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Sergio Cossu - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-Bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-Bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-Bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-Bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-Bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-Bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-Bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-Bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-Bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-Bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-Bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
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Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4 `-Bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions
Journal of Chromatography A, 2014Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5'-dihalo-4,4'-Bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, alpha, R-s) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (IO) could reasonably explain the high enantioseparation (alpha = 1.80, R-s = 8.2) observed for the 2,2'-dichloro-3,5'-diiodo-5-bromo-4,4'-Bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro-5,5'-dibromo-4,4'-Bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration.
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Optimization of the HPLC enantioseparation of 3,3 `-dibromo-5,5 `-disubstituted-4,4 `-Bipyridines using immobilized polysaccharide-based chiral stationary phases
Journal of Separation Science, 2013Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:The HPLC enantioseparation of nine atropisomeric 3,3',5,5'-tetrasubstituted-4,4'-Bipyridines was performed in normal and polar organic (PO) phase modes using two immobilized polysaccharide-based chiral columns, namely, Chiralpak IA and Chiralpak IC. The separation of all racemic analytes, the effect of the chiral selector, and mobile phase (MP) composition on enantioseparation and the enantiomer elution order (EEO) were studied. The beneficial effect of nonstandard solvents, such as tetrahydrofuran (THF), dichloromethane (DCM), and methyl t-butyl ether on enantioseparation was investigated. All selected 4,4'-Bipyridines were successfully enantioseparated on Chiralpak IA under normal or PO MPs with separation factors from 1.14 to 1.70 and resolutions from 1.3 to 6.5. Two Bipyridines were enantioseparated at the multimilligram level on Chiralpak IA. Differently, Chiralpak IC was less versatile toward the considered class of compounds and only five Bipyridines out of nine could be efficiently separated. In particular, on these columns, the ternary mixture n-heptane/THF/DCM (90: 5: 5) as MP had a positive effect on enantioseparation. An interesting phenomenon of reversal of the EEO depending on the composition of the MP for the 3,3'-dibromo-5,5'-bis-(E)-phenylethenyl-4,4'-Bipyridine along with an exceptional enantioseparation for the 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-Bipyridine (alpha = 8.33, R-s = 30.6) were observed on Chiralpak IC.
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Lithiation of Prochiral 2,2 `-Dichloro-5,5 `-dibromo-4,4 `-Bipyridine as a Tool for the Synthesis of Chiral Polyhalogenated 4,4 `-Bipyridines
Journal of Organic Chemistry, 2013Co-Authors: Victor Mamane, Emmanuel Aubert, Paola Peluso, Sergio CossuAbstract:Lithiation of the achiral tetrahalogenated 4,4'-Bipyridine 1 with alkyllithiums was investigated. n-BuLi was found to induce either the chlorine-directed deprotolithiation reaction alone or with a concomitant halogen-lithium exchange furnishing after iodine trapping chiral 4,4'-Bipyridines 2 and 6, respectively. The role of n-BuLi in the deprotolithiation process of 1 was elucidated on the basis of isolated secondary derivatives. After deprotolithiation, the lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R3SnCl (R = Me or n-Bu), and PPh2Cl. Moreover, 4,4'-Bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred selectively at the carbon-iodine bond. All compounds of this new family of atropisomeric 4,4'-Bipyridines were separated by chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly assigned by XRD (X-ray diffraction) using anomalous dispersion.
Victor Mamane - One of the best experts on this subject based on the ideXlab platform.
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Functionalized 4,4'-Bipyridines: synthesis and 2D-organization on HOPG
Journal of Organic Chemistry, 2021Co-Authors: Jimmy Richard, Victor Mamane, Jean Joseph, Can Wang, Artur Ciesielski, Jean Weiss, Paolo Samorì, Jennifer WytkoAbstract:Commercial 4,4'-Bipyridine is a popular scaffold which is primarily employed as a linker in 3D self-assembled architectures such as metallo-organic frameworks or as connector in 2D networks. The introduction of alkyl substituents on the Bipyridine skeleton is instrumental when 4,4'-Bipyridines are used as linkers to form 2D self-assembled patterns on surfaces. Here, various synthetic strategies to access 4,4'-Bipyridines functionalized at various positions are described. These easily scalable reactions have been used to introduce a range of alkyl substituents at positions 2 and 2', or 3 and 3' and at positions 2,2' and 6,6' in the case of tetra-functionalization. Scanning tunneling microscopy studies of molecular monolayers physisorbed at the graphite-solution interface revealed different supramolecular patterns whose motifs are primarily dictated by the nature and position of the alkyl chains.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-Bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-Bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-Bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-Bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-Bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-Bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-Bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-Bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-Bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-Bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-Bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
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Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4 `-Bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions
Journal of Chromatography A, 2014Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5'-dihalo-4,4'-Bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, alpha, R-s) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (IO) could reasonably explain the high enantioseparation (alpha = 1.80, R-s = 8.2) observed for the 2,2'-dichloro-3,5'-diiodo-5-bromo-4,4'-Bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro-5,5'-dibromo-4,4'-Bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration.
