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  • 1.
    Appukkuttan, Prasad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Axelsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Van der Eycken, Erik
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up2008In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, no 39, p. 5625-5628Article in journal (Refereed)
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

  • 2.
    Ashkan, Fardost
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Skillinghaug, Bobo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fredrik, Svensson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Prasad, Wakchaure
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Matyas, Wejdemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mats, Larhed
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Christian, Sköld
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Experimental and Theoretical Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-DiarylethenesManuscript (preprint) (Other academic)
  • 3.
    Axelsson, Linda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Veron, Jean-Baptiste
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Odell, Luke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles2014In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, no 15, p. 2376-2380Article in journal (Refereed)
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

  • 4.
    Belfrage, Anna Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.

    The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.

    Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

    List of papers
    1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Open this publication in new window or tab >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Show others...
    2010 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 20, no 14, p. 4004-4011Article in journal (Refereed) Published
    Abstract [en]

    Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series exhibiting macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution in the P2 cyclopentane dicarboxylic acid series improved on the metabolic stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. Pharmacokinetic properties in vivo were assessed in rat on selected compounds, where excellent exposure and liver-to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. (C) 2010 Elsevier Ltd. All rights reserved.

    Keyword
    HCV, NS3/4A protease, Inhibitors, P2 substituent, Quinazoline, Replicon assay, In vitro, DMPK, In vivo PK
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-136039 (URN)10.1016/j.bmcl.2010.05.029 (DOI)000279258800001 ()
    Available from: 2010-12-09 Created: 2010-12-09 Last updated: 2018-01-12Bibliographically approved
    2. Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
    Open this publication in new window or tab >>Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
    Show others...
    2014 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 5, p. 1790-1801Article in journal (Refereed) Published
    Abstract [en]

    Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.

    National Category
    Medicinal Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-172003 (URN)10.1021/jm301887f (DOI)000333005800011 ()
    Available from: 2012-03-31 Created: 2012-03-31 Last updated: 2018-01-12Bibliographically approved
    3. Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Open this publication in new window or tab >>Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease
    Show others...
    2016 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

    Keyword
    Hepatitis C virus; Drug resistance; Pyrazinone; NS3 protease inhibitors; R155K
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243315 (URN)10.1016/j.bmc.2016.03.066 (DOI)000376727800002 ()27160057 (PubMedID)
    Funder
    Swedish Research Council, D0571301
    Available from: 2015-02-08 Created: 2015-02-08 Last updated: 2017-12-04Bibliographically approved
    4. Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
    Open this publication in new window or tab >>Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones
    Show others...
    2015 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed) Published
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243254 (URN)10.1002/ejoc.201403405 (DOI)000349391700009 ()
    Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2017-12-04Bibliographically approved
    5. Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    Open this publication in new window or tab >>Palladium-catalyzed carbonylation of aryl iodides with sulfinamides
    (English)Manuscript (preprint) (Other academic)
    Keyword
    palladium
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry; Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-243257 (URN)
    Available from: 2015-02-06 Created: 2015-02-06 Last updated: 2015-03-11
  • 5.
    Belfrage, Anna Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Abdurakhmanov, Eldar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Oshalim, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Skogh, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Neyts, Johan
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Discovery of pyrazinone based compounds that potently inhibit the drug resistant enzyme variant R155K of the hepatitis C virus NS3 protease2016In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 24, no 12, p. 2603-2620Article in journal (Refereed)
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wildtype and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance.

  • 6.
    Belfrage, Anna Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Efficient and Selective Palladium-Catalysed C-3 Urea Couplings to 3,5-Dichloro-2(1H)-pyrazinones2015In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 5, p. 978-986Article in journal (Refereed)
    Abstract [en]

    The development of a robust palladium-catalysed urea N-arylation protocol to install various ureas at the 3-position of the 2(1H)-pyrazinone scaffold is described. The method involves Pd(OAc)2 in combination with bidentate ligands, xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C-3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta-sheet-inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone-based hepatitis C virus (HCV) NS3 protease inhibitor.

  • 7.
    Bergman, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    De Rosa, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Deuther-Conrad, Winnie
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Brust, Peter
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter2017In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 19, p. 5095-5106Article in journal (Refereed)
    Abstract [en]

    Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (+/-)-7i and (+/-)-7l had the highest affinities for VAChT. Compound (+/-)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the sigma(1) and sigma(2) receptors. Enantiomeric resolution gave (+/-)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (+/-)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [C-11]-(+/-)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved C-11-labelled VAChT PET tracers.

  • 8. Chakka, Sai Kumar
    et al.
    Francis, Vivian
    Cele, Zamani E. D.
    Sosibo, Sphelele C.
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kruger, Hendrik G.
    Maguire, Glenn E. M.
    Govender, Thavendran
    Asymmetric conjugate addition of thioglycolate to a range of chalcones using tetrahydroisoquinoline (TIQ) N,N '-dioxide ligands2012In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 23, no 8, p. 616-622Article in journal (Refereed)
    Abstract [en]

    A series of novel TIQ based N,N'-oxide ligands were synthesised and screened for their catalytic activity in the enantioselective conjugate addition of thioglycolate to chalcones. Bulky groups on the side chain of the TIQ backbone provided the highest enantioselectivity of up to 88% with 10 mol % catalyst loading. It was also observed that these reactions proceeded optimally in the presence of dichloromethane as a solvent. Screening of various metals emphasized La(OTf)(3) as the ideal pre-catalyst for this particular reaction.

  • 9.
    Chow, Shiao Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevens, Marc Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerbladh, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mild and Low-Pressure fac-Ir(ppy)3-Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis2016In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 27, p. 9155-9161Article in journal (Refereed)
    Abstract [en]

    A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)(3)-catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)(3), amines, reductants, and CO gas (released ex situ from Mo(CO)(6)), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

  • 10.
    Dahl, Kenneth
    et al.
    Karolinska Hosp, Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden..
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    11C-Acetylation of Amines with [11C]Methyl Iodide with Bis(cyclopentadienyldicarbonyliron) as the CO Source2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 38, p. 5785-5788Article in journal (Refereed)
    Abstract [en]

    We describe herein a novel approach for the direct 11C-acetylation of amines. The carbonylative protocol is palladium-mediated, uses bis(cyclopentadienyldicarbonyliron) as the CO source, and [11C]methyl iodide or [11C]methyl iodide-D3 as a radioactive precursor. A set of functionalized primary and secondary amines was 11C-labelled in radiochemical yields ranging from 7–85 %. The potential use of this method for positron emission tomography radiotracer production was additionally demonstrated by the radiosynthesis of [11C]lacosamide, [11C]melatonine, and [11C]acecainide in 44–55 % RCY.

