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International audience; The construction of novel skeletons through the recombination of natural products ring systems is attractive. Herein, a basicitycontrolled synthesis of (dihydro)furo[2,3-c]quinolin-4(5H)-one derivatives through (3 + 2) cyclization between 3-hydroxyquino-lin-2-ones and β-chlorinated nitrostyrenes was developed. In addition, preliminary study gave the chiral dihydrofuro[2,3c]quinolin-4(5H)-one derivatives with up to 83 % ee.

International audience; Since the pioneer reports of Akiyama and Terada groups on Brønsted acid organocatalysis, this field never stopped growing with the development of ingenious strategies for the activation of challenging poorly reactive substrates. The development of superacidic organocatalysts is an important way to selectively functionalize reluctant electrophiles and other approaches have also emerged such as the combination of Lewis and Brønsted acids as well as the consecutive organocatalysis and superacid activation. This concept aims to highlight these different strategies and demonstrate their complementarity.

Despite tremendous efforts towards the development of organocatalytic enantioselective Michael additions of nitroalkanes to α,β‐unsaturated carbonyl compounds, highly substituted electrophiles remain challenging. β‐Arylidene‐α‐ketolactones and α‐ketolactams are used as highly electrophilic Michael acceptors that afford the corresponding products in moderate to good yields, with high enantioselectivities.

International audience; Atropisomers possessing multiple stereogenic axes are intriguing molecules with huge potential. However, only few approaches for their enantioselective synthesis are available due to the difficulties in assembling various stereogenic axes with high enantiocontrol. Only recently, innovative methods have emerged, opening new possibilities for the synthesis of this original class of atropisomeric compounds. This Minireview describes the development of this field based on a classification of the multi-axis systems according to the distance between the stereogenic axes and the strategy used to build them.

International audience; Enantioenriched complex fused-tricyclic azepanes or bridged-polycyclic azocanes were constructed via a two-step sequence involving an enantioselective organocascade followed by superacid activation of the domino adduct. The activated oxa-bridged azepane acts as a key hidden heptacyclic chiral N-acyl iminium ion triggering a chemo- and diastereoselective intramolecular mono- or di-arylation.

International audience; A new microplate analytical procedure is described for the determination of nickel (Ni2+) ions in natural water samples. A lophine analogue fluorescent sensor was synthesized and a spectral study showed a selective fluorescence quenching effect of chemical sensor by Ni2+ under optimized conditions. Density functional theory (DFT) calculations confirmed the formation of a Ni(II)L3 complex obtained by the Job plot. The calculations showed that the fluorescence emission peak of L collapses due to the distortion of L in the complex. The simple and fast microplate procedure allowed us to quantify Ni2+ with a linear response from 1.6 to 40 µg L-1 and a quantification limit of 5.4 µg L-1 without the need of a preconcentration step. The optimized procedure using high-throughput microplate assay has been applied for the determination of Ni 2+ in natural water samples with good analytical performances.

International audience; The design of an original molecular architecture featuring an unusual sterically congested C(sp2)–C(sp3) stereogenic axis with six high rotational barriers results in the formation of six different stereoisomers. The configuration of this axis can be controlled by transition metal catalysis and one out of six stereoisomers can be produced selectively.

International audience; A reinvestigation of a chiral phosphoric-acidcatalyzedfour-component Hantzsch enantioselective synthesis of polyhydroquinolines reported in 2009 is presented. In our hands, when the reaction was performed with fidelity to the original report using a chiral enantiopure phosphoric acid catalyst, noenantioselectivity was observed. Unlike in the original report,enantioselectivity results are backed by baseline separation of the enantiomers by HPLC analyses on chiral stationary phase with UV and chiroptical detection.

International audience; A new procedure is described for the determination of Hg 2+ ions in water samples. A Rhodamine based fluorescent sensor was synthesized and the experimental conditions were specifically optimized for application to environmental samples, which requires low detection limits and high selectivity in competitive experiments with realistic concentrations of other metal ions. Incorporation of a Rhodamine-6G fluorophore to a previously described sensor and optimization of the buffer system (detection with acetic acid at pH 5.25) enabled significant enhancement of the sensitivity (detection limit = 0.27 µg.L-1) and selectivity. The optimized procedure using high-throughput microplates has been applied to tap and river waters with good results.

International audience; An expedient synthesis of a new family of configurationally stable dioxa[6]helicenes was established using a sequential helicoselective organocatalyzed heteroannulation/eliminative aromatization via enantioenriched fused 2-nitro dihydrofurans featuring both central and helical chiralities. Starting from simple achiral precursors, a broad range of these previously unknown chiral heterocyclic scaffolds were obtained with good efficiency, and their aromatization proceeded with very high enantiopurity retention in most cases.

