Kinetic effects in singlet oxygen mediated oxidations by immobilized photosensitizers on silica.

Singlet oxygen (1O2) mediated photo-oxidations are important reactions involved in numerous processes in chemical and biological sciences. While most of the current research works have aimed at improving the efficiencies of these transformations either by increasing 1O2 quantum yields or by enhancing its lifetime, we establish herein that immobilization of a molecular photosensitizer onto silica surfaces affords significant, substrate dependant, enhancement in the reactivity of 1O2. Probing a classical model reaction (oxidation of Anthracene-9, 10-dipropionic acid, ADPA or dimethylanthracene, DMA) with various spectrofluorimetric techniques, it is here proposed that an interaction between polar substrates and the silica surface is responsible for the observed phenomenon. This discovery could have a direct impact on the design of future photosensitized 1O2 processes in various applications ranging from organic photochemistry to photobiology.

Self-Sensitized Photooxidation of Naphthols to Naphthoquinones and the Use of Naphthoquinones as Visible Light Photocatalysts in Batch and Continuous Flow Reactors.

Visible light photooxidation of naphthols to produce naphthoquinones, such as the natural product juglone, has been known for decades and has been widely utilized to benchmark the performances of a variety of photocatalytic systems. We discovered that these transformations can occur without the help of a photocatalyst and, even more intriguingly, that the photocatatyst-free process provides higher yields compared to control experiments utilizing state-of-the-art photocatalysts. In addition, we demonstrate that naphthoquinones and their corresponding naphthol precursors can act as alternatives to commonly used organic and organometallic photocatalysts with applications to challenging targets, such as the antimalarial drug artemisinin. This approach was finally transposed in continuous flow reactors where high photocatalyst stability and process efficiency are demonstrated with a 23× improvement in the space-time yield.

Pyrroloquinolines, a New Platform for Developing Organic Photosensitizers: When Synthetic Methodology Meets Photophysics†.

New molecular architectures with triplet sensitization properties can have a big impact on photochemistry and photobiology. In their recent work, de Bonfils et al. have tackled this challenge in a very systematic way using a powerful synthetic strategy. This consists of an elegant yet practical organocatalyzed cyclization/oxidation rearrangement sequence which they now apply to the synthesis of pyrroloquinolines, a new scaffold for photosensitizers. However, beyond this new class of compounds, the strategy has potential to produce a myriad of compact organic chromophores with promising photoinduced intersystem crossing properties. The study therefore provides interesting clues to serve the rational design of biocompatible molecular photosensitizers but also raises puzzling questions on the intriguing excited state reactivity of these molecular architectures.

Enhancing Singlet Oxygen Photocatalysis with Plasmonic Nanoparticles.

Photocatalysts able to trigger the production of singlet oxygen species are the topic of intense research efforts in organic synthesis. Yet, challenges still exist in improving their activity and optimizing their use. Herein, we exploited the benefits of plasmonic nanoparticles to boost the activity of such photocatalysts via an antenna effect in the visible range. We synthesized silica-coated silver nanoparticles (Ag@SiO2 NPs), with silica shells which thicknesses ranged from 7 to 45 nm. We showed that they served as plasmonically active supports for tris(bipyridine)ruthenium(II), [Ru(bpy)3]2+, and demonstrated an enhanced catalytic activity under white light-emitting diode (LED) irradiation for citronellol oxidation, a key step in the commercial production of rose oxide fragrance. A maximum enhancement of the plasmon-mediated reactivity of approximately 3-fold was observed with a 28 nm silica layer along with a 4-fold enhancement in the emission intensity of the photocatalyst. Using electron energy loss spectroscopy (EELS) and boundary element method simulations, we mapped the decay of the plasmonic signal around the Ag core and provided a rationale for the observed catalytic enhancement. This work provides a systematic analysis of the promising properties of plasmonic NPs used as catalysis-enhancing supports for common homogeneous photocatalysts and a framework for the successful design of such systems in the context of organic transformations.

Palladium-Catalyzed Regioselective Allylic Oxidation of Amorphadiene, a Precursor of Artemisinin.

A regioselective Pd-catalyzed allylic oxidation of amorphadiene, a key precursor to the antimalarial drug artemisinin, is described. Amorphadiene can be obtained in high yields by fermentation, but it is currently treated as a waste in the industrial semisynthetic artemisinin process. The catalytic step described here is a substitute for the P450 enzymes involved in the artemisinin biosynthesis and opens up new opportunities to supplement a critical step in the current semisynthetic route and increase the potential of the fermentation process.

Photochemical Hydrothiolation of Amorphadiene and Formal Synthesis of Artemisinin via a Pummerer Rearrangement.

A new access to artemisinin is reported based on a selective photochemical hydrothiolation of amorphadiene, a waste product of the industrial semisynthetic route. This study highlights the discovery of two distinctive activation pathways under solvent-free conditions or using a photocatalyst promoting H-abstraction. Subsequently, a chemoselective oxidation of the resulting photochemically generated thioether, followed by a Pummerer rearrangement, affords dihydroartemisinic aldehyde, a key intermediate in the synthesis of artemisinin.

