2 -oxazolonium

FIGURE 8.20 Peptides activated at an IV-methylamino-acid residue are postulated to epimer-ize because of the formation of the oxazolonium ion. Evidence for the latter resides in spectroscopic studies,96 and the isolation of a substituted pyrrole that was formed when methyl propiolate was added to a solution of Z-Ala-MeLeu-OH in tetrahydrofuran 10 minutes after dicyclohexylcarbodiimide had been added.95 The acetylenic compound effected a 1,3-dipolar cycloaddition reaction (B), with release of carbon dioxide, with the zwitter-ion that was generated (A) by loss of a proton by the oxazolonium ion. 

A-Alkyl- and A-aryl-a-acylamino acids with a mixture of acetic anhydride and perchloric acid form 1,3-oxazolonium perchlorates... 

Cyclodehydration of l-carboxymethyl-2-pyridone with acetic anhydride and perchloric acid gave the corresponding 1,3-oxazolonium perchlorate which with triethylamine gave the dimer (72) directly. Similar dimerization of other meso-ionic l,3-oxazol-5-ones (66) have been reported. The monomer (71) could not be isolated, but acetyl (67, R = Me) and benzoyl (67, R = Ph) derivatives were prepared from a... 

German workers reported that 5-acyloxy-4(5/i/)-oxazolonium salts 24 are readily prepared by reaction of acyl cyanides and acid anhydrides in the presence of a strong acid (Scheme 6.8). Analogues like 24 are not available using the traditional methods (see above). 

Condensation products of 4(5//)-oxazolonium salts with aldehydes and orthoesters are the subject of a series of papers by Kosulina and co-workers Reaction of 2-methyl-4(5//)-oxazolonium perchlorates 44 with an ortho ester gives rise to an enol ether, which reacts with furanamides to afford the frani-eneamides 45 (Scheme 6.14). " Using electron deficient anilines in a three component condensation affords either 46 or 47 in 64-80% and 78-84% yields, respectively, depending on whether the reaction is performed in acetic acid or acetic anhydride. Electron-rich anilines are unreactive since they are merely protonated by the perchloric acid present in the reaction medium. ... 

TABLE 6.2. 2-[2-(a-HETEROARYL)ETHENYL]-4(5//)-OXAZOLONIUM PERCHLORATES FROM OXAZOLONIUM SALTS AND ALDEHYDES ... 

Figure 6.7. (E.Et-Dienes from a 2-methyl-4(5f/)-oxazolonium perchlorate.

Peptides containing the general structure 84 (Scheme 39) underwent between 50-100% cleavage in 95%TFA/H20 at room temperature in 60 minutes, that is, under routine conditions for the removal of a peptide from the resin after SPPS. The hydrolysis yielded the N-acyl-A-methyl peptide fragment 88.12041 The same peptides were also cleaved in solution but at a much slower rate (13-18 h). The hydrolysis occurs only when a carbonyl group is present at the N-terminal side of the N-methylated residue. The hydrolysis was accompanied by racemization of the N-methylated residue. The suggested mechanism involves the formation of the oxazolonium tetrahedral intermediate 87. This hydrolysis was circumvented by cleavage of the peptide (that did not contain functional side chains) from the resin with 0.1% NaOH in 50% aq MeOH (rt, 60 min). 

The next synthetic step is activation of the pendant carboxyl group and subsequent condensation with the desired C-terminal modified amino acid derivative. A readily epimerizable oxazolonium ion may form during the activation step by attack of the oxygen from the BAL-amide function to the activated carboxyl despite this risk, protocols have been developed to minimize racem-ization of this C-terminal residue (13). Features of these protocols include care-... 

Hydrogen exchange with the a-carbon-protons of the co-ordinated amino-acids in [Mo(A -C6H5)2(amino-acid)] could involve a carbanion or an oxazolonium ion intermediate. Whereas benzyl thiocyanate... 

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