Publications by authors named "Richard C D Brown"

82 Publications

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

Chem Rec 2021 Sep 24;21(9):2472-2487. Epub 2021 Jul 24.

School of Chemistry, The University of Southampton, Highfield, Southampton, SO17 1BJ, UK.

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 to many g h , 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/tcr.202100163DOI Listing
September 2021

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

Angew Chem Int Ed Engl 2021 07 17;60(30):16442-16447. Epub 2021 Jun 17.

Institute of Biophysical Chemistry and Centre for Biomolecular Magnetic Resonance, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202015797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362212PMC
July 2021

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

Sci Adv 2021 Mar 12;7(11). Epub 2021 Mar 12.

Institute for Biophysical Chemistry and Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany.

The functional mechanism of the light-driven sodium pump 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- 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- 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abf4213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954446PMC
March 2021

The synthesis of biologically active indolocarbazole natural products.

Nat Prod Rep 2021 Mar 5. Epub 2021 Mar 5.

School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0np00096eDOI Listing
March 2021

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

Analyst 2020 Jul 19;145(14):4782-4786. Epub 2020 Jun 19.

School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0an00602eDOI Listing
July 2020

Algorithmic cooling of nuclear spins using long-lived singlet order.

J Chem Phys 2020 Apr;152(16):164201

Department of Chemistry, Southampton University, Southampton SO17 1BJ, United Kingdom.

Algorithmic cooling methods manipulate an open quantum system in order to lower its temperature below that of the environment. We achieve significant cooling of an ensemble of nuclear spin-pair systems by exploiting the long-lived nuclear singlet state, which is an antisymmetric quantum superposition of the "up" and "down" Zeeman states. The effect is demonstrated by nuclear magnetic resonance experiments on a molecular system containing a coupled pair of near-equivalent C nuclei. The populations of the system are subjected to a repeating sequence of cyclic permutations separated by relaxation intervals. The long-lived nuclear singlet order is pumped well beyond the unitary limit. The pumped singlet order is converted into nuclear magnetization which is enhanced by 21% relative to its thermal equilibrium value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/5.0006742DOI Listing
April 2020

Fast destruction of singlet order in NMR experiments.

J Chem Phys 2019 Dec;151(23):234203

International Tomography Center, Siberian Branch of the Russian Academy of Science, Novosibirsk 630090, Russia.

Some nuclear spin systems support long-lived states, which display greatly extended relaxation times relative to the relaxation time of nuclear spin magnetization. In spin-1/2 pairs, such a long-lived state is given by singlet order, representing the difference of the population of the nuclear singlet state and the mean population of the three triplets. In many cases, the experiments with long-lived singlet order are very time-consuming because of the need to wait for singlet order decay before the experiment can be repeated; otherwise, spin order remaining from a previous measurement may lead to experimental artifacts. Here, we propose techniques for fast and efficient singlet order destruction. These methods exploit coherent singlet-triplet conversion; in some cases, multiple conversion steps are introduced. We demonstrate that singlet order destruction enables a dramatic reduction of the waiting time between consecutive experiments and suggest to use this approach in singlet-state Nuclear Magnetic Resonance (NMR) experiments with nearly equivalent spins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.5131730DOI Listing
December 2019

Exploring Protein Structures by DNP-Enhanced Methyl Solid-State NMR Spectroscopy.

J Am Chem Soc 2019 12 6;141(50):19888-19901. Epub 2019 Dec 6.

Institute of Biophysical Chemistry , Goethe University Frankfurt , 60438 Frankfurt am Main , Germany.

Although the rapid development of sensitivity-enhanced solid-state NMR (ssNMR) spectroscopy based on dynamic nuclear polarization (DNP) has enabled a broad range of novel applications in material and life sciences, further methodological improvements are needed to unleash the full potential of DNP-ssNMR. Here, a new methyl-based toolkit for exploring protein structures is presented, which combines signal-enhancement by DNP with heteronuclear Overhauser effect (hetNOE), carbon-carbon-spin diffusion (SD) and strategically designed isotope-labeling schemes. It is demonstrated that within this framework, methyl groups can serve as dynamic sensors for probing local molecular packing within proteins. Furthermore, they can be used as "NMR torches" to selectively enlighten their molecular environment, e.g., to selectively enhance the polarization of nuclei within residues of ligand-binding pockets. Finally, the use of C-C spin diffusion enables probing carbon-carbon distances within the subnanometer range, which bridges the gap between conventional C-ssNMR methods and EPR spectroscopy. The applicability of these methods is directly shown on a large membrane protein, the light-driven proton pump green proteorhodopsin (GPR), which offers new insight into the functional mechanism of the early step of its photocycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.9b11195DOI Listing
December 2019

Mechanism of Os-Catalyzed Oxidative Cyclization of 1,5-Dienes.