An atropisomer is a member of a subclass of restricted rotational conformers-this restricted rotation giving rise to stereogenic sigma bonds-that can be isolated as separate chemical species. Most atropisomer are six-membered-ring biaryl or heterobiaryl derivatives. The aim of this microreview is to shed light on a less common class of atropisomers, those containing at least one five-membered hetero-or carbocycle and displaying variously a stereogenic C-N, CC , or even N-N

International audience; A rapid synthesis of enantioenriched 2,3,4-trisubstituted tetrahydropyrans in good yields and stereoselectivities is reported. The first step is a domino organocatalytic reaction between ambident electrophilic and 1,4-bis-nucleophilic 1,2-ketoamides and 1,3-bis-electrophilic enals, leading to aza-oxa-bicyclo[3.2.1]octane. Then, the TiCl4/Et3SiH system ensures a chemoselective cleavage of the C−N bond and affords the desired trisubstituted tetrahydropyran in good yield and with conservation of the precursors optical purity. This final synthetic operation includes two consecutive oxocarbenium ion formation and reductions.

International audience; Achieving in a straightforward way the synthesis of enantioenriched elaborated three-dimensional molecules related to bioactive natural products remains a long-standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene-bridged benza-zocanes exhibiting three to five fully-controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7-membered ring N-acyl iminium superelectrophilic ion, evidenced by low-temperature in situ NMR experiments, triggers a challenging stereoselective Frie-del-Crafts-type cyclization.

We report the bidirectional enantioselective synthesis of bis-benzofuran atropisomeric oligoarenes featuring two distal C–C stereogenic axes. These are controlled by a two-fold central-to-axial chirality conversion upon oxidative aromatization., We report the bidirectional enantioselective synthesis of bis-benzofuran atropisomeric oligoarenes featuring two distal C–C stereogenic axes obtained by a two-fold central-to-axial chirality conversion upon oxidative aromatization. The key enantioenriched centrally chiral bis-dihydrobenzofuran precursors were synthesized via a bidirectional diastereo- and enantio-selective organocatalyzed domino reaction between simple achiral and easily accessible dihydroxylated aromatics and chloronitroalkenes. Moreover, the stereodivergent nature of the methodology was established by synthesizing both diastereomers of a non-symmetrically functionalized bis-axially chiral oligoarene.

International audience; Vinylidene-quinone methides (VQMs) are highly electrophilic chiral reagents that can be generated in situ from 2-(phenylethynyl)phenols. They were characterized for the first time in 2012 but their enantioselective organocatalytic activation was addressed only very recently. Their specific reactivity has revealed innovative strategies notably for the control of axial chirality. Vinylidene-quinone methides (VQMs) were synthesized and identified for the first time in 2012 by Freccero via excited-state intramolecular proton transfer (ESIPT) by irradiation of ortho-alkynylphenols. 1,2 These intriguing highly electrophilic intermediates are variants of well-known ortho-quinone methides (o-QMs) widely used in enantioselective transformations. 3 A critical feature of VQMs 2 is their intrinsic axial chirality that can be controlled during their generation from 2-alkynylnaphthols 1 with a chiral non-racemic organocatalyst (Scheme 1). 4 Once generated, VQMs can be involved in stereoselective cycloadditions or nucleo-philic additions with transfer of chirality. This allows access to original centrally chiral enantioenriched polycyclic pyrans 3 or to axially chiral naphthols 4. The first example of enantioselective activation of a VQM was described by the group of Irie in 2013 (Scheme 2). 5 The use of cinchonidine as the organocatalyst directly transformed symmetric bis-2-alkynylnaphthol 5a to axially chiral pyran 6a in good yield and moderate enantioselectivity through an intramolecular inverse-electron demand hetero-Diels-Alder reaction. This original strategy has been exemplified and developed last year by the group of Yan using a quinine-derived thiourea I for the organocatalytic activation. 6 Under these optimized conditions, this unique transformation proceeds highly chemo-and enantioselectively even with challenging non-symmetric bis-alkynylnaphthols 5b. Recently, DFT calculations showed that the axial chirality of the VQM intermediate is generated during the protonation step (Scheme 3). 7 First, the thiourea moiety of the catalyst acts as a Brønsted acid to activate the functionalized naphthol 5, which is deprotonated by the tertiary amine moiety of the catalyst I to form the intermediate 7. Afterward, the alkyne is enantioselectively protonated by the ammonium salt of the catalyst to give the chiral VQM intermediate 8, via the transition state 9. Then, a transfer of chirality operates during the key intramolecular [4+2]-hetero-Diels-Alder cycloaddition leading to 6. Scheme 1 Exploiting the reactivity of chiral VQMs. Scheme 2 Enantioselective synthesis of 2-aryl naphthopyran atropisomers.

