Antibiotics thiopeptide

Nicolaou in his model system for an approach to the thiopeptide antibiotic thiostrepton, in particular, the elaboration of the quinaldic acid moiety. The tetrahydroquinoline 21 was converted to the A-oxide by /n-CPBA oxidation. Subsequent treatment with TFAA, to carry out the Boekelheide reaction, was followed by hydrolysis of the resultant ester to produce 22 as a mixture of alcohols. 

The oxidation of a thiazolidine derivative to the corresponding thiazole using activated manganese dioxide in dichloromethane at 100 °C is shown in Scheme 6.100. Further manipulation of this molecule led to dimethyl sulfomycinamate, a methano-lysis product of the thiopeptide antibiotic sulfomycin I [203]. 

Moody and coworkers have employed a biomimetic hetero-Diels-Alder-aroma-tization sequence for the construction of the 2,3-dithiazolepyridine core unit in amythiamicin D and related thiopeptide antibiotics (Scheme 6.243 a) [426]. The key cycloaddition reaction between the azadiene and enamine components was carried out by microwave irradiation at 120 °C for 12 h and gave the required 2,3,6-tris(thi-azolyl)pyridine intermediate in a moderate 33% yield. Coupling of the remaining building blocks then completed the first total synthesis of the thiopeptide antibiotic... 

Macrocyclic antibiotics also include a family of thiopeptides, of which thiostrepton (Figure 2.11) is the parent compound and the most complex member. Produced by Streptomyces azureus [59], thiostrepton includes 10 rings, 11 peptide bonds, extensive unsaturation, an imine functionality, a secondary amine, and 17 stereogenic centers [60] it also contains five thiazole rings and one quinoline nucleus. 

Intermolecular [4+2] cycloaddition strategies have also been used successfully. Moody and co-workers have reported the synthesis of a core piece of the thiopeptide antibiotics through a [4+2] cycloaddition <02CC1760>. For example, 2-azadiene 7 and 2-thiazolyl dienophile 8 were submitted to microwave heating (180 °C) for 15 minutes. The substituted pyridine product 9 was isolated in modest yield. Palacios has also reported an intermolecular [4+2] approach involving 2-azadienes <02JOC2131>. 

The author and colleagues employed 3 mm micro-inverse-detection NMR probe capabilities in an effort to assign the 15N resonances of the cyclic thiopeptide antibiotic sulfomycin-I (39)." Acquiring the long-range HMBC data in a 3 mm... 

The partial assignment of the N NMR resonances of the thiopeptide antibiotic sulfomycin-I produced by Streptomyces viridochromogenes was reported <1998MRC635>. 

The first phase of the total synthesis of thiostrepton 303, a highly complex thiopeptide antibiotic, has been described. Retrosynthetic analysis of thiostrepton revealed units 304-308 as potential key building blocks. Concise and stereoselective constructions of all these intermediates have been achieved. The synthesis of the dehydropiperidine core 308 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 305 and the thiazoline-thiazole segment 306 were synthesized by a series of reactions that included asymmetric and other stereoselective processes (Scheme 113) <2005JA11159>. 

Thiazoles can also be derived from 1,4-dicarbonyl compounds, which are available through the N-H insertion reaction of rhodium carbenoids <05JA15644>. For example, the dirhodium(II) carboxylate-catalyzed reaction of diazocarbonyl compound 8 in the presence of primary amide 7 leads to the formation of a-acylaminoketone 9, which is converted into thiazole 10 by treatment with Lawessons reagent. Thiazole 10 serves as one of the six thiazole building blocks in the total synthesis of thiopeptide antibiotic amythiamicin D. 

Boeck LD, Favret ME, Wetzel RW (1992) Biosynthesis of thiopeptide antibiotic A10255 in stirred reactors using a chemically defined medium supplemented with continuous nutrient feeds. J Antibiot 45 1278-1285... 

Amythiamicins, naturally occurring thiopeptide antibiotics isolated from a strain ofAmycolatopsis sp. MI481-42F4. The amythiamicins A-D belong to the very few thiopeptides that do not contain a dehy-droalanine moiety. They inhibit both the... 

Thiopeptide antibiotics, thiazolyl peptides, naturally occurring sulfur-containing, highly modified, macrocyclic peptides. They share a number of structural motifs, including several heterocycles such as thiazoles, a dehydropiperidine, a pyridine, oxazoles, and indoles. Nearly aU of the thiopeptide antibiotics act as inhibitors of protein synthesis in bacteria. They are secondary metabolites produced by actino-mycetes, largely by the genus Streptomyces. A representative member of this family is thiostrepton [M. C. Bagleyetal., Chem. Rev. 2005, 105, 685]. 

Thiostrepton, an important member of the thiopeptide antibiotics because of its biological and medical value. It was first isolated as early as 1954 from Streptomyces azureus. It is used in animal health care as a topical antibiotic. However, its application in humans is limited by its low solubility and bioavaUability which led to development of drug resistance by the proliferating bacteria. The total synthesis was described in 2005 [Y. Xing, D. F. Draper, Biochemistry 1996, 35, 1581 K. C. Nicolaou etal.,J. Am. Chem. Soc. 2005, 127, 11159]. 

Biomimetic synthesis of heteroaromatic thiopeptide antibiotics from amino acids 07AG(E)7930. 

Another example of a well-established class of natural products containing the thiazole heterocycle is the thiopeptide antibiotics. Often referred to as thiazolyl peptides, most of these highly modified, macrocyclic peptides inhibit protein synthesis in bacteria. They display a high inhibition... 

The Hantzsch-type of pyridine synthesis was also used in the total synthesis and stereochemical assignment of the thiopeptide antibiotic micrococcin Pl. ... 

Thiopeptide antibiotics are a class of highly modified macrocyclic sulfur-containing peptides, and nearly all the thiopeptide antibioties identified to date inhibit protein synthesis in bacteria. The Bohlmann-Rahtz pyridine synthesis is a useful methodology in the synthetic approach for thiopeptide antibiotics.For example, one-step Bohlmann-Rahtz assembly of 189 and 190 in the presence of ammonium acetate in acetic acid at reflux afforded the corresponding pyridine-thiazole cores of thiopeptide antibiotics 191 in 63% yield.The TBS protecting group was also replaced by an acetate, probably as a consequence of acid-promoted cleavage and consequent Fischer-type esterification of the liberated alcohol. 

The Boekelheide reaction was applied by the Nicolaou groups in the synthesis of a model system of the thiopeptide antibiotic thiostrepton (302). The tetrahydroquinoline 303 was converted into the A -oxide by /w-CPBA oxidation followed by treatment with TFAA and then hydrolysis to afford key intermediate alcohol 304 as a diastereomeric mixture. 

The Holzapfel-Meyers-Nicolaou modification is a significant improvement over the traditional Hantzsch conditions. However, racemization can still occur in some circumstances. For example, the two-step Hantzsch reaction of thioamide 20 with bromide 19 furnishes thiazole 21 with 60-85% enantiomeric excess due to partial epimerization at the a-stereogenic center. The epimerization issue is obviated when thioamide 20 is replaced with the ketal-protected thioamide 22. Reaction of 19 with 22 delivers 23 with good optical purity (> 96% ee). This thiazole represents the core structure of the potent thiopeptide antibiotic nosiheptide. ... 

Moody and co-workers employed the Hantzsch thiazole synthesis on several occasions in their total synthesis of the thiopeptide antibiotic amythiamicin Amythiamicin D functions by inhibiting the GTP-... 

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