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This work presents a simple protocol that demonstrates the use of an inexpensive household carbon monoxide detector as a useful tool to detect the release of carbon monoxide gas from thermal cheletropic decarbonylation reactions. The carbon monoxide detection method described has been employed in a short series of reactions used in a university teaching laboratory setting, and full procedures for these are outlined. In each case, the procedure to isolate and identify the decarbonylation products has also been provided. Postprint

We report the synthesis of all‐cis 1,2,4,5‐tetrakis (trifluoromethyl)‐ and all‐cis 1,2,3,4,5,6‐hexakis (trifluoromethyl)‐ cyclohexanes by direct hydrogenation of precursor tetrakis‐ or hexakis‐ (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF3 groups are on the same face of the cyclohexyl ring. All‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all‐cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol−1. The X‐ray structure of all‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co‐ordinate chloride (K≈103) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base., All‐cis 1,2,4,5‐tetrakis (trifluoromethyl)‐ and all‐cis 1,2,3,4,5,6‐hexakis (trifluoromethyl)‐ cyclohexanes were prepared by direct aryl hydrogenation. All‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane has a high barrier to ring inversion (ΔG≠=27 kcal mol−1) and a Janus face profile with a large diffuse negative density on the fluorine face, and a focused positive density on the hydrogen face which coordinates carbonyls and halides.

Fluorinated nucleoside analogues have attracted much attention as anticancer and antiviral agents and as probes for enzymatic function. However, the lack of direct synthetic methods, especially for 2&prime, 3&prime, dideoxy-2&prime, difluoro nucleosides, hamper their practical utility. In order to design more efficient synthetic methods, a better understanding of the conformation and mechanism of formation of these molecules is important. Herein, we report the synthesis and conformational analysis of a 2&prime, difluoro and a 2&prime, deoxy-2&prime, fluoro uridine derivative and provide an insight into the reaction mechanism. We suggest that the transformation most likely diverges from the SN1 or SN2 pathway, but instead operates via a neighbouring-group participation mechanism.

Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all-cis-2,3,5,6-tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all-cis-2,3,5,6-tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn-amino-alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans-halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23-26 and the preferred conformations of these α-fluoroamides were explored by DFT, X-ray structure and 1 H-19 F HOESY NMR analysis.

We would like to acknowledge EPSRC for PhD funding through the Doctoral Training Schemes and the EPSRC National Mass Spectrometry Service Centre, Swansea for mass spectrometric analysis. The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ether-containing precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred. Postprint

This work was supported by EPSRC grants (EP/1518175), the Industrial Biotechnology Innovation Centre (IBioIC) (DMB Ph.D. studentship) and an EPSRC Doctoral Prize Fellowship (CSL). With lignin-first biorefineries likely to become a reality, controlled depolymerization of high-quality lignin streams to high value products has become a priority. Using bisulfite chemistry, access to a high-β-O-4 content water-soluble lignosulfonate has been achieved, allowing follow-on procedures in water to be conducted. We show that phenolic β-O-4 units preferential-ly react under acidic bisulfite conditions, whilst non-phenolic β-O-4 units react much more slowly. Exploiting this improved chemical understanding and inherent selectivity, a softwood lignosulfonate has been prepared in which phenolic β-O-4 α-sulfonation has occurred leaving significant native β-O-4 content. Use of an O-benzoylation protocol with lignin coupled with advanced 2D NMR methods has allowed detailed analysis of this and other commercial and industrial lignosulfonates. Conversion of the native β-O-4 to benzylic- oxidized β-O-4 units was followed by a selective reductive cleavage to give a premium aromatic monomer in pure form. Publisher PDF

This work was supported by EPSRC Ph.D. studentships EP/1654168 (JRDM). EP/1654168/1. Raw data files can be found at: https://doi.org/10.6084/m9.figshare.8034680 Recent reports demonstrate that applications of the biopolymer lignin can be helped by the use of a portion of the lignin which has an optimal molecular weight range. Unfortunately, the current methods used to determine lignin’s molecular weight are inconsistent or not widely accessible. Here, an approach that relies on 2D DOSY NMR analysis is described that provides a measure of lignin’s molecular weight. Consistent results were obtained using this well-established NMR technique across a range of lignins. Publisher PDF