J Org Chem 2019 12 13;84(23):15173-15183. Epub 2019 Nov 13.

Department of Chemistry , University of Southampton , Southampton , Hampshire SO17 1BJ , U.K.

The oxidative cyclization of 1,5-dienes by metal-oxo species is a powerful method for stereocontrolled synthesis of tetrahydrofuran diols (THF-diols), structural motifs present in many bioactive natural products. Oxidative cyclization of (2,6)-octa-2,6-diene catalyzed by OsO/NMO has been studied using density functional theory (DFT) calculations (M06-2X/aug-cc-pVDZ/Hay-Wadt VDZ (n+1) ECP), highlighting the remarkable effect of acid on the fate of the first intermediate, an Os(VI) dioxoglycolate. A strong acid promotes cyclization of the Os(VI) dioxoglycolate, or its NMO complex, through protonation of an oxo ligand to give more electrophilic species. By contrast, in the absence of acid, reoxidation may occur to afford the Os(VIII) trioxoglycolate, which is shown to favor conventional "second cycle" dihydroxylation reactivity rather than cyclization. The results of the calculations are consistent with experimental results for reactions of OsO/NMO with 1,5-dienes with acid (oxidative cyclization) and without acid (second cycle osmylation/dihydroxylation). Detailed evaluation of potential catalytic cycles supports oxidation of the cyclized Os(IV) THF-diolate intermediate to the corresponding Os(VI) species followed by slow hydrolysis and, finally, regeneration of OsO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.9b02174DOI Listing
December 2019

Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer-Moest Reaction under Flow Conditions.

Chemistry 2020 Jan 7;26(2):374-378. Epub 2019 Nov 7.

School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.

The highly strained cubane system is of great interest as a scaffold and rigid linker in both pharmaceutical and materials chemistry. The first electrochemical functionalisation of cubane by oxidative decarboxylative ether formation (Hofer-Moest reaction) was demonstrated. The mild conditions are compatible with the presence of other oxidisable functional groups, and the use of flow electrochemical conditions allows straightforward upscaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.201904479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973092PMC
January 2020

Excitation of singlet-triplet coherences in pairs of nearly-equivalent spins.

Phys Chem Chem Phys 2019 Mar;21(11):6087-6100

International Tomography Center, Siberian Branch of the Russian Academy of Science, Novosibirsk, 630090, Russia.

We present approaches for an efficient excitation of singlet-triplet coherences in pairs of nearly-equivalent spins. Standard Nuclear Magnetic Resonance (NMR) pulse sequences do not excite these coherences at all or with very low efficiency. The single quantum singlet-triplet coherences, here termed the outer singlet-triplet coherences, correspond to lines of low intensity in the NMR spectrum of a strongly-coupled spin pair (they are sometimes referred to as "forbidden transitions"), whereas the zero-quantum coherences, here termed the inner singlet-triplet coherences, do not have a direct spectral manifestation. In the present study, we investigated singlet-triplet coherences in a pair of nearly-equivalent carbon spins of the 13C-isotopomer of a specially designed naphthalene derivative with optimized relaxation properties. We propose and compare several techniques to drive the singlet-triplet coherence in strongly coupled spin pairs. First, we study different methods for efficient excitation of the outer singlet-triplet coherences. The achieved conversion efficiency of magnetization to the coherences of interest is close to the theoretically allowed maximum. Second, we propose methods to convert the outer coherences into the inner singlet-triplet coherence. The inner singlet-triplet coherence is insensitive to field inhomogeneity and can be long-lived. By probing this coherence, we perform a very precise measurement of the spin-spin J-couplings. A remarkable property of this coherence is that it can be preserved even in absence of a spin-locking radiofrequency field. Consequently, it is possible to shuttle the sample between different magnetic fields preserving the coherence. This allows one to study the field dependence of the relaxation time, TIST, of the inner singlet-triplet coherence by performing field-cycling experiments. We observed dramatic changes of the ratio TIST/T1 from about 1 (in strong fields) up to 2.4 (in weak fields), which is the evidence of a significant influence of the chemical shift anisotropy on relaxation. We have detected a remarkably long lifetime of the inner singlet-triplet coherence of about 200 s at the magnetic field of 5 mT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9cp00451cDOI Listing
March 2019

Constant-adiabaticity radiofrequency pulses for generating long-lived singlet spin states in NMR.

