Enantioselective Synthesis of Atropisomers by Oxidative Aromatization with Central-to-Axial Conversion of Chirality.

Atropisomers are fascinating objects of study by themselves for chemists but also find applications in various sub-fields of applied chemistry. Obtaining them in enantiopure form is far from being a solved challenge, and the past decades has seen a surge of methodological developments in that direction. Among these strategies, oxidative aromatization with central-to-axial conversion of chirality has gained increasing popularity. It consists of the oxidation of a cyclic non-aromatic precursors into the corresponding aromatic atropisomers. This review proposes a critical analysis of this research field by delineating it and discussing its historical background and its present state of the art to draw potential future development directions.

Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents.

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, 2-bromostyrene, 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.

Energy-Efficient Iodine Uptake by a Molecular Host⋠Guest Crystal.

Recently, porous organic crystals (POC) based on macrocycles have shown exceptional sorption and separation properties. Yet, the impact of guest presence inside a macrocycle prior to adsorption has not been studied. Here we show that the inclusion of trimethoxybenzyl-azaphosphatrane in the macrocycle cucurbit[8]uril (CB[8]) affords molecular porous host⋅guest crystals (PHGC-1) with radically new properties. Unactivated hydrated PHGC-1 adsorbed iodine spontaneously and selectively at room temperature and atmospheric pressure. The absence of (i) heat for material synthesis, (ii) moisture sensitivity, and (iii) energy-intensive steps for pore activation are attractive attributes for decreasing the energy costs. 1 H NMR and DOSY were instrumental for monitoring the H2 O/I2 exchange. PHGC-1 crystals are non-centrosymmetric and I2 -doped crystals showed markedly different second harmonic generation (SHG), which suggests that iodine doping could be used to modulate the non-linear optical properties of porous organic crystals.

Hemicryptophane Cages with a C1-Symmetric Cyclotriveratrylene Unit.

Two new hemicryptophanes combining a cyclotriveratrylene unit with either an aminotrisamide or a tris(2-aminoethyl)amine (tren) moiety have been synthesized. Although a conventional synthesis approach was used, the molecular cages obtained are devoid of the expected C3 symmetry. NMR analyses and X-ray crystal structure determination showed that these hemicryptophanes exhibited C1 symmetry due to the unusual arrangement of the substituents of the cyclotriveratrylene unit. This unprecedented arrangement is related to a change in the regioselectivity of the Friedel-Crafts reactions that led to the CTV cap. This constitutes an original approach to access enantiopure chiral molecular cages with low symmetry.

The Chloroazaphosphatrane Motif for Halogen Bonding in Solution.

Chloroazaphosphatranes, the corresponding halogenophosphonium cations of the Verkade superbases, were evaluated as a new motif for halogen bonding (XB). Their modulable synthesis allowed for synthetizing chloroazaphosphatranes with various substituents on the nitrogen atoms. The binding constants determined from NMR titration experiments for Cl-, Br-, I-, AcO-, and CN- anions are comparable to those obtained with conventional iodine-based monodentate XB receptors. Remarkably, the protonated azaphosphatrane counterparts display no affinity for anions under the same conditions. The strength of the XB interaction is, to some extent, related to the basicity of the corresponding Verkade superbase. The halogen bonding abilities of this new class of halogen donor motif were also revealed by the Δδ(31P) NMR shift observed in CD2Cl2 solution in the presence of triethylphosphine oxide (TEPO). Thus, chloroazaphosphatranes constitute a new class of halogen bond donors, expanding the repertory of XB motifs mainly based on CAr-I bonds.

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.

Origin of the enantioselectivity in organocatalytic Michael additions of ß-ketoamides to α,ß-unsaturated carbonyls: a combined experimental, spectroscopic and theoretical study.

The organocatalytic enantioselective conjugate addition of secondary ß-ketoamides to α,ß-unsaturated carbonyl compounds is reported. Use of bifunctional Takemoto's thiourea catalyst allows enantiocontrol of the reaction leading either to simple Michael adducts or spirocyclic aminals in up to 99 % ee. The origin of the enantioselectivity has been rationalised based on combined DFT calculations and kinetic analysis. This study provides a deeper understanding of the reaction mechanism, which involves a predominant role of the secondary amide proton, and clarifies the complex interactions occurring between substrates and the catalyst.

Organocatalytic enantio- and diastereoselective conjugate addition to nitroolefins: when ß-ketoamides surpass ß-ketoesters.

Our findings on the bifunctional squaramide-catalyzed enantioselective conjugate addition of ß-ketoamides to nitroolefins are disclosed. It appears that simple acyclic methylene ß-ketoamides, unlike the extensively studied ß-ketoesters, afford the products in excellent diastereoselectivities, and maintain high yields and enantioselectivities. Moreover, competition and kinetic studies were conducted to rationalize the observed reactivity and selectivity. The high level of diastereocontrol, along with the amenability of the amide group to postfunctionalization, dramatically increase the synthetic usefulness of the transformation.

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.

Organocatalytic umpolung: N-heterocyclic carbenes and beyond.

The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.

N-Heterocyclic carbene (NHC)-catalyzed intermolecular hydroacylation of cyclopropenes.

We report the first intermolecular NHC-catalyzed hydroacylation of electron-neutral olefins. Treatment of aromatic aldehydes with cyclopropenes under mild conditions affords valuable acylcyclopropanes in moderate to high yields with an excellent level of diastereocontrol. Preliminary mechanistic studies suggest that product formation occurs via a concerted syn hydroacylation pathway.

Designing N-heterocyclic carbenes: simultaneous enhancement of reactivity and enantioselectivity in the asymmetric hydroacylation of cyclopropenes.

Faster, higher, stronger! The N-heterocyclic carbene (NHC) catalyzed diastereo- and enantioselective hydroacylation of cyclopropenes affords structurally valuable acylcyclopropanes. A new family of electron-rich, 2,6-dimethoxyphenyl-substituted NHCs induces excellent reactivity and enantioselectivity. Preliminary kinetic studies unambiguously demonstrated the superiority of this family of catalysts over known NHCs in this challenging transformation.

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.

Synthesis of the landomycinone skeleton.

The synthesis of the highly functionalized tetracyclic skeleton of landomycinone (2), the aglycon of landomycins, was performed using two pivotal steps relying on metal-catalyzed reactions. They are (1) a [2 + 2 + 2] cycloaddition of alkynes promoted by Wilkinson's catalyst to build rings B and C concomitantly and (2) a ring-closing metathesis followed by aromatization to build ring D.

Palladium(0)-catalyzed cross-coupling of potassium (Z)-2-chloroalk-1-enyl trifluoroborates: a chemo- and stereoselective access to (Z)-chloroolefins and trisubstituted alkenes.

We describe the preparation of a series of new potassium trifluoroborates 1 and the study of their behaviour in a Pd(0)-catalyzed cross-coupling reaction. We found that compounds 1 are endowed with original properties as they behave as nucleophilic cross-coupling partners chemoselectively but also as ambivalent synthons. The usefulness of this methodology has been successfully illustrated by the first total synthesis of an N-acyl spermidine.

Addition of silylated nucleophiles to α-oxoketenes.

A general evaluation of silylated nucleophiles to intercept transient α-oxoketenes generated by microwave-assisted Wolff rearrangement of 2-diazo-1,3-dicarbonyl compounds is presented. Original scaffolds and synthetic intermediates are accessed in a rapid, efficient and easy-to-handle way. Mechanistic studies by DFT calculations and some post-functionalizations are discussed.