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We describe the synthesis of a range of 6’-triazolyl-dihydroxanthene-hemicyanine (DHX-hemicyanine) fused dyes through an effective copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reaction, with the dual aim of providing molecular diversity and fine tuning spectral properties of these near-infrared (NIR)-active materials. This was implemented by reacting 16 different aliphatic and aromatic azides with a terminal alkynyl-based-DHX-hemicyanine hybrid scaffold prepared in four steps and 35% overall yield from 4-bromosalicylaldehyde. The resulting triazole derivatives have been fully characterized and their optical properties determined both in organic solvents and simulated physiological conditions (phosphate buffered saline containing 5% of bovine serum albumin protein). This systematic study is a first important step towards the development of NIR-I fluorogenic "click-on" dyes or related photoactive agents for light-based diagnostic and/or therapeutic applications.

International audience; A novel class of rosamine dyes bearing a 7-substituted 4-hydroxycoumarin unit as meso-heteroaryl ring is presented. The latent C-nucleophilic character of 4-hydroxycoumarin derivatives (i.e., their C-3 position as nucleophilic center) has been drawn on in the designing of two unprecedented synthetic routes towards these atypical xanthene dyes. They are based on an effective formal Knoevenagel condensation with either pyronin derivatives or a mixed bis-aryl ether bearing both an aldehyde and a masked phenylogous amine, possibly applicable to a wide range of latent cyclic C-nucleophiles. We also report experimental and theoretical photophysical investigations of these unique coumarin-pyronin hybrid structures and particularly their form low-lying quenching states, some of dark twisted intramolecular charge transfer (TICT) nature, depending on the medium (CHCl3 and water). Furthermore, two fluorophore compounds 9 and 11 have been applied for imaging in paraformaldehyde-fixed A549 cells to gain insights into their permeation and localization.

International audience; We describe an expedient access to a 5', 6', 7'-trifluoro dihydroxanthene-hemicyanine fused scaffold in 2 steps and 54% overall yield from the corresponding salicylic aldehyde. A 6'-regioselective nucleophilic aromatic substitution (SNAr) reaction with a wide range of nitrogen, sulfur or selenium nucleophiles then gives access to 16 near-infrared (NIR) fluorophores emitting in the 710-750 nm range. We also report the experimental and theoretical photophysical investigations of these unique optical agents that include the first series of 6'-heavy atom substituted dihydroxanthenes, extending the pool of polyfluorinated markers for biomedical and material applications.

We report a rational and systematic study devoted to the structural optimisation of a novel class of protease-sensitive fluorescent probes that we recently reported (S. Debieu and A. Romieu, Org. Biomol. Chem., 2017, 15, 2575-2584), based on the "covalent-assembly" strategy and using the targeted enzyme penicillin G acylase as a model protease to build a fluorescent pyronin dye by triggering a biocompatible domino cyclisation-aromatisation reaction. The aim is to identify ad hoc probe candidate(s) that might combine fast/reliable fluorogenic "turn-on" response, full stability in complex biological media and ability to release a second molecule of interest (drug or second fluorescent reporter), for applications in disease diagnosis and therapy. We base our strategy on screening a set of active methylene compounds (C-nucleophiles) to convert the parent probe to various pyronin caged precursors bearing Michael acceptor moieties of differing reactivities. In vitro stability and fluorescent enzymatic assays combined with HPLC-fluorescence analyses provide data useful for defining the most appropriate structural features for these fluorogenic scaffolds depending on the specifications inherent to biological application (from biosensing to theranostics) for which they will be used.

We report a rational and systematic study devoted to structural optimisation of a novel class of protease-sensitive fluorescent probes recently reported by us (Org. Biomol. Chem., 2017, 15, 2575-2584), based on the "covalent-assembly" strategy and using the targeted enzyme (penicilin G acylase as model protease) to build a fluorescent pyronin dye by triggering a biocompatible domino cyclisation-aromatisation reaction. The aim is to identify ad hoc probe candidate(s) that might combine fast/reliable fluorogenic "turn-on" response, full stability in complex biological media and ability to release a second molecule of interest (drug or second fluorescent reporter), for applications in disease diagnosis and therapy. We base our strategy on screening a set of active methylene compounds (C-nucleophiles) to convert the parent probe to various pyronin caged precursors bearing Michael acceptor moieties of differing reactivity. In vitro stability and fluorescent enzymatic assays combined to HPLC-fluorescence analyses provide data useful to define the most appropriate structural features for these fluorogenic scaffolds depending on the specifications required by the biomedical application (e.g., in vivo molecular imaging, image-guided drug delivery and theranostics) for which they will be used.