International audience; Alkyl 4,5-dihydrofuran-2-carboxylates can be efficiently ob- tained via an enantioselective organocatalyzed consecutive reaction between _-keto esters and (Z)-(2-chloro-2-nitroethenyl)benzenes. The overall sequence combines a (R,R)-TUC-catalyzed Michael addition with a DABCO-promoted intramolecular O-alkylation leading to the title products as single diastereomers with enantiomeric excesses from 86% up to 97%.

A structure-activity relationship study of active molecules against chloroquine-resistant Plasmodium falciparum K1 strain is reported. Structurally simplified analogues of antiplasmodial active alkaloids presented similar levels of activity as their corresponding natural products extracted from Guiera senegalensis and Mitragyna inermis with IC50 values on chloroquine-resistant P. falciparum K1 strain of up to 10.6 μM for spirooxindoles and 13.8 μM for β-carbolines. The identification of such simpler and cheaper structural analogues is crucial to efficiently study these natural products' action mode as well as developing new cures against malaria.

International audience; alpha-Oxoketenes generated in situ by a thermal Wolff rearrangement have been found to participate as 1,2-and 1,4-ambident C-electrophilic/O-nucleophilic reagents towards donor/acceptor carbonyl-stabilized Wittig ylides. This resulted in the very direct and practical syntheses of func-tionalized allenes by a normal Wittig olefination, 4H-pyran-4-ones by an abnormal Wittig olefination, or 4H-pyranylidenes following a Wittig/abnormal Wittig cascade sequence as a function of the substrates combination employed. Mechanis-tic experimental and computational studies provided a full rational for these reactivity switches. Some unusual mecha-nistic features for Lewis acid-free Wittig olefinations were identified in this series such as the involvement of betaine intermediates and some degree of reversibility in the normal Wittig olefination. The abnormal Wittig olefination was fully uncovered.

International audience; A new strategy for the synthesis of optically active pyrrolo[ 1,4]benzo- diazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction–double cyclization sequence leading to the desired substituted benzodiazepine.

International audience; α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences. This new reactivity has been applied to the synthesis of enantioenriched azaspiro[4,5]decanone ring systems by a formal [3+3]spiroannulation, constituting a rare example of synthesis of glutarimides in an optically active form.

A focused library of chiral imidazolinium salts functionalized with urea-type hydrogen-bond donor moieties has been prepared from the chiral pool. The corresponding N-heterocyclic carbenes were evaluated as organocatalysts in three enantioselective reactions involving homoenolate intermediates generated from enals. The catalysts proved competent in enantioselective cyclopentannulation and γ-lactonization reactions, a premiere for imidazoline-based NHCs. This work conveys some new ideas and knowledge on the concepts of bifunctional enantioselective organocatalysis applied to NHCs.

International audience; Nucleophilic addition of pyridines to benzyne generates zwitterionic adducts that evolve by a rapid intramolecular proton shift to produce the corresponding pyridine carbenes, N-phenyl pyrid-2-ylidenes. In the presence of electrophilic ketones (isatin derivatives), the pyridylidenes can further react by an original bis-arylation reaction of the carbonyl compounds involving a formal pyridine C-H bond functionalisation. The overall transformation is an unprecedented three-compo- nent reaction featuring a carbene intermediate. The mechanism of this transformation was examined in detail by using both experimental and theoretical approaches. It was found that the generation of N-phenyl pyrid-2-ylidene from pyridine and benzyne is energetically favoured, and that the corresponding carbene dimer can also form easily. Under the three-component reaction conditions, the pyridylidene preferentially adds to the ketone group of the isatin derivative to produce a zwitterionic adduct amenable to an intramolecular aryl transfer reaction by a concerted nucleophilic aromatic substitution. This peculiar reactivity for a carbene was compared to possibly competitive known reactions of stable carbenes with carbonyl compounds, and the reaction was found to be under thermodynamic control. The reported method of generation of N-phenyl pyrid-2-ylidenes and their reactivity with carbonyl compounds unlock new perspectives in organic synthesis.