Chemo- and Diastereoselective Hydrosilylation of Amorphadiene toward the Synthesis of Artemisinin.

A formal synthesis of artemisinin starting from amorphadiene is described. This new route relies on the development of a catalytic chemo- and diastereoselective hydrosilylation. The practicability of this method is demonstrated by converting amorphadiene to dihydroartemisinic aldehyde using a one-pot hydrosilylation/oxidation sequence, minimizing the number of purifications and maximizing the productivity through a practical one-pot procedure. In addition, this approach can be coupled with a crystallization-induced diastereoselective transformation (CIDT) to enhance the optical purity of the key target intermediate, dihydroartemisinic aldehyde.

Crystallization-Induced Diastereoisomer Transformation of Dihydroartemisinic Aldehyde with the Betti Base.

Artemisinin is an important drug to fight malaria. It is produced either by extraction or via a semisynthetic route involving enzyme engineering. A key intermediate to produce artemisinin by the enzymatic route is dihydroartemisinic aldehyde (DHAAl). However, control of the absolute configuration of the stereocenter α to the aldehyde is highly challenging. Herein we report a protocol that allows the diastereomeric enrichment of a mixture of (11R)/(11S)-DHAAl to the desired (11R)-DHAAl by utilizing a crystallization-induced diastereomer transformation induced by the Betti base. In addition, the Betti base can be quantitatively recovered and reused after the reaction.

Photocatalysis Meets Magnetism: Designing Magnetically Recoverable Supports for Visible-Light Photocatalysis.

While magnetic supports have been widely used to immobilize homogeneous catalysts in organic chemistry, this strategy has so far found very little application in photocatalysis. Indeed, magnetic supports are dark colored, and thus compete for photon absorption with photocatalysts themselves. We have developed a series of core-shell Fe(0)-silica nanoparticles as supports for immobilizing the photosensitizer Ru(bpy)32+, featuring various silica shell thicknesses-16-34 nm SiO2-on 9 nm Fe cores. The supports and the resulting photocatalytic systems were studied for their magnetic, optical, and catalytic properties in the context of the photooxidation of citronellol, and we found that thicker silica shells lead to higher catalytic activity. We correlated this effect as well as Ru(bpy)32+ fluorescence and singlet oxygen generation to the absorption properties of the supports. We were able to reuse our optimal system three times with minimal loss of activity and achieved turnover numbers largely surpassing the performance of homogeneous Ru(bpy)32+. This work highlights the role of material design in the conception of new supports for applications in heterogeneous photocatalysis.

Stable liquid foams from a new polyfluorinated surfactant.

Liquid foams exhibiting long-term stability are a key-challenge in material design. Based on this perspective, new pyridinium polyfluorinated surfactants were synthesized from simple building blocks enabling unusually stable liquid foams. While the batch-generated foams were used for qualitative foaming evaluation, microfluidics allowed a quantitative insight into the aging effects of monodisperse foams.

Synthesis of amorpha-4,11-diene from dihydroartemisinic acid.

Amorphadiene is a natural product involved in the biosynthesis of the antimalarial drug artemisinin. A convenient four-step synthesis of amorphadiene, starting from commercially available dihydroartemisinic acid, is reported. The targeted molecule is isolated with an overall yield of 85% on a multi-gram scale in four steps with only one chromatography.

Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory.

We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases. The reactor has been applied to several photochemical reactions involving singlet oxygen (1O2) including the photo-oxidations of α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving a Schenk-ene reaction with 1O2, Hock cleavage with H+, and an oxidative cyclization cascade with triplet oxygen (3O2), from dihydroartemisinic acid was carried out as a single process in the vortex reactor.

Applying green chemistry to the photochemical route to artemisinin.

Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else-solvents, photocatalyst and aqueous acid-can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

Recent contributions from the asymmetric aza-Michael reaction to alkaloids total synthesis.

This review focuses on recent applications of the aza-Michael reaction in alkaloids total synthesis with a special emphasis on stereoselectivity. The report highlights achievements and challenges over the past five years and describes stereoselective intra- and inter-molecular conjugate addition of nitrogen-containing nucleophiles, including tandem and cascade processes. Total asymmetric syntheses of natural scaffolds, such as pyrrolidine, piperidine and "izidine" families, are depicted. Multi-step syntheses of highly challenging natural products are further detailed, assessing the scope of the stereocontrolled aza-Michael reaction as a powerful tool in alkaloid chemistry.

Solvent-free double aza-Michael under ultrasound irradiation: diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids analogues.

Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical double Michael acceptors. The key step rested on an aza-Michael addition of primary alkylamines to bis-enones. Competitive Rauhut-Currier and aza-Michael reactions have been highlighted in protic solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences.