Light-Driven Reductive Cleavage of Sulfonamides Promoted by Thiourea Organophotosensitizers.

We have developed a practical method to perform the reductive photocleavage of sulfonamides using thioureas as organophotocatalysts. This transformation, which tolerates a variety of substrates, occurs under mild reaction conditions in the presence of tetrabutylammonium borohydride as a reducing agent. Experimental and theoretical mechanistic investigations complete the study, shedding light on the nature of the active species involved in the photocatalytic process.

Intramolecular Buchwald-Hartwig N-arylation of bicyclic hydrazines: practical access to spiro[indoline-2,3'-piperidines].

In recent years, spirocycles have been the focus of medicinal chemistry, and several drugs or drug candidates incorporating these "non-planar" chemical motifs have been developed. Herein, an unusual intramolecular Buchwald-Hartwig N-arylation of bicyclic hydrazines is described. This key reaction gives access to various spiro[indoline-2,3'-piperidine] derivatives after reductive cleavage of a nitrogen-nitrogen bond. Following this strategy, unprecedented spiro compounds can be obtained in up to 42% yields over 5 steps. Our approach widens the chemical space of spirocycles and may be useful to explore new avenues of research in drug discovery.

[2.2]Paracyclophane-based coumarins: effective organo-photocatalysts for light-induced desulfonylation processes.

Herein, we demonstrate for the first time that coumarins derived from [2.2]paracyclophane (pCp) can act as effective organo-photocatalysts and promote the reductive cleavage of sulfonamides under light-irradiation. In the presence of these original compounds, photodesulfonylation reactions occur under mild conditions at low catalyst loadings in the presence of Hantzsch ester. Theoretical and experimental investigations are described, which elucidate the reaction mechanism and the nature of the active species involved in the photocatalytic process. This proof-of-concept study paves the way for further application of pCps in the field of photocatalysis.

Planar Chiral Analogues of PRODAN Based on a [2.2]Paracyclophane Scaffold: Synthesis and Photophysical Studies.

We describe the synthesis and photophysical characterization of differently substituted planar chiral analogues of PRODAN based on a [2.2]paracyclophane scaffold. This experimental and theoretical study highlights that the (chir)optical properties of the new "phane" compounds, which incorporate an electron-withdrawing propionyl moiety and an electron-donating dimethylamino group at their para or pseudo-para positions, strongly depend on their substitution patterns. In particular, for this series of molecules, a more pronounced solvatochromism and clear chiroptical behaviors are observed when the two substituents are placed on the two rings of the pCp core in a non-"co-planar" arrangement (pseudo-para derivative). This observation may help design new pCp-based luminophores with finely tuned photophysical properties.

Tuning Excited-State Properties of [2.2]Paracyclophane-Based Antennas to Ensure Efficient Sensitization of Lanthanide Ions or Singlet Oxygen Generation.

The multistep synthesis of original antennas incorporating substituted [2.2]paracyclophane (pCp) moieties in the π-conjugated skeleton is described. These antennas, functionalized with an electron donor alkoxy fragment (A1) or with a fused coumarin derivative (A2), are incorporated in a triazacyclonane macrocyclic ligand L1 or L2, respectively, for the design of Eu(III), Yb(III), and Gd(III) complexes. A combined photophysical/theoretical study reveals that A1 presents a charge transfer character via through-space paracyclophane conjugation, whereas A2 presents only local excited states centered on the coumarin-paracyclophane moiety, strongly favoring triplet state population via intersystem crossing. The resulting complexes EuL1 and YbL2 are fully emissive in red and near-infrared, respectively, whereas the GdL2 complex acts as a photosensitizer for the generation of singlet oxygen.

Enantiopure planar chiral [2.2]paracyclophanes: Synthesis and applications in asymmetric organocatalysis.

This short review focuses on enantiopure planar chiral [2.2]paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three-dimensional core and intriguing physicochemical properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, [2.2]paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of [2.2]paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition-metal catalysis, these compounds can also be used as efficient catalysts in metal-free reactions and may inspire the development of new transformations in the near future.

3D Coumarin Systems Based on [2.2]Paracyclophane: Synthesis, Spectroscopic Characterization, and Chiroptical Properties.

In this article, we report the preparation of a series of [2.2]paracyclophane-fused coumarin systems through a simple and general procedure involving a transition-metal-catalyzed cyclization of aryl alkynoates as the key step. We also highlight the influence of the [2.2]paracyclophane (pCp) motif and its "phane" interactions on the spectroscopic properties of the newly synthesized fluorophores, which emit in the blue-green region of the visible spectrum (λem up to 560 nm) and show extremely large Stokes shifts (up to 230 nm). Finally, we demonstrate that our straightforward approach can easily be used to access optically active planar chiral 3D coumarins. Compared to previously described fluorescent paracyclophanes and other organic dyes, our compact heteroaromatic derivatives show promising chiroptical properties, both in term of circular dichroism ( gabs ∼ 8 × 10 -3) and circularly polarized luminescence ( glum ∼ 5 × 10 -3), thus demonstrating a practical application of our synthetic method.

