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.

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.

Recent Achievements in Enantioselective Borrowing Hydrogen by the Combination of Iron- and Organocatalysis.

This article summarizes our recent developments in allylic alcohol functionalization by the interconnection of two catalytic cycles. By combining an iron-catalyzed borrowing hydrogen with an organocatalytic enantioselective nucleophilic addition, allylic alcohols can be converted to enantioenriched chiral aliphatic alcohols in up to 92% ee. This eco-compatible one-operation multi-catalytic process allows the classical oxidation-addition-reduction steps usually required for this transformation to be bypassed. Synthetic applications in the synthesis of different fragments of some important natural products have highlighted the great potential of this transformation.

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.

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.

An iron/amine-catalyzed cascade process for the enantioselective functionalization of allylic alcohols.

Three is a lucky number: An enantioselective transformation of allylic alcohols into ß-chiral saturated alcohols has been developed by combining two distinct metal- and organocatalyzed catalytic cycles. This waste-free triple cascade process merges an iron-catalyzed borrowing-hydrogen step with an aminocatalyzed nucleophilic addition reaction.

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.

Multicomponent reactions and ionic liquids: a perfect synergy for eco-compatible heterocyclic synthesis.

The efficiency of a chemical synthesis can be nowadays measured, not only by parameters like selectivity and overall yield, but also by its raw material, time, human resources and energy requirements, as well as the toxicity and hazard of the chemicals and the protocols involved. The development of multicomponent reactions (MCRs) in the presence of task-specific ionic liquids (ILs), used not only as environmentally benign reaction media, but also as catalysts, is a new approach that meet with the requirements of sustainable chemistry. The aim of this tutorial review is to highlight the synergistic effect of the combined use of MCRs and ILs for the development of new eco-compatible methodologies for heterocyclic chemistry.

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.

User-friendly stereoselective one-pot access to 1,4-diazepane derivatives by a cyclodehydrative three-component reaction with 1,3-dicarbonyls.

A multicomponent reaction of 1,3-dicarbonyls with 1,2-diamines and aromatic aldehydes is described for the direct stereoselective synthesis of 1,4-diazepane derivatives. Various reaction conditions were tested, including an efficient, user-friendly solvent- and catalyst-free procedure.

Synthesis and palladium-catalysed isomerisation of fused polycyclic tetrahydrofurans: efficient and stereoselective one-pot domino construction of functionalised bridged bicyclo[n.2.1] ring systems.

A new one-pot domino reaction for a general entry to functionalised bridged bicyclo[n.2.1] ring systems from alpha, alpha'-diactivated cyclic ketones and trans-1,4-dihalides is described. The sequence combines a base promoted C-O cycloalkylation reaction leading to fused polycyclic enol ethers and their in situ palladium-catalysed isomerisation.

Metal-free Michael addition initiated multicomponent oxidative cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonyls.

A simple metal-free, step-economic and selective access to pyridines from readily available substrates is reported, involving a flexible 4 A molecular sieves promoted Michael addition initiated domino three-component reaction between a 1,3-dicarbonyl, a Michael acceptor and a synthetic equivalent of ammonia.

Cholesteric bonded stationary phases for high-performance liquid chromatography: synthesis, physicochemical characterization, and chromatographic behavior of a phospho-cholesteric bonded support. A new way to mimic drug/membrane interactions?

Among the various methods exploitable to determine the bioavailability of drugs, reversed-phase liquid chromatography (RPLC) appears to be suited to creation of patterns of prediction. In this context a new stationary phase was designed in this work to reproduce, in terms of chemical structure, as accurately as possible, the main elements of cellular membranes; which include phospholipids and cholesterol molecules. An efficient synthetic pathway was developed to prepare ligands that contain a phosphate head, a long alkyl chain chemically bonded to silica, and a cholesteric moiety, in order to mimic both hydrophilic and hydrophobic interactions, and "membrane-like" organization, respectively. The new stationary phase was characterized by Fourier-transform infra red (FTIR) and (1)H-(13)C, (1)H-(31)P, and (1)H-(29)Si cross-polarization magic-angle-spinning nuclear magnetic resonance (CP MAS NMR) spectroscopy. Its chromatographic behavior has been studied by classical classification tests for RPLC columns. Despite its low surface coverage, the material produced exhibits high shape selectivity, possibly due to the organization of the grafted moieties.

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.

Organocatalytic multicomponent synthesis of enantioenriched polycyclic 1,2,3,4-tetrahydropyridines: key substrate selection enabling regio- and stereoselectivities.

We have developed the first multicomponent synthesis of enantioenriched polycyclic 1,2,3,4-tetrahydropyridines bearing three contiguous stereogenic centers under iminium activation. The key to the success of this reaction was the use of polyfunctional substrates including 2-aminophenols and scarcely used ß-ketoamides triggering a thermodynamically controlled regio- and diastereoselective sequence.