Bruno Linclau

Publications

• 11.83

  Impact points

  Stereoarrays with an all-carbon quaternary center: diastereoselective desymmetrization of prochiral malonaldehydes.

  Bruno Linclau, Elena Cini, Catherine S Oakes, Solen Josse, Mark Light, Victoria Ironmonger

  Angewandte Chemie (International ed. in English). 12/2011; 51(5):1232-5.

  Tamed by chelation: The MgBr(2) chelation of prochiral malonaldehydes allows diastereoselective monoaddition reactions with allyl stannane nucleophiles (see scheme; PG=protecting group, TBDMS=tert-butyldiphenylmethylsilyl, Tr=trityl). In the same pot, addition of a second nucleophile proceeds in hig... [more] Tamed by chelation: The MgBr(2) chelation of prochiral malonaldehydes allows diastereoselective monoaddition reactions with allyl stannane nucleophiles (see scheme; PG=protecting group, TBDMS=tert-butyldiphenylmethylsilyl, Tr=trityl). In the same pot, addition of a second nucleophile proceeds in high diastereoselectivity to generate nonsymmetric products with up to five contiguous stereogenic centers, including a chiral all-carbon quaternary center.
• 3.76

  Impact points

  Divergent synthetic approach to 6''-modified α-GalCer analogues.

  Nora Pauwels, Sandrine Aspeslagh, Gerd Vanhoenacker, Koen Sandra, Esther D Yu, Dirk M Zajonc, Dirk Elewaut, Bruno Linclau, Serge Van Calenbergh

  Organic & biomolecular chemistry. 12/2011; 9(24):8413-21.

  A synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6''-OH and the sphingosine amino groups, which enables convenient synthesis of promising 6''-modified KRN700... [more] A synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6''-OH and the sphingosine amino groups, which enables convenient synthesis of promising 6''-modified KRN7000 analogues.
• 5.50

  Impact points

  Heavily fluorinated carbohydrates as enzyme substrates: oxidation of tetrafluorinated galactose by galactose oxidase.

  Avgousta Ioannou, Elena Cini, Roxana S Timofte, Sabine L Flitsch, Nicholas J Turner, Bruno Linclau

  Chemical communications (Cambridge, England). 09/2011; 47(40):11228-30.

  Galactose oxidase (GOase) was shown to oxidise several C2/C3 fluorinated galactose analogues. Interestingly, the enzyme was able to distinguish between the 2,3-tetrafluorinated galactose and its epimeric glucose analogue, and this represents the first reported biotransformation of a heavily fluorina... [more] Galactose oxidase (GOase) was shown to oxidise several C2/C3 fluorinated galactose analogues. Interestingly, the enzyme was able to distinguish between the 2,3-tetrafluorinated galactose and its epimeric glucose analogue, and this represents the first reported biotransformation of a heavily fluorinated sugar.
• 2.03

  Impact points

  The conformation of tetrafluorinated methyl galactoside anomers: crystallographic and NMR studies.

  Bruno Linclau, Samuel Golten, Mark Light, Muriel Sebban, Hassan Oulyadi

  Carbohydrate research. 07/2011; 346(9):1129-39.

  The first single-crystal X-ray diffraction study of tetrafluorinated monosaccharide derivatives is presented. Both α- and β-methyl 2,3-dideoxy-2,2,3,3-tetrafluoro-d-galactopyranoside anomers adopt the (4)C(1) conformation. The values for the C1-O1 and C1-O5 bond lengths and the O5-C1-O1-CH(3) dihedr... [more] The first single-crystal X-ray diffraction study of tetrafluorinated monosaccharide derivatives is presented. Both α- and β-methyl 2,3-dideoxy-2,2,3,3-tetrafluoro-d-galactopyranoside anomers adopt the (4)C(1) conformation. The values for the C1-O1 and C1-O5 bond lengths and the O5-C1-O1-CH(3) dihedral angles are in line with what can be expected from the anomeric and exo-anomeric effects. The chair conformations are slightly distorted, presumably due to repulsion between 1,3-diaxial C-O and C-F bonds. The asymmetric unit of both compounds contains up to three independent molecules, which differ in the conformation of the hydroxymethyl group (including in one case a 'forbidden'gg rotamer). The molecular packing of the β-anomer shows a clear segregation between fluorinated and hydrophilic domains, while for the α-anomer the regions of fluorine segregation are broken by interleafing of OMe groups. There is one close OH⋯F contact, which is likely to arise from the crystal packing. NMR studies show that the two anomers also adopt a (4)C(1) conformation in solution (D(2)O, CDCl(3)).

• Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors

  Konrad Hohlfeld, Cyrille Tomassi, Jörg Kurt Wegner, Bart Kesteleyn, Bruno Linclau

  ACS Medicinal Chemistry Letters. 01/2011; 2:461-465.

  A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutatio... [more] A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. A number of PIs have been synthesized that show equivalent and greater activity for HIV-1 mutant strains as compared to wild-type HIV-1. The activity on the purified enzyme was confirmed for a selection of analogues.
• 5.42

  Impact points

  Synthesis and evaluation of amino-modified alpha-GalCer analogues.

  Matthias Trappeniers, René Chofor, Sandrine Aspeslagh, Yali Li, Bruno Linclau, Dirk M Zajonc, Dirk Elewaut, Serge Van Calenbergh

  Organic letters. 07/2010; 12(13):2928-31.

  Alpha-GalCer analogues featuring a phytoceramide 3- and 4-amino group have been synthesized. A Mitsunobu reaction involving phthalimide was employed for the introduction of the amino groups at the 3- and 4-positions of suitable phytosphingosine-derived precursors. The influence of these modification... [more] Alpha-GalCer analogues featuring a phytoceramide 3- and 4-amino group have been synthesized. A Mitsunobu reaction involving phthalimide was employed for the introduction of the amino groups at the 3- and 4-positions of suitable phytosphingosine-derived precursors. The influence of these modifications on the interaction with the T-cell receptor of NKT cells was investigated, as well as the capacity of the amino-modified analogues to induce a cytokine response after in vivo administration.
• 5.42

  Impact points

  A novel, versatile D-->BCD steroid construction strategy, illustrated by the enantioselective total synthesis of estrone.

  Vincent Foucher, Benedetta Guizzardi, Marinus B Groen, Mark Light, Bruno Linclau

  Organic letters. 02/2010; 12(4):680-3.

  A general steroid synthesis is presented that relies on prior formation of three stereogenic centers (C8, C13, and C14) on a D ring template, followed by C- and B-ring cyclizations. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation process, allows intro... [more] A general steroid synthesis is presented that relies on prior formation of three stereogenic centers (C8, C13, and C14) on a D ring template, followed by C- and B-ring cyclizations. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation process, allows introduction of structural variety as required. The method is illustrated by the total synthesis of estrone via a C-ring closing metathesis and a B-ring Heck cyclization.
• 1.08

  Impact points

  Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane.

  Bruno Linclau, Leo Leung, Jean Nonnenmacher, Graham Tizzard

  Beilstein journal of organic chemistry. 01/2010; 6:62.

  A large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all atte... [more] A large-scale synthesis of meso-2,3-difluoro-1,4-butanediol in 5 steps from (Z)-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleophiles failed.

• Synthesis and crystallographic analysis of meso -2,3-difluoro-1,4-butanediol and meso -1,4-dibenzyloxy-2,3-difluorobutane

  Linclau Bruno, Leung Leo, Nonnenmacher Jean, Tizzard Graham

  Beilstein Journal of Organic Chemistry. 01/2010;

  A large-scale synthesis of meso -2,3-difluoro-1,4-butanediol in 5 steps from ( Z )-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all a... [more] A large-scale synthesis of meso -2,3-difluoro-1,4-butanediol in 5 steps from ( Z )-but-2-enediol is described. Crystallographic analysis of the diol and the corresponding benzyl ether reveals an anti conformation of the vicinal difluoride moiety. Monosilylation of the diol is high-yielding but all attempts to achieve chain extension through addition of alkyl Grignard and acetylide nucleophiles failed.
• 4.22

  Impact points

  Microwave-Assisted Ester Formation Using O-Alkylisoureas: A Convenient Method for the Synthesis of Esters with Inversion of Configuration.

  Alessandra Chighine, Stefano Crosignani, Marie-Claire Arnal, Mark Bradley, Bruno Linclau

  The Journal of organic chemistry. 06/2009;

  The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds in excellent yields with very short reaction times when conducted in a monomode microwave synthesizer. Efficient processes were developed using preformed or commercially available isoureas derived from ... [more] The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds in excellent yields with very short reaction times when conducted in a monomode microwave synthesizer. Efficient processes were developed using preformed or commercially available isoureas derived from primary and secondary alcohols, with a reaction time of only 5 min or less. It was demonstrated that under these microwave conditions, ester formation proceeded in good yields with clean inversion of configuration where appropriate. The process was validated using menthol, a hindered substrate for S(N)2 reactions. In addition, starting from primary alcohols, ester formation was successfully accomplished using an in situ isourea formation procedure. A polymer-assisted solution-phase procedure was also developed by employing preformed solid-supported isoureas and by an efficient "catch and release" ester formation procedure whereby primary alcohols were caught on resin as isoureas by reaction with immobilized carbodiimide and released as esters by subsequent treatment with a carboxylic acids.
• 3.76

  Impact points

  Enantioselective synthesis of tetrafluorinated ribose and fructose.

