Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg-1 and ∼43% at 60 mg kg-1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.

A Dy4 Cubane: A New Member in the Single-Molecule Toroics Family.

Molecular materials that possess a toroidal moment associated to a non-magnetic ground state are known as single-molecule toroics (SMTs) and are usually planar molecules. Herein, we report a Dy4 cubane, namely [Dy4 (Bppd)4 (µ3 -OH)4 (Pa)4 (H2 O)4 ]⋅0.333 H2 O (where BppdH=1,3-Bis(pyridin-4-yl)propane-1,3-dione and PaH=2-Picolinic acid) for which magnetometry measurements and state-of-art ab initio calculations highlight SMT behavior in a tridimensional structure (3D-SMT). The in-depth theoretical analysis on the resulting low-lying energy states, along with their variation in function of the magnetic exchange pathways, allows further light to be shed on the description of single-molecule toroics and identify the coupling scheme that better reproduces the observed data.

Superacidic Cyclization of Activated Anthranilonitriles into 2-Unsubstituted-4-aminoquinolines.

4-Aminoquinolines were prepared in a three-step synthesis starting from substituted anthranilonitriles. The condensation on 1,1,1-trichloro-4-ethoxybut-3-enone proceeded efficiently either neat or in refluxing EtOH. Cyclization in superacidic trifluoromethanesulfonic acid provided unstable intermediate, which upon treatment with NaOEt in ethanol, afforded the expected esters. Theoretical investigations pointed out a monoprotonated nitrilium as the reactive species during the cyclization process.

Polyboramines for Hydrogen Release: Polymers Containing Lewis Pairs in their Backbone.

The one-step polycondensation of diamines and diboranes triggered by the in situ deprotonation of the diammonium salts and concomitant reduction of bisboronic acids leads to the assembly of polymer chains through multiple Lewis pairing in their backbone. These new polyboramines are dihydrogen reservoirs that can be used for the hydrogenation of imines and carbonyl compounds. They also display a unique dihydrogen thermal release profile that is a direct consequence of the insertion of the amine-borane linkages in the polymeric backbone.

Straightforward synthesis of 5-bromopenta-2,4-diynenitrile and its reactivity towards terminal alkynes: a direct access to diene and benzofulvene scaffolds.

The high-yielding synthesis of 5-bromopenta-2,4-diynenitrile (BrC5 N) was achieved for the first time. Its reactivity with triisopropylsilylacetylene and triisopropylsilylbutadiyne in the presence of copper and palladium as co-catalysts and diisopropylamine was evaluated. It revealed an unprecedented cascade reaction leading to a diene in one case and to a benzofulvene in the other case, with a unique structure. Both of them were characterized by X-ray crystallography, among other techniques. The mechanism of the reaction leading to the diene was investigated experimentally. Theoretical calculations at the DFT level suggest that the mechanism leading to the benzofulvene relies on a hexa-dehydro Diels-Alder (HDDA)-type of mechanism. This work constitutes an example of an unanticipated reactivity leading to an important increase of chemical complexity.

Efficient Pd-catalyzed allene synthesis from alkynes and aryl bromides through an intramolecular base-assisted deprotonation (iBAD) mechanism.

An optimized ligand-controlled palladium-catalyzed allene synthesis starting from alkynes and aryl bromides giving rise to allene products in a simple and direct manner is described. The methodology is performed in an inter- and intramolecular fashion with unprecedented scope and excellent yields. Based on mechanistic investigations and on DFT calculations, the role played by the carboxylic additive (i.e., PivOH) in controlling the selectivity of the reaction is discussed, allowing us to propose an intramolecular base-assisted deprotonation (iBAD) mechanism for this process.

Ligand-controlled α- and ß-arylation of acyclic N-Boc amines.

The palladium-catalyzed ligand-controlled arylation of α-zincated acyclic amines, obtained by directed α-lithiation and transmetalation, is described. Whereas PtBu3 gave rise to α-arylated Boc-protected amines, more flexible N-phenylazole-based phosphine ligands induced major ß-arylation through migrative cross-coupling.

