Engineering Azobenzene Derivatives to Control the Photoisomerization Process.

In this work, we show how the structural features of photoactive azobenzene derivatives can influence the photoexcited state behavior and the yield of the trans/cis photoisomerization process. By combining high-resolution transient absorption experiments in the vis-NIR region and quantum chemistry calculations (TDDFT and RASPT2), we address the origin of the transient signals of three poly-substituted push-pull azobenzenes with an increasing strength of the intramolecular interactions stabilizing the planar trans isomer (absence of intramolecular H-bonds, methyl, and traditional H-bond, respectively, for 4-diethyl-4'-nitroazobenzene, Disperse Blue 366, and Disperse Blue 165) and a commercial red dye showing keto-enol tautomerism involving the azo group (Sudan Red G). Our results indicate that the intramolecular H-bonds can act as a "molecular lock" stabilizing the trans isomer and increasing the energy barrier along the photoreactive CNNC torsion coordinate, thus preventing photoisomerization in the Disperse Blue dyes.

Diaryl-Pyrano-Chromenes Atropisomers: Stereodynamics and Conformational Studies.

The dynamic scenario of di-aryls-pyrano-chromenes was investigated using DFT calculations. The symmetry of the chromene scaffold and the presence of two -substituted aryls substituents can generate two / diastereoisomers and conformational enantiomers with different rotational barriers. The relative conformations and configurations were derived using NOESY-1D experiments.

Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone-Atorvastatin Prodrug.

Atorvastatins play an important role in the inhibition of HMG-CoA reductase, an enzyme present in the liver that takes part in the biosynthesis of cholesterol. In this article, we report the total synthesis of a lactone-atorvastatin prodrug with additional atropisomeric features. Conformational and experimental studies of model compounds were designed to test the stability of the chiral axis.

A Pyridyl-1,2-azaborine Ligand for Phosphorescent Neutral Iridium(III) Complexes.

A novel 1,2-azaborine (, 4-methyl-2-(pyridin-2-yl)-2,1-borazaronaphthalene, ) has been synthesized and used for the first time as a B-N alternative to common cyclometalating ligands to obtain neutral phosphorescent iridium(III) complexes (, , , and ) of general formula [Ir(CN)(NNB)], where CN indicates three different cyclometalating ligands (Hppy = 2-phenylpyridine; Hdfppy = 2-(2,4-difluoro-phenyl)pyridine; Hpqu = 2-methyl-3-phenylquinoxaline). Moreover, the azaborine-based complex was compared to the isoelectronic C═C iridium(III) complex , obtained using the corresponding 2-(naphthalen-2-yl)pyridine ligand . Due to the dual cyclometalation mode of such C═C ligand, the isomeric complex was also obtained.

Synthesis and Stereodynamic and Emission Properties of Dissymmetric Bis-Aryl Carbazole Boranes and Identification of a CPL-Active B-C Atropisomeric Compound.

We synthesized bis-aryl carbazole borane derivatives having emissive properties and axial chirality. The resolution of a thermally stable atropisomeric pair (compound ), due to a B-C chiral axis, was achieved by chiral stationary-phase high-performance liquid chromatography (CSP-HPLC). Complete photophysical properties of all compounds were measured and simulated by time-dependent density functional theory (TD-DFT) calculations of the complete fluorescence cycle, and circularly polarized luminescence spectra were obtained for the atropisomers of compound , whose absolute configuration was derived using a TD-DFT simulation of the electronic circular dichroism (ECD) spectra.

Sulfoxonium Ylides in Aminocatalysis: An Enantioselective Entry to Cyclopropane-Fused Chromanol Structures.

The 1,1a,2,7b-tetrahydrocyclopropa[]chromene, arising from fusion of chromane and cyclopropane rings is the core of medicinally relevant compounds. Engaging sulfoxonium ylides in enantioselective aminocatalytic reactions for the first time, a convenient entry to this scaffold is presented. Several ring-fused derivatives were obtained in moderate-to-good yields and enantioselectivities and with perfect diastereoselectivity at the cyclopropane, using an α,α-diphenylprolinol aminocatalyst.

Catalytic Enantioselective Access to Dihydroquinoxalinones via Formal α-Halo Acyl Halide Synthon in One Pot.

An enantioselective one-pot catalytic strategy to dihydroquinoxalinones, featuring novel 1-phenylsulfonyl-1-cyano enantioenriched epoxides as masked α-halo acyl halide synthons, followed by a domino ring-opening cyclization (DROC), is documented. A popular quinine-derived urea served as the catalyst in two out of the three steps performed in the same solvent using commercially available aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide and 1,2-phenylendiamines. Medicinally relevant 3-aryl/alkyl-substituted heterocycles are isolated in generally good to high overall yield and high enantioselectivity (up to 99 % ee).

