliary substituent of the carbene carbon. - The example shown in Scheme 11 is the only example of a Diels-Alder reaction of an amino carbene complex. Al-kenylamino and alkynylamino complexes are inert to reaction under intermolecular conditions with very reactive dienophiles, such as cyclopentadiene and Danishefsky s diene. - The aminolysis of the meth-oxy complex (48b) with the amine (75) represents the most common method for the preparation of amino carbene complexes. - It is typical that two isomeric amino carbene complexes are obtained by this procedure, and, as is the case for the complexes (76) and (77), it is also typical that these isomers about the carbene-nitrogen bond are not interconvertable, even at elevated temperatures. The ( )-isomer (76) was separated and was found to undergo an intramolecular Diels-Alder reaction at 80 °C to give the interesting tricyclic caibene complex (78). 

---