Preparation of iminosugars from aminopolyols via selective oxidation using galactose oxidase

Minimally protected aminopolyols are novel substrates for the galactose oxidase variant F2. Site-selective oxidation proceeds at the terminal primary alcohol, followed by spontaneous cyclisation to afford stable hemiaminal/hemiacetal anomers of the piperidine and azepane scaffolds, with isolated yields of up to 94%. Simultaneous deprotection and reduction occured readily to afford valuable and biologically relevant iminosugars.Science Foundation Irelan

Investigations on the operation of stereochemical drift in the Wittig reaction by NMR and variable-temperature NMR spectroscopy of oxaphosphetane intermediates and their quench products

Within the currently accepted mechanism of the Li‐salt‐free Wittig reaction, the phenomenon of stereochemical drift remains the one remaining “loose end” in an otherwise internally consistent explanation of a large body of diverse observations. The term describes the nonstereospecific decomposition of the oxaphosphetane (OPA) intermediate in reactions of certain alkylides with certain aldehydes. In this paper, it is shown that the previous examples in which drift occurs are not merely isolated aberrations from the observed norm, but rather that there is a general phenomenon in reactions of ethylides with benzaldehydes. Variable‐temperature NMR (VTNMR) spectroscopy was used to establish that the amount and diastereomeric ratio of the OPA intermediates do not change below a certain temperature. At and above the temperature at which OPA decomposition to alkene and phosphine oxide begins to occur, the alkene shows a different diastereomeric ratio to the OPA, which indicates the occurrence of stereochemical drift. In one example, owing to an apparent remarkable coincidence of rates, the diastereomeric ratio of the OPA does not change above the decomposition temperature, even though stereochemical drift occurs in the formation of the alkene product. An alternative mechanism for drift involving its catalysis by aldehyde was not confirmed. Drift was also shown not to occur in similar Wittig reactions of structurally related longer‐chain alkylides by stereospecific decomposition of OPA intermediates generated from β‐hydroxyphosphonium salts (β‐HPSs). The extremely useful (and generally applicable) NMR techniques, 1H–31P HMBC and selective 1H{31P}, which we have utilised to establish kinetic diastereomeric ratios, are described in full for the first time. Details of the determination of the relative stereochemistry of two β‐HPSs (derived from acid quenching of OPAs) by X‐ray crystallography are also given

Single-cell multi-omics analysis of the immune response in COVID-19

Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Funder: University College London, Birkbeck MRC Doctoral Training ProgrammeFunder: The Jikei University School of MedicineFunder: Action Medical Research (GN2779)Funder: NIHR Clinical Lectureship (CL-2017-01-004)Funder: NIHR (ACF-2018-01-004) and the BMA FoundationFunder: Chan Zuckerberg Initiative (grant 2017-174169) and from Wellcome (WT211276/Z/18/Z and Sanger core grant WT206194)Funder: UKRI Innovation/Rutherford Fund Fellowship allocated by the MRC and the UK Regenerative Medicine Platform (MR/5005579/1 to M.Z.N.). M.Z.N. and K.B.M. have been funded by the Rosetrees Trust (M944)Funder: Barbour FoundationFunder: ERC Consolidator and EU MRG-Grammar awardsFunder: Versus Arthritis Cure Challenge Research Grant (21777), and an NIHR Research Professorship (RP-2017-08-ST2-002)Funder: European Molecular Biology Laboratory (EMBL)Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy

Investigations on the operation of stereochemical drift in the Wittig reaction by NMR and variable-temperature NMR spectroscopy of oxaphosphetane intermediates and their quench products

Within the currently accepted mechanism of the Li‐salt‐free Wittig reaction, the phenomenon of stereochemical drift remains the one remaining “loose end” in an otherwise internally consistent explanation of a large body of diverse observations. The term describes the nonstereospecific decomposition of the oxaphosphetane (OPA) intermediate in reactions of certain alkylides with certain aldehydes. In this paper, it is shown that the previous examples in which drift occurs are not merely isolated aberrations from the observed norm, but rather that there is a general phenomenon in reactions of ethylides with benzaldehydes. Variable‐temperature NMR (VTNMR) spectroscopy was used to establish that the amount and diastereomeric ratio of the OPA intermediates do not change below a certain temperature. At and above the temperature at which OPA decomposition to alkene and phosphine oxide begins to occur, the alkene shows a different diastereomeric ratio to the OPA, which indicates the occurrence of stereochemical drift. In one example, owing to an apparent remarkable coincidence of rates, the diastereomeric ratio of the OPA does not change above the decomposition temperature, even though stereochemical drift occurs in the formation of the alkene product. An alternative mechanism for drift involving its catalysis by aldehyde was not confirmed. Drift was also shown not to occur in similar Wittig reactions of structurally related longer‐chain alkylides by stereospecific decomposition of OPA intermediates generated from β‐hydroxyphosphonium salts (β‐HPSs). The extremely useful (and generally applicable) NMR techniques, 1H–31P HMBC and selective 1H{31P}, which we have utilised to establish kinetic diastereomeric ratios, are described in full for the first time. Details of the determination of the relative stereochemistry of two β‐HPSs (derived from acid quenching of OPAs) by X‐ray crystallography are also given