  • 11.
    Dahl, Kenneth
    et al.
    Karolinska Insititute, Ctr Psychiat Res, Karolinska Hosp, Dept Clin Neurosci, SE-17176 Stockholm, Sweden..
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    C-11-Carbonylation through in Situ Generated C-11-Benzoyl Chlorides with Tetrabutylammonium Chloride as Chloride Source2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 18, p. 2648-2651Article in journal (Refereed)
    Abstract [en]

    Aromatic C-11-containing acids, amides, esters, and aldehydes were obtained through a novel C-11-carbonylative reaction. In the two-step process, aryl iodides are first reacted with (CO)-C-11 and tetrabutylammonium chloride in a palladium-mediated reaction to yield C-11-benzoyl chlorides in situ. The crude mixture is then further treated with either a hydroxide, amine, alcohol, or a hydride in a second vial to furnish the final C-11-carbonyl product. The monodentate ligand tri-tert-butylphosphonium tetrafluoroborate was proven to be crucial for obtaining high radiochemical yields (RCY). A wide range of C-11-containing carbonyl compounds were successfully radiolabeled in moderate to excellent RCYs, ranging from 41-93%. The synthetic retinoic acid tamibarotene was obtained in a RCY of 89%, whereas the Boc-protected procainamide was labelled in 68% RCY, which is a significantly increase (2-3 fold) in RCY compared to other published methods.

  • 12. Flöistrup, Erik
    et al.
    Goede, Patrick
    Strömberg, Roger
    Malm, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of estradiol backbone mimics via the Stille reaction using copper(II) oxide as co-reagent2011In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, no 2, p. 209-211Article in journal (Refereed)
    Abstract [en]

    Sterically hindered biaryls and 2-phenylbenzo[b]thiophenes that can serve as templates for mimics of the estradiol backbone were prepared in modest to good yields by the Stille reaction using CuO as a co-reagent. Due to the neutral conditions applied in the Stille reaction, protection strategies were unnecessary for hydroxy containing coupling partners. Ligandless coupling conditions were also evaluated.

  • 13.
    Gising, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Odell, Luke R
    University of Newcastle, Australia.
    Microwave-assisted synthesis of anti-tuberculosis, HIV and hepatitis C agents2014In: Microwaves in Drug Discovery and Development: Recent Advances, Future Medicine , 2014, p. 34-54Chapter in book (Refereed)
    Abstract [en]

    Microwave heating technology is ideally suited to small-scale discovery chemistry applications, as it allows for full reaction control, rapid (super)heating, short reaction times, high safety and rapid feedback. These unique properties offer unparalleled opportunities for medicinal chemists to speed up the lead optimization process in early drug discovery. To illustrate these advantages, we herein describe a number of recent applications of dedicated microwave instrumentation in the synthesis of small molecules targeting three of the most prevalent infectious diseases: tuberculosis, HIV/AIDS and hepatitis C.

  • 14.
    Holmberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlsson, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Organic Chemistry.
    Enzymatic Kinetic Resolution of 1-(3-furyl)-3-buten-1ol2005In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 16, p. 2397-2399Article in journal (Other academic)
    Abstract [en]

    The enzymatic kinetic resolution of 1-(3-furyl)-3-buten-1-ol was investigated via the enantioselective hydrolysis of the corresponding acetate. Pseudomonas fluorescens (Fluka) was found to give the highest enantiomeric ratios of the 11 lipases screened. At 51% conversion, the ee value (eep) for the product was found to be 89%, giving an enantiomeric ratio (Ep) of 58, while the ee value (ees) for the substrate was 89%, giving an enantiomeric ratio (Ep) of 38.

  • 15.
    Isaksson, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kumpina, Ilze
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Wannberg, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rapid and straightforward transesterification of sulfonyl carbamates2016In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 13, p. 1476-1478Article in journal (Refereed)
    Abstract [en]

    A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a chosen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100-120 degrees C for 20-60 min resulted in good to excellent yields (53-93%) of alkyl (arylsulfonyl)carbamates where the alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of an angiotensin II type 2 receptor (AT2R) ligand.

  • 16.
    Johannesson, Petra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Johansson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nikiforovich, Gregory V
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Synnergren, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le Greves, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Karlen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor2002In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 45, no 9, p. 1767-1777Article in journal (Refereed)
    Abstract [en]

    Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.

  • 17.
    Karlsson, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Blom, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Johansson, Miranda
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Jansson, Anna M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Scifo, Enzo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Govender, Thavendran
    Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 9, p. 2612-2621Article in journal (Refereed)
    Abstract [en]

    Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

  • 18.
    Kumaniaev, Ivan
    et al.
    Stockholm University, Department of Organic Chemistry.
    Subbotina, Elena
    Stockholm University, Department of Organic Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Galkin, Maxim V.
    Stockholm University, Department of Organic Chemistry.
    Samec, Joseph S. M.
    Stockholm University, Department of Organic Chemistry.
    Lignin depolymerization to monophenolic compounds in a flow-through system2017In: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 19, no 24, p. 5767-5771Article in journal (Refereed)
    Abstract [en]

    A reductive lignocellulose fractionation in a flow-through system in which pulping and transfer hydrogenolysis steps were separated in time and space has been developed. Without the hydrogenolysis step or addition of trapping agents to the pulping, it is possible to obtain partially depolymerized lignin (21 wt% monophenolic compounds) that is prone to further processing. By applying a transfer hydrogenolysis step 37 wt% yield of lignin derived monophenolic compounds was obtained. Pulp generated in the process was enzymatically hydrolyzed to glucose in 87 wt% yield without prior purification.

  • 19.
    Lampa, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease.

    The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.

    List of papers
    1. Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
    Open this publication in new window or tab >>Hepatitis C Virus NS3 Protease Inhibitors Comprising a Novel Aromatic P1 Moiety
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    2008 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 6, p. 2955-2967Article in journal (Refereed) Published
    Abstract [en]

    Inhibition of the hepatitis C virus (HCV) NS3 protease has emerged as an attractive approach to defeat the global hepatitis C epidemic. In this work, we present the synthesis and biochemical evaluation of HCV NS3 protease inhibitors comprising a non-natural aromatic P-1 moiety. A series of inhibitors with aminobenzoyl sulfonamides displaying submicromolar potencies in the full-length NS3 protease assay was prepared through a microwave-irradiated, palladium-catalyzed, amidocarbonylation protocol.

    Keyword
    HCV, NS3, protease inhibitor, carbonylation, acyl sulfonamide, palladium
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95748 (URN)10.1016/j.bmc.2007.12.041 (DOI)000255127700023 ()18194867 (PubMedID)
    Available from: 2007-04-13 Created: 2007-04-13 Last updated: 2018-01-13Bibliographically approved
    2. Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
    Open this publication in new window or tab >>Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
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    2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 14, p. 5413-5424Article in journal (Refereed) Published
    Abstract [en]

    Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.

    Keyword
    HCV, Protease inhibitors, Peptidomimetics, Phenylglycine, Resistance, Alkenylic acylsulfonamides
    National Category
    Natural Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-129431 (URN)10.1016/j.bmc.2010.05.027 (DOI)000279744700060 ()20541424 (PubMedID)
    Available from: 2010-08-15 Created: 2010-08-15 Last updated: 2017-12-12Bibliographically approved
    3. P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
    Open this publication in new window or tab >>P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
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    2011 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, no 16, p. 4917-4927Article in journal (Refereed) Published
    Abstract [en]

    Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.

    Keyword
    HCV, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-157240 (URN)10.1016/j.bmc.2011.06.064 (DOI)000293503000025 ()
    Available from: 2011-08-31 Created: 2011-08-22 Last updated: 2018-01-12Bibliographically approved
    4. Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
    Open this publication in new window or tab >>Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moiety
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-163354 (URN)
    Available from: 2011-12-11 Created: 2011-12-11 Last updated: 2012-01-16
    5. Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
    Open this publication in new window or tab >>Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ Region
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-163356 (URN)
    Available from: 2011-12-11 Created: 2011-12-11 Last updated: 2012-01-16
  • 20.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Novel Peptidomimetic HCV NS3 Protease Inhibitors Spanning the P2–P1´ RegionManuscript (preprint) (Other academic)
  • 21.
    Lampa, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Grandin, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ehrenberg, Angelica E.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Alogheli, Hiba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindeberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Diversely Vinylated Acyclic Pyrimidinyloxyphenylglycine-based Inhibitors of the HCV NS3 Protease and Corresponding Macrocycles: Beneficial use of an Aromatic P1 moietyManuscript (preprint) (Other academic)
  • 22.
    Mane, Rajendra S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-Catalyzed Carbonylative Synthesis of N-Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide2013In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 54, no 50, p. 6912-6915Article in journal (Refereed)
    Abstract [en]

    A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)6 as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.

  • 23.
    Mowbray, Sherry L
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kathiravan, Muthu K
    Pandey, Abhishek A
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 13161-13176Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

  • 24. Naicker, Tricia
    et al.
    Arvidsson, Per I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kruger, Hendrik G
    Maguire, Glenn E M
    Govender, Thavendran
    Tetrahydroisoquinoline-Based N-Oxides as Chiral Organocatalysts for the Asymmetric Allylation of Aldehydes2011In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2011, no 34, p. 6923-6932Article in journal (Refereed)
    Abstract [en]

    The short synthesis of a series of novel chiral N-oxideorganocatalysts and their evaluation in the asymmetric allylation reaction of aromatic and α-β-unsaturated aldehydes with allyltrichlorosilane is reported. These readily modifiable organocatalysts are the first of their kind based on the tetrahydroisoquinoline framework. The chiral homoallyl products were obtained with good chemical efficiency (up to 93 % yield) and high enantioselectivity (up to 91 % ee) under mild reaction conditions (23 °C).

  • 25.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Pd-mediated Carbonylative Synthesis of 11C-N-CyanobenzamidesManuscript (preprint) (Other academic)
  • 26.
    Nordeman, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo2014In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Introduction: The enzyme beta-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-p, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo. Methods: (11)[C]-N-1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-y1)-5-(N-methylmethylsulfonamido)-N-3-((R)-1-phenylethyl)isophthalamide, a p-secretase inhibitor, denoted here as [C-11]BSIIV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [C-11]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats. Results: The halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21-26%. [C-11]BSI-IV was obtained in 29 +/- 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 +/- 155 GBq/umol at the end of synthesis with a radiochemical purity of >99%. The predinical studies showed that [C-11]BSI-IV has a rapid metabolism in rat with excretion to the small intestines. Conclusion: [C-11]BSI-IV was obtained in sufficient amount and purity to enable predinical investigation. The predinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [C-11]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.

  • 27.
    Orrling, Kristina M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics.

    In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases.

    Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes.

    In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.

    List of papers
    1. α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
    Open this publication in new window or tab >>α-Substituted Norstatines as the Transistion-State Mimic in Inhibitors of Multiple Digestive Vacuole Malaria Aspartic Proteases
    Show others...
    2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 16, p. 5933-5949Article in journal (Refereed) Published
    Abstract [en]

    The impact of moving the P1 side-chain from the β-position to the α-position in norstatine-containing plasmepsin inhibitors was investigated, generating two new classes of tertiary alcohol-comprising α-benzylnorstatines and α-phenylnorstatines. Twelve α-substituted norstatines were designed, synthesized and evaluated for their inhibitory potencies against plasmepsin II and the plasmepsin IV orthologues (PM4) present in the digestive vacuole of all four Plasmodium species causing malaria in man. New synthetic routes were developed for producing the desired α-substituted norstatines as pure stereoisomers. The best compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nm in PM4 from P. ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to P. falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding affinities using the linear interaction energy method (LIE).