This work was supported by EPSRC PhD studentships EP/1654168 (JRDM) and EP/1518175 (DMMB) and the Industrial Biotechnology Innovation Centre (DMMB). The depolymerisation of the biopolymer lignin can give pure aromatic monomers but selective catalytic approaches remain scarce. Here, an approach was re-routed to deliver an unusual phenolic monomer. This monomer’s instability proved challenging but a degradation study identified strategies to overcome this. Heterocycles and a useful synthetic intermediate were prepared. The range of aromatics available from the b-O-4 unit in lignin was extended. Postprint

The authors acknowledge the work of Juan Karsten for the partial development of the Pure-NOMAD integration. This work has been supported by the EPSRC-Strategic Partners Project (2012, grant number EP/J501542/1) and the Impact Acceleration Account (2016, grant number EP/K503940/1). Research funders have introduced requirements that expect researchers to properly manage and publicly share their research data, and expect institutions to put in place services to support researchers in meeting these requirements. So far the general focus of these services and systems has been on addressing the final stages of the research data lifecycle (archive, share and re-use), rather than stages related to the active phase of the cycle (collect/create and analyse). As a result, full integration of active data management systems with data repositories is not yet the norm, making the streamlined transition of data from an active to a published and archived status an important challenge. In this paper we present the integration between an active data management system developed in-house (NOMAD) and Elsevier’s Pure data repository used at our institution with the aim of offering a simple workflow to facilitate and promote the data deposit process. The integration results in a new data management and publication workflow that helps researchers to save time, minimize human errors related to manually handling files, and further promote data deposit together with collaboration across the institution. Publisher PDF

The authors thank the EPSRC UK National Mass Spectrometry Facility at Swansea University for analytical services. C.H. acknowledges the Région Bretagne, France for funding. D.J. acknowledges the European Research Council and the Région des Pays de la Loire for financial support in the framework of a Starting Grant (Marches - 278845) and the LUMOMAT RFI project, respectively. This research used resources of 1) the GENCI-CINES/IDRIS, 2) the CCIPL (Centre de Calcul Intensif des Pays de Loire), 3) a local Troy cluster. E.Z.-C. acknowledges the University of St. Andrews and EPSRC (EP/M02105X/1) for financial support. We report the synthesis, characterization and the optoelectronic properties of a series of four new luminescent iridium(III) complexes 1-4 , of the form [Ir(C^N)2(N^N)]PF6 [where C^N is the nonconjugated benzylpyridinato (bnpy) and N^N is a neutral diimine ancillary ligand] with the goal of investigating the impact of the methylene spacer between the coordination moieties of the C^N ligand on the optoelectronic properties of the complexes. The crystal structures of 1-3 illustrate two possible orientations of the methylene unit of the bnpy ligand. The formation of these two separate conformers is a result of the conformational flexibility of the bnpy ligand. In complexes 3 and 4 , mixtures of the two conformers were observed by 1H-NMR spectroscopy in CDCl3 at room temperature, whereas only a single conformer is detected for 1 and 2 . Detailed DFT calculations corroborate ROESY experiments, accounting for the presence and relative populations of the two conformers. The optoelectronic properties of all four complexes, rationalized by the theoretical study, demonstrate that the interruption of conjugation in the C^N ligands results in a reduced electrochemical gap but similar triplet state energies and lower photoluminescence quantum yields compared to the reference complexes R1-R4 . Depending on the nature of the N^N ligand, we observe (1) marked variations of the ratio of the conformers at ambient temperature and (2) phosphorescence ranging from yellow to red. Postprint

Determining the conformational preferences of molecules in solution remains a considerable challenge. Recently, the use of residual dipolar coupling (RDC) analysis has emerged as a key method to address this. Whilst to date the majority of the applications have focused on biomolecules including proteins and DNA, the use of RDCs for studying small molecules is gaining popularity. Having said that, the method continues to develop, and here, we describe an early case study of the quantification of conformer populations in small molecules using RDC analysis. Having been inspired to study conformational preferences by unexpected differences in the NMR spectra and the reactivity of related natural products, we showed that the use of more established techniques was unsatisfactory in explaining the experimental observations. The use of RDCs provided an improved understanding that, following use of methods to quantify conformer populations using RDCs, culminated in a rationalisation of the contrasting diastereoselectivities observed in a ketone reduction reaction. Copyright © 2015 John Wiley & Sons, Ltd.

