The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives.

The first organophosphorus nerve agent was discovered accidently during the development of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, terrorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to serious injury or the death of the person intoxicated. The limited efficacy of current antidotes, known as AChE reactivators, pushes research towards new treatments. Numerous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. Another crucial approach resides in molecules more prone to cross the blood-brain barrier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reactivator, to tackle the task of efficiently treating victims of these chemical warfare agents.

Molecular mechanisms and evolutionary robustness of a color switch in proteorhodopsins.

Proteorhodopsins are widely distributed photoreceptors from marine bacteria. Their discovery revealed a high degree of evolutionary adaptation to ambient light, resulting in blue- and green-absorbing variants that correlate with a conserved glutamine/leucine at position 105. On the basis of an integrated approach combining sensitivity-enhanced solid-state nuclear magnetic resonance (ssNMR) spectroscopy and linear-scaling quantum mechanics/molecular mechanics (QM/MM) methods, this single residue is shown to be responsible for a variety of synergistically coupled structural and electrostatic changes along the retinal polyene chain, ionone ring, and within the binding pocket. They collectively explain the observed color shift. Furthermore, analysis of the differences in chemical shift between nuclei within the same residues in green and blue proteorhodopsins also reveals a correlation with the respective degree of conservation. Our data show that the highly conserved color change mainly affects other highly conserved residues, illustrating a high degree of robustness of the color phenotype to sequence variation.

Photoinduced Formation of Cubyl Aryl Thioethers and Synthesis of Monocubyl Analogue of Dapsone.

1,4-Disubstituted cubyl aryl thioethers were generated from the corresponding iodocubanes and aryl thiolates upon UV irradiation in dimethyl sulfoxide at room temperature. This simple procedure was found to be compatible with a variety of substituted aryl thiolates. This finding paved the way to a synthesis of the monocubyl analogue of dapsone, a key molecule in the treatment of leprosy, also known as Hansen's disease, and of acne.

Aryl-aryl cross-coupling reactions without reagents or catalysts: photocyclization of ortho-iodoaryl ethers and related compounds via triplet aryl cation intermediates.

Cyclisations of benzyl ortho-iodoaryl ethers to benzo[c]chromenes can be effected without reagents or catalysts by irradiation with UVC under flow. Reactions proceed via triplet aryl cation generation, 5-exo and 3-exo-cyclisations, and rearomatisation. They have wide scope, are easy to effect and extend to a myriad of related ring systems.

Spatio-temporal detachment of homogeneous electron transfer in controlling selectivity in mediated organic electrosynthesis.

In electrosynthesis, electron transfer (ET) mediators are normally chosen such that they are more easily reduced (or oxidised) than the substrate for cathodic (or anodic) processes; setting the electrode potential to the mediator therefore ensures selective heterogeneous ET with the mediator at the electrode, rather than the substrate. The current work investigates the opposite, and counter intuitive, situation for a successful mediated electroreductive process where the mediator (phenanthrene) has a reduction potential that is negative to that of the substrate, and the cathode potential is set negative to both (Eele < EM < Es). Simulations reveal a complex interplay between mass transport, the relative concentrations of the mediator and substrate as well as the heterogeneous and homogeneous rate constants for multiple steps, which under suitable conditions, leads to separation of the homogeneous chemistry in a reaction layer detached from the electrode. Reaction layer detachment is a spatio-temporal effect arising due to opposing fluxes of the mediator radical anion M˙- and the substrate 1, which ultimately prevents 1 from reaching the electrode, thereby affording a different reaction pathway. Simulations representative of unstirred batch (1D) and flow (2D) electrolysis are presented, which qualitatively reproduce the experimental selectivity outcomes for mediated and unmediated electroreductive cyclisation of aryl iodide 1. The potential to use highly reducing homogeneous ET agents, possessing reduction potentials beyond those of the substrates, offers exciting opportunities in mediated electrosynthesis.

1-Butyl-3-methylimidazolium tetrafluoroborate as suitable solvent for BF3: the case of alkyne hydration. Chemistry vs electrochemistry.

In order to replace the expensive metal/ligand catalysts and classic toxic and volatile solvents, commonly used for the hydration of alkynes, the hydration reaction of alkynes was studied in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIm-BF4) adding boron trifluoride diethyl etherate (BF3·Et2O) as catalyst. Different ionic liquids were used, varying the cation or the anion, in order to identify the best one, in terms of both efficiency and reduced costs. The developed method was efficaciously applied to different alkynes, achieving the desired hydration products with good yields. The results obtained using a conventional approach (i.e., adding BF3·Et2O) were compared with those achieved using BF3 electrogenerated in BMIm-BF4, demonstrating the possibility of obtaining the products of alkyne hydration with analogous or improved yields, using less hazardous precursors to generate the reactive species in situ. In particular, for terminal arylalkynes, the electrochemical route proved to be advantageous, yielding preferentially the hydration products vs the aldol condensation products. Importantly, the ability to recycle the ionic liquid in subsequent reactions was successfully demonstrated.

