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Seijiro Matsubara - One of the best experts on this subject based on the ideXlab platform.
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Catalytic Approaches to Optically Active 1,5-Benzothiazepines
2018Co-Authors: Keisuke Asano, Seijiro MatsubaraAbstract:The 1,5-benzothiazepine framework is well-known as a versatile pharmacophore, and its derivatives have numerous biological activities. Therefore, various synthetic routes to these important compounds have already been investigated. However, in light of the increase in optically active pharmaceuticals, it is of significance to also develop enantioselective synthetic methods. Among various strategies, methods based on enantioselective catalysis are generally efficient in both academia and industry with respect to different factors such as atom or step economy, economic reasons, and diversity-oriented synthesis. While various methodologies had already been investigated until the 1990s, soon after the discovery of marketed pharmaceuticals such as diltiazem, a blockbuster drug containing a 1,5-benzothiazepine unit, additional catalytic strategies also appeared. Thus, this Perspective provides an account of the progress on enantioselective catalysis for the asymmetric synthesis of 1,5-benzothiazepine derivatives.
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asymmetric net cycloaddition for access to diverse substituted 1 5 Benzothiazepines
2017Co-Authors: Yukihiro Fukata, Keisuke Asano, Koichi Yao, Ryota Miyaji, Seijiro MatsubaraAbstract:In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-Benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-Benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates.
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Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines
2017Co-Authors: Yukihiro Fukata, Keisuke Asano, Koichi Yao, Ryota Miyaji, Seijiro MatsubaraAbstract:In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-Benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-Benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates
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facile net cycloaddition approach to optically active 1 5 Benzothiazepines
2015Co-Authors: Yukihiro Fukata, Keisuke Asano, Seijiro MatsubaraAbstract:The first example of a highly enantio- and regioselective net [4 + 3] cycloaddition approach towards 1,5-Benzothiazepines is presented.
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facile net cycloaddition approach to optically active 1 5 Benzothiazepines
2015Co-Authors: Yukihiro Fukata, Keisuke Asano, Seijiro MatsubaraAbstract:The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-Benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the con...
Pál Sohár - One of the best experts on this subject based on the ideXlab platform.
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ring transformations of β lactam condensed 1 3 benzothiazines to isoquinoline and thiazole derivatives by sulfur extrusion and addition sequences
2012Co-Authors: Peter Csomos, Antal Csámpai, L Fodor, Pál SohárAbstract:The ring transformations of dichloro-β-lactam-fused 2-aryl-1,3-benzothiazines with sodium methoxide were investigated. With 2 equiv of base, the dichloro-β-lactam derivatives underwent rearrangement and dihydro-1,4-Benzothiazepines, 3,4-substituted isoquinolines and substituted thiazole disulfides were isolated. A possible reaction mechanism is proposed for the simultaneous formation of the novel products. The formation of isoquinoline and thiazole derivatives can be explained by sulfur extrusion and addition sequences.
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novel indole syntheses by ring transformation of β lactam condensed 1 3 benzothiazines into indolo 2 3 b 1 4 Benzothiazepines and indolo 3 2 c isoquinolines
2012Co-Authors: Peter Csomos, Antal Csámpai, L Fodor, Pál SohárAbstract:Abstract ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4-Benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b][1,4]Benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were obtained. The structures of the new ring systems were determined by means of NMR spectroscopy.
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expected and unexpected reactions of 1 3 benzothiazine derivatives i ring transformation of β lactam condensed 1 3 benzothiazines into 4 5 dihydro 1 4 Benzothiazepines and indolo 1 4 Benzothiazepines
2011Co-Authors: L Fodor, Peter Csomos, Antal Csámpai, Tamas Holczbauer, Alajos Kalman, Pál SohárAbstract:Abstract The ring-enlargement reactions of monochloro-β-lactam-fused 2-aryl-1,3-benzothiazines revealed that the reactions of ortho-nitro aryl-substituted derivatives with sodium methoxide in methanol provided two products, depending on the amount of the base. With 2 equiv of reagent, the expected 1,4-Benzothiazepines were obtained. Somewhat surprisingly, treatment with a large excess of sodium methoxide led to the formation of indolo-1,4-Benzothiazepines via a novel rearrangement. The structures of the new ring systems were determined by means of X-ray crystallography and NMR spectroscopy.
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A Convenient Synthesis of 1,4-Benzothiazepinesfrom 1,3-Benzothiazines via the Ring Transformation of β-Lactam-Condensed1,3-Benzothiazine Derivatives
2010Co-Authors: Lajos Fodor, Peter Csomos, Antal Csámpai, Pál SohárAbstract:A convenient synthesis was devised for rare 2,3-disubstituted 4,5-dihydro-1,4-Benzothiazepines from 2-aryl-4H-1,3-benzothiazines. The Staudinger reaction of 1,3-benzothiazines obtained with chloroacetyl chloride selectively furnished trans-monochloroβ-lactam-condensed thiazines. The ring expansion of azeto[2,1-b][1,3]benzothiazin-1-one derivatives with sodium methoxide afforded 1,4-Benzothiazepines as the sole product in good yields. The structures of the new molecules were proved by means NMR and IR spectroscopy.