The authors acknowledge the EPSRC UK National Mass Spectrometry Facility at Swansea University for mass spectrometry analysis. Financial support from: the Engineering and Physical Sciences Research Council (grant EP/J018139/1, EP/K00445X/1 (NJW, ADS, OSO), the doctoral training grant (ARN) and the CRITICAT Centre for Doctoral Training [Ph.D. studentship to SFM; Grant code: EP/L016419/1]), the Leverhulme Trust (JET), European Research Council (ERC-2013-ADG (JHN)) Alternative sources of potential feedstock chemicals are of increasing importance as the availability of oil decreases. The biopolymer lignin is viewed as a source of useful mono-aromatic compounds as exemplified by the industrial scale production of vanillin from this biomass. Alternative lignin-derived aromatics are available in pure form but to date examples of the use of these types of compounds are rare. Here we address this issue by reporting the conversion of an aromatic keto-alcohol to the anti- and syn-isomers of Descurainolide A. The key step involves a rhodium-catalyzed allylic substitution reaction. Enantioenriched allylic alcohols were generated via an isothiourea-catalyzed kinetic resolution enabling access to both the (2R,3R) and (2S,3S) enantiomers of anti-Descurainolide A. In addition we show that the ligninderived keto-alcohols can be converted into unnatural amino acid derivatives of tyrosine. Finally, these amino acids were incorporated into cyclic peptide scaffolds through the use of both chemical and an enzyme-mediated macrocylisation. Postprint

This work was supported by EPSRC (grants EP/J018139/1, EP/K00445X/1 (NJW), the EPSRC funded CRITICAT Centre for Doctoral Training (Ph.D. studentship to IP; EP/L016419/1) and EPSRC Doctoral Prize Fellowship (CSL) A new method has been developed to enable the modification of the organosolv technical lignin. Using a walnut shell butanol alkoxasolv lignin as a source of high β-O-4 content material, the β-O-4 γ-position has been selectively modified via tosylation, azidation and copper-catalyzed azide-alkyne triazole formation . In addition, extensive model studies were used to aid the detailed characterization of the modified lignin structure. The copper catalyzed click reaction was used to attach modified PEG chains and the resulting lignin-based co-polymer displayed improved thermal stability. This protocol was also used to incorporate a novel BODIPY-type fluorophore, generating a fluorescent lignin. Copper catalytic loadings were effective as low as 0.3 weight% and were found to catalyze the cycloaddition efficiently. This efficient and generic approach to preparing lignin-derived polymers is relevant to the core societal challenge of improving biorefinery efficiency. Postprint

The authors thank the Marie Curie Initial Training Network on Replication and Adaption in Networks (ReAd) for financial support (early stage researcher funding to L.M.). Triphenylphosphine oxide forms halogen-bonded (XB) complexes with pentafluoroiodobenzene and a 1,4-diaryl-5-iodotriazole. The stability of these complexes is assessed computationally and by 31P NMR spectroscopy in d8-toluene solution, where both complexes are weakly associated. This knowledge is applied to the design and synthesis of two self-complementary phosphine oxide-iodotriazole hybrids that incorporate a phosphine oxide XB acceptor and a 1,4-diphenyl-5-iodotriazole XB donor within the same molecule. The self-complementary design of these modules facilitates their assembly in both d8-toluene and, surprisingly, d2-DCM into dimers, with significant stabilities, through the formation of halogen-bonded diads. The stability of these assemblies is a result of significant levels of cooperative binding that is present in both solvents. The connection of two of these hybrid units together, using a flexible spacer, facilitates the aggregation of these modules in d2-DCM solution, through halogen bonding, forming oligomeric assemblies. Postprint

