The first total synthesis of thuggacin cmc-A and the determination of the absolute structure are described. The thuggacin family of antibiotics is of great interest due to the antibiotic activity against Mycobacterium tuberculosis. Based on the assumption that seven stereogenic centers in thuggacin cmc-A would share the same stereochemistry as thuggacin-A, all stereogenic centers of thuggacin cmc-A were strictly constructed in a stereocontrolled manner. The total synthesis allowed its stereostructure to be fully confirmed.

52 U.S. Cl. .................................... 514/438: 514/448; 514/454; 514/461; 514/471; 514/510; 514/530; 514/532, 514/535; 514/544; 514/567; 514/569; 514/717, 514/721; 514/730; 514/844; 514/859; 514/863; 514/864; 514/886 58 Field of Search ............... 549/497, 473, 498, 499, 549/501, 502, 77, 78, 79, 494,385, 389; 514/859, 886, 863, 864, 438,448, 461, 454, 471, 510,530, 532,535, 544, 567,569, 717, 721,730

This chapter contains sections titled: Introduction Formation of Five-membered Carbocycles by RCM Formation of Six-membered Carbocycles by RCM Formation of Seven-membered Carbocycles by RCM Formation of Eight-membered Carbocycles by RCM Formation of Nine-membered Carbocycles by RCM Formation of 10-membered Carbocycles by RCM Conclusion References

The rearrangement of dihydropyrans and dihydrofurans featuring appending olefins has been studied. The rearranged products bear resemblance with polyunsaturated di- and trisaccharides. Examples of functionalization prior to, or following, rearrangement are provided suggesting that the method should be useful for the synthesis of nonclassical saccharides. This work also illustrates the power of cascade methatetic processes for increasing molecular complexity starting from relatively simple heterocycles.

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.

The first examples of RCM-ROM-RCM-ROM-RCM sequences involving non-strained heterocyclic relays are described. The method can be used for the preparation Of polyunsaturated trisaccharides. (C) 2008 Elsevier Ltd. All rights reserved.

The first RCM-ROM-RCM sequence using a non-strained heterocycle as relay moiety is described. The course of the reaction strongly depends on the nature and relative configuration of the substituents in the starting trienic system. In addition, for a productive reaction to be observed, the site of initiation of the metathesis cascade is crucial. The compounds thus obtained may be useful for the synthesis of unusual polydeoxydisaccharides. (C) 2007 Elsevier Ltd. All rights reserved.

The use of vinyl- or alkynyl derivatives of the type C=C-X or C C-X (where X is an heteroatom) as substrates for metathesis increases further this reaction's versatility. Selected examples illustrating recent progress in this area of research are presented. Current scope and future potential developments are discussed. (c) 2006 Elsevier B.V. All rights reserved.

We report the synthesis of an adenosyl-derived indolylphosphonamide analogue of salicyladenosylmonophosphate involved in the plague and tuberculosis siderophore biosyntheses. The compound proved to be a potent inhibitor of the Yersinia pestis salicylate adenylation domain YbtE catalyzing the initial step of yersiniabactin biosynthesis.

Two new hydrolytically stable analogues of β-d-arabinofuranosyl-1-monophosphoryldecaprenol, the donor substrate for mycobacterial arabinosyltransferase, have been prepared. Biological evaluation of these compounds in vitro against Mycobacterium tuberculosis H37Rv strain revealed a promising activity.

4 OSW-1 analogues featuring modified carbohydrate moieties were prepared. The purpose of these modifications was to assess the importance of certain chemical functions with respect to biological activity. The synthesis and biological activity of the target molecules are shown.

Aryl acid adenylation domains are the initial enzymes for aryl-capping of catecholic siderophores in a plethora of microorganisms. In order to overcome the problem of iron acquisition in host organisms, siderophore biosynthesis is decisive for virulence development in numerous important human and animal pathogens. Recently, it was shown that growth of Mycobacterium tuberculosis and Yersinia pestis can be inhibited in an iron-dependent manner using the arylic acyl adenylate analogue 5'-O-[N-(salicyl)-sulfamoyl] adenosine that acts on the salicylate activating domains, MbtA and YbtE [Ferreras JA, Ryu JS, Di Lello F, Tan DS, Quadri LEN (2005) Nat Chem Biol1, 29-32]. The present study explores the behaviour of the 2,3-dihydroxybenzoate activating domain DhbE (bacillibactin synthesis) and compares it to that of YbtE (yersiniabactin synthesis) upon enzymatic inhibition using a set of newly synthesized aryl sulfamoyl adenosine derivatives. The obtained results underline the highly specific mode of inhibition for both aryl acid activating domains in accordance with their natively accepted aryl moiety. These findings are discussed regarding the structure-function based aspect of aryl substrate binding to the DhbE and YbtE active sites.

General considerations on the metathesis reaction are reported and illustrated by examples in the area of natural products and/or biologically active compounds.

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The preparation of a simple 1-oxa-spiro[2.4]heptane derivative is described. Observations made in the course of the synthesis show again that apparently minor structural modifications of the dienic substrate exert a strong influence on the ring-closing metathesis outcome and that the efficient construction of even simple but highly substituted systems by RCM may constitute a synthetic challenge.