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exceptional isolation of both imine and enamine desmotropes of 4 1 Benzothiazepines
2010Co-Authors: Peter Csomos, Antal Csámpai, Pál Sohár, L FodorAbstract:Abstract The desmotropy of differently substituted (R∗)-3-ethoxycarbonyl-2-aryl-3,5-dihydro-4,1-Benzothiazepines and 3-ethoxycarbonyl-2-aryl-1,5-dihydro-4,1-Benzothiazepines was investigated. The target 4,1-Benzothiazepines were obtained via the ring transformation of (2R∗,2aS∗)-2-chloro-2a-aryl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-ones with sodium ethoxide in ethanol. The β-amino ester intermediate of the ring-enlargement reaction was isolated. Surprisingly, the desmotropes obtained could be separated by column chromatography and proved to be unexpectedly stable in solution. Further comparative studies revealed the existence of only the enamine forms of regioisomeric 2-ethoxycarbonyl-3-aryl-4,5-dihydro-7,8-dimethoxy-1,4-benzothiazepine derivatives; in this case, no desmotropy occurred. The structures were proved by means of NMR and IR spectroscopy.
Peter Csomos - One of the best experts on this subject based on the ideXlab platform.
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ring transformations of β lactam condensed 1 3 benzothiazines to isoquinoline and thiazole derivatives by sulfur extrusion and addition sequences
2012Co-Authors: Peter Csomos, Antal Csámpai, L Fodor, Pál SohárAbstract:The ring transformations of dichloro-β-lactam-fused 2-aryl-1,3-benzothiazines with sodium methoxide were investigated. With 2 equiv of base, the dichloro-β-lactam derivatives underwent rearrangement and dihydro-1,4-Benzothiazepines, 3,4-substituted isoquinolines and substituted thiazole disulfides were isolated. A possible reaction mechanism is proposed for the simultaneous formation of the novel products. The formation of isoquinoline and thiazole derivatives can be explained by sulfur extrusion and addition sequences.
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novel indole syntheses by ring transformation of β lactam condensed 1 3 benzothiazines into indolo 2 3 b 1 4 Benzothiazepines and indolo 3 2 c isoquinolines
2012Co-Authors: Peter Csomos, Antal Csámpai, L Fodor, Pál SohárAbstract:Abstract ortho-Nitrophenyl-substituted condensed 1,3-benzothiazines proved to be a useful core unit in indole syntheses under non-reductive conditions. Thus, the treatment of ortho-nitro-2-aryl-2a-chloro-4H-azeto[2,1-b][1,3]benzothiazin-1-ones with sodium methoxide in methanol provided indolo-1,4-Benzothiazepines via a novel rearrangement. Through the sulfur extrusion reaction of indolo[2,3-b][1,4]Benzothiazepines, further alkaloid-type indole derivatives, indolo[3,2-c]isoquinolines, were obtained. The structures of the new ring systems were determined by means of NMR spectroscopy.
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expected and unexpected reactions of 1 3 benzothiazine derivatives i ring transformation of β lactam condensed 1 3 benzothiazines into 4 5 dihydro 1 4 Benzothiazepines and indolo 1 4 Benzothiazepines
2011Co-Authors: L Fodor, Peter Csomos, Antal Csámpai, Tamas Holczbauer, Alajos Kalman, Pál SohárAbstract:Abstract The ring-enlargement reactions of monochloro-β-lactam-fused 2-aryl-1,3-benzothiazines revealed that the reactions of ortho-nitro aryl-substituted derivatives with sodium methoxide in methanol provided two products, depending on the amount of the base. With 2 equiv of reagent, the expected 1,4-Benzothiazepines were obtained. Somewhat surprisingly, treatment with a large excess of sodium methoxide led to the formation of indolo-1,4-Benzothiazepines via a novel rearrangement. The structures of the new ring systems were determined by means of X-ray crystallography and NMR spectroscopy.
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A Convenient Synthesis of 1,4-Benzothiazepinesfrom 1,3-Benzothiazines via the Ring Transformation of β-Lactam-Condensed1,3-Benzothiazine Derivatives
2010Co-Authors: Lajos Fodor, Peter Csomos, Antal Csámpai, Pál SohárAbstract:A convenient synthesis was devised for rare 2,3-disubstituted 4,5-dihydro-1,4-Benzothiazepines from 2-aryl-4H-1,3-benzothiazines. The Staudinger reaction of 1,3-benzothiazines obtained with chloroacetyl chloride selectively furnished trans-monochloroβ-lactam-condensed thiazines. The ring expansion of azeto[2,1-b][1,3]benzothiazin-1-one derivatives with sodium methoxide afforded 1,4-Benzothiazepines as the sole product in good yields. The structures of the new molecules were proved by means NMR and IR spectroscopy.