    Keyword
    malaria, plasmepsin, inhibitors, microwave-assisted synthesis, molecular dynamics, Linear interaction energy mehtod
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100961 (URN)10.1016/j.bmc.2009.06.065 (DOI)000268762900020 ()
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2018-01-13Bibliographically approved
    2. Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating
    Open this publication in new window or tab >>Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating
    2002 (English)In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 5, no 7, p. 571-574Article in journal (Refereed) Published
    Abstract [en]

    A general procedure for the synthesis of a large variety of compounds comprising an alpha, beta-unsaturated carbonyl functionality was developed. The use of one-pot cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for various formations including heterocycles of different ring sizes and unsaturated amides in combination with microwave dielectric heating is described. The method was used to synthesize a small library of unsaturated amides.

    Keyword
    microwave heating, one-pot synthesis, cascade reaction, library synthesis, (triphenylphosphoranylidene)ethenone, organic-synthesis, cumulated ylides, chemistry
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-100964 (URN)000181710400008 ()12470270 (PubMedID)1386-2073 (ISBN)
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. An efficient method to perform milliliter-scale PCR utilizing highly controlled microwave thermocycling
    Open this publication in new window or tab >>An efficient method to perform milliliter-scale PCR utilizing highly controlled microwave thermocycling
    2004 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 7, no 7, p. 790-791Article in journal (Refereed) Published
    Abstract [en]

    This communication describes the development of a controlled microwave methodology for rapid milliliter-scale PCR.

    Keyword
    organic-chemistry, DNA, selection, proteins, site
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-100963 (URN)10.1039/b317049g (DOI)15045065 (PubMedID)1359-7345 (ISBN)
    Available from: 2009-04-14 Created: 2009-04-14 Last updated: 2017-12-13Bibliographically approved
  • 28.
    Roslin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Exploring Palladium-Mediated 11C/12C-Carbonylation Reactions: PET Tracer Development Targeting the Vesicular Acetylcholine Transporter2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented herein describes the utilization and exploration of palladium-mediated incorporations of carbon monoxide and/or [11C]carbon monoxide into compounds and structural motifs with biological relevance.

    The first part of the thesis describes the design, synthesis and 11C-labeling of prospective PET tracers for the vesicular acetylcholine transporter (VAChT), a target affected in several neurodegenerative diseases. Different parts of the benzovesamicol scaffold were modified in papers I and II to probe the binding to VAChT. The key motif was an amide functional group, which enabled the use of palladium-mediated 11C/12C-carbonylations to synthesize and evaluate two different sets of structurally related ligands.

    The second part of the thesis describes the exploration of different aspects of palladium-mediated 11C/12C-carbonylation reactions. The utilization of unactivated alkyl iodides and bromides as coupling partners in a carbonylative Suzuki-Miyaura reaction was described in paper III. The combination of palladium-catalysis together with visible light irradiation enabled their functionalization via an alkyl radical. The mild conditions, namely the ambient temperature and pressure of carbon monoxide, and the accessible reaction set-up further added to the utility of the method. A palladium(II)-mediated oxidative 11C-carbonylation for synthesis of 11C-labeled ureas was described in paper IV. Utilizing only amines in addition to a palladium-source and [11C]carbon monoxide, the method proved to be facile and robust, thus representing a simplification in relation to methods using other 11C-synthons for synthesis of 11C-labeled ureas. Finally, a palladium(0)-catalyzed carbonylation reaction for synthesis of acylamidines was presented in paper V. The versatility of the method was demonstrated by one-pot cyclizations to form oxadiazoles and triazoles together with the corresponding 11C-carbonylation reaction to produce 11C-labeled acylamidines and an oxadiazole.

    The work described herein has thus contributed structural information in the search for a PET tracer for VAChT and identified a viable lead structure for future investigations. Furthermore, investigation of reaction conditions that would allow use of either elusive or accessible substrates led to the development of methods for synthesis and/or 11C-labeling of various carbonylated compounds.

    List of papers
    1. Synthesis and Labelling of a Piperazine-Based Library of 11C-Labeled Ligands for Imaging of the Vesicular Acetylcholine Transporter
    Open this publication in new window or tab >>Synthesis and Labelling of a Piperazine-Based Library of 11C-Labeled Ligands for Imaging of the Vesicular Acetylcholine Transporter
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    2014 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 57, no 8, p. 525-532Article in journal (Refereed) Published
    Abstract [en]

    The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [C-11]-(+/-)5a-f, were C-11-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [C-11]-(+/-)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/mu mol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [C-11]-(+/-)5d and [C-11]-(+/-)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.

    Keyword
    vesicular acetylcholine transporter, carbonylation, PET, library, C-11-labeling, vesamicol
    National Category
    Radiology, Nuclear Medicine and Medical Imaging Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-231333 (URN)10.1002/jlcr.3208 (DOI)000340169500004 ()24991704 (PubMedID)
    Available from: 2014-09-07 Created: 2014-09-07 Last updated: 2018-01-11
    2. Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter
    Open this publication in new window or tab >>Synthesis and In Vitro Evaluation of 5-Substituted Benzovesamicol Analogs containing N-Substituted Amides as Potential Positron Emission Tomography Tracers for the Vesicular Acetylcholine Transporter
    Show others...
    2017 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 25, no 19, p. 5095-5106Article in journal (Refereed) Published
    Abstract [en]

    Herein, new ligands for the vesicular acetylcholine transporter (VAChT), based on a benzovesamicol scaffold, are presented. VAChT is acknowledged as a marker for cholinergic neurons and a positron emission tomography tracer for VAChT could serve as a tool for quantitative analysis of cholinergic neuronal density. With an easily accessible triflate precursor, aminocarbonylations were utilized to evaluate the chemical space around the C5 position on the tetrahydronaphthol ring. Synthesized ligands were evaluated for their affinity and selectivity for VAChT. Small, preferably aromatic, N-substituents proved to be more potent than larger substituents. Of the fifteen compounds synthesized, benzyl derivatives (+/-)-7i and (+/-)-7l had the highest affinities for VAChT. Compound (+/-)-7i was chosen to investigate the importance of stereochemistry for binding to VAChT and selectivity toward the sigma(1) and sigma(2) receptors. Enantiomeric resolution gave (+/-)-7i and (-)-7i, and the eutomer showed seven times better affinity. Although racemate (+/-)-7i was initially promising, the affinity of (-)-7i for VAChT was not better than 56.7 nM which precludes further preclinical evaluation. However, the nanomolar binding together with the ready synthesis of [C-11]-(+/-)-7i shows that (-)-7i can serve as a scaffold for future optimizations to provide improved C-11-labelled VAChT PET tracers.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332288 (URN)10.1016/j.bmc.2017.01.041 (DOI)
    Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2018-02-08Bibliographically approved
    3. Palladium and Visible-Light Mediated Carbonylative Suzuki-Miyaura Coupling of Unactivated Alkyl Halides and Aryl Boronic Acids
    Open this publication in new window or tab >>Palladium and Visible-Light Mediated Carbonylative Suzuki-Miyaura Coupling of Unactivated Alkyl Halides and Aryl Boronic Acids
    2017 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, p. 6895-6898Article in journal (Refereed) Published
    Abstract [en]

