Oxazole-containing peptides

A new method for the solid phase synthesis of oxazole-containing peptides 105 was developed, based on cyclodehydration followed or preceded by oxidation in a biomimetic fashion. The oxazole nucleus was obtained starting from threonine or serine and the method is compatible with most protecting groups <06OL2417>. 

Scheme 38 Structures of Dihydrooxazole- and Oxazole-Containing Peptides...

Another possible method for the selective introduction of thioamide bonds into cyclic peptides is the use of oxazoles. 513-515 The oxazoles, which can be generated in serine- or threonine-containing peptides by the use of the Burgess reagent [(methoxycarbonyl-sulfamoyl)triethylammonium hydroxide inner salt) or under Mitsunobu conditions (see Section 6.8.5.2.2.2), are thionylated with hydrogen sulfide and triethylamine. A disadvantage of this method is that it is limited to serine- and/or threonine-containing peptides. 

The oxazole-containing cyclic peptides are synthesized predominately by the direct use of suitably protected 2-(l-aminoalkyl)oxazole-4-carboxylic acids since oxidation of the ox-azolidine precursors to the oxazole ring with Mn0215581 or Ni0215861 (or even with H20215641 or... 

Other notable oxazole-containing natural products that have received intense scrutiny include macrolide phorbox-azoles and cyclic peptide diazonamide (Figure 6). The structure of diazonamide has been revised from the original assignments as the result of an elegant total synthesis study <2003AGE4961>. 

Both the genera Halidona and Sigmadocia belong to the same family of Chalinidae, order Haplosclerida, which is well known for its oxazole-containing qfclic peptides, the haliclonamides (see Chapter 19). 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

The synthesis of oxazole- and dihydrooxazole-containing cyclic peptides has gained considerable interest in view of the structural characterization of the natural products. In fact, in various cases a final structural elucidation was provided only by total synthesis as originally proposed structures had to be corrected because of epimerization, difficult stereochemical assignment, and/or impurities.1523,524,554,5551... 

Examples of the cyclodehydration of peptide segments containing serine or threonine residues or the corresponding oxo amides to oxazoles are given in Table 2, Section 11.2.3.5. 

To a large extent, similar methods are used for the preparation of thiazole-, dihydrothiazole-, and thiazolidine-based peptides as presented in Section 11.2.3 for the preparation of the corresponding oxazole- and dihydrooxazole-based peptides. However, the oxidation of dihydrothiazole and thiazolidines to the aromatic heterocycles is considerably more facile than for the analogous oxygen-containing substrates. 

Kobayashi J, Itagaki F, Shigemori H, Takao T, Shimonishi Y (1995) Keramamides E, G, H, and J, New Cyclic Peptides Containing an Oxazole or a Thiazole Ring from a Theonella sponge. Tetrahedron 51 2525... 

A library of cyclic peptides was obtained by the cyclooligomerization of mixtures of azole-based amino acids. This synthetic approach was applied to the synthesis of bistratamide H and didmolamide A, cyclic peptides containing oxazole rings <07OBC1541>. Other cyclic scaffolds based on oxazole peptides were published <07EJO1779 07T9862 07NAR3272>. 

The azide procedure for peptide synthesis and particularly for fragment condensations is considered to be a mainly racemization free method. This low racemization tendency of azides was explained by several theories, which have been reviewed.t l The most plausible cause of racemization is the formation of oxazoles (Scheme 3) and the related enolization. In presence of bases the a-carbon proton is readily abstracted to form an anionic oxazol-5(4//)-one resonance system.For the formation of the oxazol-5(4//)-one the influence of the substituent Y on the a-carbonyl is essential. Since the a-carbonyl group of amino acid azides are less activated and thus relatively insensitive to oxygen containing nucleophiles such as water and alcohols, oxazol-5(4//)-one formation is largely prevented. It was proposed that the soft electron shell of the azide shields the a-carbonyl atom, so that only strong nucleophiles can attack it.t 1 The reactivity towards amines can be explained in a manner analogous to the aminolysis of anchimerically assisted active esters.h 1... 

The cyclamides are small cyclic peptides that characteristically contain multiple thiazole, thiazoline, oxazole, and oxazoline rings, which are derived from cysteine, serine, and threonine residues. Some of the first examples of this class to be described were the patellamides (53-55) from the tunicate Lissoclinum patella, although it was later determined they were produced by the symbiotic cyanobacterium Prochloron sp. The structures were solved by a combination of acid hydrolysis and GC analysis, coupled with 2D NMR. Smaller cyclic peptides from this class include the hexapeptides westiellamide (56) and microcyclamide (57) from M. aeruginosa Many members of the class possess cytotoxic properties, although their biological function or mechanism of action is not fully understood. In contrast to many cyanobacterial peptides, aside from the unusual heterocyclic residues, these peptides generally contain only ribosomal amino acids. 

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