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.

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.

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.

Innovations in targeting RNA by fragment-based ligand discovery.

A subset of functional regions within large RNAs fold into complex structures able to bind small-molecule ligands with high affinity and specificity. Fragment-based ligand discovery (FBLD) offers notable opportunities for discovery and design of potent small molecules that bind pockets in RNA. Here we share an integrated analysis of recent innovations in FBLD, emphasizing opportunities resulting from fragment elaboration via both linking and growing. Analysis of elaborated fragments emphasizes that high-quality interactions form with complex tertiary structures in RNA. FBLD-inspired small molecules have been shown to modulate RNA functions by competitively inhibiting protein binding and by selectively stabilizing dynamic RNA states. FBLD is creating a foundation to interrogate the relatively unknown structural space for RNA ligands and for discovery of RNA-targeted therapeutics.

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.