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Wolfgang Kreis - One of the best experts on this subject based on the ideXlab platform.
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progesterone 5β reductases iridoid synthases prise gatekeeper role of highly conserved phenylalanines in substrate preference and trapping is supported by molecular dynamics simulations
Journal of Biomolecular Structure & Dynamics, 2016Co-Authors: Jan Petersen, Harald Lanig, Jennifer Munkert, Peter Bauer, Frieder Mulleruri, Wolfgang KreisAbstract:Vein Patterning 1 (VEP1)-encoded progesterone 5β-reductases/iridoid synthases (PRISE) belong to the short-chain dehydrogenase/reductase superfamily of proteins. They are characterized by a set of highly conserved amino acids in the substrate-binding pocket. All PRISEs are capable of reducing the activated C=C double bond of various Enones enantioselectively and therefore have a potential as biocatalysts in bioorganic synthesis. Here, recombinant forms of PRISEs of Arabidopsis thaliana and Digitalis lanata were modified using site-directed mutagenesis (SDM). In rDlP5βR, a set of highly conserved amino acids in the vicinity of the catalytic center was individually substituted for alanine resulting in considerable to complete loss of Enone reductase activity. F153 and F343, which can be found in most PRISEs known, are located at the outer rim of the catalytic cavity and seem to be involved in substrate binding and their role was addressed in a series of SDM experiments. The wild-type PRISE accepted progesterone (large hydrophobic 1,4-Enone) as well as 2-cyclohexen-1-one (small hydrophilic 1,4-Enone), whereas the double mutant rAtP5βR_F153A_F343A converted progesterone much better than the wild-type enzyme but almost lost its capability of reducing 2-cyclohexen-1-one. Recombinant Draba aizoides P5βR (rDaP5βR) has a second pair of phenylalanines at position 156 and 345 at the rim of the binding site. These two phenylalanines were introduced into rAtP5βR_F153A_F343A and the resulting quadruple mutant rAtP5βR_F153A_F343A_V156F_V345F partly recovered the ability to reduce 2-cyclohexen-1-one. These results can best be explained by assuming a trapping mechanism in which phenylalanines at the rim of the substrate-binding pocket are involved. The dynamic behavior of individual P5βRs and mutants thereof was investigated by molecular dynamics simulations and all calculations supported the 'gatekeeper' role of phenylalanines at the periphery of the substrate-binding pocket. Our findings provide structural and mechanistic explanations for the different substrate preferences seen among the natural PRISEs and help to explain the large differences in catalytic efficiency found for different types of 1,4-Enones.
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Progesterone 5β-reductases/iridoid synthases (PRISE): gatekeeper role of highly conserved phenylalanines in substrate preference and trapping is supported by molecular dynamics simulations
2015Co-Authors: Jan Petersen, Harald Lanig, Jennifer Munkert, Peter Bauer, Frieder Müller-uri, Wolfgang KreisAbstract:Vein Patterning 1 (VEP1)-encoded progesterone 5β-reductases/iridoid synthases (PRISE) belong to the short-chain dehydrogenase/reductase superfamily of proteins. They are characterized by a set of highly conserved amino acids in the substrate-binding pocket. All PRISEs are capable of reducing the activated C=C double bond of various Enones enantioselectively and therefore have a potential as biocatalysts in bioorganic synthesis. Here, recombinant forms of PRISEs of Arabidopsis thaliana and Digitalis lanata were modified using site-directed mutagenesis (SDM). In rDlP5βR, a set of highly conserved amino acids in the vicinity of the catalytic center was individually substituted for alanine resulting in considerable to complete loss of Enone reductase activity. F153 and F343, which can be found in most PRISEs known, are located at the outer rim of the catalytic cavity and seem to be involved in substrate binding and their role was addressed in a series of SDM experiments. The wild-type PRISE accepted progesterone (large hydrophobic 1,4-Enone) as well as 2-cyclohexen-1-one (small hydrophilic 1,4-Enone), whereas the double mutant rAtP5βR_F153A_F343A converted progesterone much better than the wild-type enzyme but almost lost its capability of reducing 2-cyclohexen-1-one. Recombinant Draba aizoides P5βR (rDaP5βR) has a second pair of phenylalanines at position 156 and 345 at the rim of the binding site. These two phenylalanines were introduced into rAtP5βR_F153A_F343A and the resulting quadruple mutant rAtP5βR_F153A_F343A_V156F_V345F partly recovered the ability to reduce 2-cyclohexen-1-one. These results can best be explained by assuming a trapping mechanism in which phenylalanines at the rim of the substrate-binding pocket are involved. The dynamic behavior of individual P5βRs and mutants thereof was investigated by molecular dynamics simulations and all calculations supported the ‘gatekeeper’ role of phenylalanines at the periphery of the substrate-binding pocket. Our findings provide structural and mechanistic explanations for the different substrate preferences seen among the natural PRISEs and help to explain the large differences in catalytic efficiency found for different types of 1,4-Enones.