The European Research Council (ERC) and the Engineering and Physical Sciences Research Council (EPSRC) are gratefully acknowledged for their support. The role of counterions in chemistry mediated by gold complexes stretches much further than merely providing charge balance to cationic gold species. Interplay between their basicities and coordination strengths influences interactions with both the gold center and substrates in catalysis. Actual monogold-(I) active species are generally believed to be monocoordinated species, formed from the abstraction or the decoordination of a second ligand from precursor complexes, but only a small amount of experimental evidence exists to underpin the existence of these transient species. The formation of a bench-stable neutral IPrCI-gold(I) tetrafluoroborate complex is reported herein. Experimental studies by X-ray diffraction analysis and NMR spectroscopy and theoretical studies by DFT calculations were conducted to determine the composition, structure, and behavior of this complex. The absence of an auxiliary ligand resulted in inner-sphere coordination of the counterion in the solid state. In solution, an equilibrium between two conformations was found with the counterion occupying inner-sphere and outer-sphere positions, respectively. Stoichiometric and catalytic reactivity studies with the tetrafluoroborate complex have been conducted. These confirmed the lability of the inner-sphere coordinating counterion that gives the IPrCI-gold(I) fragment behavior similar to that of related systems. Postprint

The authors thank the Royal Society for a University Research Fellowship (ADS), the EPSRC (EP/J018139/1, DSBD), and GSK (Case award to SRS) for funding. They also thank the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC grant agreement number 279850 for additional funding, and the EPSRC UK National Mass Spectrometry Service Centre at Swansea University. The scalable, chromatography-free synthesis of the chiral isothiourea benzotetramisole (BTM) in two steps from commercially available materials is presented. A detailed procedure for the synthesis of both enantiomers and the racemate on ca. 10 gram scale is disclosed. Postprint

Counting backwards: The cyanobactin class of heterocyclases, exemplified by TruD, possess an almost unique combination of processivity, specificity, chemical versatility, and promiscuity. TruD is shown by biochemical assay to be an adenylase, and processes cysteines in a defined order. The entire substrate leader can be removed and TruD will process a single specific cysteine residue; however the role of leader is to permit processivity through a balance of recognition. ATP/AMP=adenosine tri/monophosphate; PPi=pyrophosphate.

NHC-mediated enantioselective formal [4+2] cycloadditions of alkylarylketenes with γ-substituted-β,γ-unsaturated α-ketophosphonates is described. A substrate-dependent switch in diastereoselectivity was observed, with γ-aryl α-ketophosphonates providing preferentially the syn-dihydropyranone-phosphonates and γ-methyl α-ketophosphonates favouring the anti-dihydropyranone-phosphonate. In addition, ketene generation in situ retained high levels of stereoselectivity and led to improved product yields when compared with the corresponding two-step procedure.

Coupling of two acenaphthene backbones through a phosphorus atom in a geminal fashion gives the first geminally bis(peri-substituted) tridentate phosphine 1. The rigid nature of the aromatic backbone and overall crowding of the molecule result in a rather inflexible ligand, with the three phosphorus atoms forming a relatively compact triangular cluster. Phosphine 1 displays restricted dynamics on an NMR time scale, which leads to the anisochronicity of all three phosphorus nuclei at low temperatures. Strained bis- and tris(sulfides) 2 and 3 and the bis(selenide) 4 have been isolated from the reaction of 1 with sulfur and selenium, respectively. These chalcogeno derivatives display pronounced in-plane and out-of-plane distortions of the aromatic backbones, indicating the limits of their angular distortions. In addition, we report metal complexes with tetrahedral [(1)Cu(MeCN)][BF4] (5), square planar [(1)PtCl][Cl] (6), trigonal bipyramidal [(1)FeCl2] (7), and octahedral fac-[(1)Mo(CO)3] (8) geometries. In all of these complexes the tris(phosphine) backbone is distorted, however to a significantly smaller extent than that in the mentioned chalcogenides 2-4. Complexes 5 and 8 show fluxionality in (31)P and (1)H NMR. All new compounds 1-8 were fully characterized, and their crystal structures are reported. Conclusions from dynamic NMR observations were augmented by DFT calculations.

This work was supported by EPSRC Ph.D. studentships (EP/1518175 (DMB), EP/1517938 (AN)), the Industrial Biotechnology Innovation Centre (Ph.D. studentship to DMB), CRITICAT Centre for Doctoral Training (Ph.D. studentship to IP; EP/L016419/1), EPSRC grants EP/J018139/1 and EP/K00445X/1 (SOJO) and an EPSRC Doctoral Prize Fellowship (CSL). Understanding the structure of technical lignins resulting from acid-catalysed treatment of lignocellulosic biomass is important for their future applications. Here we report an investigation into the fate of lignin under acidic aqueous organosolv conditions. In particular we examine in detail the formation and reactivity of non-native Hibbert ketone structures found in isolated organosolv lignins from both Douglas fir and beech woods. Through the use of model compounds combined with HSQC, HMBC and HSQC-TOCSY NMR experiments we demonstrate that, depending on the lignin source, both S and G lignin-bound Hibbert ketone units can be present. We also show that these units can serve as a source of novel mono-aromatic compounds following an additional lignin depolymerisation reaction. Postprint

This work was financially supported by the EPSRC and COST actions CM0802 PhoSciNet and SM1302 SIPs. The authors would like to thank the University of St Andrews NMR Service and the EPSRC UK National Mass Spectrometry Facility at Swansea University (NMSF). Tris(acenaphthyl) and bis(acenaphthyl) substituted pnictogens (iPr2P-Ace)3E ( 2 – 4 ) (E = As, Sb, Bi; Ace = acenaphthene-5,6-diyl) and (iPr2P-Ace)2EPh ( 5 and 6 ), (E = As, Sb) were synthesised and fully characterised by multinuclear NMR, HRMS, elemental analysis and single crystal X-ray diffraction. The molecules adopt propeller-like geometries with the restricted rotational freedom of the sterically encumbered iPr2P-Ace groups resulting in distinct NMR features. In the tris(acenaphthyl) species ( 2 – 4 ) the phosphorus atoms are isochronous in the 31P{1H} NMR spectra, and the rotation of the three acenaphthyl moieties around E–Cipso bond is locked. On the other hand, the bis(acenaphthyl) species show a fluxional behaviour, resulting in an AX to A2 spin system transition in the 31P{1H} VT NMR spectra. This allowed elucidation of remarkable through-space couplings of 8TSJPP 11.5 Hz (for 5 ) and 25.8 Hz (for 6 ) at low temperature. In addition, detailed lineshape analysis of the thermodynamic parameters of the restricted rotation of the “propeller blades” in 5 was performed in the intermediate temperature region and also at coalescence. The lone pairs on the pnictogen atoms in 2 – 6 are oriented such that they form a bowl shaped area which is somehow buried within the molecule. Postprint Postprint

Computational and experimental data are used to demonstrate that the halogen bond (XB) donor properties of neutral 1,4-diaryl-5-iodo-1,2,3-triazoles are competitive with the classic pentafluoroiodobenzene XB donor., The halogen bond (XB) donor properties of neutral 1,4-diaryl-5-iodo-1,2,3-triazoles are explored using a combination of computational and experimental results and are shown to be competitive in halogen bonding efficiency with the classic pentafluoroiodobenzene XB donor. The SNAr reactivity of these donors permits the facile assembly of an iodotriazole functionalised with a 3-oxypyridine XB acceptor, thus generating a molecular scaffold capable of undergoing dimerisation through the formation of two halogen bonds. The formation of this halogen-bonded dimer is demonstrated by 1H and DOSY NMR experiments and a plausible structure generated using DFT calculations.

The catalysis of reactions involving fluoropyruvate as donor by N-acetyl neuraminic acid lyase (NAL) variants was investigated. Under kinetic control, the wild-type enzyme catalysed the reaction between fluoropyruvate and N-acetyl mannosamine to give a 90 : 10 ratio of the (3R,4R)- and (3S,4R)-configured products; after extended reaction times, equilibration occurred to give a 30 : 70 mixture of these products. The efficiency and stereoselectivity of reactions of a range of substrates catalysed by the E192N, E192N/T167V/S208V and E192N/T167G NAL variants were also studied. Using fluoropyruvate and (2R,3S)- or (2S,3R)-2,3-dihydroxy-4-oxo-N,N-dipropylbutanamide as substrates, it was possible to obtain three of the four possible diastereomeric products; for each product, the ratio of anomeric and pyranose/furanose forms was determined. The crystal structure of S. aureus NAL in complex with fluoropyruvate was determined, assisting rationalisation of the stereochemical outcome of C–C bond formation.