J Chem Phys 2019 Feb;150(6):064201

International Tomography Center, Siberian Branch of the Russian Academy of Science, Novosibirsk 630090, Russia.

A method is implemented to perform "fast" adiabatic variation of the spin Hamiltonian by imposing the constant adiabaticity condition. The method is applied to improve the performance of singlet-state Nuclear Magnetic Resonance (NMR) experiments, specifically, for efficient generation and readout of the singlet spin order in coupled spin pairs by applying adiabatically ramped RF-fields. Test experiments have been performed on a specially designed molecule having two strongly coupled C spins and on selectively isotopically labelled glycerol having two pairs of coupled protons. Optimized RF-ramps show improved performance in comparison, for example, to linear ramps. We expect that the methods described here are useful not only for singlet-state NMR experiments but also for other experiments in magnetic resonance, which utilize adiabatic variation of the spin Hamiltonian.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1063/1.5079436DOI Listing
February 2019

Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.

J Med Chem 2018 09 31;61(17):7630-7639. Epub 2018 Aug 31.

Département de Toxicologie et Risques Chimiques , Institut de Recherche Biomédicale des Armées , 91220 Brétigny-sur-Orge , France.

Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00592DOI Listing
September 2018

Solid-state NMR analysis of the sodium pump Krokinobacter rhodopsin 2 and its H30A mutant.

J Struct Biol 2019 04 4;206(1):55-65. Epub 2018 Jun 4.

Institute for Biophysical Chemistry and Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max von Laue Strasse 9, 60438 Frankfurt am Main, Germany. Electronic address:

Krokinobacter eikastus rhodopsin 2 (KR2) is a pentameric, light-driven ion pump, which selectively transports sodium or protons. The mechanism of ion selectivity and transfer is unknown. By using conventional as well as dynamic nuclear polarization (DNP)-enhanced solid-state NMR, we were able to analyse the retinal polyene chain between positions C10 and C15 as well as the Schiff base nitrogen in the KR2 resting state. In addition, 50% of the KR2 C and N resonances could be assigned by multidimensional high-field solid-state NMR experiments. Assigned residues include part of the NDQ motif as well as sodium binding sites. Based on these data, the structural effects of the H30A mutation, which seems to shift the ion selectivity of KR2 primarily to Na, could be analysed. Our data show that it causes long-range effects within the retinal binding pocket and at the extracellular Na binding site, which can be explained by perturbations of interactions across the protomer interfaces within the KR2 complex. This study is complemented by data from time-resolved optical spectroscopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsb.2018.06.001DOI Listing
April 2019

Singlet-assisted diffusion-NMR (SAD-NMR): redefining the limits when measuring tortuosity in porous media.

Phys Chem Chem Phys 2018 May;20(20):13705-13713

Chemistry, University of Southampton, SO17 1BJ, Southampton, UK.

Long-lived singlet order is exploited in diffusion NMR experiments to successfully measure the tortuosity of randomly packed spheres with diameters ranging from 500 to 1000 μm. The pore spaces in such packings have characteristic length scales well beyond the length scale limit set by spin relaxation in conventional NMR-diffusion experiments. Diffusion times of up to 240 s were used to obtain the restricted diffusion coefficient as a function of diffusion time in the long-time diffusion regime. Experimental results were validated with numerical simulations and data from X-ray micro-computed tomography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8cp00145fDOI Listing
May 2018

Synthesis of isotopically labeled all-trans retinals for DNP-enhanced solid-state NMR studies of retinylidene proteins.

J Labelled Comp Radiopharm 2018 11 2;61(13):922-933. Epub 2018 Feb 2.

Department of Chemistry, University of Southampton, Southampton, UK.

Three all-trans retinals containing multiple C labels have been synthesized to enable dynamic nuclear polarization enhanced solid-state magic angle spinning NMR studies of novel microbial retinylidene membrane proteins including proteorhodpsin and channelrhodopsin. The synthetic approaches allowed specific introduction of C labels in ring substituents and at different positions in the polyene chain to probe structural features such as ring orientation and interaction of the chromophore with the protein in the ground state and in photointermediates. [10-18- C ]-All-trans-retinal (1b), [12,15- C ]-all-trans-retinal (1c), and [14,15- C ]-all-trans-retinal (1d) were synthesized in in 12, 8, and 7 linear steps from ethyl 2-oxocyclohexanecarboxylate (5) or β-ionone (4), respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jlcr.3576DOI Listing
November 2018

Chromophore Distortions in Photointermediates of Proteorhodopsin Visualized by Dynamic Nuclear Polarization-Enhanced Solid-State NMR.

