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Antibiotic-resistant infections present significant challenges to patients. As a result, there is considerable need for new antibacterial therapies that eradicate pathogenic bacteria through non-conventional mechanisms. Our group has identified a series of halogenated phenazine (HP) agents that induce rapid iron starvation that leads to potent killing of methicillin-resistant Staphylococcus aureus biofilms. Here, we report the design, chemical synthesis and microbiological assessment of a HP-quinone ether prodrug model aimed to (1) eliminate general (off-target) iron chelation, and (2) release an active HP agent through the bioreduction of a quinone trigger. Here, we demonstrate prodrug analogue HP-29-Q to have a stable ether linkage that enables HP release and moderate to good antibacterial activities against lab strains and multi-drug resistant clinical isolates.

The constitutions of five metabolites formed during co-metabolic, anaerobic degradation of diethyl ether by the denitrifying betaproteobacterium Aromatoleum sp. strain HxN1 were elucidated by comparison of mass spectrometric and gas chromatographic data with those of synthetic reference standards. Furthermore, the absolute configurations of two stereogenic centers in the metabolites were established. Based on these results a degradation pathway for diethyl ether by Aromatoleum sp. HxN1 analogous to that of n-hexane is proposed. Synthesis of both enantiomers of methyl (E)-4-ethoxy-2-pentenoate was accomplished by etherification of ethyl (R)- or (S)-lactate, followed by hydrolysis of the ester group and reduction to furnish 2-ethoxy-1-propanol. The primary alcohol was converted by a Swern oxidation followed by a Horner-Wadsworth-Emmons reaction to methyl (E)-4-ethoxy-2-pentenoate that was finally hydrogenated to methyl 4-ethoxypentanoate. Methyl (S)-4-ethoxy-3-oxopentanoate was prepared by conversion of (S)-2-ethoxypropanoyl chloride with Meldrum's acid. Reduction of the resulting β-oxoester with NaBH4 or baker's yeast gave both diastereoisomers of methyl 4-ethoxy-3-hydroxypentanoate. The stereocenter at C-3 of the main diastereoisomer produced with baker's yeast was determined by Mosher ester analysis to be (R)-configurated. Dimethyl 2-(1-ethoxyethyl)succinate was prepared by Michael addition of nitroethane to diethyl maleate, followed by conjugate addition of sodium ethanolate, hydrolysis and esterification with diazomethane.

Parthenolide (PTL) strongly inhibits the detyrosination of microtubules and accelerates neuronal growth. In order to access cyclic ether derivatives of PTL, ring-closing metathesis (RCM) was investigated in comparison to intramolecular sulfone alkylation. Incompatibility of RCM with epoxides was found in this setting. Biological evaluation for tubulin carboxypeptidase inhibition indicated that the epoxide is crucial for parthenolide's activity.

An efficient C-C bond formation strategy between aromatic/heteroaromatic π-nucleophiles and Lewis acid activated aldehydes is described. This aromatic electrophilic substitution reaction of arenes or heteroarenes is facilitated by Lewis acid AlBr3. Aromatic rings with electron donating substituents are excellent nucleophilic counterparts in this reaction, generating carbinols in excellent yields (61-94%). The formation of triarylmethanes is also witnessed in the case of certain reactive aldehydes and aromatic π-nucleophiles through reactive carbocation formation. The formation of triarylmethane is reduced to a greater extent via retardation of the second π-nucleophile addition through a Lewis base, for example, pyridine, coordination with an aluminium alkoxide intermediate. Various aliphatic aldehydes also underwent Friedel-Crafts type hydroxyalkylation and generated the expected carbinols in moderate yields (41-53%) in the presence of AlBr3. This protocol has been successfully applied to the synthesize of the (±)-carbinoxamine, a therapeutically important histamine H1 antagonist, in a one-pot manner.

Three novel diglycerol tetraether lipids with one membrane-spanning chain have been synthesized. These lipids contain only two or four racemic methyl branches at selected positions of the hydrophobic chains in contrast to natural lipids from archaebacterial membranes with an isoprenoid substitution pattern. The insertion of the methyl moieties was realized starting from either (RS)-citronellyl bromide or the inexpensive methyl malonic acid ethyl ester. For chain elongation the Cu-catalysed Grignard coupling reaction was used. The preparation of diglycerol tetraethers was either performed by condensing suitable blocked monoglycerol diethers by Grubbs metathesis or by reaction of the transmembrane C32-chain with blocked glycerols followed by further alkylation steps. Finally, we could show that the resulting lipids can form closed lipid vesicles comparable to the optically pure counterparts. Therefore, these much simpler lipids compared to the natural lipids from archaebacterial membranes are also suitable for preparation of stable tailored liposomes.

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors., (This journal is © The Royal Society of Chemistry 2012)

A simple protocol for the synthesis of N-perfluoroacylated and N-acylated glycals of neuraminic acid, with a secondary cyclic amine (morpholine or piperidine) at the 4α position, has been set-up, starting from peracetylated N-acetylneuraminic acid methyl ester that undergoes, sequentially to its direct N-transacylation followed by a C-4 amination, a β-elimination, and a selective hydrolysis of the ester functions, without affecting the sensitive perfluorinated amide., (This journal is © The Royal Society of Chemistry 2012)

An asymmetric synthesis of (+)-castanospermine is presented in which enol ether metathesis-hydroboration/oxidation is used for stereoselective installation of the trans-trans hydroxyl groups on the piperidine ring of the alkaloid.

Recently, highly oxidized and structurally diverse triterpene polyethers, which are thought to be biogenetically squalene-derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial organisms. However, it is often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic quaternary carbon centers. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, we report total assignments of the previously incomplete stereostructures of an epoxy tri-THF diol, intricatetraol and enshuol, members of the oxasqualenoids, through the first asymmetric total syntheses of the natural products, the configurations of which are difficult to determine by other means. Since this article is basically written as a communication without detailed experimental procedures and spectroscopic data, original papers with full data should follow.

A current goal in synthetic chemistry is the design and synthesis of molecules that adopt well defined conformations-so called foldamers. In this manuscript we describe a modular approach for construction of rod shaped para-oligobenzamide molecules. Our approach permits regiospecific incorporation of side chains through a phenolic ether linkage on the scaffold; a feature that partly restricts the conformation of the rod through intramolecular hydrogen-bonding.

LPS from Rhizobium sin-1 (R. sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-alpha) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo beta-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R. sin-1 lipid A derivative in which the beta-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-alpha production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R. sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferon-inducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R. sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-alpha and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

6,6'-Linked ethers derived from D-allose, D-galactose, D-glucose, and D-mannose have been prepared in order to allow comparisons with the reported 6,6'-linked hexopyranose coyolosa, an hypoglycemic compound which has been isolated by extraction of the root of the palm Acrocomia mexicana. Comparison of NMR data from the ethers and their derived peracetates with corresponding reported data from coyolosa and its peracetate indicate that coyolosa is not a 6,6'-linked disaccharide. The synthesised compounds are representatives of a novel class of disaccharide derivatives which are linked tail to tail in contrast to the more usual head to tail(e.g. maltose) or head to head(e.g. trehalose) disaccharides.