Some N-substituted proline derivatives catalyse the reactions of alkyl aldehydes with electrophilic partners, and others give negligible amounts of product. The key reaction between the aldehyde and the proline derivative has been studied, and a rationale for the reactivity observed is presented. Simple proline amides derived from aromatic amines (poor catalysts) form stable imidazolidinones quite rapidly at the expense of enamines, the latter being detected, if at all, for less than an hour. Less basic proline amides form a kinetic diastereomer of an imidazolidinone that very slowly inverts its stereochemistry to give a final thermodynamic product. The stereochemistry of these diastereomers was fully assigned by 1H NMR, NOE, and TOCSY experiments. A proline amide derived from an alkylamine (good catalyst) forms high concentrations of enamine that is only slowly (days) converted into a single diastereomer of an inert imidazolidinone. In contrast, another good catalyst, a proline sulfonamide, immediately forms a reactive imidazolidinone, that rapidly ring-opens and exchanges with other aldehydes. This presumably drip-feeds iminium ions and enamines into the catalytic cycle. Thus, there are two quite different mechanistic regimes that lead to efficient catalysis. These mechanistic insights should now allow some element of rational design of prolinamides for enamine reactions using aldehydes.

The Escherichia coli serotype O9a O-antigen polysaccharide (O-PS) is a model for glycan biosynthesis and export by the ATP-binding cassette transporter-dependent pathway. The polymannose O9a O-PS is synthesized as a polyprenol-linked glycan by mannosyltransferase enzymes located at the cytoplasmic membrane. The chain length of the O9a O-PS is tightly regulated by the WbdD enzyme. WbdD first phosphorylates the terminal non-reducing mannose of the O-PS and then methylates the phosphate, stopping polymerization. The 2.2 A resolution structure of WbdD reveals a bacterial methyltransferase domain joined to a eukaryotic kinase domain. The kinase domain is again fused to an extended C-terminal coiled-coil domain reminiscent of eukaryotic DMPK (Myotonic Dystrophy Protein Kinase) family kinases such as Rho-associated protein kinase (ROCK). WbdD phosphorylates 2-α-d-mannosyl-d-mannose (2α-MB), a short mimic of the O9a polymer. Mutagenesis identifies those residues important in catalysis and substrate recognition and the in vivo phenotypes of these mutants are used to dissect the termination reaction. We have determined the structures of co-complexes of WbdD with two known eukaryotic protein kinase inhibitors. Although these are potent inhibitors in vitro, they do not show any in vivo activity. The structures reveal new insight into O-PS chain-length regulation in this important model system.

The reaction of chiral N-arylnitrones with carbocyclic alkylarylketenes generates spirocyclic oxindoles in good yields and with excellent levels of enantioselectivity (90-99% ee) via a pericyclic cascade process.

Syntheses and full characterisation data (including single crystal diffraction) of three 1,2-diphosphonium dicationic species with the naphthalene-1,8-diyl (Nap) backbone are reported. The oxidation of Nap[P(NMe(2))(2)](2) with P(2)I(4) to its 1,2-dication was achieved. meso- and rac-forms of "all carbon" 1,2-diphosphonium dications were obtained in good yields and purity by double alkylation of the parent diphosphine (1,2-diphenyl-1,2-diphosphaacenaphthene) with methyl triflate or trimethyloxonium tetrafluoroborate. Each methylating reagent produces one of the rac- or meso-forms of the dication diastereospecifically. Structural parameters of the new dications are discussed with respect to other phosphorus 1,2-dications. DFT (B3LYP) computations revealed the significant role of the naphthalene backbone in stabilisation of the dicationic motif and helped to assess the energy cost of the steric clash of a variety of groups attached to the peri-positions of naphthalene. The synthesis and single crystal X-ray data of the extremely crowded Nap[P(Se)(OiPr)(2)](2) are discussed, and are contrasted with the unsuccessful synthesis of Nap(PtBu(2))(2) from NapLi(2) and ClPtBu(2).