J Am Chem Soc 2017 11 3;139(45):16143-16153. Epub 2017 Nov 3.

Institute for Biophysical Chemistry & Centre for Biomolecular Magnetic Resonance, Goethe-University Frankfurt , Frankfurt 60438, Germany.

Proteorhodopsin (PR) is the most abundant retinal protein on earth and functions as a light-driven proton pump. Despite extensive efforts, structural data for PR photointermediate states have not been obtained. On the basis of dynamic nuclear polarization (DNP)-enhanced solid-state NMR, we were able to analyze the retinal polyene chain between positions C10 and C15 as well as the Schiff base nitrogen in the ground state in comparison to light-induced, cryotrapped K- and M-states. A high M-state population could be achieved by preventing reprotonation of the Schiff base through a mutation of the primary proton donor (E108Q). Our data reveal unexpected large and alternating C chemical shift changes in the K-state propagating away from the Schiff base along the polyene chain. Furthermore, two different M-states have been observed reflecting the Schiff base reorientation after the deprotonation step. Our study provides novel insight into the photocycle of PR and also demonstrates the power of DNP-enhanced solid-state NMR to bridge the gap between functional and structural data and models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.7b05061DOI Listing
November 2017

Flow Electrolysis Cells for the Synthetic Organic Chemistry Laboratory.

Chem Rev 2018 05 18;118(9):4573-4591. Epub 2017 Sep 18.

Chemistry , University of Southampton , Southampton SO17 1BJ , U.K.

Electrosynthesis has much to offer to the synthetic organic chemist. But in order to be widely accepted as a routine procedure in an organic synthesis laboratory, electrosynthesis needs to be presented in a much more user-friendly way. The literature is largely based on electrolysis in a glass beaker or H-cells that often give poor performance for synthesis with a very slow rate of conversion and, often, low selectivity and reproducibility. Flow cells can lead to much improved performance. Electrolysis is participating in the trend toward continuous flow synthesis, and this has led to a number of innovations in flow cell design that make possible selective syntheses with high conversion of reactant to product with a single passage of the reactant solution through the cell. In addition, the needs of the synthetic organic chemist can often be met by flow cells operating with recycle of the reactant solution. These cells give a high rate of product formation while the reactant concentration is high, but they perform best at low conversion. Both approaches are considered in this review and the important features of each cell design are discussed. Throughout, the application of the cell designs is illustrated with syntheses that have been reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.chemrev.7b00360DOI Listing
May 2018

A Two-Directional Synthesis of (+)-β-Isosparteine.

Org Lett 2017 07 13;19(13):3502-3504. Epub 2017 Jun 13.

Department of Chemistry, University of Southampton , Southampton, Hampshire SO17 1BJ, U.K.

A two-directional synthesis of (+)-β-isosparteine is described in five steps from glutaric acid, where the entire carbon and nitrogen backbone of the alkaloid, possessing the requisite relative and absolute stereochemistry at its four stereogenic centers, is assembled using a double imino-aldol reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.7b01475DOI Listing
July 2017

Electrochemical Deprotection of para-Methoxybenzyl Ethers in a Flow Electrolysis Cell.

Org Lett 2017 04 4;19(8):2050-2053. Epub 2017 Apr 4.

Department of Chemistry, University of Southampton , Southampton, Hampshire SO17 1BJ, U.K.

Electrochemical deprotection of p-methoxybenzyl (PMB) ethers was performed in an undivided electrochemical flow reactor in MeOH solution, leading to the unmasked alcohol and p-methoxybenzaldehyde dimethyl acetal as a byproduct. The electrochemical method removes the need for chemical oxidants, and added electrolyte (BFNEt) can be recovered and reused. The method was applied to 17 substrates with high conversions in a single pass, yields up to 92%, and up to 7.5 g h productivity. The PMB protecting group was also selectively removed in the presence of some other common alcohol protecting groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.7b00641DOI Listing
April 2017

Synthesis of carbon-13 labeled oxalates exhibiting extended nuclear singlet state lifetimes.

J Labelled Comp Radiopharm 2017 02 19;60(2):135-139. Epub 2016 Dec 19.

