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International audience; Apratoxin A is a potent anticancer natural product whose key polyketide fragment constitutes a considerable challenge for organic synthesis, with five prior syntheses requiring 12 to 20 steps for its preparation. By combining di erent redoxeconomical catalytic stereoselective transformations, the key polyketide fragment could be rapidly prepared. Followed by a siteselective protection of the diol, this strategy enables the preparation of the apratoxin A fragment in only six steps, representing the shortest route to this polyketide.

Cationic polycyclic aromatic compounds containing one or more nitrogen atom(s), also known as azonia polycyclic aromatic compounds, form a valuable class of molecules because of their fluorescent and/or medicinal properties. N-Arylated hydroisoquinoline derivatives were synthesized through an aryne aza-Diels–Alder cycloaddition/N-arylation sequence. A subsequent two-electron oxidation allowed the synthesis of some axially chiral cationic benzo[c]phenanthridinium derivatives. The structural and optical properties of some of these molecules were determined. Their chirality was evidenced experimentally by single-crystal X-ray diffraction and 1H NMR spectroscopy, and their conformational behavior was examined by computational DFT methods.

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.

International audience; The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1'bi-2,2'-naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two-step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9'-bianthracenyl-based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4-ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.

International audience; Using a specially designed prototype of a nonracemic aryne atropisomer with a low barrier to enantiomerization (ca. 36 kJ•mol −1), it was possible to determine the kinetic constant of its cycloaddition with furan in solution by a combination of theoretical calculations and experimental measurements. It was found that the reaction half-life of this aryne atropisomer in solution with 100 equivalents of furan as the trapping reagent is

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; The regioselectivity of molecular sieves-promoted oxidative three-component reaction between -ketoesters, aromatic o-diamines and acrolein, leading to pyrido[1,2-a]benzimidazoles, has been investigated by a combination of experimental and theoretical studies. Molecular sieves act both as heterogeneous catalyst and dehydrating agent and their role has been modeled in the theoretical approach. The modulation of the reactivity of the aromatic diamine partner as a function of the nature of the substituents of the aromatic ring and its influence on the regioselectivity of the reaction could be rationalized.

International audience; The enantioselective construction of fluorohydrins featuring a tetrasubstituted stereocenter embedded in complex frameworks represents an important challenge. Herein, we report a multicatalytic strategy enabling the stereoselective preparation of a new type of scaffold containing such a challenging fluorohydrin motif. The sequence is based on an organo-catalyzed fluorination of α-disubstituted aldehydes followed by a diastereoselective copper-catalyzed decarboxylative aldol reaction. Reduction of the generated β-hydroxy ketone followed by a Lewis base-catalyzed kinetic resolution enables the isolation of original fluorinated 1,3-diols with perfect diastereoand enantio-control.

International audience; Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically > 99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er > 95 : 5).

The stereoselective syntheses of spirobicyclic and tetracyclic pyrazolidinones are reported based on a (3+2) annu- lation between hydrazones and α-oxoketenes. Some of these conformationally constrained molecules were resolved as enantiopure materials by HPLC techniques and evaluated as amino- catalysts for iminium activation in a model Diels–Alder cyclo- addition.

International audience; An original two-step organocatalytic syn- thesis of optically active glutarimides from 2- oxocyclobutane carboxamides is described featuring an isothiourea-catalyzed two-atom ring-expansive rearrangement.

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; The progress in enantioselective organocatalysis have enabled efficient and highly stereoselective syntheses of cyclobutane derivatives, through (2 + 2) annulation reactions, overcoming the geometrical constraints inherent to these small cyclic molecules. More importantly, and taking advantage of their strain-releasing fragmentation, some cyclobutane derivatives, especially cyclobutanones and cyclobutenones, can now be regarded as versatile four-carbon atoms units amenable to the enantioselective construction of larger rings by (4 + n) annulation reactions to produce, five-, six-, seven-and eightmembered cyclic products. These recent developments concerning the enantioselective synthetic chemistry of cyclobutane derivatives under organocatalytic conditions are reviewed herein.

International audience; Enantioenriched aryne atropisomers having a biaryl stereogenic axis vicinal to the reactive triple bond are demonstrated to exist. These reaction intermediates are easily produced in situ and can undergo the standard aryne cycloaddition chemistry in an enantiospecific manner. Notably, the aryne atropisomers herein have allowed the practical syntheses of a small nanographene as well as some triptycene and anthracene derivatives that embed stereogenic axes of controlled absolute configurations.