Charcoal forms a crucial source of archaeological and palaeoenvironmental data, providing a record of cultural activities, past climatic conditions and a means of chronological control via radiocarbon (14C) dating. Key to this is the perceived resistance of charcoal to post-depositional alteration, however recent research has highlighted the possibility for alteration and degradation of charcoal in the environment. An important aspect of such diagenesis is the potential for addition of exogenous “humic acids’ (HAs), to affect the accuracy of archaeological and palaeoenvironmental reconstructions based upon chemical analyses of HA-containing charcoal. However the release of significant quantities of HA from apparently pristine charcoals raises the question whether some HA could be derived via diagenetic alteration of charcoal itself. Here we address this question through comparison of freshly produced charcoal with samples from archaeological and geological sites exposed to environmental conditions for millennia using elemental (C/H/O) and isotopic (δ13C) measurements, Fourier Transform Infrared Spectroscopy (FTIR) and proton Liquid-State Nuclear Magnetic Resonance (1H NMR). The results of analyses show that the presence of highly carboxylated and aromatic alkali-extractable HA in charcoal from depositional environments can often be attributable to the effects of post-depositional processes, and that these substances can represent the products of post-depositional diagenetic alteration in charcoal.

Variable temperature NMR analysis and computational methods have been used to develop a detailed understanding of the 1H NMR spectra of a family of medium-sized ring containing compounds. The family consists of analogues containing 10-, 11- and 12-membered rings and in all cases the NMR spectra at room temperature showed a series of diastereotopic methylene signals despite the lack of a stereogenic centre in these systems. On repeating the NMR analysis at higher temperatures, all the signals coalesced for the 12-membered ring system consistent with full interconversion of ring conformers. This was not observed in the analogous 10- and 11-membered ring systems with the interchange of conformers remaining slow on the NMR timescale. However, 1D gs-NOESY/EXSY NMR experiments showed that in the smaller ring systems interconversion of diastereotopic protons did occur. Computational studies suggest that the dynamic process observed by NMR for the 10- and 11-membered rings systems is different from that observed in the 12-membered ring containing compound.

The oxidative cleavage of the known anti-psoriasis drug 1 to give 2 has been reported previously. Due to the importance of accessing medium-sized ring containing systems via oxidative cleavage, this reaction has been revisited revealing additional information about the structure of 2. Alternative reaction products were identified when the reaction was carried out in the presence of water. The conversion of 1 to 2 has also been carried out using ruthenium tetroxide. A detailed variable temperature NMR and computational study of the restricted rotation of the N-aryl ring in 2 is presented.

A range of pyrazolidin-3-ones have been prepared and their activity as catalysts for iminium-ion promoted Diels–Alder reactions evaluated. Systematic variation of the C(5)- and N(2)-substituents indicates that the incorporation of an electron withdrawing substitutent at N(2) and either a Ph or CF3 substitution at C(5) results in optimal catalytic activity. The diastereoisomeric resolution of a model C(5)-Ph substituted pyrazolidinone and its ability to impart modest levels of asymmetric induction in the organocatalytic Diels–Alder reaction is also demonstrated.

An isotopically labelled building block, 2,3,4,6-tetra- O -acetyl-1-thio-β- d -[ 13 C 6 ]glucopyranose ( 4 ), is obtained from the commercially available [ 13 C 6 ]- d -glucose. This hexa- 13 C -labelled thioglucose can be employed to make any glucosinolate ( 8 ) for use as an internal standard for isotopic dilution LCMS analysis. Herein three typical glucosinolates in their hexa- 13 C -labelled form: [ glucose - 13 C 6 ]gluconasturtiin, [ glucose - 13 C 6 ]sinigrin and [ glucose - 13 C 6 ]glucoerucin are synthesised by coupling the isotopically labelled thioglucose ( 4 ) with the corresponding hydroximoyl chlorides followed by sulfation with pyridine sulfur trioxide and deacetylation with a catalytic amount of potassium methoxide, respectively.

A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.

