Valery V Fokin

The Scripps Research Institute, La Jolla, California, United States

Are you Valery V Fokin?

Claim your profile

Publications (139)829.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
    Angewandte Chemie 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: High-molecular-weight polysulfates are readily formed from aromatic bis(silyl ethers) and bis(fluorosulfates) in the presence of a base catalyst. The reaction is fast and proceeds well under neat conditions or in solvents, such as dimethyl formamide or N-methylpyrrolidone, to provide the desired polymers in nearly quantitative yield. These polymers are more resistant to chemical degradation than their polycarbonate analogues and exhibit excellent mechanical, optical, and oxygen-barrier properties.
    Angewandte Chemie International Edition 08/2014; · 11.34 Impact Factor
  • James S. Oakdale, Rakesh K. Sit, Valery V. Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: (Cyclopentadienyl)(cyclooctadiene) ruthenium(II) chloride [CpRuCl(cod)] catalyzes the reaction between nitrile oxides and electronically deficient 1-choro-, 1-bromo-, and 1-iodoalkynes leading to 4-haloisoxazoles. Organic azides are also suitable 1,3-dipoles, resulting in 5-halo-1,2,3-triazoles. These air-tolerant reactions can be performed at room temperature with 1.25 equivalents of the respective 1,3-dipole relative to the alkyne component. Reactive 1-haloalkynes include propiolic amides, esters, ketones, and phosphonates. Post-functionalization of the halogenated azole products can be accomplished by using palladium-catalyzed cross-coupling reactions and by manipulation of reactive amide groups. The lack of catalysis observed with [Cp*RuCl(cod)] (Cp*=pentamethylcyclopentadienyl) is attributed to steric demands of the Cp* (η5-C5Me5) ligand in comparison to the parent Cp (η5-C5H5). This hypothesis is supported by the poor reactivity of [(η5-C5Me4CF3)RuCl(cod)], which serves as a an isosteric mimic of Cp* and as an isoelectronic analogue of Cp.
    Chemistry 07/2014; · 5.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The siglec family of sialic acid-binding proteins are endocytic immune cell receptors that are recognized as potential targets for cell directed therapies. CD33 and CD22 are prototypical members and are validated candidates for targeting acute myeloid leukaemia and non-Hodgkin's lymphomas due to their restricted expression on myeloid cells and B-cells, respectively. While nanoparticles decorated with high affinity siglec ligands represent an attractive platform for delivery of therapeutic agents to these cells, a lack of ligands with suitable affinity and/or selectivity has hampered progress. Herein we describe selective ligands for both of these siglecs, which when displayed on liposomal nanoparticles, can efficiently target the cells expressing them in peripheral human blood. Key to their identification was the development of a facile method for chemo-enzymatic synthesis of disubstituted sialic acid analogues, combined with iterative rounds of synthesis and rapid functional analysis using glycan microarrays.
    Chemical Science 06/2014; 5(6):2398-2406. · 8.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate.
    Journal of Medicinal Chemistry 02/2014; 57(4):1378-89. · 5.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A convenient one-pot asymmetric synthesis of 2,3-dihydropyrroles from in situ generated triflated triazoles and olefins is described that further expands the utility of azavinyl carbene chemistry and provides access to an important class of cyclic enamides. Mechanistic investigations support the involvement of triflated cyclopropylaldimine intermediates in the formation of 2,3-dihydropyrrole. To the best of our knowledge, this is the first example of a chiral Brønsted acid catalyzed rearrangement of cyclopropylimines into enantioenriched 2,3-dihydropyrroles.
    Angewandte Chemie 02/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: A convenient one-pot asymmetric synthesis of 2,3-dihydropyrroles from in situ generated triflated triazoles and olefins is described that further expands the utility of azavinyl carbene chemistry and provides access to an important class of cyclic enamides. Mechanistic investigations support the involvement of triflated cyclopropylaldimine intermediates in the formation of 2,3-dihydropyrrole. To the best of our knowledge, this is the first example of a chiral Brønsted acid catalyzed rearrangement of cyclopropylimines into enantioenriched 2,3-dihydropyrroles.
    Angewandte Chemie International Edition 02/2014; · 11.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rhodium(II) azavinyl carbenes, conveniently generated from 1-sulfonyl-1,2,3-triazoles, undergo a facile, mild and convergent formal 1,3-insertion into N-H and O-H bonds of primary and secondary amides, various alcohols, and carboxylic acids to afford a wide range of vicinally bis-functionalized Z-olefins with perfect regio- and stereoselectively. Utilizing the distinctive functionality installed through these reactions, a number of subsequent rearrangements and cyclizations expand the repertoire of valuable organic building blocks constructed by reactions of transition metal carbene complexes, including α-allenyl ketones and amino-substituted heterocycles.
    Journal of the American Chemical Society 12/2013; · 10.68 Impact Factor