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Optimization of the HPLC enantioseparation of 3,3 `-dibromo-5,5 `-disubstituted-4,4 `-Bipyridines using immobilized polysaccharide-based chiral stationary phases
Journal of Separation Science, 2013Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:The HPLC enantioseparation of nine atropisomeric 3,3',5,5'-tetrasubstituted-4,4'-Bipyridines was performed in normal and polar organic (PO) phase modes using two immobilized polysaccharide-based chiral columns, namely, Chiralpak IA and Chiralpak IC. The separation of all racemic analytes, the effect of the chiral selector, and mobile phase (MP) composition on enantioseparation and the enantiomer elution order (EEO) were studied. The beneficial effect of nonstandard solvents, such as tetrahydrofuran (THF), dichloromethane (DCM), and methyl t-butyl ether on enantioseparation was investigated. All selected 4,4'-Bipyridines were successfully enantioseparated on Chiralpak IA under normal or PO MPs with separation factors from 1.14 to 1.70 and resolutions from 1.3 to 6.5. Two Bipyridines were enantioseparated at the multimilligram level on Chiralpak IA. Differently, Chiralpak IC was less versatile toward the considered class of compounds and only five Bipyridines out of nine could be efficiently separated. In particular, on these columns, the ternary mixture n-heptane/THF/DCM (90: 5: 5) as MP had a positive effect on enantioseparation. An interesting phenomenon of reversal of the EEO depending on the composition of the MP for the 3,3'-dibromo-5,5'-bis-(E)-phenylethenyl-4,4'-Bipyridine along with an exceptional enantioseparation for the 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-Bipyridine (alpha = 8.33, R-s = 30.6) were observed on Chiralpak IC.
Emmanuel Aubert - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-Bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-Bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-Bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-Bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-Bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-Bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-Bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-Bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-Bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-Bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-Bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
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Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4 `-Bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions
Journal of Chromatography A, 2014Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5'-dihalo-4,4'-Bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, alpha, R-s) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (IO) could reasonably explain the high enantioseparation (alpha = 1.80, R-s = 8.2) observed for the 2,2'-dichloro-3,5'-diiodo-5-bromo-4,4'-Bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro-5,5'-dibromo-4,4'-Bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration.
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Optimization of the HPLC enantioseparation of 3,3 `-dibromo-5,5 `-disubstituted-4,4 `-Bipyridines using immobilized polysaccharide-based chiral stationary phases
Journal of Separation Science, 2013Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:The HPLC enantioseparation of nine atropisomeric 3,3',5,5'-tetrasubstituted-4,4'-Bipyridines was performed in normal and polar organic (PO) phase modes using two immobilized polysaccharide-based chiral columns, namely, Chiralpak IA and Chiralpak IC. The separation of all racemic analytes, the effect of the chiral selector, and mobile phase (MP) composition on enantioseparation and the enantiomer elution order (EEO) were studied. The beneficial effect of nonstandard solvents, such as tetrahydrofuran (THF), dichloromethane (DCM), and methyl t-butyl ether on enantioseparation was investigated. All selected 4,4'-Bipyridines were successfully enantioseparated on Chiralpak IA under normal or PO MPs with separation factors from 1.14 to 1.70 and resolutions from 1.3 to 6.5. Two Bipyridines were enantioseparated at the multimilligram level on Chiralpak IA. Differently, Chiralpak IC was less versatile toward the considered class of compounds and only five Bipyridines out of nine could be efficiently separated. In particular, on these columns, the ternary mixture n-heptane/THF/DCM (90: 5: 5) as MP had a positive effect on enantioseparation. An interesting phenomenon of reversal of the EEO depending on the composition of the MP for the 3,3'-dibromo-5,5'-bis-(E)-phenylethenyl-4,4'-Bipyridine along with an exceptional enantioseparation for the 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-Bipyridine (alpha = 8.33, R-s = 30.6) were observed on Chiralpak IC.