  Bruno Linclau, A James Boydell, Roxana S Timofte, Kylie J Brown, Victoria Vinader, Alexander C Weymouth-Wilson

  Organic & biomolecular chemistry. 03/2009; 7(4):803-14.

  A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.... [more] A perfluoroalkylidene lithium mediated cyclisation approach for the enantioselective synthesis of a tetrafluorinated aldose (ribose) and of a tetrafluorinated ketose (fructose), both in the furanose and in the pyranose form, is described.
• 3.23

  Impact points

  The Synthesis and in vivo Evaluation of 2',2'-Difluoro KRN7000.

  Leo Leung, Cyrille Tomassi, Katrien Van Beneden, Tine Decruy, Matthias Trappeniers, Dirk Elewaut, Yifang Gao, Tim Elliott, Aymen Al-Shamkhani, Christian Ottensmeier, Jörn M Werner, Anthony Williams, Serge Van Calenbergh, Bruno Linclau

  ChemMedChem. 02/2009;
• 8.58

  Impact points

  6'-derivatised alpha-GalCer analogues capable of inducing strong CD1d-mediated Th1-biased NKT cell responses in mice.

  Matthias Trappeniers, Katrien Van Beneden, Tine Decruy, Ulrik Hillaert, Bruno Linclau, Dirk Elewaut, Serge Van Calenbergh

  Journal of the American Chemical Society. 01/2009; 130(49):16468-9.
• 4.22

  Impact points

  A Linchpin Carbacyclization Approach for the Synthesis of Carbanucleosides.

  Leo Leung, Vicky Gibson, Bruno Linclau

  The Journal of organic chemistry. 12/2008;

  A convenient synthesis of carbanucleosides, with both enantiomers equally accessible, is reported. The key step is a tandem linchpin cyclization process to give access to substituted carbafuranose derivatives having the correct relative stereochemistry for subsequent nucleobase introduction with inv... [more] A convenient synthesis of carbanucleosides, with both enantiomers equally accessible, is reported. The key step is a tandem linchpin cyclization process to give access to substituted carbafuranose derivatives having the correct relative stereochemistry for subsequent nucleobase introduction with inversion of configuration at C1. This was illustrated by the synthesis of 2',3'-dideoxycarbathymidine via a convergent nucleobase introduction and of 2',3'-dideoxy-6'-hydroxycarbauridine via a linear nucleobase introduction. Both methods relied on Mitsunobu chemistry, and the first example of the Mukaiyama modification of the Mitsunobu reaction involving nucleobases as nucleophiles is reported.
• 5.42

  Impact points

  Enantioselective synthesis of tetrafluorinated glucose and galactose.

  Roxana S Timofte, Bruno Linclau

  Organic letters. 10/2008; 10(17):3673-6.

  Polyfluorinated carbohydrates have emerged as interesting probes to investigate "polar hydrophobicity" effect(s) in protein-carbohydrate interactions. A convenient enantioselective synthesis of tetrafluorinated analogues of two of the most important monosaccharides, D-glucose and D-galacto... [more] Polyfluorinated carbohydrates have emerged as interesting probes to investigate "polar hydrophobicity" effect(s) in protein-carbohydrate interactions. A convenient enantioselective synthesis of tetrafluorinated analogues of two of the most important monosaccharides, D-glucose and D-galactose, is reported, as well as our first results regarding the glycosylation of these sugar analogues.
• 5.42

  Impact points

  Synthesis and In Vivo Evaluation of 4-Deoxy-4,4-difluoro-KRN7000.

  Leo Leung, Cyrille Tomassi, Katrien Van Beneden, Tine Decruy, Dirk Elewaut, Tim Elliott, Aymen Al-Shamkhani, Christian Ottensmeier, Serge Van Calenbergh, Joern Werner, Tony Williams, Bruno Linclau

  Organic letters. 10/2008;

  The synthesis of 4-deoxy-4,4-difluoro-KRN7000 starting from phytosphingosine is described. Key steps include a regioselective benzylation of azidophytosphingosine and a deoxofluor-mediated fluorination of the corresponding 4-ketone. This fluorination failed completely when the adjacent 3-OH was prot... [more] The synthesis of 4-deoxy-4,4-difluoro-KRN7000 starting from phytosphingosine is described. Key steps include a regioselective benzylation of azidophytosphingosine and a deoxofluor-mediated fluorination of the corresponding 4-ketone. This fluorination failed completely when the adjacent 3-OH was protected as benzyl ether but proceeded well when a benzoyl group was used. The biological evaluation reveals a bias toward Th1 cytokine induction upon Natural Killer T cell activation.
• 3.23

  Impact points

  Synthesis and in vitro evaluation of alpha-GalCer epimers.