Highly Enantioselective Asymmetric Transfer Hydrogenation: A Practical and Scalable Method To Efficiently Access Planar Chiral [2.2]Paracyclophanes.

We report herein a general, practical method based on asymmetric transfer hydrogenation (ATH) to control the planar chirality of a range of substituted [2.2]paracyclophanes (pCps). Our strategy enabled us to perform both the kinetic resolution (KR) of racemic compounds and the desymmetrization of centrosymmetric meso derivatives on synthetically useful scales. High selectivities (up to 99% ee) and good yields (up to 48% for the KRs and 74% for the desymmetrization reactions) could be observed for several poly-substituted paracyclophanes, including a series of bromine-containing molecules. The optimized processes could be run up to the gram scale without any loss in the reaction efficiencies. Because of its broad applicability, the ATH approach appears to be the method of choice to access planar chiral pCps in their enantiopure form.

Magneto-structural correlation in lanthanide luminescent [2.2]paracyclophane-based single-molecule magnets.

The association of lanthanide ions and paracyclophane derivatives has been very scarcely reported in the literature. In this study, elaboration of five coordination lanthanide complexes involving the 1,4(1,4)-dibenzenacyclohexaphane-12,43-diylbis(diphenylphosphine oxide) ligand (L) was achieved with the determination of single-crystal X-ray diffraction structures of four mononuclear complexes of formula [Ln(hfac)3(L)] (hfac- = 1,1,1,5,5,5-hexafluoroacetylacetonate) (Ln = Dy(III) (1-Dy) and Yb(III) (2-Yb)) and [Ln(tta)3(L)] (tta- = 2-tenoyl-trifluoroacetylacetonate) (Ln = Dy(III) (3-Dy) and Yb(III) (4-Yb)) and one dinuclear complex [Na(Dy2(hfac)6(L)2)](BArF) (BArF- = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) (5-Dy). The compounds were characterized using elemental analysis, IR spectroscopy, DC and AC magnetic measurements and photophysical investigations. L is an efficient organic chromophore for the sensitization of both visible Dy(III) (1-Dy) and near-infrared Yb(III) (2-Yb and 4-Yb) luminescence. The combination of excitation and emission spectra allowed the determination of the crystal field spitting of both the 2F7/2 ground state and 2F5/2 excited state for 2-Yb and 4-Yb. Moreover, 3-Dy and the two Yb(III) derivatives displayed field-induced single-molecule magnet (SMM) behaviour with slow magnetic relaxation occurring through the Raman process only for 2-Yb and 4-Yb, whereas a combination of Orbach and Raman processes was identified for 3-Dy.

DNA vs. mirror-image DNA: a universal approach to tune the absolute configuration in DNA-based asymmetric catalysis.

Mirror mirror on the wall: By taking advantage of the unique structural features of L-DNA, the first examples of left-helical enantioselective induction in the field of DNA-based asymmetric catalysis were realized. Most importantly, this approach is the only one that allows a reliable and predictable access to both enantiomers for any given reaction.

Synthesis and photophysical properties of a series of cyclopenta[b]naphthalene solvatochromic fluorophores.

The synthesis and photophysical properties of a series of naphthalene-containing solvatochromic fluorophores are described within. These novel fluorophores are prepared using a microwave-assisted dehydrogenative Diels-Alder reaction of styrene, followed by a palladium-catalyzed cross coupling reaction to install an electron donating amine group. The new fluorophores are structurally related to Prodan. Photophysical properties of the new fluorophores were studied and intriguing solvatochromic behavior was observed. For most of these fluorophores, high quantum yields (60-99%) were observed in methylene chloride in addition to large Stokes shifts (95-226 nm) in this same solvent. As the solvent polarity increased, so did the observed Stokes shift with one derivative displaying a Stokes shift of ~300 nm in ethanol. All fluorophore emission maxima, and nearly all absorption maxima were significantly red-shifted when compared to Prodan. Shifting the absorption and emission maxima of a fluorophore into the visible region increases its utility in biological applications. Moreover, the cyclopentane portion of the fluorophore structure provides an attachment point for biomolecules that will minimize disruptions of the photophysical properties.

Small-Molecule 3D Ligand for RNA Recognition: Tuning Selectivity through Scaffold Hopping.