    Herein, a simple and efficient method for the palladium-catalyzed carbonylation of aryl boronic acids with unactivated alkyl iodides and bromides under visible-light irradiation, ambient temperature and low CO-pressure is presented. Notably, the procedure uses readily available equipment and an inexpensive palladium catalyst to generate the key alkyl radical intermediate. These mild conditions enabled the synthesis of a range of functionalized aryl alkyl ketones including the antipsychotic drug, melperone.

    Place, publisher, year, edition, pages
    ROYAL SOC CHEMISTRY, 2017
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-329634 (URN)10.1039/c7cc02763j (DOI)000404282900021 ()
    Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-10-26
    4. Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
    Open this publication in new window or tab >>Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation
    Show others...
    2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, p. 1688-Article in journal (Refereed) Published
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332289 (URN)
    Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2017-11-30
    5. Acylamidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C-Labeling
    Open this publication in new window or tab >>Acylamidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C-Labeling
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-332292 (URN)
    Available from: 2017-10-26 Created: 2017-10-26 Last updated: 2017-10-26
  • 29.
    Roslin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Nordeman, Patrik
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of 11C-Labelled Ureas by Palladium(II)-Mediated Oxidative Carbonylation2017In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 10, p. 1688-Article in journal (Refereed)
  • 30.
    Roslin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Visible-Light Photocatalysis as an Enabling Tool for the Functionalization of Unactivated C(sp(3))-Substrates2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2017, no 15, p. 1993-2007Article, review/survey (Refereed)
    Abstract [en]

    Over the past decade, visible-light photocatalysis has emerged as one of the brightest and most dynamic fields in modern organic chemistry. By employing a transition-metal- or organic-dye-based photocatalyst in conjunction with a low-energy visible-light source, this synthetic manifold allows the facile generation of radical intermediates that can subsequently be directed through a wide range of transformations. Although initial studies focused largely on the functionalization of stabilized radical intermediates, over the past few years significant efforts have been directed towards the functionalization of challenging unactivated radical precursors. In this review we summarize the recent developments in the use of visible-light photocatalysis for the functionalization of unactivated C(sp(3))-substrates.

  • 31.
    Roy, Tamal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wetzel, Alexander
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 10, p. 2738-2741Article in journal (Refereed)
    Abstract [en]

    We report a highly diastereoselective synthesis of cydopentene-spirooxindole derivatives via an intramolecular Heck-Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF-water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.

  • 32.
    Russo, Francesco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olofsson, Kristofer
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave-Heated Transition Metal-Catalyzed Coupling Reactions2012In: Microwaves in Organic Synthesis / [ed] de la Hoz, A, Loupy, A, Weinheim: Wiley-VCH Verlagsgesellschaft, 2012, 3, p. 607-672Chapter in book (Refereed)
  • 33.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(II)-Catalyzed Addition Reactions: Synthesis of Aryl Amidines and Aryl Ketones2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-catalyzed reactions have become one of the most important tools in modern organic chemistry due to its ability to catalyze the formation of new carbon-carbon bonds.

    The aim of the work presented in this thesis was to develop new palladium(II)-catalyzed addition reactions. In this work, cyanamides were investigated as a new substrate to give aryl amidines as products. The first protocol developed employed aryltrifluoroborates as the aryl partner, and the insertion of the aryl group into un-, mono-, and di-substituted cyanamides was successful for a wide variety of aryltrifluoroborates. An alternative method of generating the necessary intermediate for insertion into the cyanamide is the decarboxylative formation of aryl-palladium from aryl carboxylic acids. A protocol was developed for this reaction, but was unfortunately limited to a small number of ortho-substituted electron-rich aryl carboxylic acids. The mechanism was investigated by the means of DFT calculations and ESI-MS studies, and the rate-determining step was suggested to be the 1,2-carbopalladation based upon those results. A translation of the batch protocol to continuous-flow conditions was also demonstrated. The ideal method of generating the aryl-palladium species is by C-H bond activation, and this approach was demonstrated with indoles, giving a variety of 3-amidinoindoles as products. The mechanism was investigated by DFT calculations and a plausible catalytic cycle was proposed.

    A continuous-flow application of a desulfitative palladium(II)-catalyzed addition to nitriles to give ketones was developed. In addition, different reactor materials were evaluated in the microwave heated reactor cavity. Thus the reaction was shown to proceed with microwave heating in a borosilicate glass and an aluminum oxide reactor, and also in conditions mimicking conventional heating in a silicon carbide reactor.

    Finally, a protocol was developed for the convenient synthesis of sodium aryl sulfinates from Grignard and lithium reagents using a solid sulfur dioxide source as a safe alternative to the gas. The products of this protocol can be used as aryl-palladium precursors by a desulfitative process.