Department of Chemistry, University of Southampton, Southampton, UK.

Unsymmetrical perdeuterated doubly C labelled oxalates exhibit extended lifetimes in the nuclear singlet state. Synthesis of 1,2 C oxalates from commercially available precursors is described, facilitating preparation of unsymmetrical oxalates in a controlled manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jlcr.3479DOI Listing
February 2017

A Short Diastereoselective Total Synthesis of (±)-Vibralactone.

Org Lett 2016 12 31;18(23):5971-5973. Epub 2016 Oct 31.

Department of Chemistry, University of Southampton , Southampton, Hampshire SO17 1BJ, U.K.

A total synthesis of the (±)-vibralactone has been achieved in 11 steps and 16% overall yield from malonic acid. Key steps include a highly diastereoselective allylation of an α-formyl ester containing an all carbon α-quaternary center, a Pd-catalyzed deallylative β-lactonization, and an aldehyde-selective Wacker oxidation of a terminal alkene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.6b03007DOI Listing
December 2016

Correction: Substituent interference on supramolecular assembly in urea gelators: synthesis, structure prediction and NMR.

Soft Matter 2016 Jun 2;12(24):5489. Epub 2016 Jun 2.

Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.

Correction for 'Substituent interference on supramolecular assembly in urea gelators: synthesis, structure prediction and NMR' by Francesca Piana et al., Soft Matter, 2016, 12, 4034-4043.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6sm90091gDOI Listing
June 2016

Substituent interference on supramolecular assembly in urea gelators: synthesis, structure prediction and NMR.

Soft Matter 2016 05 29;12(17):4034-43. Epub 2016 Mar 29.

Chemistry, University of Southampton, Southampton, SO17 1BJ, UK.

Eighteen N-aryl-N'-alkyl urea gelators were synthesised in order to understand the effect of head substituents on gelation performance. Minimum gelation concentration values obtained from gel formation studies were used to rank the compounds and revealed the remarkable performance of 4-methoxyphenyl urea gelator 15 in comparison to 4-nitrophenyl analogue 14, which could not be simply ascribed to substituent effects on the hydrogen bonding capabilities of the urea protons. Crystal structure prediction calculations indicated alternative low energy hydrogen bonding arrangements between the nitro group and urea protons in gelator 14, which were supported experimentally by NMR spectroscopy. As a consequence, it was possible to relate the observed differences to interference of the head substituents with the urea tape motif, disrupting the order of supramolecular packing. The combination of unbiased structure prediction calculations with NMR is proposed as a powerful approach to investigate the supramolecular arrangement in gel fibres and help understand the relationships between molecular structure and gel formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6sm00607hDOI Listing
May 2016

N-Heterocyclic Carbene-Mediated Microfluidic Oxidative Electrosynthesis of Amides from Aldehydes.

Org Lett 2016 Mar 17;18(5):1198-201. Epub 2016 Feb 17.

Department of Chemistry, University of Southampton , Southampton, Hampshire SO17 1BJ, U.K.

A flow process for N-Heterocyclic Carbene (NHC)-mediated anodic oxidative amidation of aldehydes is described, employing an undivided microfluidic electrolysis cell to oxidize Breslow intermediates. After electrochemical oxidation, the reaction of the intermediate N-acylated thiazolium cation with primary amines is completed by passage through a heating cell to achieve high conversion in a single pass. The flow mixing regimen circumvented the issue of competing imine formation between the aldehyde and amine substrates, which otherwise prevented formation of the desired product. High yields (71-99%), productivities (up to 2.6 g h(-1)), and current efficiencies (65-91%) were realized for 19 amides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.6b00339DOI Listing
March 2016

Enlightening the photoactive site of channelrhodopsin-2 by DNP-enhanced solid-state NMR spectroscopy.

Proc Natl Acad Sci U S A 2015 Aug 27;112(32):9896-901. Epub 2015 Jul 27.

