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Florence Mongin - One of the best experts on this subject based on the ideXlab platform.
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Polar [3 + 2] cycloaddition of ketones with electrophilically activated carbonyl ylides. Synthesis of spirocyclic Dioxolane indolinones.
Organic and Biomolecular Chemistry, 2008Co-Authors: Ghenia Bentabed-ababsa, Thierry Roisnel, Aicha Derdour, Jose A Sáez, Luis R Domingo, Florence MonginAbstract:The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted Dioxolanes and spirocyclic Dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained.
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polar 3 2 cycloaddition of ketones with electrophilically activated carbonyl ylides synthesis of spirocyclic Dioxolane indolinones
Organic and Biomolecular Chemistry, 2008Co-Authors: Ghenia Bentabedababsa, Thierry Roisnel, Aicha Derdour, Jose A Sáez, Luis R Domingo, Florence MonginAbstract:The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted Dioxolanes and spirocyclic Dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained.
Patrick H. Dussault - One of the best experts on this subject based on the ideXlab platform.
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3 alkoxy 1 2 Dioxolanes synthesis and evaluation as potential antimalarial agents
ACS Medicinal Chemistry Letters, 2011Co-Authors: Charles E Schiaffo, Matthias Rottman, Sergio Wittlin, Patrick H. DussaultAbstract:A number of 3-alkoxy-1,2-Dioxolanes exhibit promising levels of antimalarial activity against Plasmodium falciparum. A new route to the 1,2-Dioxolane core is reported based on tandem peroxidation/cyclization of enones.
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asymmetric synthesis of 1 2 Dioxolane 3 acetic acids synthesis and configurational assignment of plakinic acid a
Journal of Organic Chemistry, 2006Co-Authors: Peng Dai, Tony K Trullinger, Xuejun Liu, Patrick H. DussaultAbstract:The first asymmetric synthesis of 1,2-Dioxolane-3-acetic acids is reported. Key features include the stereoselective opening of enantiomerically enriched oxetanes by hydrogen peroxide, conversion of the resulting 4-hydroperoxy-2-alkanols to 3-alkoxy-1,2-Dioxolanes, and Lewis acid mediated homologation of the latter with a thioester silyl ketene acetal. The approach is modeled on 3,5-dimethyl-5-hexadecyl-1,2-Dioxolane-3-acetic acid (1a), an unnamed natural product, and an optimized strategy is applied to the synthesis of four stereoisomers of plakinic acid A (2), allowing a configurational assignment of this incompletely characterized natural product.
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Lewis acid-mediated displacements of alkoxyDioxolanes: synthesis of a 1,2-Dioxolane natural product.
Organic Letters, 1999Co-Authors: Patrick H. DussaultAbstract:Addition of electron-rich alkenes to the peroxycarbenium ions derived from Lewis acid-mediated ionization of 3-alkoxy-1,2-Dioxolanes provides an efficient route for the synthesis of substituted 1,2-Dioxolanes. The methodology is illustrated with a rapid synthesis of a 1,2-Dioxolane natural product related to the plakinic acids.
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Reaction of 1O2 with alkoxyallylstannanes: Synthesis of 1,2-Dioxolanes and allyl hydroperoxides
Tetrahedron Letters, 1995Co-Authors: Patrick H. Dussault, U. R. ZopeAbstract:Abstract The reaction of 1 O 2 with chiral alkoxyallylstannanes provides a new route for the stereoselective synthesis of 1,2-Dioxolanes and allyl hydroperoxides. Dioxolane formation, which proceeds through ring opening of the intermediate perepoxide upon migration of the stannyl group, is shown to be favored by the presence of an electron-donating group and by steric factors suppressing the more typical H-ene reaction.
Bernhard Wunsch - One of the best experts on this subject based on the ideXlab platform.
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synthesis and sar studies of chiral non racemic dexoxadrol analogues as uncompetitive nmda receptor antagonists
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Ashutosh Banerjee, Dirk Schepmann, Jens Kohler, Ernstulrich Wurthwein, Bernhard WunschAbstract:A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having ( S )-configuration at the 2-position of the piperidine ring and 4-position of the Dioxolane ring were considered. Key steps in the synthesis were an imino-Diels–Alder reaction of enantiomerically pure imine ( S )- 13 , which had been obtained from d -mannitol, with Danishefsky’s Diene 14 and the replacement of the p -methoxybenzyl protective group with a Cbz-group. It was shown that ( S , S )-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the Dioxolane ring) and axial orientation of the C-4-substituent ((4 S )-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety (( S , S , S )- 5 , K i = 28 nM), a fluorine atom (( S , S , S )- 6 , WMS-2539, K i = 7 nM) and two fluorine atoms (( S , S )- 7 , K i = 48 nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ 1 and σ 2 receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity.
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Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.
Current Topics in Medicinal Chemistry, 2006Co-Authors: Bernhard WunschAbstract:: In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both Dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-Dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.
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Preparation of Chiral 2-(2-Bromobenzyl)-1,3-Dioxolanes and Their Addition to Acylimines
European Journal of Organic Chemistry, 1998Co-Authors: Bernhard Wunsch, Sven NerdingerAbstract:A series of enantiomerically pure 2-(2-bromobenzyl)-1,3-Dioxolanes 10 has been prepared by transacetalization of the dimethyl acetal 8 or the enol ether 7 with enantiomerically pure C2 symmetric 1,2-diols. We investigated the ability of the chiral 1,3-Dioxolane moiety to control the diastereoselectivity during the addition of the aryllithium intermediates 18 to the acylimines 17. Those reactive aryllithium species were generated by bromine/lithium exchange at the bromo acetals 10. In this series the best diastereoselectivity was obtained by addition of the aryllithium intermediate 18b to the acylimine 17a to yield the diastereomeric addition products 19c/20c in a ratio of 72:28. After separation, the main diastereomer 19c was cyclized to afford the dihydroisoquinoline (R)-21, which was then hydrogenated to give the NMDA antagonistic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (R)-2. The chiral auxiliary, the diol 9b, cleaved during the cylization of 19c, could be recovered in 89% yield.