    List of papers
    1. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
    Open this publication in new window or tab >>Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates
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    2012 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, no 9, p. 2394-2397Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-167719 (URN)10.1021/ol300813c (DOI)000303492200052 ()
    Available from: 2012-01-31 Created: 2012-01-31 Last updated: 2017-12-08Bibliographically approved
    2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Open this publication in new window or tab >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Show others...
    2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, p. 13803-13810Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

    Keyword
    decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
    Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved
    3. Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation
    Open this publication in new window or tab >>Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation
    Show others...
    2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 15, p. 4066-4069Article in journal (Refereed) Published
    Abstract [en]

    We report a facile synthesis of 3-amidino indoles from indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via C-H bond activation of the indole in its 3-position followed by a 1,2-addition of the resulting indole-palladium σ-complex to a cyanamide, which provides the corresponding amidine. The preference for 4,5-diazafluoren-9-one (DAF) as the ligand is investigated using DFT calculations, and a plausible reaction pathway is presented.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2017
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-326815 (URN)10.1021/acs.orglett.7b01836 (DOI)000407307900031 ()28741950 (PubMedID)
    Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2018-01-13Bibliographically approved
    4. Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    Open this publication in new window or tab >>Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, p. 2005-2011Article in journal (Refereed) Published
    Abstract [en]

    A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2016
    Keyword
    Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-304719 (URN)10.1021/acs.oprd.6b00306 (DOI)000388430300017 ()
    Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2017-11-30Bibliographically approved
    5. Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    Open this publication in new window or tab >>Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    2016 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 5, p. 533-536Article in journal (Refereed) Published
    Abstract [en]

    Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

    Keyword
    Sodium sulfinate, Sulfur dioxide surrogate, DABSO
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-276924 (URN)10.1016/j.tetlet.2015.12.073 (DOI)000369557300007 ()
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
  • 34.
    Rydfjord, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Roslin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Roy, Tamal
    Abbas, Alaa
    Stevens, Marc
    Larhed, Mats
    Odell, Luke R.
    Acylamidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and 11C-LabelingManuscript (preprint) (Other academic)
  • 35.
    Sawant, Rajiv T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Stevens, Marc Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rapid Access to Polyfunctionalized 3,4-Dihydroquinazolinones through a Sequential N-Acyliminium Ion Mannich Reaction Cascade2015In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 35, p. 7743-7755Article in journal (Refereed)
    Abstract [en]

    A microwave-promoted one-pot, three-component sequential cyclization-Mannich reaction of unactivated ketones, o-formyl carbamates and primary amines has been developed. Cyclic N-acyliminium ions are generated in situ from the carbamate and amine starting materials. This metal-free cascade protocol provides rapid access to structurally diverse 3,4-dihydroquinazolinones in good to excellent yields with high regioselectivity for the terminal methyl group, in the case of unsymmetrical methyl alkyl ketones. Key features of the developed protocol include its operational simplicity, ease of product purification, and wide functional group tolerance.

  • 36.
    Skillinghaug, Bobo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(II)-Catalysed Heck and Addition Reactions: Exploring Decarboxylative and Desulfitative Processes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed.

    This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave-assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed.

    List of papers
    1. Experimental and Theoretical Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes
    Open this publication in new window or tab >>Experimental and Theoretical Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-304720 (URN)
    Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2016-10-10
    2. Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies
    Open this publication in new window or tab >>Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones from Sodium Arylsulfinates and Nitriles: Scope, Limitations, and Mechanistic Studies
    Show others...
    2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 24, p. 12018-12032Article in journal (Refereed) Published
    Abstract [en]

    A fast and efficient protocol for the palladium(II)-catalyzed production of aryl ketones from sodium arylsulfinates and various organic nitriles under controlled microwave irradiation has been developed. The wide scope of the reaction has been demonstrated by combining 14 sodium arylsulfinates and 21 nitriles to give 55 examples of aryl ketones. One additional example illustrated that, through the choice of the nitrile reactant, benzofurans are also accessible. The reaction mechanism was investigated by electrospray ionization mass spectrometry and DFT calculations. The desulfitative synthesis of aryl ketones from nitriles was also compared to the corresponding transformation starting from benzoic acids. Comparison of the energy profiles indicates that the free energy requirement for decarboxylation of 2,6-dimethoxybenzoic acid and especially benzoic acid is higher than the corresponding desulfitative process for generating the key aryl palladium intermediate. The palladium(II) intermediates detected by ESI-MS and the DFT calculations provide a detailed understanding of the catalytic cycle.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-240562 (URN)10.1021/jo501875n (DOI)000346759500020 ()25295849 (PubMedID)
    Available from: 2015-01-08 Created: 2015-01-07 Last updated: 2017-12-05Bibliographically approved
    3. Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    Open this publication in new window or tab >>Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
    2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, p. 2005-2011Article in journal (Refereed) Published
    Abstract [en]

    A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2016
    Keyword
    Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-304719 (URN)10.1021/acs.oprd.6b00306 (DOI)000388430300017 ()
    Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2017-11-30Bibliographically approved
    4. Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    Open this publication in new window or tab >>Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO2
    2016 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 5, p. 533-536Article in journal (Refereed) Published
    Abstract [en]

    Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

    Keyword
    Sodium sulfinate, Sulfur dioxide surrogate, DABSO
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-276924 (URN)10.1016/j.tetlet.2015.12.073 (DOI)000369557300007 ()
    Funder
    Knut and Alice Wallenberg Foundation
    Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
  • 37.
    Skillinghaug, Bobo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of sodium aryl sulfinates from aryl bromides employing 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) as a bench-stable, gas-free alternative to SO22016In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 57, no 5, p. 533-536Article in journal (Refereed)
    Abstract [en]

    Abstract A convenient two-step protocol for the synthesis of sodium aryl sulfinates from aryl bromides and the SO2 surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) has been developed. A wide range of aryl bromides with respect to electronic properties were employed to give the corresponding sodium arylsulfinates in good to excellent yields. The protocol is especially efficient for electron poor aryl bromides which are often difficult to prepare using existing methods.

  • 38.
    Skillinghaug, Bobo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones2016In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, p. 2005-2011Article in journal (Refereed)
    Abstract [en]

    A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

  • 39.
    Skogh, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Friis, Stig D.
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Skrydstrup, Troels
    Aarhus Univ, Carbon Dioxide Activat Ctr CADIAC, Interdisciplinary Nanosci Ctr iNANO, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.;Aarhus Univ, Dept Chem, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark..
    Johansson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-Catalyzed Aminocarbonylation in Solid-Phase Peptide Synthesis: A Method for Capping, Cyclization, and Isotope Labeling2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 11, p. 2873-2876Article in journal (Refereed)
    Abstract [en]

    A new synthetic approach for introducing N-capping, groups onto peptides attached to a solid support, Combining aminocarbonylation under mild conditions Wing a palladacycle precatalyst and, solid-phase peptide synthesis is reported. The use of la silacarboxylic acid as an in situ CO-releasing molecule allowed the reaction to be performed single vial. The method also enables versatile substitution of side chains, side-chain to side-chain cyclizations, and selective aryl labeling of modified peptides.

