Total Synthesis of Thuggacin cmc-A and Its Structure Determination.

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.

A diverted total synthesis of mycolactone analogues: an insight into Buruli ulcer toxins.

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.

OSW-1 analogues: modification of the carbohydrate moiety.

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.

Inhibition of aryl acid adenylation domains involved in bacterial siderophore synthesis.

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.

Metathesis reactions. General considerations.

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

The application of olefin metathesis to the synthesis of biologically active macrocyclic agents.

Recent developments of the metathesis reaction in the area of biologically active molecules are presented. Scope and limitations of ring-closing metathesis to form medium and large rings are discussed and illustrated by the epothilone synthesis. Applications of the metathesis reaction related to medicinal chemistry, including solid phase synthesis and combinatorial chemistry are presented.

Controlled synthesis of cis or trans isomers of 1,3-disubstituted tetrahydroisoquinolines and 2,5-disubstituted pyrrolidines.

[reactions: see text] The stereoselective outcome of Pd(II)- or Ag(I)-catalyzed intramolecular N-alkylation to afford 1,3-disubstituted 1,2,3,4-tetrahydroisoquinolines was examined. In the absence of additional substituents, Pd(II) allows a facile access to the cis isomers, while Ag(I) favors formation of the trans isomers. The same observation was made for the synthesis of 2,5-disubstituted pyrrolidines. Possible reasons for the observed stereoselectivities are discussed.

Enantioselective approaches to potential MetAP-2 reversible inhibitors.

[reaction: see text] Enantioselective deprotonation of 4-substituted cyclohexanones and highly stereoselective conjugate addition of higher order mixed cuprates were the key steps in a concise synthesis of fumagalone-related molecules. The origin of the (low) biological activity of the new compounds as compared to fumagalone is briefly discussed.

Copper-mediated cross-coupling of H-phosphonates with vinyliodonium salts: a novel very mild synthesis of 2-arylvinylphosphonates.

We report a novel, very mild, highly stereoselective preparation of 2-arylvinylphosphonates at room temperature that involves the copper iodide-mediated cross-coupling of H-phosphonates with vinyliodonium tetrafluoroborates. [Structure: see text]

MetAP-2 inhibitors based on the fumagillin structure. Side-chain modification and ring-substituted analogues.

The preparation of a series of new fumagillin-derived MetAP-2 inhibitors is described. The synthetic approach was designed so as to permit modification of the fumagillin backbone at sites inaccessible through semisynthesis or previously existing total syntheses. An Evans aldolization and a ring-closing metathesis allowed the preparation of a pivotal intermediate which could then be functionalized in various ways using already established or newly developed methodologies.

Silicon tether-aided coupling metathesis: application to the synthesis of attenol A.

A new synthesis of attenol A is described. Key features of this work include a crucial silicon tether-aided coupling metathesis step and the use of iodoetherification as an efficient protection method for 1,5-ene-ols. [reaction: see text]