Ferrocene-derived P,N ligands : synthesis and application in enantioselective catalysis

Due to their unique steric and electronic properties, air-stability and modular structure, chiral hybrid P,N-ferrocenyl ligands play a prominent role in the field of asymmetric catalysis. This report aims to give a concise introduction to the syntheses of chiral hybrid P,N-ferrocenyl ligands and presents an overview of their application in enantioselective catalysis. This review is of special interest to chemists working on ligand design and asymmetric catalysis, as well as to the broader organic and inorganic community

Divergent strategy for the synthesis of α-aryl-substituted fosmidomycin analogues

Fosmidomycin is the first representative of a new class of antimalarial drugs acting through inhibition of 1-deoxy-D-xylulose 5-phosphate ( DOXP) reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway for the synthesis of isoprenoids. This work describes a divergent strategy for the synthesis of a series of alpha-aryl-substituted fosmidomycin analogues, featuring a palladium-catalyzed Stille coupling as the key step. An alpha-(4-cyanophenyl)fosmidomycin analogue emerged as the most potent analogue in the present series. Its antimalarial activity clearly surpasses that of the reference compound fosmidomycin

Ruthenium-catalyzed cascade C-H activation/annulation of N-alkoxybenzamides : reaction development and mechanistic insight

A highly selective ruthenium-catalyzed C-H activation/annulation of alkyne-tethered N-alkoxybenzamides has been developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse annulation follows the Ru(ii)-Ru(iv)-Ru(ii) pathway involving N-O bond cleavage prior to alkyne insertion. This is highly different compared to the conventional mechanism of transition metal-catalyzed C-H activation/annulation with alkynes, involving alkyne insertion prior to N-O bond cleavage. Via this pathway, the in situ generated acetic acid from the N-H/C-H activation step facilitates the N-O bond cleavage to give the Ru-nitrene species. Besides the conventional mechanism forming the products via standard annulation, an alternative and novel Ru(ii)-Ru(iv)-Ru(ii) mechanism featuring N-O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C-H activation/annulation

Synthesis and evaluation of α,β-unsaturated α-aryl-substituted fosmidomycin analogues as DXR inhibitors

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Synthesis and biological evaluation of cyclopropyl analogues of fosmidomycin as potent Plasmodium falciparum growth inhibitors

A series of fosmidomycin analogues featuring restricted conformational mobility has been synthesized and evaluated as inhibitors of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase and as growth inhibitors of P. falciparum. The enantiomerically pure trans-cyclopropyl N-acetyl analogue 3b showed comparable inhibitory activity as fosmidomycin toward E. coli DOXP reductoisomerase and proved equally active when tested in vitro for P. falciparum growth inhibition. Conversely, the alpha-phenyl cis-cyclopropyl analogue 4 showed virtually no inhibition of the enzyme

Synthesis, trehalase hydrolytic resistance and inhibition properties of 4-and 6-substituted trehalose derivatives

Although trehalose has recently gained interest because of its pharmaceutical potential, its clinical use is hampered due to its low bioavailability. Hence, hydrolysis-resistant trehalose analogues retaining biological activity could be of interest. In this study, 34 4- and 6-O-substituted trehalose derivatives were synthesised using an ether- or carbamate-type linkage. Their hydrolysis susceptibility and inhibitory properties were determined against two trehalases, i.e. porcine kidney and Mycobacterium smegmatis. With the exception of three weakly hydrolysable 6-O-alkyl derivatives, the compounds generally showed to be completely resistant. Moreover, a number of derivatives was shown to be an inhibitor of one or both of these trehalases. For the strongest inhibitors of porcine kidney trehalase IC50 values of around 10 mM could be determined, whereas several compounds displayed sub-mM IC50 against M. smegmatis trehalase. Dockings studies were performed to explain the observed influence of the substitution pattern on the inhibitory activity towards porcine kidney trehalase

Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents

International audienceWe report the design and synthesis of a series of non-nucleoside MtbTMPK inhibitors (1-14) based on the gram-positive bacterial TMPK inhibitor hit compound 1. A practical synthesis was developed to access these analogues. Several compounds show promising MtbTMPK inhibitory potency and allow the establishment of a structure-activity relationship, which is helpful for further optimization

Rational design of an improved transglucosylase for production of the rare sugar nigerose

The sucrose phosphorylase from Bifidobacterium adolescentis (BaSP) can be used as a transglucosylase for the production of rare sugars. We designed variants of BaSP for the efficient synthesis of nigerose from sucrose and glucose, thereby adding to the inventory of rare sugars that can conveniently be produced from bulk sugars