ADP-heptose is a newly identified pathogen-associated molecular pattern of Shigella flexneri.

During an infection, the detection of pathogens is mediated through the interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. ß-Heptose 1,7-bisphosphate (ßHBP), an intermediate of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a bacterial PAMP. It was reported that ßHBP sensing leads to oligomerization of TIFA proteins, a mechanism controlling NF-κB activation and pro-inflammatory gene expression. Here, we compare the ability of chemically synthesized ßHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. We find that, unlike bacterial lysate, ßHBP fails to initiate rapid TIFA oligomerization. It only induces delayed signaling, suggesting that ßHBP must be processed intracellularly to trigger inflammation. Gene deletion and complementation analysis of the LPS biosynthesis pathway revealed that ADP-heptose is the bacterial metabolite responsible for rapid TIFA oligomerization. ADP-heptose sensing occurs down to 10-10 M. During S. flexneri infection, it results in cytokine production, a process dependent on the kinase ALPK1. Altogether, our results rule out a major role of ßHBP in S. flexneri infection and identify ADP-heptose as a new bacterial PAMP.

Synthetic Studies toward the C14-C29 Fragment of Mirabalin.

A convergent synthesis of one isomer of the C14-C29 fragment of mirabalin is disclosed. The key steps include a Marshall allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization, which allow the control of 10 out of 25 stereogenic centers present in the molecule.

Iron- and indium-catalyzed reactions toward nitrogen- and oxygen-containing saturated heterocycles.

A myriad of natural and/or biologically active products include nitrogen- and oxygen-containing saturated heterocycles, which are thus considered as attractive scaffolds in the drug discovery process. As a consequence, a wide range of reactions has been developed for the construction of these frameworks, much effort being specially devoted to the formation of substituted tetrahydropyrans and piperidines. Among the existing methods to form these heterocycles, the metal-catalyzed heterocyclization of amino- or hydroxy-allylic alcohol derivatives has emerged as a powerful and stereoselective strategy that is particularly interesting in terms of both atom-economy and ecocompatibility. For a long time, palladium catalysts have widely dominated this area either in Tsuji-Trost reactions [Pd(0)] or in an electrophilic activation process [Pd(II)]. More recently, gold-catalyzed formation of saturated N- and O-heterocycles has received growing attention because it generally exhibits high efficiency and diastereoselectivity. Despite their demonstrated utility, Pd- and Au-complexes suffer from high costs, toxicity, and limited natural abundance, which can be barriers to their widespread use in industrial processes. Thus, the replacement of precious metals with less expensive and more environmentally benign catalysts has become a challenging issue for organic chemists. In 2010, our group took advantage of the ability of the low-toxicity and inexpensive FeCl3 in activating allylic or benzylic alcohols to develop iron-catalyzed N- and O-heterocylizations. We first focused on N-heterocycles, and a variety of 2,6-disubstituted piperidines as well as pyrrolidines were synthesized in a highly diastereoselective fashion in favor of the cis-compounds. The reaction was further extended to the construction of substituted tetrahydropyrans. Besides triggering the formation of heterocycles, the iron salts were shown to induce a thermodynamic epimerization, which is the key to reach the high diastereoselectivities observed in favor of the most stable cis-isomers. It is worth noting that spiroketals could be prepared by using this method, which was successfully applied to a synthetic approach toward natural products belonging to the bistramide family. We then turned our attention to heterocycles incorporating two heteroatoms such as isoxazolidines. These frameworks can be found in biologically active natural products, and in addition, they can be transformed into 1,3-amino alcohols, which are of importance in organic chemistry. The use of FeCl3·6H2O allowed the access to a large variety of 3,5-disubstituted isoxazolidines from δ-hydroxylamino allylic alcohol derivatives with good yields and diastereoselectivities in favor of the cis-isomer. Recently, a Lewis acid-catalyzed synthesis of six- and five-membered ring carbonates starting from linear tert-butyl carbonates was reported. In some cases, the mild and chemoselective InCl3 was preferred over FeCl3·6H2O to avoid side-product formation. The resulting cyclic carbonates were easily transformed into 1,3- or 1,2-diols, and a total synthesis of (3S,5S)-alpinikatin was achieved.

Heck coupling using a vinyliodo-MIDA boronate: an efficient and modular access to polyene frameworks.

A simple Heck coupling between an alkenyl iodo-boronate and a variety of terminal olefins is disclosed. This method gives access to a wide range of dienic moieties including valuable bis-functionalized dienes. The synthetic potential of the coupling reaction is demonstrated by a short and modular preparation of several tetraenic compounds.

Synthetic strategy toward the C44-C65 fragment of mirabalin.

A convergent and flexible stereoselective synthesis of one isomer of the C44-C65 fragment of mirabalin is described. The key steps include organocatalytic aldolization, ruthenium-catalyzed asymmetric hydrogenation, amide formation, Marshall stereoselective allenylation, and the Nozaki-Hiyama-Kishi reaction.

FeCl3·6H2O, a catalyst for the diastereoselective synthesis of cis-isoxazolidines from N-protected δ-hydroxylamino allylic acetates.

An ecofriendly and diastereoselective synthesis of cis-3,5-disubstituted isoxazolidines through the FeCl3·6H2O-catalyzed cyclization of δ-hydroxylamino allylic acetates is described. The synthetic potential of these products is highlighted by the preparation of several functionalized 1,3-amino alcohol precursors.

Optimization of a Novel Series of TRPV4 Antagonists with In Vivo Activity in a Model of Pulmonary Edema.

High-throughput screening and subsequent hit optimization identified 1-piperidinylbenzimidazoles, exemplified by compound 1, as TRPV4 inhibitors. Lead optimization identified potent TRPV4 blocker 19, which has good target activity and pharmacokinetic properties. Inhibitor 19 was then profiled in an in vivo rat model, demonstrating its ability to inhibit TRPV4-mediated pulmonary edema.