Peptides dehydropeptides

Therefore, suitable unsaturated oxazolones can be used as intermediates to prepare dehydropeptides wherein the synthetic strategy used will depend on the position of the double bond in the final compound. If the double bond is located in the N-terminal amino acid, ring opening of the oxazolone 516 with the appropriate amino acid or peptide generates the desired dehydropeptide 517 directly. 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

Synthesis of Peptides by Hydrogenation of Dehydropeptides. In addition to the interest in dehydropeptides in their own right, these compounds are also used to prepare non-proteinogenic peptides by simple reduction. For example, the electrochemical reduction of dehydropeptides derived from 2,3-dimethoxybenzaldehyde has been described. ... 

Many other examples of Az-peptides are listed in the literature and suggest that Az-amino acids are usually more stable than the E isomers [76]. However, some dehydropeptides like the neurotoxins roquefortine 11 and oxaline 12, isolated from Penicillium roqueforti and Penicillium oxalicum, respectively, both contain a A His residue (Fig. 13.13) [77]. Phomopsin A 13 (Fig. 13.13), an antimitotic agent produced by Phomopsis leptostromiformis, is also a A -peptide as it contains A Asp and A Ile residues [78,79]. 

Numerous studies dealing with dehydropeptides have used model AzPhe-peptides owing to their easy chemical synthesis [76]. Preparative procedures are now available to produce various dehydroamino acids such as ALeu [90] and AVal [91] and efficient stereoselective methods are described for the synthesis of A -amino acids [92-94]. In particular, photoisomerization of AzPhe is a straightforward route to produce A Phe-containing peptides [95,96]. For example, UV irradiation of the tripeptide Boc-Ala-AzPhe-Val-OMe gave Boc-Ala-AEPhe-Val-OMe (Fig. 13.15) [97]. 

The conformational effects introduced by A-amino acyl residues in synthetic dehydropeptides have also been extensively studied and were shown to generate and/or to stabilize particular secondary structures in peptides. Much more is known about the conformational preferences of peptides containing Az-residues... 

The effect of Ca-Cp unsaturations in dehydropeptides may also be critical in metal ion binding, in particular in stabilizing the metallopeptide complexes much more efficiently than the corresponding saturated peptides. In particular, the configuration of the A-amino acyl moiety influences the ability of the peptide to bind Cu(II) and Ni(II) ions [113]. For example, the Z isomer of Gly-APhe-Gly has a higher affinity for Cu2+ than the E isomer [114]. 

A dehydropeptide has been cyclized to an imidazole derivative to serve as a model for the biosynthesis of luciferin from a crustacean." Unequivocal evidence for the lichen metabolite cyc/o-(R-/3-phenyl-i3-Ala-Pro)2 was provided by total synthesis. The cyclization step (20% yield) was achieved by ONP peptide-bond formation in pyridine at high dilution (6 mmole to 3000 ml). Nine isomeric cyclohexapeptides have been synthesized as models for the study of molecular interactions. ... 

N-Protected a, 8-dehydroamino-acids and a,j8-dehydroamino-esters can be coupled simply by formation of the acid chloride of the former using PClg. " Dehydropeptides can also be prepared by reaction of a-amino-acid chlorides with adducts of a-azido-a,j8-unsaturated esters and triethyl phosphite. " Peptides can be cyclized using diphenylphosphoryl azide, on a large scale if necessary, in 40—50% yields in favourable cases. ... 

Asymmetric Hydrogenation of Amino-acids.—The conversion of dehydropeptides into optically active peptides has been studied in detail this year. The double asymmetric hydrogenation of (291) leads to A -acetyl-(S)-phenylalanyl-(S)-phenylalanine methyl ester (292) with a diastereoselectivity of 98 2 (Scheme 143). This approach has been applied to the synthesis of enkephalin and of... 

The a,p-double bond in amino acid derivatives and peptides represents, in addition to the amino and carboxy groups, the introduction of a third highly reactive function into the molecule. It is therefore pertinent in a discussion of the a,P-dehydroamino acids to devote some attention to their primary addition products, such as derivatives of a-mercapto- and a-hydroxy-a-amino acids. Further topics relevant in this context are their relationship to P-hydroxy- and P-mercapto-a-amino acid derivatives (elimination-addition sequence), as well as syntheses and reactions of pyruvoylamino acids, which result from the hydrolysis of dehydropeptides and can possibly serve as precursors of the latter by condensation with amino acid amides. On the other hand, p,y- and y S-dehydroamino acids will be excluded from the scope of this discussion. The isolated double bonds of these compounds undergo the normal olefin reactions and display no unusual characteristics. 

Morin, R. B.. and E. M. Gordon Chemistiy of Dehvdropeptides. Formation of Dehydropeptides by Oxidation of Peptide Oxazolones. Tetrahedron Letters 1973,2163. 

Barrett, G. C., L. A. Chowdhury, and A. A. Usmani Formation of Dehydropeptides from Peptides. A Model System Establishing a Mechanism For the Biogenesis of Peptide Amides and a-Keto Acids. Tetrahedron Letters 1978, 2063. 

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