Enantioselective Synthesis of Heteroatom-Linked Non-Biaryl Atropisomers.

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide-ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom-linked non-biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non-biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview.

Enantioselective Organocatalysis and Superacid Activation: Challenges and Opportunities.

Since the pioneer reports of the groups of Akiyama and Terada 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.

Hidden Heptacyclic Chiral N-Acyl Iminium Ions: A New Entry to Enantioenriched Polycyclic Azepanes and Azocanes by Superacid-Promoted Intramolecular Pictet-Spengler Reaction.

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.

Simultaneous Control of Central and Helical Chiralities: Expedient Helicoselective Synthesis of Dioxa[6]helicenes.

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.

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes.

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.

Enantioenriched Methylene-Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations.

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 benzazocanes 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 Friedel-Crafts-type cyclization.

Design and synthesis of simplified speciophylline analogues and ß-carbolines as active molecules against Plasmodium falciparum.

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 ß-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.

Normal, Abnormal, and Cascade Wittig Olefinations of α-Oxoketenes.

α-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 functionalized 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. Mechanistic experimental and computational studies provided a full rational for these reactivity switches. Some unusual mechanistic 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.

Enantioselective Syntheses of Furan Atropisomers by an Oxidative Central-to-Axial Chirality Conversion Strategy.

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.

Combining Organocatalysis with Central-to-Axial Chirality Conversion: Atroposelective Hantzsch-Type Synthesis of 4-Arylpyridines.

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.

α,ß-Unsaturated acyl cyanides as new bis-electrophiles for enantioselective organocatalyzed formal [3+3]spiroannulation.

α,ß-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.

Padlocking dihydrofurannulation for the control of small degree of helicity built on a fused-tetracyclic core.

Enantioselective construction of small molecules displaying a configurationally stable helical shape built on a fused-tetracyclic core is a daunting synthetic challenge even more pronounced when five-membered rings are incorporated in the structure. The resulting higher configurational lability strongly hampers their access, and therefore the development of new efficient methodologies is timely and highly desirable. In this context, we describe a padlocking approach via the enantioselective organocatalytic domino furannulation of appropriately designed achiral fused-tricyclic precursors resulting in the synthesis of configurationally locked helically chiral tetracyclic scaffolds featuring one or two five-membered rings with the simultaneous control of central and helical chiralities.

Stereoselective multiple bond-forming transformations (MBFTs): the power of 1,2- and 1,3-dicarbonyl compounds.

Although long known, 1,2- and 1,3-dicarbonyl compounds have recently come more and more to prevalence as ideal substrates for the invention of new stereoselective multiple bond-forming transformations (MBFTs). Herein, a critical appraisal is presented of some of the most spectacular of these MBFTs, which allow the formation from three up to six bonds in highly step- and atom-economical processes.

Temporary intramolecular generation of pyridine carbenes in metal-free three-component C-H bond functionalisation/aryl-transfer reactions.

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-component 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.

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6' Steric Bulk of Cinchona Alkaloid.

A C6' bulky substituted quinine-catalyzed SNV reaction between 3-substituted oxindole and (E)-3-(nitromethylene)-oxindole was developed. This enantioselective C(sp3)-C(sp2) coupling furnished bisoxindole scaffolds featuring a vinyl-substituted all-carbon quaternary stereocenter with high stereoselectivities. In addition, the gram-scale synthesis and synthetic post-transformations were conducted to demonstrate the potential synthetic usefulness.

Asymmetric organocascades involving the formation of two C-heteroatom bonds from two distinct heteroatoms.

In the vast and expanding world of enantioselective organocascades, the ones in which two C-heteroatom bonds are created from two distinct heteroatoms are rare. These fascinating domino processes constitutes real synthetic challenges and allow very convenient syntheses of diverse optically active heterocycles and also highly functionalised acyclic derivatives.

Determination of dissolved nickel in natural waters using a rapid microplate fluorescence assay method.

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 Ni2+ in natural water samples with good analytical performances.

Exploiting the divergent reactivity of α-isocyanoacetate: multicomponent synthesis of 5-alkoxyoxazoles and related heterocycles.

A novel multicomponent synthesis of 5-alkoxyoxazoles, based on a new reactivity profile of α-isocyanoacetates, is described. Thus, simply heating a solution of amine, aldehyde, and α-(EWG-phenyl)-α-isocyanoacetate or α-(4-pyridyl)-α-isocyanoacetate (EWG=electron-withdrawing group) in toluene provided 5-alkoxyoxazoles in good to excellent yields. Reaction of the 5-alkoxyoxazoles with various α,ß-unsaturated acyl chlorides led to the formation of epoxytetrahydropyrrolo[3,4-b]pyridin-5-ones by a domino N-acylation/Diels-Alder cycloaddition sequence. Subsequent fragmentation under basic conditions provided 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-ones. A four-component synthesis of the pyridin-5-one compounds, without isolation of the 5-alkoxyoxazole, was subsequently developed.

Sub-ppb mercury detection in real environmental samples with an improved rhodamine-based detection system.

A new procedure is described for the determination of Hg2+ 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.

On the Enantioselective Phosphoric-Acid-Catalyzed Hantzsch Synthesis of Polyhydroquinolines.

A reinvestigation of a chiral phosphoric-acid-catalyzed four-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, no enantioselectivity 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.