Visible light induced degradation of perfluorooctanoic acid using iodine deficient bismuth oxyiodide photocatalyst

A bismuth oxyiodide photocatalyst having coexistent iodine deficient phases viz. Bi4O5I2 and Bi5O7I was prepared by using a solvothermal method followed by calcination process. This has been used for the degradation of model perfluoroalkyl acids such as perfluorooctanoic acid at low concentrations (1 ppm) under simulated solar light irradiation. 94% PFOA degradation with a rate constant of 1.7 h− 1 and 65% defluorination of PFOA have been achieved following 2 h of photocatalysis. The degradation of PFOA happened by the parallel direct redox reactions with high energy photoexcited electrons at the conduction band, electrons in iodine vacancies and superoxide radicals. The degradation intermediates were analyzed by electrospray ionization-mass spectrometry in the negative mode. The catalyst was converted to a more iodine deficient Bi5O7I phase during photocatalysis following creation of iodine vacancies, some of which were compensated by the fluoride ions released from degraded PFOA</p

Mechanistic Insight into the Formation of Tetraarylazadipyrromethenes

The tetraarylazadipyrromethene chromophore class has gained increasing attention in the past decade for a diverse set of scientific interests and applications. The most direct synthetic route available for their generation is heating of 4-nitro-1,3-diarylbutan-1-ones with an ammonium source in an alcohol solvent. Despite the practical simplicity, the reaction pathway(s) for these conversions are lengthy and unclear. To gain insight into the steps involved, 15N labeling experiments with MS and NMR analysis were utilized for conversion of 4-nitro-1,3-diphenylbutan-1-one 1 into tetraphenylazadipyrromethene 2 with 15NH4OAc. To permit examination of later stages of the reaction sequence to 2, the 15N-labeled potential intermediate 3,5-diphenyl-1H-pyrrol-2-amine 10 was synthesized. A study of the dimerization pathway utilizing 15N-labeled 10 revealed an unprecedented nitrogen rearrangement in the final stages of the pathway involving a ring-opening/closing of a pyrrole ring. Utilizing 15N labeling experiments we have shown that 2,4-diphenylpyrrole 8 can also react under the reaction conditions with 3,5-diphenyl-2H-pyrrol-2-imine 7 (from oxidation of 10) to produce 2. Overall in the conversion of 1 into 2, two related pathways are ongoing concurrently; the first involves a dimerization of 3,5-diphenyl-2H-pyrrol-2-imine 7, and the other a reaction of 7 with 2,4-diphenylpyrrole 8

Applying Metallo-Organic Ligand Design Principles to the Stereoselective Synthesis of a Peptide-Based Pd2L4X4 Cage

The rational and controlled synthesis of metallo-organic cages using polyaromatic ligands is well established in the literature. There is a strong interest to advance this field towards the use of chiral ligands capable of yielding cages in a stereoselective manner. Herein, we demonstrate that the classical approach for designing metallo-organic cages can be translated to polyproline peptides, a biocompatible class of chiral ligands. We have successfully designed a series of polyprolines, which mimic the topology of ditopic polyaromatic ligands, to yield the stereoselective synthesis of a novel Pd lantern cage. This work will pave the way towards the stereospecific synthesis of more complex, functionalized peptide cages

Palladium(II)-Catalyzed Rearrangement and Oligomerization Reactions of <i>cis</i>-Bicyclo[4.2.0]oct-7-ene