Domino Michael-aldol annulation of cycloalkane-1,3-diones with enals affords a general route to 6-hydroxybicyclo[3.3.1]nonane-2,9-diones and 2-hydroxybicyclo[3.2.1]octane-6,8-diones, notably in one-pot procedures under convenient conditions. The annulation is shown to be compatible with one or more substituents at six positions of the bicyclo[3.3.1]nonane-2,9-dione scaffold. In some cases, the relative configuration of the product can be controlled by the appropriate choice of solvent, base and temperature for the annulation. In contrast to the chair–chair conformations usually adopted, the bicyclo compounds derived from 2,4,4-trimethylcyclohexane-1,3-dione possessed boat-chair conformations. Oxidation of the annulation products gave the corresponding bicyclo triketones.

Synthesis of 3-fluoro-2-hetarylindoles through addition of hetarenes to 3,3-difluoroindolium ions generated in situ by Zn(OTf)2-catalyzed oxazolidine ring opening is described. Indoles, pyrroles and alkyl-substituted furans can be used as hetaryl nucleophiles to afford a range of 3-fluoro-2-hetarylindole products 6 in 56–95 % yields. A diverse array of 3,3-difluorinated 2-hetarylindolines 7 can also be synthesized in 43–84 % yields by a tandem sequential process that involves hetarene nucleophilic addition, HF elimination and fluorocyclization reactions. Our study by 1H NMR and UV/Vis spectroscopy reveals that 3,3-difluorinated 2-hetarylindolines possess interesting substituent-dependent acidochromic properties. UV absorption and fluorescence spectra of selected compounds 6 and 7 are also studied.

International audience; The effective synthesis of extended conjugated N, N-dialkylamino-nor-dihydroxanthene-based fluorophores is described from diversely functionalized salicylic aldehydes. The access to these original fluorescent derivatives proceeded in two steps through a one-pot construction of the unusual nor-dihydroxanthene (nor-DHX) scaffold followed by a diversification step providing a wide variety of nor-DHXhemicyanine fused dyes emitting in the range of 730790 nm. The versatility of our approach has enabled a further extension to the late-stage introduction of negatively/posi-tively charged polar groups onto their terminal nitrogen heterocyclic subunit, thereby giving access to the first watersoluble and/or bioconjugatable members of this emerging class of NIR fluorophores. Our water-solubilizing method is easily implementable, and the nor-DHX-hemicyanine skeleton maintains satisfying fluorescence quantum yields (520%) under physiological conditions. Finally, the bioconjugation ability of fluorescent derivatives bearing a free carboxylic acid was demonstrated through the covalent labeling of a model protein, namely, bovine serum albumin.

A five-step synthesis of the 6-6-6 tricyclic skeleton of the diterpene wickerol A is described. The synthesis features a diastereoselective d-proline-mediated Robinson annulation and N-heterocyclic carbene-catalyzed Stetter reaction as key transformations to give the tricyclic carbon skeleton of this promising anti-influenza A natural product.

(+)-Hyperforin (1) is a polyprenylated acylphloroglucinol (PPAP) natural product isolated in 1971 from Hypericum perforatum. Also known as St. John's wort, Hypericum perforatum is a popular medicinal plant because of its antidepressant properties. (+)-Hyperforin (1) is the main component of the plant and has attracted the interest of the scientific community since it was identified as the agent responsible for the antidepressant activity. The subsequent discovery that it also displayed a wide range of biological activities triggered the interest of synthetic chemists because of its appealing, compact molecular structure. This microreview presents an overview of the synthetic studies reported so far for the racemic and enantioselective syntheses of (+)-hyperforin (1) and analogues, and attempts to shed light on the intriguing structure–activity relationships (SARs) of the natural product.

International audience; A late-stage amination of a bifunctional dihydroxanthene (DHX) scaffold is reported to access a wide variety of new near-infrared (NIR) chromophores/fluorophores. The divergent approach allows the coupling of aliphatic and aromatic amines and readily provides molecular diversity shedding light on the structure fluorescence relationship of this emerging class of NIR fluorophores.

With their fascinating biological profiles and stunningly complex molecular architectures, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have long provided a fertile playing field for synthetic organic chemists. In particular, the recent advent of innovative synthetic methods and strategies together with C-C bond-forming reactions and asymmetric catalysis have revitalized this field tremendously. Consequently, PPAP targets which once seemed beyond reach have now been synthesized. This Review aims to highlight the recent achievements in the total synthesis of PPAPs, as well as notable methods developed for the construction of the bicyclo[3.3.1] core of these chemically and biologically intriguing molecules.

Asymmetric entry to the bicyclic core structure of (+)-hyperforin is presented. The developed synthetic strategy features a carefully orchestrated stereochemical relay from the single chiral center residing within (–)-Wieland–Miescher ketone and an intramolecular aldol reaction to cast the [3.3.1] bicyclic scaffold found in a diverse array of polycyclic polyprenylated acylphloroglucinols.

