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International audience; A chiral phosphathiahelicene scaffold displaying a phosphole and a thiophene unit as the terminal rings of the helical sequence has been synthesized and characterized by spectroscopic methods and X-ray diffraction studies. The phosphine oxides (HelPhos-V oxides) have been obtained following a robust and scalable synthetic approach, based on a nickel-promoted alkynes cyclotrimerization reaction. Then, late-stage functionalization has been carried out via a bromination/palladium coupling reaction sequence. The HelPhos-V gold(I) complexes have been used as catalysts in the unprecedented enantioselective [2+2] cyclization of N-homoallenyl tryptamine derivatives, to afford indolenine-fused cyclobutanes in good isolated yields, with enantiomeric excesses up to 93%.

Different 2-arylated oxazolo[4,5-b]pyrazines, obtained by palladium(II)-catalyzed domino reaction from 2,3-dichloropyrazine and the corresponding carboxamides, were functionalized by deprotometallation. Employing lithium 2,2,6,6-tetramethylpiperidine, in order to form a lithio derivative, and then trapping it by iodolysis, proved to be inefficient. However, the presence of a zinc-based in situ trap allowed most substrates to be functionalized. Deprotonation of the pyrazine ring was observed in the presence of tolyl and anisyl groups at the oxazole 2-position. In contrast, with chlorophenyl and thienyl groups in this 2-position, deprotonation rather occurred on these groups either competitively or exclusively. The regioselectivities were discussed in the light of calculated pK(a) values of the substrates in THF. Finally, in the case of 2-phenyloxazolo[4,5-b]pyrazine, we converted the mixture of 5- and 6-iodinated products into the corresponding 5,6-diiodide, which was further functionalized by a double Suzuki coupling.

Phosphole-based phosphahelicenes have been prepared which entail unprecedented phosphinamide functions. One of these diastereomeric phosphinamides displays an unusual propensity to intermolecular photochemical [2+2] cyclization leading to a bis phosphahelicene. The reaction affords the head-to-tail heterochiral diastereomer with total regio- and diastereoselectivity. The reaction has been observed not only in solution but also in the solid state, as a single-crystal-to-single-crystal process, under either X-ray or sunlight irradiation. The solid state arrangement of the starting compound strongly prefigures the geometry of the final dimeric species and accounts for the particular ease by which this reaction takes place. The second diastereomer of the phosphinamide does not undergo dimerization under analogous photochemical conditions, due to an unfavourable arrangement in the solid state.

This review presents an updated state of art of the catalytic uses of chiral phosphorus compounds characterized by a helical scaffold as the key stereogenic element of their structures. These include both helical scaffolds with appended phosphorus functions and helical scaffolds with embedded phosphorus-containing rings (phosphahelicenes). Catalytic applications of helical phosphines in both transition metal catalysis and organocatalysis are presented.

International audience; Phosphahelicenes with thiophosphinic acid and ester functions have been obtained via the oxidative photocyclisation of olefins bearing both a benzophenanthrene and a benzophosphole unit. When the method has been extended to olefins bearing a partially saturated benzophospholene unit, a divergent regioselectivity of the photocyclisation step has been observed, leading to new helicenes where the phosphorus function is located on the external rim of the helical backbone. The observed regioselectivity correlates well with the free-valence numbers of the atoms involved in the photocyclisation reaction (DFT calculations).

A convenient entry to yne-amides, useful building blocks for chemical synthesis whose synthesis can be rather difficult – especially in the acyclic series – is reported. They were found to be readily obtained by a simple ring opening of the corresponding, readily available yne-oxazolidinones with organolithium reagents. Surprisingly, no competitive carbolithiation of the highly reactive nitrogen-substituted alkyne or propargylic lithiation were observed, this method therefore providing a useful entry to yne-amides which can be obtained in fair to good yields.

The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-substituted oxazolopyridines, and in perspective, application of the recently published novel heterocycle oxazolopyrazine in medicinal chemistry studies.

A new tactic for the synthesis and selective functionalization of [1,2,4]triazolo[4,3-a]pyrazines has been developed using an oxidative cyclization as key step. Furthermore, novel strategies for introducing diverse substituents in all positions of the heterocycle were identified.

More than two decades ago, the quinoxalinedione scaffold was shown to act as an α-amino acid bioisoster. Following extensive structure–activity relationship (SAR) studies, the antagonists DNQX, CNQX, and NBQX in the ionotropic glutamate receptor field were identified. In this work, we revisit the quinoxalinedione scaffold and explore the incorporation of an acid functionality in the 6-position. The SAR studies disclose that by this strategy it was possible to tune in iGluR selectivity among the AMPA, NMDA, and KA receptors, and to some extent also obtain full receptor subtype selectivity. Highlights of the study of 44 new analogues are compound 2m being a high affinity ligand for native AMPA receptors (IC50= 0.48 μM), analogues 2e,f,h,k,v all displayed selectivity for native NMDA receptors, and compounds 2s,t,u are selective ligand for the GluK1 receptor. Most interestingly, compound 2w was shown to be a GluK3-preferring ligand with full selectivity over native AMPA, KA and NMDA receptors.

A one-pot, two-step reaction for the synthesis of benzo[4,5]thiazolo[2,3- c ][1,2,4]triazoles and related heterocycles under mild conditions was herein developed. The key step of this transformation is an oxidative cyclization employing PhI(OAc) 2 as reagent. Scope and limitations (group functionality tolerance and sterics) were studied showing the robustness of the present methodology which can be used as potential access to new fused heterocycle libraries.

Optimized reaction conditions for the Pd-catalyzed domino reaction between 2,3-dichloropyrazine and primary amides to form oxazolopyrazine derivatives are presented.