Inversions in the periselectivity of formal aza-Diels&ndash, Alder cycloadditions between &alpha, oxoketenes generated by a thermally-induced Wolff rearrangement and 1-azadienes were observed experimentally as a function of the &alpha, oxoketene and the 1-azadiene, as well as the reaction temperature and time. Some unexpected inversion in the diastereoselectivity was observed, too. These variations in selectivities were fully rationalized by computational modeling using density functional theory (DFT) methods.

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.

International audience; In order to prepare more efficiently key 1,3-diol fragments, we have devised a base-promoted redox-neutral condensation of ketones with alcohols. This diastereoselective alcohol−aldolization enables bypassing the classical oxidation and reduction steps necessary for the preparation of this crucial backbone by an overall redox-neutral formal borrowing hydrogen process. The starting alcohols constitute both the precursors of the in situ generated reactive aldehydes and the hydride source necessary for the chemoselective reduction of the aldol adduct intermediates. I n order to minimize steps and waste generation associated with the stereoselective elaboration of complex organic scaffolds, the invention of redox-neutral approaches is crucial. 1 These transformations, such as the popular borrowing hydrogen , have the power to avoid unnecessary operations and stoichiometric reagents associated with stepwise oxidation and reduction sequences, a step further toward eco-compatible synthesis. 2 The elaboration of 1,3-diols, a common motif found in a wide variety of natural products and drugs (Scheme 1a), is a classic example of a synthetic sequence often involving successive undesired redox steps. 3 This key architecture is usually constructed via aldol reaction between a carbonyl and an aldehyde (Scheme 1b). However, the starting aldehyde is often prepared by oxidation of the corresponding alcohol, and the aldol adduct must then be reduced to form the desired 1,3-diol. As a result, such a sequence implies two undesired time-and energy-consuming redox steps. In order to limit redox issues, different alternatives have been proposed such as the aldol Tishchenko-type disproportionation. However, this reaction occurs from the aldehyde oxidation level and requires an additional equivalent of aldehyde to promote the reduction of the aldol product through intramolecular hydride transfer. 4 Most interestingly, a broad range of elegant metal-catalyzed redox-neutral couplings have been developed such as the allylations of alcohols. 5 While these strategies elegantly enable constructing alcohols directly from the same oxidation state, further derivatizations of the obtained alkenes through redox manipulation is mandatory to obtain complex polyol scaffolds. Given 1,3-diols oxidation state, in order to obtain the best synthetic ef f iciency, their elaboration should imply a redox-neutral cascade construction by aldol condensation directly between a ketone and an alcohol. Inspired by the synthetic economies provided by borrowing hydrogen approaches, we present a new conceptual alcohol−aldolization for the direct construction of anti-1,3-diols

The thermal 6π aza-Diels-Alder cycloadditions between α-oxoketenes

Tetrahydropyridines are important heterocycles present in many molecules of natural and non‐natural origins that exhibit a wide array of biological activities. With several sp3‐hybridized carbon atoms in their structure, they often include one or several stereogenic centers, whose control represents a great synthetic challenge. For the past two decades, enantioselective organocatalysis has developed as a very powerful strategy to perform the synthesis of enantioenriched compounds, including heterocycles. In this Microreview, we wish to provide the readers with a general overview about the organocatalytic strategies that have been used to achieve the preparation of diversified families of tetrahydropyridines, thereby providing elements of reflection for further developments.

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; A bicatalyzed three-component cascade between simple aliphatic enolizable aldehydes, a fluorine source, and keto acids has allowed the diastereoselective and enantioselective direct synthesis of carbonyl-elongated vicinal fluorohydrins. The obtained complex acyclic functionalized molecules, possessing up to four stereogenic centers controlled in usually >95% ee, hold great promise for further synthetic developments and rapid incorporation in bioactive elaborated structures.

International audience; We report a molecular design and concept using p-system elongation and steric effects from helicenes surrounding a triphenylene core toward stable chiral polycyclic aromatic hydrocarbons (PAHs) with a maximal p-distortion to tackle their aromaticity, supramolecular and molecular properties. The selective syntheses, and the structural, conformational and chiroptical properties of two diastereomeric large multi-helicenes of formula C90H48 having a triphenylene core and embedding three [5]helicene units on their inner edges and three [7]helicene units at their periphery are reported based on diastereoselective and, when applicable, enantiospecific (!) Yamamoto-type cyclotrimerizations of racemic or enantiopure 9,10-dibromo[7]helicene. Both molecules have an extremely distorted triphenylene core, and one of them exhibits the largest torsion angle recorded so far for a benzene ring (twist = 36.9º). The analysis of aromaticity distribution in these model molecules using magnetic criteria revealed a non-aromatic character of their triphenylene cores and provides a new look at aromaticity in threedimensional PAHs. One diastereomer can complex up to three silver(I) ions in the bay region (cavities) of its peripheral [7]helicene units, opening the door to chiral cationic metal-nanographene hybrids.

