Thiazoline Peptides

1-Thiazoline Peptides. Hirotsu et al. have continued their studies of model compounds and reactions designed to provide the basic information for a projected total synthesis of bacitracin A. 

The synthesis displays interesting stereochemical features. Thus, ethyl 2-(l -benzyloxycarbonylaminoethyl)-(J )-2-thiazoline-4-carboxylate (197) was obtained (0 by the imino-ether route , by condensing L-2-benzyloxy-carbonylaminopropioimino ethyl ether (198) and ethyl L-cysteinate hydrochloride (route A) and (ii) by the dehydration of benzyloxycarbonyl-L-alanyl-L-cysteine ethyl ester (199) (route B). Acidic hydrolysis of the 

Hirotsu, T. Shiba, and T. Kaneko, Bull. Chem. Soc. Japan, 1970, 43, 1564. 

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Benzylthio or 2-benzyloxy derivatives of A-2-thiazoline-5-one (224) are readily opened by amines to give the amide derivatives (225) (Scheme 115) (459. 471). Compound 225 can be cyclized thermally to the corresponding thiohydantoins (459). Similarly, treatment of 4-substituted-2-phenylthiazol-5(4H)-ones (226) with amino acids, peptides, or hydrazine affords the corresponding Nfcti-thiobenzamidoacetylated derivatives (227) (Scheme 116) (455). 

A direct conversion of the oxazoline (44) to the thiazoline (45) can be achieved by the thiolysis of the oxazoline (44) with H2S in methanol in the presence of triethylamine followed by cyclodehydration with Burgess reagent. This method is essentially free from racemisation and has been used in the transformation of peptide substrates <95TL6395>. 

Cyclodehydration of p-hydroxythioamides under Mitsunobu conditions (Method a) has provided peptide thiazoline in 80% yield with 78 22 ratio of A B and 56% de. Treatment of p-hydroxythioamides with Me02CNS02NEt3,... 

The carbon in the isothiocyanate grouping is highly susceptible to nucleophilic attack by the peptide s free amino group. Overall addition to the C=N creates a thiourea derivative. Making the conditions strongly acidic then promotes nucleophilic attack by the sulfur of the thiourea on to the carbonyl of the first peptide bond, producing a five-membered thiazoline heterocycle. Proton loss occurs from the nitrogen, and this creates an intermediate that is equivalent to the addition product in simple acid-catalysed amide... 

Under these reducing conditions of hydrolysis of tryptophan peptides, cystine is reduced to cysteine and its coelution with proline using standard buffer gradients, makes quantitation difficult. Thus, cysteine and cystine are generally derivatized prior to acid hydrolysis by oxidation to cysteic acid with performic acid 21 or alkylation, upon reduction in the case of cystine, with iodoacetic acid 21 or, more appropriately, with 4-vmylpyridine)22 23 50 Conversion of cysteine into 5- 3-(4-pyridylethyl)cysteine bears the additional advantage of suppressing epimerization via the thiazoline intermediate, thus allowing for standardization of the acid-hydrolysis dependent racemization of cysteine in synthetic peptides)24 ... 

That the Indo-Pacific (Fig. 7.1.II) is an area of high natural product diversity was first revealed by the studies carried out in the 1970 s at the Roche Research Institute on the Great Barrier Reef (Baker 1980). Studies worldwide have since confirmed this richness, unsurpassed by any other area, either in the sea or on land. The variety of small peptides from the Indo-Pacific is impressive, characterized, particularly with the ascidians, by the condensation of the cysteine NH2 and SH groups with the COOH group of an adjacent amino acid. Thiazole and thiazoline rings are formed, which alternate with the normal peptide bonds formed by the other amino acids (Chart 7.2.P1-3). Correspondingly, threonine forms methyloxazoline moieties (Chart 7.2. A, 7.2.P1,7.2.P2). These condensations inqiose a drastic conformational bias to peptides (Abbenante 1996). 

Bisebromoamide is cytotoxic linear peptide isolated from the marine cyanobacterium Lyngbya sp. (Teruya et al., 2009). Structure of bisebromoamide contains rich unusual amino acid derivatives with D-amino acids, N-methylated amino acids, a brominated tyrosine, a modified 4-methylpro-line, a 2-substituted thiazoline-4-methyl-4-carboxylic acid unit, and a rare... 

Lissoclinum species of tunicates produce a range of cyclic peptides, which contain thiazole, thiazoline and oxazoline rings. Most belong to the general families patellamides (octapeptides), lissoclinamides (heptapeptides) or bistratamides (hexapeptides) [22],... 

The synthesis of thiazoles from dihydrothiazoles (thiazolines) has experienced broad application as a method for incorporating thiazoles into the backbone of peptides (see also Vol. E 22 b, Section 6.8.5.2.2). The ability to incorporate thiazoles into the backbone of peptides by oxidation of dihydrothiazole precursors is consequently limited to the methods available for the synthesis of the required dihydrothiazole precursors. The most straightforward approach would allow for a peptide containing natural amino acids to serve as a precursor to... 

The thiazoline and thiazole rings are present in many cyclic peptides isolated from marine organisms. Most of these types of compound have been isolated from tunicates belonging to the Lissoclinum and Didemnum genus, from sponges of the genus Theonella, and from the sea hare mollusc Dolabella auricularia. The isolation of closely related compounds from cyanobacteria pointed out the symbiont origin of these metabolites. 

Other Thiazole/Thiazoline-containing Cyclic Peptides... 

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

The strategy of this synthesis is different from that for the examples described above. Heathcock assembles a peptide chain of the S-protected 2-methylcysteines and closes all four thiazoline rings simultaneously at the end. The synthesis of the peptide (Scheme 16) starts with the coupling of the 2-methylcysteine compounds ent-25 and 26. 

Now an oxazoline thiazoline conversion is achieved by nucleophilic opening of the tris(oxazolines) to the 2-methylcysteine peptide 79 with thioacetic acid. For the ring closure Wipf uses titanium tetrachloride according to Heathcocks protocol. The side chain of tris(thiazoline) 80 is oxidized with benzenesele-nic acid to provide the desired natural product thiangazole 4. 

The thiazole ring is synthesized biochemically by enzymatic post-translational modifications of cysteine-containing peptides. Heterocyclization between cysteine side-chains and neighboring carbonyl groups produces dihydrohetero-aromatic thiazolines as initial products followed by a two-electron redox reaction yielding either thiazole or thiazo-lidine rings (Scheme 104). All three oxidation states are seen in natural products. 

As illustrated in Scheme 134, both distereoisomers of thiazolidine 535 prepared from commercially available amino acid derivatives 533 and 534 can serve as /3-turn mimetics in the secondary structure of peptides and proteins therefore, they play an important role in many molecular recognition events in biological systems <2002TL1197>. A similar application can be found with thiazoline lactams <1999TL477>. 

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