A convenient entry to yne-amides, useful building blocks for chemical synthesis whose synthesis can be rather difficult – especially in the acyclic series – is reported. They were found to be readily obtained by a simple ring opening of the corresponding, readily available yne-oxazolidinones with organolithium reagents. Surprisingly, no competitive carbolithiation of the highly reactive nitrogen-substituted alkyne or propargylic lithiation were observed, this method therefore providing a useful entry to yne-amides which can be obtained in fair to good yields.

An efficient and general synthesis of allenamides derived from oxazolidinones and hydantoins is reported. Upon activation with a combination of a copper catalyst and a 2,2′-bipyridine derivative in the presence of an inorganic base, propargylic bromides were found to be suitable reagents for the direct allenylation of nitrogen nucleophiles by a formal copper-catalyzed SN2′ reaction. Besides the availability of the starting materials, notable features of this route to allenamides are its mild reaction conditions, the reaction being performed at room temperature in most cases, and its applicability to the preparation of mono-, di-, as well as trisubstituted allenamides.

Due to their combined stability and peculiar reactivity, ynamides have emerged as remarkably useful building blocks for chemical synthesis. The development of general and robust methods for their preparation resulted in a massive interest for their chemistry. This notably resulted in the development of incredibly efficient processes starting from these building blocks which also recently found various applications in medicinal chemistry and natural product synthesis. Our efforts and contributions to the chemistry of ynamides, for which we have developed several reactions both for their preparation and for their use in synthesis, are overviewed in this highlight review.

An efficient and general synthesis of allenamides derived from oxazolidinones and hydantoins is reported. Upon activation with a combination of a copper catalyst and a 2,2'-bipyridine derivative in the presence of an inorganic base, propargylic bromides were found to be suitable reagents for the direct allenylation of nitrogen nucleophiles by a formal copper-catalyzed S(N)2' reaction. Besides the availability of the starting materials, notable features of this route to allenamides are its mild reaction conditions, the reaction being performed at room temperature in most cases, and its applicability to the preparation of mono-, di-, as well as trisubstituted allenamides.

The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-substituted oxazolopyridines, and in perspective, application of the recently published novel heterocycle oxazolopyrazine in medicinal chemistry studies.

Herein we describe the first structure–activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4′, or 5′ positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4′ position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 A resolution. Compound 2e induces a D1–D2 domain opening in GluA2-LBD of 17.3–18.8° and 2f a domain opening in GluK1-LBD of 17.0–17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

A short synthesis of 8-chloro[1,2,4]triazolo-[4,3-a]pyrazines (III) using a two-step, one-pot oxidative cyclization method is reported.

2-Furfural, 1H-indole-3-carbaldehyde and (3-formylphenyl)boronic acid lead to complex reaction mixtures and degradation.

Optimized reaction conditions for the Pd-catalyzed domino reaction between 2,3-dichloropyrazine and primary amides to form oxazolopyrazine derivatives are presented.

Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent inhibitors UCPH-101 and UCPH-102. In the present study, we set out to improve the solubility properties of these EAAT1 inhibitors with the objective to develop analogs more suited as pharmacological tools for in vivo studies of EAAT1 in terms of their bioavailability. A total of 23 novel UCPH-101/102 analogs were designed, synthesized and characterized pharmacologically at EAAT1-3 in a [(3)H]-D-aspartate uptake assay. Most notably, the potent EAAT1 inhibition displayed of UCPH-101 and UCPH-102 was retained in analog 1d in which the napht-1-yl group in the 7-position of UCPH-102 has been replaced by an o-biphenyl moiety. In contrast, EAAT1 activity was dramatically compromised in analogs 1e and 1f comprising m- and p-biphenyl groups as 7-substituents, respectively. Analog 1d displayed low bioavailability after oral administration in rats, and this problem was addressed by the synthesis of a series of analogs with different chloro, fluoro, methoxy, triflouromethyl and carboxy substitution patterns at the o-biphenyl group of 1d (1h-1s) and m- and p-pyridine analogs of 1d (1t and 1v). Unfortunately, all of the modifications resulted in substantial decreased EAAT1 inhibitory activity, which supports the notion of a very lipophilic binding pocket in EAAT1 for the aromatic 7-substituent in these ligands. In conclusion, while we have not succeeded in developing UCPH-101/102 analogs possessing improved bioavailability properties, this study does offer interesting SAR information about this inhibitor class, and analog 1d seems to be an interesting lead for future SAR studies with focus on the development of more potent EAAT1 inhibitors.

The excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate from the synaptic cleft. To date, five subtypes EAAT1-5 have been identified for which selective inhibitors have been discovered for EAAT1 and EAAT2. By screening of a commercially available compound library consisting of 4,000 compounds, N-acyl-N-phenylpiperazine analog (±)- exo -1 was identified to be a non-selective inhibitor at EAAT1-3 displaying IC50 values in the mid-micromolar range (10 μ M, 40 μ M and 30 μ M at EAAT1, 2 and 3, respectively). Subsequently, we designed and synthesized a series of analogs to explore the structure-activity-relationship of this scaffold in the search for analogs characterized by increased inhibitory potency and/or EAAT subtype selectivity. Despite extensive efforts, all analogs of (±)- exo -1 proved to be either inactive or to have least 3-fold lower inhibitory potency than the lead, and furthermore none of the active analogs displayed selectivity for a particular subtype amongst the EAAT1-3. On the basis of our findings, we speculate that (±)- exo -1 binds to a recess (deepening) on the EAAT proteins than a well-defined pocket.