Dipeptides, cyclization

Dipeptides, cyclization to piperazinediones, 57, 189 Diphenylamine, in Skraup reaction, 55, 302 Diphosphabenzvalene,... 

Dipeptide cyclization toward the protonation of free carboxyl groups followed by the release of water and the formation of new intramolecular peptide bonds. 

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline 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. 

The principal pathway for the decomposition of aspartame begins with the cleavage of the ester bond, which may or may not be accompanied by cyclization (Eig. 2). The resultant diketopipera2ine and/or dipeptide can be further hydroly2ed into individual amino acids (qv). 

A recent report describes the conversion of A-formyl- and N-acetyl-L-leucine into optically active azlactones with dicyclohexyl-carbodiimide (DCC) [Eq. (29)]. Other cyclization reagents, e.g. acetic anhydride, POCI3, SOCI2, and polyphosphoric acid, cause racemiza-tion. These azlactones react with optically active amino acid esters to give esters of dipeptides with retention of activity. 

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Similarly, acylation of the dipeptide 410 with bromoacetyl chloride followed by base-induced cyclization gives the pyrazinylacetate ester 411 <2001BML1251>. Compound 410 is itself cyclized with />-toluenesulfonic acid to give the (iV-alkylated indole) equivalent of 406 <200JME3518>. 

In the synthesis of the azabicyclic core of the Stemona alkaloids, methyl (2/W,3.9/ ,3a/W)-2-(2-cthoxycarbonylethyl)-hexahydropyrrolo[l,2- ]isoxazole-3-carboxylate was hydrogenolyzed over 10% Pd-C in EtOAc and acetic acid at room temperature to give after cyclization the bicyclic lactam 153 <2005JOC3157> (Equation 22). This route was also used to produce pyrrozilidinone-based dipeptide isosteres <2005T8836>. 

Janetka and Rich (78) have utilized the considerable stability of ruthenium-77-arene systems in the synthesis of cyclic tripeptides as analogs of the protease inhibitor K-13 (cf. 34, Scheme 28). Their approach involves the construction of linear tripeptide complexes (35) using diimide/HOBt coupling of [Ru(Cp)(Boc-p-Cl-PheOH)]PF6 (Cp = 775-C5H5) with the appropriate dipeptide ester. Cyclization of 35 affords the biphenyl ether 36, which on photolysis (350 nm) gives 34. 

FIGURE 6.24 The cis and trans forms of the amide bond of a dipeptide ester and cyclization of the compound to the piperazine-2,5-dione. The tendency to cyclize is greater when the carboxy-terminal residue is proline or an IV-methylamino acid. In these cases the predominating form is cis, which places the amino and ester groups closer together. 

The traditional method for preparing activated esters of A -protected dipeptides is combination of the A-protected amino acid with the amino acid ester (Figure 7.16). The latter is obtained by A-deprotection of the diprotected amino acid in an acidic milieu. Coupling is achievable using the carbodiimide, mixed-anhydride, and acyl-azide methods. Success with this approach indicates that the esterified residues react preferentially with the other derivatives and not among themselves. The chain cannot be extended to the protected tripeptide ester because the dipeptide ester cyclizes too... 

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. 

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