International audience; This review highlights the different enantioselective catalyst-controlled cascades creating multiple alcohol functions through the formation of several carbon-carbon bonds. Through subsequent simple derivatiza-tion, these strategies ensure the rapid preparation of 1,3-polyols. Thanks to the use of efficient metal-or organo-catalysts, these cascades enable the selective assembly of multiple substrates considerably limiting operations and waste generation. For this purpose, several mono-or bi-directional approaches have been devised allowing successive CC bond-forming events. The considerable synthetic economies these cascades enable have been demonstrated in the preparation of a wide variety of complex bioactive natural products, notably polyketides.

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; The thermal 6π aza-Diels−Alder cycloadditions between α-oxoketenes, in situ derived from a thermally induced Wolff rearrangement of 2-diazo-1,3-diketones, and N-(5-pyrazolyl)imines as prototypical electron-rich 2-azadienes lead to two distinct sets of products, essentially as a function of the nature of the α-oxoketenes involved. For instance, cyclic five-membered α-oxoketenes lead preferentially to spiro hydropyridin-4-ones, which involves the α-oxoketenes as the 2π partners at their C=C double bond and the N-(5-pyrazolyl)imines as the 4π partners at their 2-azadiene moiety. In contrast, other cyclic and acyclic α-oxoketenes lead preferentially to 1,3-oxazin-4-ones, which now involves the α-oxoketenes as the 4π partners at their 1-oxadiene moiety and the N-(5- pyrazolyl)imines as the 2π partners at their C=N double bond. A computational modeling study using DFT methods allowed rationalizing this change of periselectivity: the formation of spiro hydropyridin-4-ones is under thermodynamic control while the formation of 1,3-oxazin-4-ones is kinetically controlled, and slightly thermodynamically disfavored in the five-membered ring series. The competing cyclodimerization of the α-oxoketenes is also studied in detail.

International audience; To improve the supramolecular properties of organic compounds, chemists continuously need to identify new tools. Herein, the influence of the stereoselective insertion of halogen atoms (F or Cl) on different supramolecular properties is analyzed. Inserting anti-halohydrins in polyols considerably strengthens the H-bonding networks and other supramolecular interactions. This behavior resulted in improved anion binding, H-bonding catalysis, or organogel properties of the designed polyols with strong perspectives for applications in other classes of substrates.

An enantioselective aldolization on perfluorinated aldehydes has been developed. The reaction can create in one step ketodiols, precursors of crucial perfluorinated 1,3,5-triols featuring selective chiral anion recognition ability., Fluorine is able to confer unique properties to organic molecules but the scarcity of natural organofluorine sources renders the development of new synthetic methods highly desirable. Using a chiral BOX/Cu combination, enantioselective decarboxylative aldolization of perfluorinated aldehydes has been developed. Most notably, the reaction occurring under mild conditions and with high enantiocontrol can create ketodiols in one single synthetic operation, which are precursors of crucial perfluorinated 1,3,5-triols. In addition, the reaction performed with chloral, validates the proposed transition state model based on steric interactions and provides the first enantioselective synthesis of hexachlorinated ketodiol of great synthetic utility. The ability of perfluorinated 1,3,5-triols to form a central hydrogen-bonding framework allows strong coordination of anions and the chirality obtained through the catalyst-controlled synthetic sequence demonstrates the selective chiral anion recognition ability of polyols.

International audience; An efficient and quick access toward a series of (E)-2-arylideneaminopyrroles 6 and to their benzyne-promoted aza-Diels−Alder cycloaddition products is provided. These products are three pyrrolo[2,3-c]isoquinolines 8a−c substituted in position 5 with different electron-acceptor (A) or electron-donor (D) aryl groups. Intermediates and products were obtained in good yields (up to 78 and 84%, respectively), and their structures were determined on the basis of NMR measurements and HRMS analysis. Photophysical properties of 8a−c were investigated, finding good Stokes shift in different solvents, but only the product 8c showed appreciable fluorescence intensity since its 5-aryl group (2,4-Cl 2 Ph) could favor the twisted intramolecular charge transfer effect. In addition, a riveting relationship between solvent viscosity and fluorescence intensity was found. Structures of 6 and 8 were studied and confirmed by single-crystal X-ray diffraction, observing that their electronic distributions effect the supramolecular assembly but with only long-distance hydrophobic interactions. A CE-B3LYP model was used to study the energetic topology and understand the crystal architecture of compounds as well as find a connection with both the synthetic and photophysical results.