A flow electrochemistry-enabled synthesis of 2-substituted N-(methyl-d)piperidines.

A synthesis of N-monodeuteriomethyl-2-substituted piperidines is described. An efficient and readily scalable anodic methoxylation of N-formylpiperidine in an undivided microfluidic electrolysis cell delivers methoxylated piperidine 3, which is a precursor to a N-formyliminium ion and enables C-nucleophiles to be introduced at the 2-position. The isotopically labelled N-deuteriomethyl group is installed using the Eschweiler-Clarke reaction with formic acid-d2 and unlabelled formaldehyde. Monodeuterated N-methyl groups in these molecular systems possess small isotropic proton chemical shift differences important in the investigation of molecules that are able to support long-lived nuclear spin states in solution nuclear magnetic resonance.

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell.

In this paper we present the first electrochemical generation of NHC carried out in a divided flow cell. The flow cell operated in the recycle mode. The need for a divided cell derived from the anodic electroactivity of the electrogenerated carbene. In order to have NHC accumulation in the catholyte, the Nafion membrane (cell separator) was pretreated with an alkaline solution. The formation of NHC was quantified as its reaction product with elemental sulfur. The NHC was successfully used as organocatalyst in two classical umpolung reactions of cinnamaldehyde: its cyclodimerization and its oxidative esterification.

Cathodic Radical Cyclisation of Aryl Halides Using a Strongly-Reducing Catalytic Mediator in Flow.

Electro-reductive radical cyclisation of aryl halides affords the corresponding hetero- and carbo-cycles in an undivided flow reactor equipped with steel and carbon electrodes using an organic mediator. A dissolving metal anode is not needed, and the mediator can be employed in a sub-stoichiometric amount (0.05 equiv), increasing the practical utility of cathodic radical cyclisation. The methodology is applied to O-, N-, and C-tethers, yielding tricyclic fused and spiro systems. In the absence of mediator, the major pathway is hydrogenolysis of the C-X bond, a 2 e- process occurring at the cathode. Predominance of the radical pathway in presence of a strongly reducing mediator (M) is consistent with homogeneous electron-transfer in a reaction layer detached from the cathode surface, where the flux of M.- leaving the electrode is such that little aryl halide reaches the cathode.

Transition-Metal-Mediated Chemo- and Stereoselective Total Synthesis of (-)-Galanthamine.

An asymmetric synthetic route to (-)-galanthamine (1), a pharmacologically active Amaryllidaceae alkaloid used for the symptomatic treatment of early onset Alzheimer's disease, was successfully established with very high levels of stereocontrol. The key to achieving high chemo- and stereo-selectivity in this approach was the use of transition-metal-mediated reactions, namely, enyne ring-closing metathesis, Heck coupling, and titanium-based asymmetric allylation.

Self-Optimization of Continuous Flow Electrochemical Synthesis Using Fourier Transform Infrared Spectroscopy and Gas Chromatography.

A continuous-flow electrochemical synthesis platform has been developed to enable self-optimization of reaction conditions of organic electrochemical reactions using attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) and gas chromatography (GC) as online real-time monitoring techniques. We have overcome the challenges in using ATR FT-IR as the downstream analytical methods imposed when a large amount of hydrogen gas is produced from the counter electrode by designing two types of gas-liquid separators (GLS) for analysis of the product mixture flowing from the electrochemical reactor. In particular, we report an integrated GLS with an ATR FT-IR probe at the reactor outlet to give a facile and low-cost solution to determining the concentrations of products in gas-liquid two-phase flow. This approach provides a reliable method for quantifying low-volatile analytes, which can be problematic to be monitored by GC. Two electrochemical reactions the methoxylation of 1-formylpyrrolidine and the oxidation of 3-bromobenzyl alcohol were investigated to demonstrate that the optimal conditions can be located within the pre-defined multi-dimensional reaction parameter spaces without intervention of the operator by using the stable noisy optimization by branch and FIT (SNOBFIT) algorithm.

The Longer Route can be Better: Electrosynthesis in Extended Path Flow Cells.