GC/MS analysis of the crude reaction mixtures from Friedel-Crafts acylation: Unambiguous identification and differentiation of 3-aroylbenzofurans from their 4- and 6-regioisomers.

Rationale: 3-Aroylbenzofurans and their 2-nitrophenyl derivatives constitute fundamental intermediates for the synthesis of target compounds with pharmaceutical properties. However, their preparation via the Friedel-Crafts acylation of 2-phenylbenzofurans, using Lewis acid as catalyst, often leads to mixtures of regioisomeric aroylbenzofurans that can be challenging to distinguish, thus preventing the reaction characterization.

Method: We report a method for the unambiguous identification and differentiation of the desired 3-benzoyl isomers from their 4- and 6-regioisomers in a crude reaction mixture using gas chromatography coupled to multiple-stage mass spectrometric (GC/MS ) analysis performed in collision-induced dissociation (CID) mode.

A new ionone derivative from Boiss. (Solanaceae).

Boiss also called 'Awsadj' is a subshrub belonging to the Solanaceae family and producing red berries. In the present work, we report the isolation of a new compound, ((1 R,3aR,7aS)-3a,7-dimethyl-1-((E)-prop-1-en-1-yl)-1,3a,4,7a-tetrahydroisobenzofuran-5(3H)-one ()). Three known compounds were also isolated for the first time from , and identified as isoscopoletin (, 3,4,5-trimethoxybenzyl alcohol (), and (+)-isolariciresinol ().

Conformational and Stereodynamic Behavior of Five- to Seven-Membered 1-Aryl-2-iminoazacycloalkanes.

The stereodynamic behavior of 1-arylpyrrolidin-2-imines, having a C-N stereogenic axis, has been studied by means of dynamic nuclear magnetic resonance and density functional theory calculations, evaluating the steric effect of -aryl substituents. The rotational barrier due to / isomerism about the -C=N-H bond was also determined. The dynamic stereochemistry of homologous six- and seven-membered iminoazacycloalkane rings and their oxo-analogues was also comparatively investigated, evidencing a ring size effect.

Metal and Oxidant-Free Brønsted Acid-Mediated Cascade Reaction to Substituted Benzofurans.

Substituted hydroxy-benzofurans are easily accessible by treatment of resorcinols and 1,2-diaza-1,3-dienes (DDs) under acidic conditions. The reaction happens through an uncommon Michael reaction between aromatic derivatives as aromatic C(sp)-H nucleophiles and DDs as acceptors. Also, the behavior of different phenols and 2-naphthol was investigated.

Axial Chirality at the Boron-Carbon Bond: Synthesis, Stereodynamic Analysis, and Atropisomeric Resolution of 6-Aryl-5,6-dihydrodibenzo[][1,2]azaborinines.

6-Aryl-5,6-dihydrodibenzo[][1,2]azaborinines display restricted rotation at the boron-carbon aryl bond, yielding conformational isomers or atropisomers. The stereodynamic processes were monitored by variable-temperature NMR (D-NMR), dynamic enantioselective HPLC (D-HPLC), or kinetic racemization measurements. The absolute configuration of stable atropisomers (compound , Δ = 26.

Predictive chirality sensing via Schiff base formation.

Among the large number of chiroptical sensors that have been developed to date, few allow rational determination of the absolute configuration of chiral substrates together with quantitative ee analysis. We have prepared and tested stereodynamic N-aryl aminobenzaldehyde sensors that bind chiral amines via Schiff base formation. The covalent binding of the amine substrate generates a conformational bias in the chromophoric sensor moiety which results in characteristic CD signals.

Determination of the absolute configuration of conformationally flexible molecules by simulation of chiro-optical spectra: a case study.

The assignment of the absolute configuration (AC) of two conformational flexible organic molecules by means of TD-DFT simulation of the electronic circular dichroism (ECD) spectra is presented. The factors leading to a reliable assignment were evaluated in the various steps of the process. The effects of different functionals and basis sets in the geometry optimization step is very limited in terms of the resulting optimized geometries, whereas the inclusion of the solvent in the calculations has a much larger effect on the correct evaluation of the conformational ratio.

Synergistic Catalysis: Highly Enantioselective Acetyl Aza-arene Addition to Enals.

A novel catalytic enantioselective methodology based on synergistic catalysis for the synthesis of chiral 2-acyl pyridines and pyrazines is reported. The strategy involves the metal-Lewis acid activation of acetyl aza-arenes and the secondary-amine activation of enals. The proposed mechanism is supported by DFT calculations.

Conformational Analysis and Absolute Configuration of Axially Chiral 1-Aryl and 1,3-Bisaryl-xanthines.