Institute of Biophysical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany; Centre for Biomolecular Magnetic Resonance, Goethe University Frankfurt, 60438 Frankfurt, Germany;

Channelrhodopsin-2 from Chlamydomonas reinhardtii is a light-gated ion channel. Over recent years, this ion channel has attracted considerable interest because of its unparalleled role in optogenetic applications. However, despite considerable efforts, an understanding of how molecular events during the photocycle, including the retinal trans-cis isomerization and the deprotonation/reprotonation of the Schiff base, are coupled to the channel-opening mechanism remains elusive. To elucidate this question, changes of conformation and configuration of several photocycle and conducting/nonconducting states need to be determined at atomic resolution. Here, we show that such data can be obtained by solid-state NMR enhanced by dynamic nuclear polarization applied to (15)N-labeled channelrhodopsin-2 carrying 14,15-(13)C2 retinal reconstituted into lipid bilayers. In its dark state, a pure all-trans retinal conformation with a stretched C14-C15 bond and a significant out-of-plane twist of the H-C14-C15-H dihedral angle could be observed. Using a combination of illumination, freezing, and thermal relaxation procedures, a number of intermediate states was generated and analyzed by DNP-enhanced solid-state NMR. Three distinct intermediates could be analyzed with high structural resolution: the early [Formula: see text] K-like state, the slowly decaying late intermediate [Formula: see text], and a third intermediate populated only under continuous illumination conditions. Our data provide novel insight into the photoactive site of channelrhodopsin-2 during the photocycle. They further show that DNP-enhanced solid-state NMR fills the gap for challenging membrane proteins between functional studies and X-ray-based structure analysis, which is required for resolving molecular mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1507713112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538646PMC
August 2015

N-Heterocyclic Carbene-Mediated Oxidative Electrosynthesis of Esters in a Microflow Cell.

Org Lett 2015 Jul 15;17(13):3290-3. Epub 2015 Jun 15.

†Department of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, U.K.

An efficient N-heterocyclic carbene (NHC)-mediated oxidative esterification of aldehydes has been achieved in an undivided microfluidic electrolysis cell at ambient temperature. Productivities of up to 4.3 g h(-1) in a single pass are demonstrated, with excellent yields and conversions for 19 examples presented. Notably, the oxidative acylation reactions were shown to proceed with a 1:1 stoichiometry of aldehyde and alcohol (for primary alcohols), with remarkably short residence times in the electrolysis cell (<13 s), and without added electrolyte.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.5b01459DOI Listing
July 2015

Synthesis of an isotopically labeled naphthalene derivative that supports a long-lived nuclear singlet state.

Org Lett 2015 May 21;17(9):2150-3. Epub 2015 Apr 21.

Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, U.K.

The synthesis of an octa-alkoxy substituted isotopically labeled naphthalene derivative, shown to have excellent properties in singlet NMR experiments, is described. This highly substituted naphthalene system, which incorporates an adjacent (13)C spin pair, is readily accessed from a commercially available (13)C2-labeled building block via sequential thermal alkynyl- and arylcyclobutenone rearrangements. The synthetic route incorporates a simple desymmetrization approach leading to a small difference in the chemical shifts of the (13)C spin pair, a design constraint crucial for accessing nuclear singlet order.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.5b00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516318PMC
May 2015

A Nuclear Singlet Lifetime of More than One Hour in Room-Temperature Solution.

Angew Chem Weinheim Bergstr Ger 2015 Mar 4;127(12):3811-3814. Epub 2015 Feb 4.

School of Chemistry, University of Southampton, University Road, Southampton, SO17 1BJ (UK).

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are supremely important techniques with numerous applications in almost all branches of science. However, until recently, NMR methodology was limited by the time constant for the decay of nuclear spin magnetization through contact with the thermal molecular environment. Long-lived states, which are correlated quantum states of multiple nuclei, have decay time constants that may exceed by large factors. Here we demonstrate a nuclear long-lived state comprising two C nuclei with a lifetime exceeding one hour in room-temperature solution, which is around 50 times longer than . This behavior is well-predicted by a combination of quantum theory, molecular dynamics, and quantum chemistry. Such ultra-long-lived states are expected to be useful for the transport and application of nuclear hyperpolarization, which leads to NMR and MRI signals enhanced by up to five orders of magnitude.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ange.201411978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955235PMC
March 2015

Real-space imaging of macroscopic diffusion and slow flow by singlet tagging MRI.

J Magn Reson 2015 Mar 31;252:130-4. Epub 2015 Jan 31.

School of Chemistry, University of Southampton, SO17 1BJ Southampton, UK.

Magnetic resonance imaging can be used to study motional processes such as flow and diffusion, but the accessible timescales are limited by longitudinal relaxation. The spatially selective conversion from magnetization to long-lived singlet order in designer molecules makes it possible to tag a region of interest for an extended period of time, of the order of several minutes. Here we exploit this concept of "singlet tagging" to monitor diffusion over a macroscopic scale as well as very slow flow.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmr.2015.01.016DOI Listing
March 2015
-->