Thierry Roisnel - One of the best experts on this subject based on the ideXlab platform.
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Reaction between ferrocene-carboxaldehyde and dioxaphospholene: Characterization and crystal structures of an unexpected bisferrocenylDioxolane
Journal of Organometallic Chemistry, 2013Co-Authors: Guillermo Ahumada, Thierry Roisnel, Carolina Manzur, David Carrillo, Jean-rené HamonAbstract:Reacting an 1:1 stoichiometric molar ratio of ferrocenecarboxaldehyde and 2,2,2-trimethoxy-4,5-dimethyl-1,3,2-dioxaphospholene, neat, at room temperature for one week, leads to the diastereoselective formation of a bis-ferrocenyl 1,3-Dioxolane complex 1-(4-methyl-2,5-diferrocenyl-1,3-dioxolan-4-yl)ethanone (1), in 30% isolated yield. The compound has been fully characterized by FT-IR, mono- and two-dimensional 1H and 13C NMR spectroscopy, elemental analysis, and cyclic voltammetry. Complex 1 has also been characterized by single crystal X-ray analysis.
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Polar [3 + 2] cycloaddition of ketones with electrophilically activated carbonyl ylides. Synthesis of spirocyclic Dioxolane indolinones.
Organic and Biomolecular Chemistry, 2008Co-Authors: Ghenia Bentabed-ababsa, Thierry Roisnel, Aicha Derdour, Jose A Sáez, Luis R Domingo, Florence MonginAbstract:The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted Dioxolanes and spirocyclic Dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained.
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polar 3 2 cycloaddition of ketones with electrophilically activated carbonyl ylides synthesis of spirocyclic Dioxolane indolinones
Organic and Biomolecular Chemistry, 2008Co-Authors: Ghenia Bentabedababsa, Thierry Roisnel, Aicha Derdour, Jose A Sáez, Luis R Domingo, Florence MonginAbstract:The [3 + 2] cycloaddition reaction between carbonyl ylides generated from epoxides and ketones (ethyl pyruvate, ethyl phenylglyoxylate, isatin, N-methylisatin and 5-chloroisatin) to give substituted Dioxolanes and spirocyclic Dioxolane indolinones was investigated. The effect of microwave irradiation on the outcome of the reaction was studied. The thermal reaction between 2,2-dicyano-3-phenyloxirane and N-methylisatin was theoretically studied using DFT methods. This reaction is a domino process that comprises two steps. The first is the thermal ring opening of the epoxide to yield a carbonyl ylide intermediate, whereas the second step is a polar [3 + 2] cycloaddition to yield the final spiro cycloadducts. The cycloaddition presents a low stereoselectivity and a large regio- and chemoselectivity. Analysis of the electrophilicity values and the Fukui functions of the reagents involved in the cycloaddition step allowed the chemical outcome to be explained.
Sergio Wittlin - One of the best experts on this subject based on the ideXlab platform.
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comparative antimalarial activities and adme profiles of ozonides 1 2 4 trioxolanes oz277 oz439 and their 1 2 Dioxolane 1 2 4 trioxane and 1 2 4 5 tetraoxane isosteres
Journal of Medicinal Chemistry, 2013Co-Authors: Xiaofang Wang, Yuxiang Dong, Jacques Chollet, Sergio Wittlin, Susan A. Charman, Francis C K Chiu, Kasiram Katneni, Janne MannilaAbstract:To ascertain the structure–activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-Dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both Dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
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3 alkoxy 1 2 Dioxolanes synthesis and evaluation as potential antimalarial agents
ACS Medicinal Chemistry Letters, 2011Co-Authors: Charles E Schiaffo, Matthias Rottman, Sergio Wittlin, Patrick H. DussaultAbstract:A number of 3-alkoxy-1,2-Dioxolanes exhibit promising levels of antimalarial activity against Plasmodium falciparum. A new route to the 1,2-Dioxolane core is reported based on tandem peroxidation/cyclization of enones.
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spiro and dispiro 1 2 Dioxolanes contribution of iron ii mediated one electron vs two electron reduction to the activity of antimalarial peroxides
Journal of Medicinal Chemistry, 2007Co-Authors: Xiaofang Wang, Josefina Santo Tomas, Yuxiang Dong, Christopher Snyder, Jacques Chollet, Christian Scheurer, Sergio Wittlin, Darren J. Creek, Susan A. Charman, Jonathan L. VennerstromAbstract:Fourteen spiro- and dispiro-1,2-Dioxolanes were synthesized by peroxycarbenium ion annulations with alkenes in yields ranging from 30% to 94%. Peroxycarbenium ion precursors included triethylsilyldiperoxyketals and -acetals derived from geminal dihydroperoxides and from a new method employing triethylsilylperoxyketals and -acetals derived from ozonolysis of alkenes. The 1,2-Dioxolanes were either inactive or orders of magnitude less potent than the corresponding 1,2,4-trioxolanes or artemisinin against P. falciparum in vitro and P. berghei in vivo. In reactions with iron(II), the predominant reaction course for 1,2-Dioxolane 3a was two-electron reduction. In contrast, the corresponding 1,2,4-trioxolane 1 and the 1,2,4-trioxane artemisinin undergo primarily one-electron iron(II)-mediated reductions. The key structural element in the latter peroxides appears to be an oxygen atom attached to one or both of the peroxide-bearing carbon atoms that permits rapid β-scission reactions (or H shifts) to form primary...