  • 40.
    Sköld, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Kleimark, Jonatan
    Department of Chemistry, University of Gothenburg.
    Trejos, Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nilsson Lill, Sten O.
    Department of Chemistry, University of Gothenburg.
    Norrby, Per-Ola
    Department of Chemistry, University of Gothenburg.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids2012In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, p. 4714-4722Article in journal (Refereed)
    Abstract [en]

    The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

  • 41.
    Stevens, Marc
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sawant, Rajiv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of sulfonyl azides via diazotransfer using an imidazole-1-sulfonyl azide salt: scope and ¹⁵N NMR labeling experiments2014In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 11, p. 4826-4831Article in journal (Refereed)
    Abstract [en]

    Imidazole-1-sulfonyl azide hydrogen sulfate is presented as an efficient reagent for the synthesis of sulfonyl azides from primary sulfonamides. The described method is experimentally simple and high-yielding and does not require the addition of Cu salts. Furthermore, 15N NMR mechanistic studies show the reaction proceeds via a diazo transfer mechanism. Imidazole-1-sulfonyl azide hydrogen sulfate provides a considerable advantage over existing diazo transfer reagents in terms of impact stability, cost, and ease of use

  • 42.
    Svensson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Methods in Medicinal Chemistry: Mechanistic Investigations and Virtual Screening Development2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis.

    In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally.

    The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods.

    Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind.

    Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

    List of papers
    1. Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Open this publication in new window or tab >>Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile
    Show others...
    2013 (English)In: Organometallics, ISSN 0276-7333, E-ISSN 1520-6041, Vol. 32, no 2, p. 490-497Article in journal (Refereed) Published
    Abstract [en]

    The reaction mechanism of palladium(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system.

    National Category
    Medical and Health Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-196041 (URN)10.1021/om3009525 (DOI)000314332100017 ()
    Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2017-12-06Bibliographically approved
    2. Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Open this publication in new window or tab >>Decarboxylative Palladium(II)-Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation
    Show others...
    2013 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 41, p. 13803-13810Article in journal (Refereed) Published
    Abstract [en]

    A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2CCF3)(2)], 6-methyl-2,2-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11mmolh(-1) by using a glass reactor with an inner diameter of 3mm at a flow rate of 1mLmin(-1).

    Keyword
    decarboxylation, density functional calculations, mass spectrometry, microwave chemistry, palladium
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-210180 (URN)10.1002/chem.201301809 (DOI)000325135800026 ()
    Available from: 2013-11-04 Created: 2013-11-04 Last updated: 2017-12-06Bibliographically approved
    3. Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Open this publication in new window or tab >>Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-Diarylethenes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keyword
    palladium, DFT, mechanism, styrene
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259441 (URN)
    Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2015-10-01
    4. Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    Open this publication in new window or tab >>Virtual Screening Data Fusion Using Both Structure- and Ligand-Based Methods
    2012 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 52, no 1, p. 225-232Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening is widely applied in drug discovery, and significant effort has been put into improving current methods. In this study, we have evaluated the performance of compound ranking in virtual screening using five different data fusion algorithms on a total of 16 data sets. The data were generated by docking, pharmacophore search, shape similarity, and electrostatic similarity, spanning both structure- and ligand-based methods. The algorithms used for data fusion were sum rank, rank vote, sum score, Pareto ranking, and parallel selection. None of the fusion methods require any prior knowledge or input other than the results from the single methods and, thus, are readily applicable. The results show that compound ranking using data fusion improves the performance and consistency of virtual screening compared to the single methods alone. The best performing data fusion algorithm was parallel selection, but both rank voting and Pareto ranking also have good performance.

    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-169381 (URN)10.1021/ci2004835 (DOI)000299351600021 ()
    Available from: 2012-02-28 Created: 2012-02-28 Last updated: 2018-01-12Bibliographically approved
    5. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Open this publication in new window or tab >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
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    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Structural Biology Pharmaceutical Chemistry
    Research subject
    Chemistry with specialization in Bioorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2017-08-24Bibliographically approved
    6. Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
    Open this publication in new window or tab >>Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates
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    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-960X, Vol. 55, no 9, p. 1984-1993Article in journal (Refereed) Published
    Abstract [en]

    Transition state- and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over five million compounds and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259442 (URN)10.1021/acs.jcim.5b00359 (DOI)000362056900018 ()26252078 (PubMedID)
    Funder
    Carl Tryggers foundation Swedish Research Council
    Available from: 2015-08-05 Created: 2015-08-04 Last updated: 2018-01-11Bibliographically approved
  • 43.
    Svensson, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fardost, Ashkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Skillinghaug, Bobo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wakchaure, Prasad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wejdemar, Matyas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Mechanistic Investigation of Palladium(II)-Catalyzed Decarboxylative Synthesis of Electron Rich Styrenes and 1,1-DiarylethenesManuscript (preprint) (Other academic)
  • 44.
    Sävmarker, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Deoxybenzoins from Stille carbonylative cross-couplings using molybdenum hexacarbonyl2010In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, no 52, p. 6886-6889Article in journal (Refereed)
    Abstract [en]

    Stille-type carbonylative cross-couplings, employing palladium catalysis and Mo(CO)6 as the carbon monoxide carrier, were used for the preparation of deoxybenzoins. Straightforward transformations were conveniently performed in closed vessels at 100 C, providing the products in good yields. Benzyl bromides and chlorides were used as coupling partners with aryl and heteroaryl stannanes. This mild three-component carbonylation employs the destabilizing agent DBU to promote smooth release of carbon monoxide from Mo(CO)6, which made this protocol operationally simple and minimized the formation of Stille diarylmethane products.