This personal account provides an overview of work conducted in my research group, and through collaborations with other chemists and engineers, to develop flow electrolysis cells and apply these cells in organic electrosynthesis. First, a brief summary of my training and background in organic synthesis is provided, leading in to the start of flow electrosynthesis in my lab in collaboration with Derek Pletcher. Our work on the development of extended path electrolysis flow reactors is described from a synthetic organic chemist's perspective, including laboratory scale-up to give several moles of an anodic methoxylation product in one day. The importance of cell design is emphasised with regards to achieving good performance in laboratory electrosynthesis with productivities from hundreds of mg h-1 to many g h-1 , at high conversion in a selective fashion. A simple design of recycle flow cell that can be readily constructed in a small University workshop is also discussed, including simple modifications to improve cell performance. Some examples of flow electrosyntheses are provided, including Shono-type oxidation, anodic cleavage of protecting groups, Hofer-Moest reaction of cubane carboxylic acids, oxidative esterification and amidation of aldehydes, and reduction of aryl halides.

The Desensitized Channelrhodopsin-2 Photointermediate Contains 13 -cis, 15 -syn†Retinal Schiff Base.

Channelrhodopsin-2 (ChR2) is a light-gated cation channel and was used to lay the foundations of optogenetics. Its dark state X-ray structure has been determined in 2017 for the wild-type, which is the prototype for all other ChR variants. However, the mechanistic understanding of the channel function is still incomplete in terms of structural changes after photon absorption by the retinal chromophore and in the framework of functional models. Hence, detailed information needs to be collected on the dark state as well as on the different photointermediates. For ChR2 detailed knowledge on the chromophore configuration in the different states is still missing and a consensus has not been achieved. Using DNP-enhanced solid-state MAS NMR spectroscopy on proteoliposome samples, we unambiguously determined the chromophore configuration in the desensitized state, and we show that this state occurs towards the end of the photocycle.

The synthesis of biologically active indolocarbazole natural products.

Covering: up to 2020The indolocarbazoles, in particular indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, are an important class of natural products that exhibit a wide range of biological activities. There has been a plethora of synthetic approaches to this family of natural products, leading to advances in chemical methodology, as well as affording access to molecular scaffolds central to protein kinase drug discovery programmes. In this review, we compile and summarise the synthetic approaches to the indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, spanning the period from their isolation in 1980 up to 2020. The selected natural products include indolocarbazoles not functionalised at indolic nitrogen, pyranosylated indolocarbazoles, furanosylated indolocarbazoles and disaccharideindolocarbazoles.

Probing the photointermediates of light-driven sodium ion pump KR2 by DNP-enhanced solid-state NMR.

The functional mechanism of the light-driven sodium pump Krokinobacter eikastus rhodopsin 2 (KR2) raises fundamental questions since the transfer of cations must differ from the better-known principles of rhodopsin-based proton pumps. Addressing these questions must involve a better understanding of its photointermediates. Here, dynamic nuclear polarization-enhanced solid-state nuclear magnetic resonance spectroscopy on cryo-trapped photointermediates shows that the K-state with 13-cis retinal directly interconverts into the subsequent L-state with distinct retinal carbon chemical shift differences and an increased out-of-plane twist around the C14-C15 bond. The retinal converts back into an all-trans conformation in the O-intermediate, which is the key state for sodium transport. However, retinal carbon and Schiff base nitrogen chemical shifts differ from those observed in the KR2 dark state all-trans conformation, indicating a perturbation through the nearby bound sodium ion. Our findings are supplemented by optical and infrared spectroscopy and are discussed in the context of known three-dimensional structures.

Quantitative UHPSFC-MS analysis of elemental sulfur in mineral oil via derivatisation with triphenylphosphine: application to corrosive sulfur-related power transformer failure.

An ultrahigh-performance supercritical fluid chromatography-mass spectrometry (UHPSFC-MS) method has been developed as a rapid and reliable analytical method for the detection and quantification of elemental sulfur in mineral transformer oil. The method described in this paper is based on the selective reaction of elemental sulfur with triphenylphosphine (TPP). The derivatisation of elemental sulfur requires minimal sample preparation and resulted in the formation of a single compound, namely triphenylphosphine sulfide (TPPS). This derivative is quantified from the complex oil composition using electrospray ionisation-mass spectrometry (ESI-MS) in selected ion monitoring (SIM) mode, and the reported UHPSFC-MS method allows detection and quantification of the derivative at ppb levels. As sulfur contamination in mineral transformer oil has been linked to costly failures of oil/paper-based power transformers due to corrosion, the analytical approach is demonstrated through its application to mineral oil samples from in service and decommisioned power transformers. The method is ideal as a routine test or to confirm the presence of elemental sulfur in samples where corrosion has occurred.