One solution to the global crisis of antibiotic resistance is the discovery of novel antimicrobial compounds for clinical application. Marine organisms are an attractive and, as yet, relatively untapped resource of new natural products. Cell extracts from the marine diatom, Phaeodactylum tricornutum, have antibacterial activity and the fatty acid, eicosapentaenoic acid (EPA), has been identified as one compound responsible for this activity. During the isolation of EPA, it became apparent that the extracts contained further antibacterial compounds. The present study was undertaken to isolate these additional antibacterial factors using silica column chromatography and reverse-phase high-performance liquid chromatography. Two antibacterial fractions, each containing a pure compound, were isolated and their chemical structures were investigated by mass spectrometry and nuclear magnetic resonance spectroscopy. The antibacterial compounds were identified as the monounsaturated fatty acid (9Z)-hexadecenoic acid (palmitoleic acid; C16:1 n-7) and the relatively unusual polyunsaturated fatty acid (6Z, 9Z, 12Z)-hexadecatrienoic acid (HTA; C16:3 n-4). Both are active against Gram-positive bacteria with HTA further inhibitory to the growth of the Gram-negative marine pathogen, Listonella anguillarum. Palmitoleic acid is active at micro-molar concentrations, kills bacteria rapidly, and is highly active against multidrug-resistant Staphylococcus aureus. These free fatty acids warrant further investigation as a new potential therapy for drug-resistant infections.

Gamma-aminobutyric acid or GABA (1) is one of the major inhibitory amino acid neurotransmitters of the central nervous system. This article describes the first synthesis of both the (R)- and (S)- enantiomers of 3-fluoro-GABA (2, 3F-GABA). DFT calculations were carried out in a continuum solvent model (PCM-B3LYP) to estimate the preferred conformations of 3F-GABA in aqueous solution. NMR coupling constants were calculated for each conformer and were then used to simulate the NMR spectra to evaluate the solution conformation of 3F-GABA. A preliminary evaluation of the 3F-GABA enantiomers shows that they act similarly as agonists of cloned GABA(A) receptors; however, they behave quite differently in a whole animal (Xenopus laevis tadpole model).

The reaction of bis(bromomethyl)quinoxaline N-oxides with amines is interesting from a reaction mechanism perspective and due to the reported biological activity of compounds in this general class. The complex mechanism of this reaction (particularly in the case of primary amines) is complicated further when C6 or C7 substituted mono-N-oxides are considered. In this study, the synthesis and subsequent characterization of a series of 2,3-bis(bromomethyl)quinoxaline 1-N-oxides is reported. Experimental and computational evidence is used to show that the observed product ratios from the reaction with diethylamine reflect the influence of both the C6/C7 substituent and the N-oxide functional group on the initial nucleophilic substitution reaction.

This work was supported by grants from the ERC 339367 (J.H.N. and M.J.) and BBSRC BB/K015508/1 (J.H.N and M.J.). We acknowledge use of the Diamond (beamlines I02 and I24) and ESRF (beamline ID29) synchrotrons. JHN is Royal Society Wolfson Merit Award Holder and a 1000 talent scholar of the Chinese Government at Sichuan University. Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways, and many of the resulting products have potential as therapeutics. The ATP-dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have a conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate, suggesting that recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal that the substrate leader peptide binds to and extends the β-sheet of a conserved domain of LynD, whereas catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity, and it appears to be a conserved strategy in other peptide-modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered. Postprint

This work was generously supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are ‘up’, is prepared in a 12-step protocol. The molecule adopts a classic chair conformation with alternate C–F bonds aligned triaxially, clustering three highly electronegative fluorine atoms in close proximity. This generates a cyclohexane with a high molecular dipole (μ = 6.2 D), unusual in an otherwise aliphatic compound. X-ray analysis indicates that the intramolecular Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq­ distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the molecules pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in organic chemistry. Derivatives have potential as new motifs for the design of functional organic molecules or for applications in supramolecular chemistry design. Postprint

SPN thanks the European Research Council(227817) (Advanced Investigator Award ‘FUNCAT’), the EU(CP-FP 211468) (Seventh Framework Programme Project ‘EUMET’), and the Engineering and Physical Sciences Research Council for funding. SPN is a Royal Society Wolfson Merit Award holder. AP thanks the Spanish MINECO for a Ramón y Cajal contract (RYC-2009-05226) and European Commission for a Career Integration Grant (CIG09-GA-2011-293900). The commercially-available metathesis pre-catalyst M23 has been evaluated alongside new complex [RuCl2((3-phenyl)indenylidene)(PPh3)(SIPrOMe)] (1), which bears a para-methoxy-substituted N-heterocyclic carbene ligand. Several model metathesis reactions could be conducted using only parts-per-million levels of ruthenium catalyst. The effects of the different NHC ligands on reactivity have been explored. Postprint