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Lithiation of Prochiral 2,2 `-Dichloro-5,5 `-dibromo-4,4 `-Bipyridine as a Tool for the Synthesis of Chiral Polyhalogenated 4,4 `-Bipyridines
Journal of Organic Chemistry, 2013Co-Authors: Victor Mamane, Emmanuel Aubert, Paola Peluso, Sergio CossuAbstract:Lithiation of the achiral tetrahalogenated 4,4'-Bipyridine 1 with alkyllithiums was investigated. n-BuLi was found to induce either the chlorine-directed deprotolithiation reaction alone or with a concomitant halogen-lithium exchange furnishing after iodine trapping chiral 4,4'-Bipyridines 2 and 6, respectively. The role of n-BuLi in the deprotolithiation process of 1 was elucidated on the basis of isolated secondary derivatives. After deprotolithiation, the lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R3SnCl (R = Me or n-Bu), and PPh2Cl. Moreover, 4,4'-Bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred selectively at the carbon-iodine bond. All compounds of this new family of atropisomeric 4,4'-Bipyridines were separated by chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly assigned by XRD (X-ray diffraction) using anomalous dispersion.
Paola Peluso - One of the best experts on this subject based on the ideXlab platform.
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Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors
Molecules, 2020Co-Authors: Alessandro Dessì, Emmanuel Aubert, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, Mariateresa Allocca, Patrick Pale, Victor Mamane, Sergio CossuAbstract:The 3,3 ,5,5-tetrachloro-2-iodo-4,4-Bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-Bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-Bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-Bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-Bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-Bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-Bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Chiral Hexahalogenated 4,4′-Bipyridines
The Journal of organic chemistry, 2016Co-Authors: Victor Mamane, Emmanuel Aubert, Sergio Cossu, Paola Peluso, Patrick PaleAbstract:The preparation of 27 isomers of chiral hexahalogeno-4,4′-Bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-Bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-Bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-Bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.
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Insights into the impact of shape and electronic properties on the enantioseparation of polyhalogenated 4,4 `-Bipyridines on polysaccharide-type selectors. Evidence of stereoselective halogen bonding interactions
Journal of Chromatography A, 2014Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:Starting from the high-performance liquid chromatography (HPLC) enantioseparation data collected by using twelve polyhalogenated 2,2'-dichloro-3-substituted-5,5'-dihalo-4,4'-Bipyridines as test probes on seven polysaccharide-based chiral stationary phases (CSPs) under multimodal elution, the impact of substitution pattern, shape and electronic properties of the molecules on the separation behaviour was investigated through the evaluation of the chromatographic parameters (k, alpha, R-s) and molecular properties determined by means of quantum chemistry calculations. The computational/chromatographic screening furnished relevant structure-chromatographic behaviour relationships and some molecular interactions involved in the chiral discrimination process could be identified. In particular, a halogen bonding interaction (IO) could reasonably explain the high enantioseparation (alpha = 1.80, R-s = 8.2) observed for the 2,2'-dichloro-3,5'-diiodo-5-bromo-4,4'-Bipyridine on Lux Cellulose-1. To the best of our knowledge, this is the first report supporting the involvement of a stereoselective halogen bonding interaction in polysaccharide-based CSPs. Moreover, having at disposal a sufficient set of data, the unknown absolute configurations of the eluted enantiomers of 3-methyl-, 3-thiomethyl- and 3-diphenylphosphinoyl-2,2'-dichloro-5,5'-dibromo-4,4'-Bipyridines could be deduced by chromatographic correlation with the enantiomer elution order (EEO) of the related compounds of known absolute configuration.