Palladium-catalyzed ß-arylation of silyl ketene acetals and application to the synthesis of benzo-fused δ-lactones.

Silyl ketene acetals are shown to be competent nucleophiles in Pd-catalyzed migrative C(sp(3))-H arylations. Compared to the parent ester lithium enolates, they possess decreased reactivity but enhanced chemoselectivity. This behavior was exploited through the synthesis of valuable benzo-fused δ-lactones such as 1-isochromanones and dihydrocoumarins.

On the mechanism of the palladium-catalyzed ß-arylation of ester enolates.

The palladium-catalyzed ß-arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the α/ß-arylation reactions of ortho- and meta-fluorobromobenzene was described. Selective ß-arylation was observed for the reaction of o-fluorobromobenzene with a range of biarylphosphine ligands, whereas α-arylation was predominantly observed with m-fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of α-/ß-arylated products. Next, the effect of the substitution pattern of the aryl bromide reactant was studied with DavePhos as the ligand. We showed that electronic factors played a major role in the α/ß-arylation selectivity, with electron-withdrawing substituents favoring ß-arylation. Kinetic and deuterium-labeling experiments suggested that the rate-limiting step of ß-arylation with DavePhos as the ligand was the palladium-enolate-to-homoenolate isomerization, which occurs by a ßH-elimination, olefin-rotation, and olefin-insertion sequence. A dimeric oxidative-addition complex, which was shown to be catalytically competent, was isolated and structurally characterized. A common mechanism for α- and ß-arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to ß-arylation was kinetically favored over the pathway leading to α-arylation, with the palladium-enolate-to-homoenolate isomerization being the rate-limiting step of the ß-arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate-limiting step changed with PCy(3) and PtBu(3) ligands, and with the latter, α-arylation became kinetically favored. The trend in selectivity observed experimentally with differently substituted aryl bromides agreed well with that observed from the calculations. The presence of electron-withdrawing groups on these bromides mainly affected the α-arylation pathway by disfavoring C-C reductive elimination. The higher activity of the ligands of the biaryldialkylphosphine ligands compared to their corresponding trialkylphosphines could be attributed to stabilizing interactions between the biaryl backbone of the ligands and the metal center, thereby preventing deactivation of the ß-arylation pathway.

A new class of conjugated strigolactone analogues with fluorescent properties: synthesis and biological activity.

A new class of strigolactone analogues has been synthesized. They differ from known molecules, both of natural and synthetic origin, in two main features. The conjugated system extends from the enol ether bridge to the A ring, the B ring is a heterocycle while the C ring is a cyclic ketone instead of a gamma-lactone. The key step of the synthesis is a Nazarov cyclization on activated substrates. Bioassays using Orobanche seeds have revealed that all the molecules strongly stimulate germination; in particular the oxygen containing analogues are the most active. Interestingly, some of the new molecules show fluorescent properties.

Synthesis of Weinreb amides via Pd-catalyzed aminocarbonylation of heterocyclic-derived triflates.

The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO atmospheric pressure and at room temperature. The carbonylative coupling can be efficiently carried out with 2% of catalyst in the presence of Xantphos as a ligand. The amides smoothly react with nucleophiles to afford acylated aza-, oxa-, and thio-heterocycles. The proposed methodology could be advantageously exploited for the synthesis of dienones in which one of the double bonds is embedded in a heterocyclic moiety, as useful substrates for Nazarov cyclization.

The Lewis acid-catalyzed nazarov reaction of 2-(n-methoxycarbonylamino)-1,4-pentadien-3-ones.

[reaction: see text] A highly efficient carbonylative Suzuki-Miyaura coupling reaction of lactam-derived vinyl triflates and alkenylboronic acids afforded 2-(N-methoxycarbonylamino)-1,4-pentadien-3-ones as suitable substrates for the Nazarov reaction. The most competent Lewis acids for the Nazarov reaction were Cu(OTf)(2) (2 mol %) and Sc(OTf)(3) (3 mol %) in DCE, which provided the Nazarov products in excellent yield. As both the carbonylative coupling and the subsequent Nazarov reaction were high yielding, the overall methodology is a concise and efficient route to [1]pyrindine systems.