Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Addition of Vindoline to p-Benzoquinone: Regiochemistry, Stereochemistry and Symmetry Considerations.

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This "windshield wiper" effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 µM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.

Triarylmethyl-based biradical as a superoxide probe.

Superoxide radical represents one of the most biologically relevant reactive oxygen species involved in numerous physiological and pathophysiological processes. Superoxide measurement through the decay of an electron paramagnetic resonance (EPR) signal of a triarylmethyl (TAM) radical possesses the advantage of a high selectivity and relatively high rate constant of TAM reaction with the superoxide. Hereby we report a straightforward synthesis and characterization of a TAM-TAM biradical showing a high reactivity with superoxide (second-order rate constant, (6.7 ± 0.2) × 103 M-1 s-1) enabling the measurement of superoxide radical by following the increase of a sharp EPR signal associated with the formation of a TAM-quinone-methide monoradical product.

Riding the Wave of Monodentate Ligand Revival: From the A/B Concept to Noncovalent Interactions.

The rediscovery of chiral monodentate ligands made in the period 1999-2003 had important consequences in enantioselective transition-metal catalysis, such as the introduction of the A/B concept (i.e., use of monodentate ligand mixtures) and, later, a renewed interest in supramolecular ligands capable of ligand-ligand and ligand-substrate interactions. This Personal Account summarizes the contributions made by our research group in this area in the period 2004-2015, which reflect the abovementioned developments. Within this area, we introduced some original concepts, such as 1) the use of chiral tropos ligand mixtures; 2) the development of new strategies to maximize heterocomplex formation from combinations of simple monodentate ligands; 3) the investigation of new ligand-ligand interactions to achieve selective heterocomplex formation; and 4) the development of highly efficient and synthetically accessible supramolecular ligands.

Recent Advances in Sensing Using Atropoisomeric Molecular Receptors.

We describe recent advances in chiroptical chemical sensors, in which the design and implementation is based upon the introduction of atropoisomerically chiral moiety within the molecular skeleton. This report include examples of acyclic, macrocyclic, and polymeric receptors that contain this motif. Although the main applications are in the enantioselective sensing of analytes, we report here some cases where the chiral receptors can in fact be used to senseachiral species. Using circular dichroism (CD) spectroscopy as the technique to detect a receptor-analyte interaction, we can distinguish two main sensor categories: that in which the CD signal of a stereolabile, CD-silent probe is activated upon binding, and that in which the signal of a CD-active probe is modulated upon binding. Particular emphasis will be given to cases in which CD spectroscopy is used orthogonally to other means of detection.

Tautomerism and atropisomerism in free-base (meso)-strapped porphyrins: static and dynamic aspects.

We report herein some outstanding examples of atropisomerism and tautomerism in five (meso-)strapped porphyrins. Porphyrins S0-S4 have been synthesised, characterised and studied in detail by spectroscopic and spectrometric techniques, and their isomeric purity verified by HPLC analysis. In particular, they exhibit perfectly well-defined NMR spectra that display distinct patterns depending on their average symmetry at room temperature: C2v , D2d , C2h , C2v , and D2h for S0-S4, respectively. NH tautomerism was evidenced by variable-low-temperature (1) H NMR experiments in [D2 ]dichloromethane performed on S0 (Δ${G{{{\ne}\hfill \atop {\rm 298K}\hfill}}}$=48±1 kJ mol(-1) ) and S1 (Δ${G{{{\ne}\hfill \atop {\rm 298K}\hfill}}}$=55±3 kJ mol(-1) ), which has led to an understanding of the average spectra observed for the five porphyrins at room temperature. On the other hand, S2 and S3 are stable atropisomers at room temperature, easily separated and characterised, as a result of restricted rotation of their strapped bridges due to their high rotational barrier energies. Upon heating to 82 °C, they slowly equilibrate to a thermodynamic ratio of 64:36 in favour of the more stable S2 isomer. This atropisomerisation process was evidenced by (1) H NMR spectroscopy and monitored by HPLC, from which high rotational energy barriers of 115.2 (Δ${G{{{\ne}\hfill \atop {\rm S2}\rightarrow {\rm S3}\hfill}}}$) and 116.9 kJ mol(-1) (Δ${G{{{\ne}\hfill \atop {\rm S2}\rightarrow {\rm S3}\hfill}}}$) were deduced.

Synthesis, chiroptical properties and density functional theory calculations of 3,3'-biphenyl-2,2'-bitropone.

The synthesis of new bitropone derivatives, namely, 3,3'-biphenyl-2,2'-bitropone and 7,7'-biphenyl-2,2'-bitropone, are reported. Isolation of enantiomers arising from restricted rotation around the C-C bond connecting the tropone moieties was attempted by means of chiral high performance liquid chromatography (HPLC). No separation was obtained for 7,7'-biphenyl-2,2'-bitropone. For 3,3'-biphenyl-2,2'-bitropone, difficulties were encountered because of the low separation factor of the peaks and the presence of a rapid racemization process. However, quantitative chiroptical data on the antipodes were obtained by linking a circular dichroism (CD) spectrometer and a UV-vis spectrophotometric detector in series to the HPLC instrument. The analysis of the CD and UV-vis spectra in terms of absolute conformations was done with the help of theoretical calculations performed at the Density Functional Theory (DFT) level. The most stable conformations of the 3,3'-biphenyl-2,2'-bitropone in its ground state were obtained. Starting from these minimum energy conformations, it was possible to compute theoretical CD and UV absorption spectra that fit well with the experimental ones. From this comparison the absolute configuration to the antipodes was assigned. Finally, the effect of the presence of the two lateral phenyl substituents on the structure of the bitropone and hence on the CD spectrum is discussed.