The xanthine scaffold is known to be the forefather of a class of biological active molecules. Xanthine is a planar framework in which an aryl substituent linked in the 1 or 3 position is driven out of the xanthine plane because of the steric hindrance exerted by the two carbonyls. This work analyses the stereodynamics of some 1-aryl and 1,3-bisaryl-xanthines and describes the steric requirements needed to produce stable heteroaromatic atropisomers or diastereoisomers, with one or two N-C stereogenic axes.

Axial Chirality about Boron-Carbon Bond: Atropisomeric Azaborines.

The preparation of atropisomeric 2,1-borazaronaphthalenes is described. Resolution of the atropisomeric pair was achieved by preparative Chiral Stationary Phase HPLC (CSP-HPLC). The absolute configuration of the stereogenic axis was derived from Time-Dependent DFT (TD-DFT) simulation of the Electronic Circular Dichroism spectra (ECD).

Enantioselective Preparation, Conformational Analysis and Absolute Configuration of Highly Substituted Aziridines.

The first example of organocatalytic aziridination reaction of α-substituted-α,β-unsaturated ketones is presented. The reaction was found to be highly enantio- and diastereoselective, yielding N-tosylated aziridines. Low-temperature nuclear magnetic resonance (NMR) spectra allowed for the determination of the N-inversion barrier, that was found to be quite lower with respect to unsubstituted aziridines.

Long-range bonding/nonbonding interactions: a donor-acceptor resonance studied by dynamic NMR.

Long-range bonding interactions were evaluated using variable-temperature NMR spectroscopy and suitable 2'-CH2X-substituted phenylpyridines (X = Me, NMe2, OMe, F). It was found that the arylpyridyl rotational barriers were lower when electronegative atoms were bound to the α carbon of the 2' moiety. This effect was ascribed to a stabilizing interaction in the transition state due to the lone pair of the heterocyclic nitrogen with the α carbon.

Catalytic highly enantioselective transfer hydrogenation of β-trifluoromethyl nitroalkenes. An easy and general entry to optically active β-trifluoromethyl amines.

In the presence of a thiourea catalyst, β-CF3 nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of β-CF3 amine precursors with a tertiary stereocentre at the β-position. This reaction represents the first general catalytic enantioselective approach to this important class of β-CF3 amines.

Axial chirality of 4-arylpyrazolo[3,4-b]pyridines. Conformational analysis and absolute configuration.

The stereodynamic behavior of a series of pyrazolo[3,4-b]pyridines was studied. The restricted rotations of the aryl substituent in position 4 of the heteroaromatic ring and of the benzoyl group in position 5 generated conformational enantiomers or conformational diastereoisomers depending on the local symmetry of the aryl substituent, with very high rotational barriers despite the absence of ortho-substituents. The energy barriers for the rotation of the 5-benzoyl group and the 4-aromatic ring were measured by dynamic NMR and rationalized by DFT calculations.

Remote control of axial chirality: aminocatalytic desymmetrization of N-arylmaleimides via vinylogous Michael addition.

Remote control of the axial chirality of N-(2-t-butylphenyl)succinimides was realized via the vinylogous Michael addition of 3-substituted cyclohexenones to N-(2-t-butylphenyl)maleimides. 9-Amino(9-deoxy)epi-quinine promoted the enantioselective desymmetrization, leading to atropisomeric succinimides with two adjacent stereocenters.

The experimental observation of the intramolecular NO₂/CO interaction in solution.

The weak electrostatic interaction between nitro and carbonyl moieties has been observed by means of variable-temperature NMR spectroscopy. Its energetic contribution was evaluated to be about 3 kcal mol(-1) by DFT calculations, and confirmed by the measurement of internal energy barriers to the rotation of suitable nitroaryl rings.

Atropisomers of arylmaleimides: stereodynamics and absolute configuration.

4-Aryl-3-bromo-N-benzylmaleimides and 3,4-biaryl-N-benzylmaleimides have been synthesized by a modified Suzuki cross-coupling reaction from 3,4-dibromo-N-benzylmaleimide. The conformational studies by dynamic NMR and DFT calculations showed that the interconversion barrier between the two available skewed conformations is under steric control. When the aryl group was a 2-methylnaphthyl, thermally stable atropisomers were isolated by enantioselective HPLC and their absolute configurations were assigned by TD-DFT simulations of the ECD spectra.

Atropisomers of hindered triarylisocyanurates: structure, conformation, stereodynamics, and absolute configuration.

The syn and anti diastereoisomers of some 1,3,5-triarylisocyanurate derivatives were isolated and their configuration assigned by NOE experiments and by X-ray diffraction. The kinetics of the syn/anti interconversion were determined, and the experimental activation energies matched satisfactorily the values predicted by DFT computations. Low-temperature NMR spectra were employed to determine the rotation barrier of N-bonded unhindered aryl substituents: these barriers, too, are satisfactorily reproduced by DFT computations.