  • Brady T Worrell, Shelby P Ellery, Valery V Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: Fully loaded: Readily accessible and shelf-stable 1-bismuth(III) acetylides react rapidly and regiospecifically with organic azides in the presence of a copper(I) catalyst. The reaction tolerates many functional groups and gives excellent yields of the previously unreported 5-bismuth triazolides. This uniquely reactive intermediate is functionalized under mild reaction conditions to give fully substituted 1,2,3-triazoles.
    Angewandte Chemie International Edition 10/2013; · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis, and the bacterial pathogens Helicobacter pylori, Clostridium difficile, and Bacteroides fragilis. Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.
    Proceedings of the National Academy of Sciences 10/2013; · 9.81 Impact Factor
  • Valery V. Fokin
    ChemInform 06/2013; 44(25).
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Siglec family of sialic acid-binding proteins are differentially expressed on white blood cells of the immune system and represent an attractive class of targets for cell-directed therapy. Nanoparticles decorated with high-affinity Siglec ligands show promise for delivering cargo to Siglec-bearing cells, but this approach has been limited by a lack of ligands with suitable affinity and selectivity. Building on previous work employing solution-phase sialoside library synthesis and subsequent microarray screening, we herein report a more streamlined 'on-chip' synthetic approach. By printing a small library of alkyne sialosides and subjecting these to 'on-chip' click reactions, the largest sialoside analog library to date was generated. Siglec-screening identified a selective Siglec-7 ligand, which when displayed on liposomal nanoparticles, allows for targeting of Siglec-7+ cells in peripheral human blood. In silico docking to the crystal structure of Siglec-7 provides a rational for the affinity gains observed for this novel sialic acid analog.
    ACS Chemical Biology 04/2013; · 5.44 Impact Factor
  • B T Worrell, J A Malik, V V Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the C-N bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.
    Science 04/2013; · 31.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1,2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization.
    Bioorganic & medicinal chemistry letters 03/2013; · 2.65 Impact Factor
  • Stepan Chuprakov, Sen Wai Kwok, Valery V Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazole-diazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle.
    Journal of the American Chemical Society 03/2013; · 10.68 Impact Factor
  • 01/2013; 90:96-104.
  • Mikhail Zibinsky, Valery V Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: As easy as 1,2,3: Readily available and shelf-stable 1-sulfonyl-1,2,3-triazoles react with aldehydes and aldimines in the presence of Rh(II) catalysts to produce 4-oxazolines and 1,2,5-trisubstituted imidazoles.
    Angewandte Chemie International Edition 12/2012; · 11.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The copper catalyzed azide alkyne cycloaddition (CuAAC) reaction – the quintessential ‘click’ reaction – was used to synthesise dimers of the neuraminidase inhibitor zanamivir in high yields. The effect upon anti-viral activity of varying the linker length and the number of triazole units was explored. All dimers were tested for anti-viral activity against influenza A/Sydney/5/97 and B/Harbin/7/94 in a cytopathic effect (CPE) assay.
    Medicinal Chemistry Communication 11/2012; 4:383-386. · 2.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Room for expansion: An efficient, regioselective, and convergent method for the ring expansion and rearrangement of 1-sulfonyl-1,2,3-triazoles under rhodium(II)-catalyzed conditions is described. These denitrogenative reactions form substituted enaminone and olefin-based products. The enaminone products can be further functionalized to give various heterocycles and ketone derivatives, thus rendering the sulfonyl triazole traceless.
    Angewandte Chemie International Edition 11/2012; · 11.34 Impact Factor
  • Brady T Worrell, Jason E Hein, Valery V Fokin
    [Show abstract] [Hide abstract]
    ABSTRACT: A good exchange: 5-Iodo-1,2,3-triazoles undergo facile substitution reactions with fluoride salts, thus providing ready access to 5-fluorotriazoles. The latter can be further elaborated with various nucleophiles to furnish fully substituted 1,2,3-triazole compounds.
    Angewandte Chemie International Edition 10/2012; · 11.34 Impact Factor

Publication Stats

6k Citations
829.44 Total Impact Points

Institutions

  • 2001–2014
    • The Scripps Research Institute
      • • Skaggs Institute for Chemical Biology
      • • Department of Chemistry
      La Jolla, California, United States
  • 2010–2013
    • Mahidol University
      • • Faculty of Pharmacy
      • • Department of Pharmaceutical Chemistry
      Bangkok, Bangkok, Thailand
  • 2012
    • Institute for Medical Research and Occupational Health
      Zagrabia, Grad Zagreb, Croatia
  • 2010–2012
    • University of California, San Diego
      • Skaggs School of Pharmacy and Pharmaceutical Sciences
      San Diego, CA, United States
  • 2007
    • McGill University
      • Department of Chemistry
      Montréal, Quebec, Canada
    • University of California, Santa Barbara
      • Materials Research Laboratory
      Santa Barbara, California, United States
  • 2006
    • University of Toronto
      • Department of Chemistry
      Toronto, Ontario, Canada