In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients' well-being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.

The design and synthesis of novel water-soluble far-red emitting phenol-based fluorophores derived from 7-hydroxycoumarin are described. These hemicyanine-coumarin hybrids display promising spectroscopic features such as large apparent Stokes shift (ranging from 60 to 140 nm) and fluorescence emission maxima between 620 and 720 nm in physiological conditions. Their utility was then illustrated by the preparation of an original fluorogenic probe of penicillin G acylase (PGA) whose fluorescence is unveiled through an enzyme-initiated domino reaction.

The self-immolative spacer para-aminobenzyl alcohol (PABA) was used as a key component in the design of new protease-sensitive fluorogenic probes whose parent phenol-based fluorophore is released through an enzyme-initiated domino reaction. First, the conjugation of the phenylacetyl moiety to 7-hydroxycoumarin (umbelliferone) and 7-hydroxy-9 H-(9,9-dimethylacridin-2-one) (DAO) by means of the heterobifunctional PABA linker has led to pro-fluorophores 6a and 6d whose enzyme activation by penicillin amidase was demonstrated. The second part of this study was devoted to the extension of this latent fluorophore strategy to the caspase-3 protease, a key mediator of apoptosis in mammalian cells. Fluorogenic caspase-3 substrates 11 and 13 derived from umbelliferone and DAO, respectively, were prepared. It was demonstrated that pro-fluorophore 11 is a sensitive fluorimetric reagent for the detection of this cysteine protease. Furthermore, in vitro assays with fluorogenic probe 13 showed a deleterious effect of biological thiols on fluorescence of the released acridinone fluorophore DAO that, to our knowledge, had not been reported until now.

The straightforward synthesis of a Cs symmetrical calix[6]arene possessing carboxylic acid groups as well as an ammonium arm is described. This calixarene can encapsulate ammonium ions through a highly selective recognition process thanks to the presence of an internal ion-paired cap that preorganizes the cavity and constitutes an efficient binding site.

The design and synthesis of novel self-immolative spacer systems aiming at the release of phenol-containing compounds are described. The newly designed traceless linkers proved to be conveniently stable under physiological conditions and operate through spontaneous decomposition of an hemithioaminal intermediate under neutral aqueous conditions. Their utility was then illustrated by the preparation of original fluorogenic substrates of penicillin amidase whose strong fluorescence is unveiled through enzyme-initiated domino reactions.

International audience; An expedient synthesis of amino-(nor)dihydroxanthene-based fluorophores is reported, proceeding in two steps from commercially available salicylic aldehydes. The synthesis relies on the one-pot construction of the (nor)dihydroxanthene scaffolds through an oxa-Michael/retro-Michael/vinylogous aldol/dehydration cascade sequence. Further extension of the π-conjugated systems through a condensation reaction with a 2,4,6-trisubstituted pyrylium salt led to a novel class of near-infrared (NIR) fluorescent dyes with absorption/emission maxima in polar media in the ranges of 705–778 and 785–828 nm, respectively.

We report a flexible de novo synthesis of phenolic dihydroxanthene fluorophores. The synthesis relies on a one-pot formation of an aldehyde intermediate which can be diversified in 60–70% overall yield, providing an efficient access to this family of near-infrared emitting fluorophores.

We report a flexible de novo synthesis of phenolic dihydroxanthene fluorophores. The synthesis relies on a one-pot formation of an aldehyde intermediate which can be diversified in 60–70% overall yield, providing an efficient access to this family of near-infrared emitting fluorophores.

The synthesis of various 3-fluoro-2-hetarylindoles through addition of indoles, pyrroles, or alkyl-substituted furans to 3,3-difluoroindolium ions generated in situ by zinc triflate-catalyzed oxazolidine ring opening is described.

Review: [chemical approaches directed toward the total synthesis of (+)-hyperforin and its analogues; 140 refs.

The use of an O-nucleophile tethered to the indole nitrogen atom enables the synthesis of polycyclic fluorinated indoline derivatives from simple precursors in moderate yields.

A strategy involving the use of a self-immolative linker has been investigated for the chemiluminescent sensing of proteases. The reactive linker enabled the release of a 1,2-dioxetane light precursor. As a proof of principle, caspase-3, a key peptidase involved in apoptosis has been targeted. An in vitro assay has been carried out and proved the decomposition of the linker and the selectivity for caspase-3.

Cascade fluorofunctionalisation of 2,3-unsubstituted indoles featuring the formation of C–C, C–F and C–O bonds via electrophilic fluorination using N-fluorobenzenesulfonimide is described. The use of an O-nucleophile tethered to the nitrogen of indoles enables the synthesis of polycyclic fluorinated indoline derivatives from simple precursors in 40–63% yields.