  • 45.
    Sävmarker, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nilsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. ORGFARM.
    Sjöberg, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl N-Methyliminodiacetic Acid (MIDA) Boronates2012In: ChemistryOpen, ISSN 2191-1363, Vol. 1, no 3, p. 140-146Article in journal (Refereed)
  • 46.
    Sävmarker, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rydfjord, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates2012In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, no 9, p. 2394-2397Article in journal (Refereed)
    Abstract [en]

    A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O2CCF3), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.

  • 47.
    Trejos, Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium-Catalysed Couplings in Organic Synthesis: Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

    This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

    In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

    The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η2 Pd-BQ donation-back-donation interaction.

    Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

    In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

    Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

    List of papers
    1. Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
    Open this publication in new window or tab >>Stereoselective Heck arylation of a functionalized cyclopentenyl ether using (S)-N-methyl-pyrrolidine as the stereochemical controller
    Show others...
    2008 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 64, no 37, p. 8746-8751Article in journal (Refereed) Published
    Abstract [en]

    The study of a series of palladium(0)-catalyzed C2-arylations of a 1-cyclopentenyl ether equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary is reported. Stereoselective Heck monoarylations were performed using aryl iodides under classical heating conditions for 1.7-3.0 h at 80 degrees C and in one case using 30 min of microwave irradiation at 110 degrees C. To further explore the scope and nature of this stereoselective methodology, aryl bromides were also utilized as arylating agents, using 20 min of microwave processing at 120-130 degrees C. High to excellent diastereopurities (90-98% de) were obtained according to H-1 NMR and GC-MS analyses. The prolinol fragment apparently controlled the chastereoselectivity of the Heck reaction by presenting the arylpalladium species from the preferred side of the double bond. By X-ray structure diffraction analysis of an N-quaternized Heck product, the absolute configuration of the new stereocenter was established as (R), Supporting a Si-face migratory insertion.

    Keyword
    Heck reaction, microwave, vinyl ether, palladium catalysis; stereoselective
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-104394 (URN)10.1016/j.tet.2008.06.099 (DOI)000258841100022 ()0040-4020 (ISBN)
    Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2018-01-13Bibliographically approved
    2. Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
    Open this publication in new window or tab >>Palladium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction
    2009 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 48, p. 7587-7589Article in journal (Refereed) Published
    Abstract [en]

    A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.

    National Category
    Pharmaceutical Sciences
    Research subject
    Organic Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-124718 (URN)10.1039/b918358b (DOI)000272238900039 ()20024288 (PubMedID)
    Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2018-01-12Bibliographically approved
    3. Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
    Open this publication in new window or tab >>Chelation-Mediated Palladium(II)-Catalyzed Domino Heck-Mizoroki/Suzuki-Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding
    2011 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 76, no 8, p. 2433-2438Article in journal (Refereed) Published
    Abstract [en]

    A palladium(II)-catalyzed Heck-Mizoroki/Suzuki-Miyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one-pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the beta-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetalation and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-152784 (URN)10.1021/jo1018188 (DOI)000289187300004 ()21417443 (PubMedID)
    Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2018-01-12Bibliographically approved
    4. Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
    Open this publication in new window or tab >>Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids
    2012 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 1, no 1, p. 49-56Article in journal (Refereed) Published
    Abstract [en]

    A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlagsgesellschaft, 2012
    Keyword
    chirality, domino reactions, palladium, stereoselective catalysis, water effects
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-172735 (URN)10.1002/open.201100010 (DOI)000328606600008 ()
    Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
    5. Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
    Open this publication in new window or tab >>Transmetallation Versus β-Hydride Elimination: The Role of 1,4 Benzoquinone in Chelation-Controlled Arylation Reactions with Arylboronic Acids
    Show others...
    2012 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 15, p. 4714-4722Article in journal (Refereed) Published
    Abstract [en]

    The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion sigma-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the s-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlagsgesellschaft, 2012
    National Category
    Organic Chemistry Theoretical Chemistry
    Research subject
    Chemistry
    Identifiers
    urn:nbn:se:uu:diva-172740 (URN)10.1002/chem.201102678 (DOI)000302162500033 ()
    Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07Bibliographically approved
    6. Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Open this publication in new window or tab >>Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
    Show others...
    2012 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 6, p. 2724-2736Article in journal (Refereed) Published
    Abstract [en]

    In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

    Keyword
    HIV, AIDS, protease inhibitor, aspartic protease, lactam, tertiary alcohol, X-ray
    National Category
    Medicinal Chemistry
    Research subject
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-160186 (URN)10.1021/jm201620t (DOI)000301767000017 ()
    Available from: 2011-10-17 Created: 2011-10-17 Last updated: 2018-01-12Bibliographically approved
    7. Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Open this publication in new window or tab >>Investigations on the 4-quinolone-3-carboxylic acid motif. 1. Synthesis and structure-activity relationship of a class of human immunodeficiency virus type 1 integrase inhibitors
    Show others...
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 16, p. 5125-9Article in journal (Refereed) Published
    Abstract [en]

    A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-99766 (URN)10.1021/jm8003784 (DOI)000258637400032 ()18665580 (PubMedID)
    Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2018-01-13Bibliographically approved
  • 48.
    Trejos, Alejandro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alkenes with Metal-Directing Groups as Reaction Components2013In: Science of Synthesis: Cross-Coupling and Heck-Type Reactions, Volume 3, Metal-Catalyzed Heck-Type Reactions and C-C Cross Coupling via C–H Activation / [ed] Mats Larhed, Stuttgart: Georg Thieme Verlag KG, 2013, p. 345-390Chapter in book (Refereed)
  • 49.
    Trejos, Alejandro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β, α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids2012In: ChemistryOpen, ISSN 2191-1363, Vol. 1, no 1, p. 49-56Article in journal (Refereed)
    Abstract [en]

    A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78% isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino b,a-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

  • 50.
    Westman, Jacob
    et al.
    Personal Chemistry AB.
    Orrling, Kristina M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating2002In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 5, no 7, p. 571-574Article in journal (Refereed)
    Abstract [en]

    A general procedure for the synthesis of a large variety of compounds comprising an alpha, beta-unsaturated carbonyl functionality was developed. The use of one-pot cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for various formations including heterocycles of different ring sizes and unsaturated amides in combination with microwave dielectric heating is described. The method was used to synthesize a small library of unsaturated amides.

12 1 - 50 of 58
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