  Matthias Trappeniers, Stijn Goormans, Katrien Van Beneden, Tine Decruy, Bruno Linclau, Aymen Al-Shamkhani, Tim Elliott, Christian Ottensmeier, Joern M Werner, Dirk Elewaut, Serge Van Calenbergh

  ChemMedChem. 08/2008; 3(7):1061-70.

  alpha-GalCer (also known as KRN7000) is an immunomodulatory glycolipid that is known to potently activate invariant natural killer T (NKT) cells upon CD1d-mediated stimulation. Because Th1 and Th2 cytokines, which are released after alpha-GalCer presentation, antagonize each other's effects, alp... [more] alpha-GalCer (also known as KRN7000) is an immunomodulatory glycolipid that is known to potently activate invariant natural killer T (NKT) cells upon CD1d-mediated stimulation. Because Th1 and Th2 cytokines, which are released after alpha-GalCer presentation, antagonize each other's effects, alpha-GalCer analogues that induce a biased Th1/Th2 response are highly awaited. In this context, we report the synthesis and in vitro evaluation of alpha-Gal-D-xylo-Cer and two alpha-Gal-L-lyxo-Cer analogues, one with the natural acyl chain, the other with a truncated chain.
• 5.65

  Impact points

  Invariant NKT cells promote CD8+ cytotoxic T cell responses by inducing CD70 expression on dendritic cells.

  Vadim Y Taraban, Sonya Martin, Kathrine E Attfield, Martin J Glennie, Tim Elliott, Dirk Elewaut, Serge Van Calenbergh, Bruno Linclau, Aymen Al-Shamkhani

  Journal of immunology (Baltimore, Md. : 1950). 05/2008; 180(7):4615-20.

  Activation of invariant NK T (iNKT) cells with the glycolipid alpha-galactosylceramide promotes CD8(+) cytotoxic T cell responses, a property that has been used to enhance the efficacy of antitumor vaccines. Using chimeric mice, we now show that the adjuvant properties of iNKT cells require that CD4... [more] Activation of invariant NK T (iNKT) cells with the glycolipid alpha-galactosylceramide promotes CD8(+) cytotoxic T cell responses, a property that has been used to enhance the efficacy of antitumor vaccines. Using chimeric mice, we now show that the adjuvant properties of iNKT cells require that CD40 triggering and Ag presentation to CD8(+) T cells occur on the same APCs. We demonstrate that injection of alpha-galactosylceramide triggers CD70 expression on splenic T cell zone dendritic cells and that this is dependent on CD40 signaling. Importantly, we show that blocking the interaction between CD70 and CD27, its costimulatory receptor on T cells, abrogates the ability of iNKT cells to promote a CD8(+) T cell response and abolishes the efficacy of alpha-GalCer as an adjuvant for antitumor vaccines. These results define a key role for CD70 in linking the innate response of iNKT cells to the activation of CD8(+) T cells.
• 5.50

  Impact points

  An enantioselective desymmetrisation approach to C9-substituted trans-hydrindene rings based on a diastereotopic group-selective intramolecular Diels-Alder reaction.

  Nadia Azzi, Ed Griffen, Mark Light, Bruno Linclau

  Chemical communications (Cambridge, England). 01/2007;

  The synthesis of an achiral skipped bis(1,3-diene) substrate was achieved, which was shown to undergo an enantioselective, diastereotopic group-selective, intramolecular Diels-Alder reaction.... [more] The synthesis of an achiral skipped bis(1,3-diene) substrate was achieved, which was shown to undergo an enantioselective, diastereotopic group-selective, intramolecular Diels-Alder reaction.
• 5.42

  Impact points

  Enantioselective synthesis and selective monofunctionalization of (4R,6R)-4,6- dihydroxy-2,8-dioxabicyclo[3.3.0]octane.

  Bruno Linclau, Martin J Jeffery, Solen Josse, Cyrille Tomassi

  Organic letters. 01/2007; 8(25):5821-4.

  An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol unit. [reaction: see text]... [more] An efficient, enantioselective synthesis of a disubstituted bis-THF scaffold 5 is described, as well as an efficient differentiation of the 1,3-diol unit. [reaction: see text]