In this tutorial review, recent advances in the synthesis of cyclopropane-containing natural products are discussed, highlighting the application of novel synthetic methodologies and innovative synthetic strategies in the construction of highly functionalized cyclopropanes. The examples showcased herein aim to inspire students and practitioners of organic synthesis to seek further advances in the chemical synthesis of cyclopropanes, both in the context of target-oriented syntheses and method developments.

With their fascinating biological profiles and stunningly complex molecular architectures, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have long provided a fertile playing field for synthetic organic chemists. In particular, the recent advent of innovative synthetic methods and strategies together with C-C bond-forming reactions and asymmetric catalysis have revitalized this field tremendously. Consequently, PPAP targets which once seemed beyond reach have now been synthesized. This Review aims to highlight the recent achievements in the total synthesis of PPAPs, as well as notable methods developed for the construction of the bicyclo[3.3.1] core of these chemically and biologically intriguing molecules.

In this tutorial review, recent advances in the synthesis of cyclopropane-containing natural products are discussed, highlighting the application of novel synthetic methodologies and innovative synthetic strategies in the construction of highly functionalized cyclopropanes. The examples showcased herein aim to inspire students and practitioners of organic synthesis to seek further advances in the chemical synthesis of cyclopropanes, both in the context of target-oriented syntheses and method developments.

In the long lasting battle against cancer, Nature sometimes gives a helping hand to researchers to find new drugs for the treatment of diseases and improvement of patients' well-being. Englerin A has emerged as a promising anticancer candidate as well as being an exciting synthetic challenge for organic chemists. This focus review summarizes the total syntheses reported to date and the synthetic approaches toward analogues of this fascinating natural product.

Synthesis and chemiluminescent properties of a new 1,2-dioxetane chemiluminophore bearing a 7-hydroxycoumarin moiety are presented. The 1,2-dioxetane decomposition ended up with strong and long-lived emission of light. This new structure opens way to the development of a new generation of bright chemiluminescent bio-probes.

Total synthesis of echinopine A and B have been accomplished, based on a strategy that involved two transition-metal-mediated ene-yne cycloisomerizations. A modified Pd-catalyzed enyne cycloisomerization/intramolecular Diels-Alder cascade rendered a more streamlined synthesis of tricyclic ketone 15, and a Ru-catalyzed ene-yne cycloisomerization/cyclopropanation resembled the late-stage [5/7] → [3/5/5/7] ring-forming sequence in the proposed biosynthetic pathway.

International audience; Synthesis and chemiluminescent properties of a new 1,2-dioxetane chemiluminophore bearing a 7-hydroxycoumarin moiety are presented. The 1,2-dioxetane decomposition ended up with strong and long-lived emission of light. This new structure opens way to the development of a new generation of bright chemiluminescent bio-probes.

Echinopines A and B [(+)-1 and (+)-2], two naturally occurring compounds characterized with a unique [3.5.5.7] carbon framework, have been synthesized in both enantiomeric and racemic forms. Their total synthesis involves a novel intramolecular rhodium-catalyzed cyclopropanation (4 → 16) and a samarium diiodide-mediated ring closure (3 → 37).

A new generation of dioxetane-based chemiluminescent substrates suitable for detecting protease activities is described. Our strategy involves the use of a self-cleavable spacer as the key molecular component of these protease-sensitive chemiluminescent probes. Among the assayed strategies, the PABA (para-aminobenzylic alcohol) linker associated with an ether linkage enables the release of the light-emitting phenolic 1,2-dioxetane moiety through an enzyme-initiated domino reaction. To validate this strategy, two proteolytic enzymes were chosen: penicillin amidase and caspase-3, and the corresponding self-cleavable chemiluminescent substrates were synthesised. Their evaluation using an in vitro assay has enabled us to prove the decomposition of the linker under physiological conditions and the selectivity for the targeted enzyme.

We report the expedient synthesis of 8-disubstituted bicyclo[3.2.1]octane-3-ones and 9-disubstituted bicyclo[3.3.1]octane-3-ones through the double Michael addition (DMA) of carbon nucleophiles to 7 and 8-membered ring dienones. The reaction proceeds in 42–96% yield with an interesting control of the stereochemistry of the bridged secondary, tertiary or quaternary centre.

International audience; This study focuses on the disassembly-behavior of self-immolative pro-fluorescent linkers under physiological conditions and through an enzyme-initiated domino reaction. The targeted linkers are based on para-aminobenzylalcohol (PABA) or hemithioaminal derivatives of para-carboxybenzaldehyde or glyoxilic acid. We found that a fine tuning of the kinetic properties could be obtained through the modulation of the linker structure, giving either a fast signal response or free-adaptable systems suitable for the design of protease-sensitive fluorogenic probes or prodrug systems.