Asit K Chakraborti - One of the best experts on this subject based on the ideXlab platform.
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fluoroboric acid adsorbed on silica gel hbf4 sio2 as a new highly efficient and reusable heterogeneous catalyst for thia michael addition to α β unsaturated carbonyl compounds
Tetrahedron Letters, 2008Co-Authors: Gaurav Sharma, Raj Kumar, Asit K ChakrabortiAbstract:Abstract Fluoroboric acid adsorbed on silica-gel (HBF 4 –SiO 2 ) has been found to be a new and highly efficient heterogeneous catalyst for thia-Michael addition to α,β-unsaturated carbonyl compounds under solvent-free conditions. In the case of 1,3-diaryl-2-propEnones, the reactions are best carried out in MeOH. The rate of thia-Michael addition was dependent on the steric hindrance at the β-carbon of the α,β-unsaturated carbonyl substrate as well as surrounding the thiol moiety and was exploited for selective thia-Michael addition during intermolecular competition between two Enones with a common thiol and between two aryl/alkyl thiols for a common Enone. The methodology finds application for one-pot syntheses of 2,3-dihydro-1,5-benzothiazepines.
Paultheo Von Zezschwitz - One of the best experts on this subject based on the ideXlab platform.
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copper catalyzed enantioselective 1 4 addition of alkyl groups to n sulfonyl imines
Chemical Communications, 2014Co-Authors: Johannes Westmeier, Paultheo Von ZezschwitzAbstract:In copper(I)/phosphoramidite-catalyzed asymmetric 1,4-additions of dialkylzinc, N-sulfonyl imines are more reactive and furnish higher enantiomeric excesses than the respective cycloalk-2-Enones. This enables formation of a quaternary stereocenter as well as a cis-selective addition to an imine derived from 5-methylcyclohex-2-Enone. The 1,4-adducts can be transformed in stereodivergent reductions yielding cis- or trans-3-alkylcycloalkyl amides.
Michael J Krische - One of the best experts on this subject based on the ideXlab platform.
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diastereoselective cycloreductions and cycloadditions catalyzed by co dpm 2 silane dpm 2 2 6 6 tetramethylheptane 3 5 dionate mechanism and partitioning of hydrometallative versus anion radical pathways
Journal of the American Chemical Society, 2002Co-Authors: Long Cheng Wang, Hyeyoung Jang, Yeonsuk Roh, Vincent M. Lynch, Arthur J Schultz, Xiaoping Wang, Michael J KrischeAbstract:In the presence of phenylsilane and 5 mol % cobalt(II) bis(2,2,6,6-tetramethylheptane-3,5-dionate), aryl-substituted monoEnone monoaldehydes and bis(Enones) undergo reductive cyclization to afford syn-aldol and anti-Michael products, respectively. For both aldol and Michael cycloreductions, five- and six-membered ring formation occurs in good yield with high levels of diastereoselectivity. Cycloreduction of monoEnone monoaldehyde 1a in the presence of d3-phenylsilane reveals incorporation of a single deuterium at the Enone β-position as an equimolar mixture of epimers, inferring rapid isomerization of the kinetically formed cobalt enolate prior to cyclization. The deuterated product was characterized by single-crystal neutron diffraction analysis. For bis(Enone) substrates, modulation of the silane source enables partitioning of the competitive Michael cycloreduction and [2 + 2] cycloaddition manifolds. A study of para-substituted acetophEnone-derived bis(Enones) reveals that substrate electronic features...