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exceptional isolation of both imine and enamine desmotropes of 4 1 Benzothiazepines
2010Co-Authors: Peter Csomos, Antal Csámpai, Pál Sohár, L FodorAbstract:Abstract The desmotropy of differently substituted (R∗)-3-ethoxycarbonyl-2-aryl-3,5-dihydro-4,1-Benzothiazepines and 3-ethoxycarbonyl-2-aryl-1,5-dihydro-4,1-Benzothiazepines was investigated. The target 4,1-Benzothiazepines were obtained via the ring transformation of (2R∗,2aS∗)-2-chloro-2a-aryl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-ones with sodium ethoxide in ethanol. The β-amino ester intermediate of the ring-enlargement reaction was isolated. Surprisingly, the desmotropes obtained could be separated by column chromatography and proved to be unexpectedly stable in solution. Further comparative studies revealed the existence of only the enamine forms of regioisomeric 2-ethoxycarbonyl-3-aryl-4,5-dihydro-7,8-dimethoxy-1,4-benzothiazepine derivatives; in this case, no desmotropy occurred. The structures were proved by means of NMR and IR spectroscopy.
Balasubramanian Narasimhan - One of the best experts on this subject based on the ideXlab platform.
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synthesis characterization biological evaluation and qsar studies of 11 p substituted phenyl 12 phenyl 11a 12 dihydro 11h indeno 2 1 c 1 5 Benzothiazepines as potential antimicrobial agents
2013Co-Authors: Satbir Mor, Preeti Pahal, Balasubramanian NarasimhanAbstract:The condensation reaction of (E)-benzylideneindanones (I) with o-aminobenzenethiols (II) proceeds diastereoselectively to furnish novel title benzothiazepine derivatives (III) (16 examples) as single diastereoisomers.
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synthesis characterization biological evaluation and qsar studies of 11 p substituted phenyl 12 phenyl 11a 12 dihydro 11h indeno 2 1 c 1 5 Benzothiazepines as potential antimicrobial agents
2012Co-Authors: Satbir Mor, Preeti Pahal, Balasubramanian NarasimhanAbstract:A novel series of 11-p-substituted phenyl-12-phenyl-11a,12-dihydro-11H-indeno[2,1-c][1,5]Benzothiazepines (3) has been synthesized and screened for their antimicrobial activity against Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria and fungi (Aspergillus fumigates and Candida albicans). The antimicrobial evaluation data indicated that the compounds, 3d, 3g, 3h, 3k-3p exhibited very promising antibacterial activity and the derivatives 3k, 3l, 3o and 3p exhibited high antifungal activity. The QSAR studies carried out to find out the correlation between the antimicrobial activity and physicochemical properties of synthesized Benzothiazepines (3) indicated the predominance of electronic parameters in describing their antimicrobial activity.
Keisuke Asano - One of the best experts on this subject based on the ideXlab platform.
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Catalytic Approaches to Optically Active 1,5-Benzothiazepines
2018Co-Authors: Keisuke Asano, Seijiro MatsubaraAbstract:The 1,5-benzothiazepine framework is well-known as a versatile pharmacophore, and its derivatives have numerous biological activities. Therefore, various synthetic routes to these important compounds have already been investigated. However, in light of the increase in optically active pharmaceuticals, it is of significance to also develop enantioselective synthetic methods. Among various strategies, methods based on enantioselective catalysis are generally efficient in both academia and industry with respect to different factors such as atom or step economy, economic reasons, and diversity-oriented synthesis. While various methodologies had already been investigated until the 1990s, soon after the discovery of marketed pharmaceuticals such as diltiazem, a blockbuster drug containing a 1,5-benzothiazepine unit, additional catalytic strategies also appeared. Thus, this Perspective provides an account of the progress on enantioselective catalysis for the asymmetric synthesis of 1,5-benzothiazepine derivatives.
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asymmetric net cycloaddition for access to diverse substituted 1 5 Benzothiazepines
2017Co-Authors: Yukihiro Fukata, Keisuke Asano, Koichi Yao, Ryota Miyaji, Seijiro MatsubaraAbstract:In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-Benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-Benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates.
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Asymmetric Net Cycloaddition for Access to Diverse Substituted 1,5-Benzothiazepines
2017Co-Authors: Yukihiro Fukata, Keisuke Asano, Koichi Yao, Ryota Miyaji, Seijiro MatsubaraAbstract:In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-Benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-Benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates
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facile net cycloaddition approach to optically active 1 5 Benzothiazepines
2015Co-Authors: Yukihiro Fukata, Keisuke Asano, Seijiro MatsubaraAbstract:The first example of a highly enantio- and regioselective net [4 + 3] cycloaddition approach towards 1,5-Benzothiazepines is presented.
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facile net cycloaddition approach to optically active 1 5 Benzothiazepines
2015Co-Authors: Yukihiro Fukata, Keisuke Asano, Seijiro MatsubaraAbstract:The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-Benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the con...