In the presence of several Pd­(II) catalysts, <i>cis</i>-bicyclo­[4.2.0]­oct-7-ene (<b>4a</b>) was found to undergo olefin isomerization (“ring walking”) and oligomerization, resulting in the formation of <i>cis</i>-bicyclo­[4.2.0]­oct-2-ene (<b>4d</b>) and the low-molecular-mass cycloaliphatic oligomers <b>5a</b>–<b>d</b>, respectively. The catalysts studied are [Pd­(NCEt)₄]­[BF₄]₂ (<b>1</b>), [(η³-allyl)­Pd­(solv)₂]­[SbF₆] (<b>2</b>; solv = CH₂Cl₂), [(1,10-phenanthroline)­Pd­(CH₃)­(NC­(CH₂)₆CH₃)]­[SbF₆] (<b>6</b>), and [(2,9-dimethyl-1,10-phenanthroline)­Pd­(CH₃)­(NC­(CH₂)₆CH₃)]­[SbF₆] (<b>7</b>). Isomerization included the formation of both <b>4d</b> and the olefinic end groups of <b>5a</b>–<b>d</b> and ranged from 94% using catalyst <b>7</b> to 29% employing catalyst <b>2</b>. Ab initio and DFT calculations at the LMP2/6-31G** and B3LYP/6-31G** levels show that the thermodynamic stabilities of the bicyclo[4.2.0]­octene isomers increase in the order 7-ene <b>4a</b> < 1(8)-ene <b>4b</b> < 1-ene <b>4c</b> ≈ 1(6)-ene <b>4e</b> ≈ 3-ene <b>4f</b> < 2-ene <b>4d</b>. A mechanism of isomerization via subsequent β-hydride eliminations and olefin reinsertions is proposed. These results are in contrast to the reactions of bicyclo[3.2.0]­hept-6-ene (<b>3a</b>) catalyzed by <b>1</b>, <b>2</b>, and <b>7</b> and the reaction of <b>4a</b> catalyzed by Cp₂ZrCl₂/MAO (Cp = η⁵-C₅H₅), all of which produced polymers in good yields (73–99%)

The hepatitis B virus preS1 domain hijacks host trafficking proteins by motif mimicry

Hepatitis B virus (HBV) is an infectious, potentially lethal human pathogen. However, there are no effective therapies for chronic HBV infections. Antiviral development is hampered by the lack of high-resolution structures for essential HBV protein-protein interactions. The interaction between preS1, an HBV surface-protein domain, and its human binding partner, γ2-adaptin, subverts the membrane-trafficking apparatus to mediate virion export. This interaction is a putative drug target. We report here atomic-resolution descriptions of the binding thermodynamics and structural biology of the interaction between preS1 and the EAR domain of γ2-adaptin. NMR, protein engineering, X-ray crystallography and MS showed that preS1 contains multiple γ2-EAR-binding motifs that mimic the membrane-trafficking motifs (and binding modes) of host proteins. These motifs localize together to a relatively rigid, functionally important region of preS1, an intrinsically disordered protein. The preS1-γ2-EAR interaction was relatively weak and efficiently outcompeted by a synthetic peptide. Our data provide the structural road map for developing peptidomimetic antivirals targeting the γ2-EAR-preS1 interaction

Mechanistic Insight into the Formation of Tetraarylazadipyrromethenes

The tetraarylazadipyrromethene chromophore class has gained increasing attention in the past decade for a diverse set of scientific interests and applications. The most direct synthetic route available for their generation is heating of 4-nitro-1,3-diarylbutan-1-ones with an ammonium source in an alcohol solvent. Despite the practical simplicity, the reaction pathway(s) for these conversions are lengthy and unclear. To gain insight into the steps involved, ¹⁵N labeling experiments with MS and NMR analysis were utilized for conversion of 4-nitro-1,3-diphenylbutan-1-one <b>1</b> into tetraphenylazadipyrromethene <b>2</b> with ¹⁵NH₄OAc. To permit examination of later stages of the reaction sequence to <b>2</b>, the ¹⁵N-labeled potential intermediate 3,5-diphenyl-1<i>H</i>-pyrrol-2-amine <b>10</b> was synthesized. A study of the dimerization pathway utilizing ¹⁵N-labeled <b>10</b> revealed an unprecedented nitrogen rearrangement in the final stages of the pathway involving a ring-opening/closing of a pyrrole ring. Utilizing ¹⁵N labeling experiments we have shown that 2,4-diphenylpyrrole <b>8</b> can also react under the reaction conditions with 3,5-diphenyl-2<i>H</i>-pyrrol-2-imine <b>7</b> (from oxidation of <b>10</b>) to produce <b>2</b>. Overall in the conversion of <b>1</b> into <b>2</b>, two related pathways are ongoing concurrently; the first involves a dimerization of 3,5-diphenyl-2<i>H</i>-pyrrol-2-imine <b>7</b>, and the other a reaction of <b>7</b> with 2,4-diphenylpyrrole <b>8</b>