Polysubstituted chiral cyclohexanes and cyclohexenes are important building blocks in organic synthesis. From historical and pioneering reports to the most recent accounts, this review focuses on domino enantioselective organocatalytic methodologies that have allowed the control of the relative and absolute configurations of up to six stereogenic centers in the construction of these versatile molecular architectures. 1 Introduction 2 Two-Component Transformations 2.1 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 2.2 Michael-Initiated Domino Reactions with Nitroolefins 2.3 Non Michael-Initiated Domino Reactions 3 Multicomponent and Related Transformations 3.1 Pseudo-Three-Component Reactions 3.1.1 Michael-Initiated Domino Reactions with Nitroolefins 3.1.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.2 Consecutive Reactions 3.2.1 Michael-Initiated Domino Reactions with Nitroolefins 3.2.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 3.3 Multicomponent Reactions 3.3.1 Michael-Initiated Domino Reactions with Nitroolefins 3.3.2 Michael-Initiated Domino Reactions with α,β-Unsaturated Carbonyl Compounds 4 Conclusion

International audience; For the first time, enantiomerically enriched atropoisomeric furans have been accessed using a central- to-axial chirality conversion strategy. Hence, oxidation of the enantioenriched dihydrofuran precursors gave rise to axially chiral furans with high enantiopurities accounting from excellent conversion percentages (cp) in most cases.

International audience; Atropisomerism is a fundamental property of molecules featuring a hindered rotation around a chemical bond. If six-membered ring biaryl or heterobiaryl atropisomers are the most popular ones, the focus of this feature article will be put on less common and more challenging five-membered ring containing atropisomers displaying either a stereogenic C–N or C–C bond. After an historical background, a description of the latest flourishing enantioselective strategies for the construction of this attractive family of atropisomers will be presented.

In this feature article, a general perspective of the research program aimed towards the preparation of polycyclic heterocycles by the means of enantioselective organocatalytic multicomponent reactions is presented. Guidelines for reaction design, including the selection of substrates and organocatalysts are discussed. For all transformations, scope and limitations are presented, along with post-functionalization to afford diversified heterocyclic scaffolds. 1 Introduction 2 Type I Products: 1,4,5,6-Tetrahydropyridines 3 Type II Products: 1,2,3,4-Tetrahydropyridines 4 Type III Products: Bridged Perhydropyridines 5 Conclusion and Perspective

Suitably substituted enantioenriched 4-aryl-1,4-dihydro-pyridines prepared by an organocatalytic enantioselective Michael addition were oxidized with MnO2 into axially chiral 4-arylpyridines with central-to-axial chirality conversion. Moderate to complete percentages (cp) were observed, and a model for the conversion of chirality is discussed.

International audience; Synthetic applications of cyclobutanones other than ring expansion and fragmentation reactions are rare. Herein, highly efficient diastereo- and enantioselective organocatalytic Michael additions of 2-substituted cyclobutanone derivatives to nitroalkenes are reported allowing the stereocontrolled creation of " all-carbon " quaternary centers. The approach relies on both the use of Brønsted base/hydrogen-bond donor bifunctional organocatalysts, and importantly, the specific stabilization and activation of cyclobutanone with a secondary amide moiety. The reaction was found to nicely accommodate a broad scope of substrates, allowing the control of up to three contiguous stereogenic centers. This work has opened new synthetic opportunities.

International audience; α Oxoketenes generated in situ by a microwave assisted Wolff rearrangement-at 170°C were found to react with stabilized sulfur ylides in (4 + 1) annulation processesto afford functionalized 3 hydroxyfurans.-Theoretical mechanistic investigations revealed that the reaction proceeds in two steps via a short-lived betaine intermediate, a general feature of the reactions of α oxoketenes-with stable phosphorous, nitrogen, and sulfur ylides.

A new strategy for the synthesis of optically active pyrrolo[1,4]benzodiazepine-2,5-diones has been developed. The approach is based on an initial Michael addition of functionalized 1,2-ketoamides on nitroalkenes, with a reduction–double cyclization sequence leading to the desired substituted benzodiazepine.

International audience; Suitably substituted enantioenriched 4-aryl-1,4-dihydro-pyridines prepared by an organocatalytic enantioselective Michael addition were oxidized with MnO2 into axially chiral 4-arylpyridines with central-to-axial chirality conversion. Moderate to complete conversion percentages (cp) were observed, and a model for the conversion of chirality is discussed.

International audience; A review. The syntheses of four-​membered carbocycles are much less described than those of three-​membered ones. Because of the nature of their structures, domino approaches are clearly the methods of choice for their construction. Among them, transition-​metal- and organo-​catalyzed strategies are clearly the most popular ones, allowing the stereoselective construction of contiguous stereogenic centers in high selectivities, though catalytic and asym. approaches are mainly described using organocatalyts in MIRC processes.