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organocatalytic michael cycloisomerization of bis Enones the intramolecular rauhut currier reaction
Journal of the American Chemical Society, 2002Co-Authors: Long Cheng Wang, Hyeyoung Jang, Ana Liza Luis, Kyriacos Agapiou, Michael J KrischeAbstract:The utilization of Enones as latent enolates enables regioselective enolate formation from chemically robust presursors. In this communication, we report a catalytic Michael cycloisomerization of bis(Enones) under Morita−Baylis−Hillman conditions. Upon exposure to 10 mol % tributylphosphine, bis(Enone) substrates afford both five- and six-membered ring products. Notably, unsymmetrical bis(Enones) possessing sufficient steric or electronic bias yield single isomeric products.
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Anion radical chain cycloaddition of tethered Enones: intramolecular cyclobutanation and Diels-Alder cycloaddition.
Organic letters, 2002Co-Authors: Yeonsuk Roh, Hye‐young Jang, Vincent M. Lynch, Nathan L. Bauld, Michael J KrischeAbstract:[reaction: see text] The anion radicals of certain bis(Enones), generated by cathodic reduction, are observed to participate in intramolecular cyclobutanation, yielding bicyclo[3.2.0]heptane derivatives through an anion radical chain mechanism. Evidence for stepwise cycloaddition involving distonic anion radical intermediates is presented. In addition to the novel anion radical cyclobutanations, an unprecedented intramolecular anion radical Diels-Alder product is observed. Parallel trends in substrate scope vis-a-vis the Co-catalyzed bis(Enone) cyclobutanation are discussed.
Tehshik P Yoon - One of the best experts on this subject based on the ideXlab platform.
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photocatalytic reductive cyclizations of Enones divergent reactivity of photogenerated radical and radical anion intermediates
Chemical Science, 2011Co-Authors: Laura Ruiz Espelt, Ilia A Guzei, Tehshik P YoonAbstract:Photocatalytic reactions of Enones using metal polypyridyl complexes proceed by very different reaction manifolds in the presence of either Lewis or Bronsted acid additives. Previous work from our lab demonstrated that photocatalytic [2 + 2] cycloadditions of Enones required the presence of a Lewis acidic co-catalyst, presumably to activate the Enone and stabilize the key radical anion intermediate. On the other hand, Bronsted acid activators alter this reactivity and instead promote reductive cyclization reactions of a variety of aryl and aliphatic Enonesvia a neutral radical intermediate. These two distinct reactive intermediates give rise to transformations differing in the connectivity, stereochemistry, and oxidation state of their products. In addition, this reductive coupling method introduces a novel approach to the tin-free generation of β-ketoradicals that react with high diastereoselectivity and with the high functional group compatibility typical of radical cyclization reactions.
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visible light photocatalysis of radical anion hetero diels alder cycloadditions
Tetrahedron, 2011Co-Authors: Anna E Hurtley, Michael A Ischay, Megan A Cismesia, Tehshik P YoonAbstract:We have discovered a photocatalytic intramolecular hetero-Diels–Alder reaction of tethered bis(Enones). This transformation involves the intermediacy of an Enone radical anion and constitutes the formal coupling of an electron-deficient heterodiene with an electronically mismatched Enone dienophile. The diastereoselectivity and regioselectivity of the process are high, and the dihydropyran products are amenable to a variety of synthetically useful transformations.
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efficient visible light photocatalysis of 2 2 Enone cycloadditions
Journal of the American Chemical Society, 2008Co-Authors: Michael A Ischay, Mary E Anzovino, Tehshik P YoonAbstract:We report that Ru(bipy)3Cl2 can serve as a visible light photocatalyst for [2+2] Enone cycloadditions. A variety of aryl Enones participate readily in the reaction, and the diastereoselectivity in the formation of the cyclobutane products is excellent. We propose a mechanism in which a photogenerated Ru(bipy)3+ complex promotes one-electron reduction of the Enone substrate, which undergoes subsequent radical anion cycloaddition. The efficiency of this process is extremely high, which allows rapid, high-yielding [2+2] cyclizations to be conducted using incident sunlight as the only source of irradiation.
