Thiopeptides

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. 

These oligomers for which synthetic routes have been developed, are formally obtained by either the introduction of a peptide bond isostere (e.g. y9-thiopeptides [263],... 

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... 

Conformation and stability of thiopeptides (formed by replacing the amide oxygen atom with a sp2 sulfur atom) have been investigated by calculations. It has been confirmed that insertion of a thioamide linkage into a peptide structure is not conformationally neutral. It is predicted to be more rigid than peptide and produces substantial changes in peptide structure, primarily in the residues on the C-terminal side of the thioamide.78 80... 

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 enzyme contains five posttranslationally modified amino acids near the active site N-methyl-histidine, 5-methylarginine, 2-methylglutamine, 2-methyl-cysteine, and thioglycine in a thiopeptide bond. The latter may be the site of radical formation.4583 13... 

The steric bulk of the thioamide sulfur results in conformational changes that have been documented in cyclopentapeptide and cyclohexapeptide model systems (for more details see Vol. E22b, Section 6.8.5.2.1). For example, in c[-Proi(>[C(=S)-NH]Gly-Pro-Gly-D-Phe-], the first synthetic cyclic thiopeptide, an intramolecular y-turn seen in the all-amide parent compound by NMR methods was perturbed by the putative interaction of sulfur with the adjacent Pro s (3-protons.[9 On the other hand, in a cyclic hexapeptide, the enhanced H-bond donor capacity of the thioamide NH led to the formation of a relatively strong intramolecular H-bond stabilized (3-turn, which was frame shifted compared to that found in its all-amide parent peptide. 10 ... 

The procedure has been applied to the synthesis of thiopeptides [137] and, particularly, for the thionation of cyclosporine [164],... 

Scheme 17 Chemoselective Ligation of Thiopeptides to a Maleimide-Functionalized Template 981...

The P-turn-containing template molecule (see also Section 13.1.1.1.2) (0.352mmol) was dissolved in anhyd DMF (0.25 mL), TV-maleoy I - (5- a I ani n e V-hydroxysuccinimide ester (35 1.4 mmol, 4 equiv with respect to the e-amino groups of lysine residues) was added and the mixture was stirred at rt. The formation of the functionalized template molecule 36 was followed by analytical HPLC and was complete after 1 h. A soln of the thiopeptide 37 (1.408 mmol) in H20, pH 6-7, was added. The formation of the corresponding TASP molecule 38 occurred within 10 min. The mixture was lyophilized and the target TASP 38 was isolated as the major component by preparative HPLC yield 85%. 

New Routes to Thiopeptides Using 2,4-Bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-Disulfide as Suifuration Reagent... 

A monograph on the use of flash vacuum thermolysis techniques (FVT) has been edited by Vallee [17] and a specific review on thioketones and thioaldehydes has appeared [18]. Overviews have focused on carbohydrates bearing the thiocarbonyl group [19] and on thiopeptides [20]. 

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 derivatives of nitrobenzotriazole a-aminothionic acids, used as thioacylating agents in the synthesis of thiopeptides and nitrobenzotriazole thioacylating reagents, have been obtained in a similar way (Scheme 2.119) (624, 625],... 

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... 

Thiopeptides. Lawesson s reagent is effective for transformation of protected dipeptides into the corresponding thiopeptides (11. 55), but not for higher peptides, possibly because of the limited solubility of the reagent. For monothionation of oligopeptides, Belleau et al. recommend the related reagent 1, prepared from diphenyl ether, which is... 

T. Sifferlen, M. Rueping, K. Gademann, B. Jaun, D. Seebach, P-Thiopeptides Synthesis, NMR Solution Structure, CD Spectra, and Photochemistry , Helv. Chim. Acta 1999, 82, 2067 -2093. 

Schiller P. The measurement of intramolecular distances by energy transfer. Biochem. Fluores Concepts. 1975 285-303. Wiczk W, Gryczynski I, Szmacinski H, Johnson M, Kruszynski M, Sboinska J. Distribution of distances in thiopeptides by fluorescence energy transfer and frequency-domain fluorometry. Biophys. Chem. 1988 32 43-19. 

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>. 

Micrococcin PI 408 is a structurally complex thiopeptide its structure has been confirmed <2002TL2367>. 

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