Thiopeptides thiostrepton

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. 

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. 

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>. 

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]. 

Thiostrepton (bryamycin, thiactin). C72H85N19O18S5, Mr 1664.91, mp. 246-255 C, [a]go -98.5 (CH3COOH), a bicyclic thiopeptide produced by Streptomyces aureus with activity against Gram-positive bacteria and used as a fodder additive in animal breeding. T. inhibits protein biosynthesis, the mechanism of action corresponds to that of the structurally related nosiheptide. The biosynthesis of T. is the subject of intense investigation, it is assumed that the core peptide chain is formed non-ribosomally via a multi-enzyme complex. 

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. 

Keller and coworkers succeeded in the preparation of several aromatic carboxylic acid-activating starter enzymes involved in the biosynthesis of actinomycin (4-methyl-3-hydroxyanthranilic acid) (105,113,114), triostin (qninoxaline-2-carboxylic acid) (105,115), and mikamycin (3-hydroxypicolinic acid) (105,116). More recently, related enzymes have been identified in the Actinomycetes that form the thiopeptides nosihep-tide and thiostreptone (117,118), and in the pristinamyctn biosynthetic system (de Crecy-Lagard V, personal communication). Whether direct acylation of the pantetheine-attached starter amino acid occurs, or an additional transferase frinction is required, has not been settled. 

Figure I ScTuciures of thiopeptide aniibiotics. The amino acids incoipoiaied into chioHrepron and nosihepcide are represented as peptide chains, and the quinaldk (thiostrepton) and indnlic acid (nosihepttde) moieties are shown to arise from tryptophan.

Clearly, numerous biosynthetic reactions are required to synthesize thiopeptide antibiotics. The amino acid compositions of thiostrepton and nosiheptide were determined by feeding experiments, but these studies could not provide information about the... 

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