Thiazole amino acids

Chemical manganese dioxide (CMD). This form of Mn02 is used for batteries it is available from I. C. Sample office (Cleveland, Ohio, 44101). Shioiri et al. report it is superior to commercial activated Mn02 (Aldrich) and more convenient than freshly prepared activated Mn02 for dehydrogenation of 2-(l-ami-noalkyl)thiazolidine-4-carboxylic acids to the corresponding thiazoles (thiazole amino acids). 

A thiazolium amino acid (Taz) has been developed which can be utilized to mimic TDP-dependent enzyme function [52]. In this strategy, illustrated in Fig. 15, the commercially available amino acid 4-thiazolylalanine is incorporated into peptides by solid phase peptide synthesis. Prior to deprotection of the amino acid side chains and cleavage of the peptide from the resin, the thiazole amino acid is alkylated with an alkyl halide to generate the corresponding thiazolium amino acid having various N3-substituents (BzTaz = 3-benzyl-Taz, NBTaz = 3-nitrobenzyl-Taz). 

Synthesis of thiazole amino acids as precursors of marine cytotoxic cyclic peptides 91YZ1. 

Enantiomerically pure thiazoline and thiazole amino acids can be synthesized by condensation reactions between cysteine esters and chiral imino ethers derived from amino acids (Scheme 110)... 

In a similar way, the dipeptide (449) reacts with the thiazole amino acid (450) in the presence of benzotriazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) to give the corresponding tripeptide (451) (Equation (93)) <92CLI005>. 

The structure of the un-named alkaloid (19) obtained from a Thermoac-tinomyces strain has been confirmed by a simple synthesis from tryptamine and the thiazole amino-acid (20), prepared from (+)-(5)-alanine (Scheme 2). ... 

Further products prepared by the thionyl chloride method in solution are Dolastatin, a thiazole amino acid component (gln)Thz (70% yield) [1110], 4-phenyl-3-furoxanecarbonitrile (55% yield) [1111], ethyl 5-cyano-l-(l,l-dimethyl-ethyl)-lH-pyrazolo-4-carboxylate (61% yield) [1112], ethyl 2-anilino-4-chloro-5-cya-nothiophene-3-carboxylate (77% yield) [1113], and 4-cyanoisoxazole from its oxime tosylate (47% yield) [1114]. 

A related synthesis involved the preparation of a thiazole amino acid used in... 

The Indian ocean sea hare Dolabella auricularia has been found to be an exceptionally productive source of new bioactive products. Pettit et al (561,562) reported discovery of nine antineoplastic and/or cytotoxic substances in D. auricularia. Some 100 kg of the wet sea hare afforded about 1 mg each of these substances designated dolastatins 1-9. The primary structure of Dolastatin 3 was proposed as cyclo [Pro-Leu-Val-(gln)ThZ (gly)Thz] (871) (562) containing two unusual thiazole amino acids and the absolute configurations of each amino acid unit were speculated to bear the usual L-configuration on biosynthetic grounds. However, synthetic studies showed that structure 871 requires revision (562a, 562b). 

If wewakazole contains oxazole amino acids, trichamide and venturamides A and B contain two thiazole amino acids. These compounds were isolated from Trichodesmium erythraeum and Oscillatoria sp. (Buenaventura Bay, Panama). Trichamide A is the first natural product to be isolated from T. erythraeum venturamides A and B have antimalarial activities, with IC50 values around 5 xM. 

The application of this technique has shown that, in most cases, thiazole amino acids have the absolute configuration R. If these thiazole amino acids are the result of cyclization/dehydration between an amino acid and a cysteine, oxazole amino acids may be formed from a serine through a similar mechanism. To facilitate the writing of formulas, the symbols Tzl (thiazole), Tzn (thiazoline), Ozl (oxazole) and Ozn (oxazoline) are often used, and, depending on the nature of the alkyl group, we add the symbol of the normal amino acid (o-LeuTzl, o-ValTzl,... 

Biskupiak, J.E. and Ireland, C.M. (1983) Absolute configuration of thiazole amino acids in peptides./. Org. Chem., 48, 2302-2304. 

In this chapter we intend to outline the general methods by which the thiazolic ring is synthetized from open-chain compounds. The conversion of one thiazole compound to another is not discussed here, but in appropriate later chapters. Thus the conversion of thiazole carboxylic acids, halogeno-, amino-, hydroxy-, and mercaptothiazoles, to the corresponding unsubstituted thiazoles is treated in Chapters IV through VII, respectively. 

The condensation of thioacetic acid with amino acids under drastic conditions provides a useful new synthesis of thiazoles (Scheme 146) (668, 669). Instead of the amino acid, Af-acyl <279) or N-thioacylamino acids (278) are used. 

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Numerous variations of this reaction have been studied, principally those involving a prior inclusion of the nuclear sulfur atom in a thioacylamino compound. Thus, thiobenz-amido acetaldehyde diethyl acetal (8) underwent ring closure to 2-phenylthiazole (9) on gentle heating (57JCS1556). Similarly, iV-thioacyl a-amino acids also undergo ready ring closure to thiazoles. 

Other common five-membered heterocyclic amines include imidazole and thiazole. Imidazole, a constituent of the amino acid histidine, has two nitrogens, only one of which is basic. Thiazole, the five-membered ring system on which the structure of thiamin (vitamin Bt) is based, also contains a basic nitrogen that is alkylated in thiamin to form a quaternary ammonium ion. 

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... 

Strecker aldehyde are generated by rearrangement, decarboxylation and hydrolysis. Thus the Strecker degradation is the oxidative de-amination and de-carboxylation of an a-amino acid in the presence of a dicarbonyl compound. An aldehyde with one fewer carbon atoms than the original amino acid is produced. The other class of product is an a-aminoketone. These are important as they are intermediates in the formation of heterocyclic compounds such as pyrazines, oxazoles and thiazoles, which are important in flavours. 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

Further efforts in related series afforded structurally similar DPP-4 inhibitors such as acid 13 (E. Parmee, unpublished results), thiazole 14 [35] and cyclopentylglycine 15 (Figure 17.3) [36], Although 15 did not show improved selectivity over DPP-8/9,13 and 14 showed some improvement in selectivity over these counterscreens. Nevertheless, none of these compounds exhibited sufficient selectivity to merit further pursuit zwitterion 13 also possesses low oral bioavailability in rats (F < 1%). Consequently, focus in the a-amino acid series shifted to acyclic derivatives. 

The oxidation state of thiazolines and oxazolines can be adjusted by additional tailoring enzymes. For instance, oxidation domains (Ox) composed of approximately 250 amino acids utilize the cofactor FMN (flavin mononucleotide) to form aromatic oxazoles and thiazoles from oxazolines and thiazolines, respectively. Such domains are likely utilized in the biosynthesis of the disorazoles, " diazonimides, bleomycin, and epothiolone. The typical domain organization for a synthetase containing an oxidation domain is Cy-A-PCP-Ox however, in myxothiazol biosynthesis one oxidation domain is incorporated into an A domain. Alternatively, NRPSs can utilize NAD(P)H reductase domains to convert thiazolines and oxazolines into thiazolidines and oxazolidines, respectively. For instance, PchC is a reductase domain from the pyochelin biosynthetic pathway that acts in trans to reduce a thiazolyinyl-Y-PCP-bound intermediate to the corresponding thiazolidynyl-Y-PCP. ... 

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