Targeting RNAs with small molecules is considered the next frontier for drug discovery. In this context, the development of compounds capable of binding RNA structural motifs of low complexity with high affinity and selectivity would greatly expand the number of targets of potential therapeutic value. In this study, we demonstrate that tuning the three-dimensional shape of promiscuous nucleic acid binders is a valuable strategy for the design of new selective RNA ligands. Indeed, starting from a known cyanine, the simple replacement of a phenyl ring with a [2.2]paracyclophane moiety led to a new compound able to discriminate between nucleic acids showing different structural characteristics with a marked affinity and selectivity for an octahairpin loop RNA sequence. This shape modification also affected the in cellulo behavior of the cyanine. These results suggest that scaffold hopping is a valuable strategy to improve the selectivity of RNA/small-molecule interactions and highlight the need to explore a new chemical space for the design of selective RNA ligands.

Expanding biohybrid-mediated asymmetric catalysis into the realm of RNA.

The recent development of biohybrid catalytic systems has allowed synthetic chemists to reach high levels of selectivity on a wide variety of valuable synthetic transformations. In this context, DNA-based catalysts have emerged as particularly appealing tools. Interestingly, while long RNA sequences (ribozymes) are known to catalyse specific biochemical reactions with remarkable efficiencies, RNA-based catalysts involving a catalytically active metal complex interacting in a non-covalent fashion with short sequences have never been evaluated to date. We report here our results, which have led to the first example involving a short RNA-based catalyst.

DNA-cellulose: an economical, fully recyclable and highly effective chiral biomaterial for asymmetric catalysis.

The challenge in DNA-based asymmetric catalysis is to perform a reaction in the vicinity of the helix by incorporating a small-molecule catalyst anchored to the DNA in a covalent, dative, or non-covalent yet stable fashion in order to ensure high levels of enantio-discrimination. Here, we report the first generation of a DNA-based catalyst bound to a cellulose matrix. The chiral biomaterial is commercially available, trivial to use, fully recyclable and produces high levels of enantioselectivity in various Cu(II)-catalyzed asymmetric reactions including Friedel-Crafts alkylations and Michael additions. A single-pass, continuous-flow process is also reported affording fast conversions and high enantioselectivities at low catalyst loadings thus offering a new benchmark in the field of DNA-based asymmetric catalysis.

Microwave-assisted intramolecular dehydrogenative Diels-Alder reactions for the synthesis of functionalized naphthalenes/solvatochromic dyes.

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to the preparation of new organic dyes. Although numerous strategies have been reported to access naphthalene scaffolds, many procedures still present limitations in terms of incorporating functionality, which in turn narrows the range of available substrates. The development of versatile methods for direct access to substituted naphthalenes is therefore highly desirable. The Diels-Alder (DA) cycloaddition reaction is a powerful and attractive method for the formation of saturated and unsaturated ring systems from readily available starting materials. A new microwave-assisted intramolecular dehydrogenative DA reaction of styrenyl derivatives described herein generates a variety of functionalized cyclopenta[b]naphthalenes that could not be prepared using existing synthetic methods. When compared to conventional heating, microwave irradiation accelerates reaction rates, enhances yields, and limits the formation of undesired byproducts. The utility of this protocol is further demonstrated by the conversion of a DA cycloadduct into a novel solvatochromic fluorescent dye via a Buchwald-Hartwig palladium-catalyzed cross-coupling reaction. Fluorescence spectroscopy, as an informative and sensitive analytical technique, plays a key role in research fields including environmental science, medicine, pharmacology, and cellular biology. Access to a variety of new organic fluorophores provided by the microwave-assisted dehydrogenative DA reaction allows for further advancement in these fields.

Attachable solvatochromic fluorophores and bioconjugation studies.

The synthesis and utility of attachable cyclopenta[b]naphthalene solvatochromic fluorophores related to Prodan are described. Two fluorophores were selected for functionalization and bioconjugation studies. The skeletons were chemically modified to include reactive functional groups and showed minimal alteration of the optical properties when compared to the parent dyes. The functionalized fluorophores were covalently attached to the carboxyl group of a fatty acid, and azido- and thiol-containing amino acids, demonstrating their potential for labeling biomolecules.

A thermal dehydrogenative Diels-Alder reaction of styrenes for the concise synthesis of functionalized naphthalenes.

Functionalized naphthalenes are valuable building blocks in many important areas. A microwave-assisted, intramolecular dehydrogenative Diels-Alder reaction of styrenyl derivatives to provide cyclopenta[b]naphthalene substructures not previously accessible using existing synthetic methods is described. The synthetic utility of these uniquely functionalized naphthalenes was demonstrated by a single-step conversion of one of these cycloadducts to a fluorophore bearing a structural resemblance to Prodan.

Gold(I)-catalyzed cyclization of ß-allenylhydrazones: an efficient synthesis of multisubstituted N-aminopyrroles.

The gold(I)-catalyzed cycloisomerization of ß-allenylhydrazones provides an efficient access to multisubstituted N-aminopyrroles, which are obtained in good to excellent yields. This new intramolecular cyclization method can be applied either to alkyl- or aryl-substituted allenes. The reaction proceeds under mild conditions with short reaction times through a selective intramolecular 1,2-alkyl or -aryl migration extending the general scope of the reaction.