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Optimization of the HPLC enantioseparation of 3,3 `-dibromo-5,5 `-disubstituted-4,4 `-Bipyridines using immobilized polysaccharide-based chiral stationary phases
Journal of Separation Science, 2013Co-Authors: Paola Peluso, Emmanuel Aubert, Victor Mamane, Sergio CossuAbstract:The HPLC enantioseparation of nine atropisomeric 3,3',5,5'-tetrasubstituted-4,4'-Bipyridines was performed in normal and polar organic (PO) phase modes using two immobilized polysaccharide-based chiral columns, namely, Chiralpak IA and Chiralpak IC. The separation of all racemic analytes, the effect of the chiral selector, and mobile phase (MP) composition on enantioseparation and the enantiomer elution order (EEO) were studied. The beneficial effect of nonstandard solvents, such as tetrahydrofuran (THF), dichloromethane (DCM), and methyl t-butyl ether on enantioseparation was investigated. All selected 4,4'-Bipyridines were successfully enantioseparated on Chiralpak IA under normal or PO MPs with separation factors from 1.14 to 1.70 and resolutions from 1.3 to 6.5. Two Bipyridines were enantioseparated at the multimilligram level on Chiralpak IA. Differently, Chiralpak IC was less versatile toward the considered class of compounds and only five Bipyridines out of nine could be efficiently separated. In particular, on these columns, the ternary mixture n-heptane/THF/DCM (90: 5: 5) as MP had a positive effect on enantioseparation. An interesting phenomenon of reversal of the EEO depending on the composition of the MP for the 3,3'-dibromo-5,5'-bis-(E)-phenylethenyl-4,4'-Bipyridine along with an exceptional enantioseparation for the 3,3'-dibromo-5,5'-bis-ferrocenylethynyl-4,4'-Bipyridine (alpha = 8.33, R-s = 30.6) were observed on Chiralpak IC.
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Lithiation of Prochiral 2,2 `-Dichloro-5,5 `-dibromo-4,4 `-Bipyridine as a Tool for the Synthesis of Chiral Polyhalogenated 4,4 `-Bipyridines
Journal of Organic Chemistry, 2013Co-Authors: Victor Mamane, Emmanuel Aubert, Paola Peluso, Sergio CossuAbstract:Lithiation of the achiral tetrahalogenated 4,4'-Bipyridine 1 with alkyllithiums was investigated. n-BuLi was found to induce either the chlorine-directed deprotolithiation reaction alone or with a concomitant halogen-lithium exchange furnishing after iodine trapping chiral 4,4'-Bipyridines 2 and 6, respectively. The role of n-BuLi in the deprotolithiation process of 1 was elucidated on the basis of isolated secondary derivatives. After deprotolithiation, the lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R3SnCl (R = Me or n-Bu), and PPh2Cl. Moreover, 4,4'-Bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred selectively at the carbon-iodine bond. All compounds of this new family of atropisomeric 4,4'-Bipyridines were separated by chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly assigned by XRD (X-ray diffraction) using anomalous dispersion.
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Organic Syntheses - Discussion Addendum for:Efficient Synthesis of Halomethyl‐2,2'‐Bipyridines: 4,4'‐Bis(Chloromethyl)‐2,2'‐Bipyridine
Organic Syntheses, 2014Co-Authors: Tiandong Liu, Cassandra L. FraserAbstract:Halogenation of dimethyl-2, 2 -Bipyridines via trimethylsilyl (TMS) intermediates and electrophilic halide reagents, CX3CX3 (X = Cl, Br or F), is a very useful method for Bipyridine (bpy) derivation. 2-4 This approach benefits from nearly quantitative yields, few by-products, and low cost reagents. In the past decade, there have been only a few improvements reported for this reaction, but many Bipyridine derivatives have been prepared using this method. Many Bipyridine analogues have been accessed via TMS-bpy intermediates.
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Organic Syntheses - Efficient Synthesis of Halomethyl‐2,2′‐Bipyridines: 4,4′‐Bis(Chloromethyl)‐2,2′‐Bipyridine
Organic Syntheses, 2003Co-Authors: Adam P. Smith, Jaydeep J. S. Lamba, Cassandra L. FraserAbstract:4, 4′-Bis(chloromethyl)2, 2′-Bipyridine R 4, 4′-Dimethyl-2, 2′-Bipyridine I 4, 4′-Bis[trimethylsilyl) methyl]-2, 2′ bepyridine P 4, 4′-Bis[chloromethyl)2, 2′-Bipyridine Keywords: heterocycles, six-membered, one nitrogen; organometallic compounds, silicon; metalation reactions, silicon; replacement reactions, miscellaneous; heterocycles, six-membered, one nitrogen; halogen compounds, chloro compounds; methylpyridines, selective monohalogenation
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An improved synthesis of hydroxymethyl Bipyridines
Tetrahedron Letters, 2000Co-Authors: Adam P. Smith, Perry S. Corbin, Cassandra L. FraserAbstract:Abstract This account describes quick and efficient syntheses of 4,4′-bis(hydroxymethyl)-2,2′-Bipyridine and 4-hydroxymethyl-2,2′-Bipyridine from 4,4′-dimethyl-2,2′-Bipyridine and 4-methyl-2,2′-Bipyridine, respectively, via (trimethylsilyl)methyl-, bromomethyl-, and acetoxymethyl- intermediates.
