Laurent Micouin

Cis ‐1,3‐functionalized carbocycles and saturated heterocycles are ubiquitous motifs in natural products, pharmaceuticals, and bioactive compounds. Traditional synthetic approaches, relying on chiral pools or stepwise functionalization of acyclic precursors, often face challenges in stereocontrol and substitution diversity. Polyheterocyclic intermediates have emerged as powerful platforms to address these limitations by embedding multiple heteroatoms within rigid frameworks, enabling predictable stereochemical relay during subsequent transformations. This review highlights strategies that exploit such intermediates to access cis ‐1,3‐diamines, amino alcohols, and related motifs across four‐ to six‐membered rings and larger polycyclic systems. Key principles include facial shielding, stabilization of reactive intermediates, and selective functionalization driven by strain or symmetry‐breaking. Representative methodologies—cycloadditions, rearrangements, nucleophilic openings, C–H functionalizations, and ring homologations—allow rapid construction of densely functionalized scaffolds with multiple contiguous stereocenters from simple precursors. These approaches not only streamline access to stereodefined, highly substituted frameworks but also offer modularity for late‐stage diversification, making them highly valuable for medicinal chemistry, natural product synthesis, and the design of conformationally constrained building blocks.

[2.2]Paracyclophanes (pCps) are rigid scaffolds consisting of two aromatic rings held in a cofacial arrangement by ethylene bridges. This distinctive geometry enforces through‐space π−π interactions, confers unusual reactivity, ensures configurational stability, and imparts planar chirality onto the systems. While functionalization of the aromatic rings is well‐established, selective modification of the ethylene bridges remains a major synthetic challenge. This review surveys current strategies for the preparation of bridge‐functionalized pCps, including construction of the cyclophane core from substituted precursors, direct derivatization of the parent scaffold, and functionalization of strained or deck‐substituted derivatives. Particular emphasis is placed on exploiting bridge reactivity to access novel molecular architectures, especially via contractive annulation approaches. Representative examples demonstrate how radical, photochemical, and stepwise transformations enable the installation of diverse substituents, the formation of π‐extended motifs at bridge positions, and the assembly of unprecedented strained polycyclic systems. Despite notable progress, challenges in yield, selectivity, and scalability remain, and enantiopure bridge‐functionalized [2.2]pCps are still largely unexplored. Continued methodological development is therefore expected to expand the utility of pCps as versatile building blocks for advanced materials, organometallic ligands, and catalytic systems, positioning the bridge as a strategic platform for accessing new structural and functional possibilities in contemporary cyclophane chemistry.

This study reports the design, synthesis, and structure–property analysis of an original family of three‐dimensional cyanine dyes based on the [2.2]paracyclophane (pCp) scaffold. By converting planar polymethine chromophores into three‐dimensional architectures, we developed fluorogenic dyes with enhanced selectivity for single‐stranded RNA containing stem‐loop motifs. Comparative studies with planar analogs show that benzothiazole‐ and benzoselenazole‐containing pCp derivatives exhibit strong fluorescence turn‐on upon nucleic‐acid binding, with responses varying by nucleic acid type and structure. Circular dichroism analyses suggest that these three‐dimensional dyes interact with RNA via a nonintercalative mode, distinct from classical planar intercalators. Expanding upon preliminary findings, this work explores an extended series of pCp‐derived cyanines, revealing how three‐dimensionality modulates both photophysical behavior and nucleic‐acid recognition. These results provide new directions for the design of selective RNA‐targeting ligands and for future exploration of their interactions with more complex RNA architectures.

Organoaluminum compounds are a unique class of organometallics, valued for their strong Lewis acidity and distinctive reactivity. Since Ziegler’s pioneering work in the mid-20th century, they have become important in catalysis and polymer production, benefiting from aluminum’s abundance, low cost, and low toxicity. However, their use in organic synthesis remains limited due to the complexity of their preparation—typically involving transmetalation steps that often reduce their advantages. Coordinating solvents used in these steps can also suppress the compounds’ Lewis acidity. This review explores alternative, more direct methods of synthesizing organoaluminum compounds and highlights recent progress in this area.

RNA targeting represents an original and promising approach to the discovery of new therapeutic tools against numerous diseases. The majority of intracellular RNAs are noncoding RNAs that play key regulatory functions in many physiological processes. Among these RNAs, long noncoding RNAs (lncRNAs) constitute the largest class of noncoding transcripts and have been shown to play important functional roles in development and disease processes. In this work, we developed a set of biochemical assays for the discovery of efficient small-molecule lncRNA ligands selective for their target, focusing on MALAT1 lncRNA. The latter bears a particular structure including a triple helical region important for its function, and it has been linked to cancer cells' proliferation. However, its role in cancer still needs to be completely elucidated. The application of these assays to an original library of RNA binders allowed for the discovery of unprecedented ligands of the MALAT1 triple helix able to inhibit and destabilize the triple helical MALAT1 structure. The set of screening and validation assays developed could find application in the discovery of new MALAT1 binders, and the new chemical scaffolds discovered in this study represent promising chemical probes for the study of the biological role of MALAT1 in disease.

This study presents efficient synthetic pathways for preparing novel azaspirocycles. These methodologies involve functionalizing key bicyclic hydrazines with a substituent on one of their bridgehead carbon atoms. The desired spirocyclic cores were successfully obtained through double reductive amination reactions, intramolecular cyclizations, and cleavages of the N−N bond. The isolated molecules possess unique three‐dimensional structures, suggesting potential applications in medicinal chemistry and drug discovery. With the growing interest in targeting nucleic acids as a complementary approach to protein‐targeting strategies for developing novel active compounds, we investigated the potential of the synthesized azaspirocycles as RNA binders. As a proof of concept, we highlight the promising activity of some compounds as strong binders of HIV‐1 TAR RNA and inhibitors of Tat/TAR interactions.

Lanthanide coordination complexes involving [2.2]paracyclophane (pCp) were designed. A magneto-structural correlation was realized for the Yb(iii) luminescent field-induced single-molecule magnets (SMMs).

α‐Silylated diazoalkynes are stabilized diazo compounds that can selectively react with carboxylic residues in buffered aqueous media. In‐situ fluoride induced desilylation increases this reactivity, leading to a very fast reaction. Application to the selective functionalization of RNase A, followed by post‐functionalization using click chemistry, is described. These new reagents expand the toolbox for native protein modification at carboxylic residues.

Herein, we demonstrate for the first time that coumarins derived from [2.2]paracyclophane (pCp) can act as effective organophotocatalysts 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.

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.