- Enantioselective Total Syntheses of (R)- A nd (S)-Naphthotectone, and Stereochemical Assignment of the Natural Product
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Both isomers of naphthotectone, an isoprenoid quinone from Verbenaceae Tectona grandis possessing interesting biological activities, were enantioselectively obtained by two different synthetic routes in which the carbon side-chain of the naphthoquinone core was introduced using either a Sonogashira or a Heck coupling reaction. In both cases, the naphthoquinone core of the final products was obtained by a late-stage anodic treatment. (R)-Naphthotectone was obtained in six steps from leuconaphthazarin with an overall yield of 38 % and an enantiomeric excess of 86 %. This compound was found to have the same absolute configuration as the natural product at its C-3′ stereogenic center. (S)-Naphthotectone was obtained in five steps from leuconaphthazarin with an overall yield of 36 % and an enantiomeric excess of 80 %. Naphthotectone was synthesized in both racemic and enantioenriched forms by two different synthetic strategies using Pd coupling reactions and anodic treatment as key steps. The stereochemistry of the natural product has been assigned.
- Guerrero-Vásquez, Guillermo A.,Galarza, Flávia A. D.,Molinillo, José M. G.,Andrade, Carlos Kleber Z.,Macías, Francisco A.
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- The role of phosphate in a multistep enzymatic reaction: Reactions of the substrate and intermediate in pieces
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Several mechanistically unrelated enzymes utilize the binding energy of their substrate's nonreacting phosphoryl group to accelerate catalysis. Evidence for the involvement of the phosphodianion in transition state formation has come from reactions of the substrate in pieces, in which reaction of a truncated substrate lacking its phosphorylmethyl group is activated by inorganic phosphite. What has remained unknown until now is how the phosphodianion group influences the reaction energetics at different points along the reaction coordinate. 1-Deoxy-d-xylulose-5-phosphate (DXP) reductoisomerase (DXR), which catalyzes the isomerization of DXP to 2-C-methyl-d-erythrose 4-phosphate (MEsP) and subsequent NADPH-dependent reduction, presents a unique opportunity to address this concern. Previously, we have reported the effect of covalently linked phosphate on the energetics of DXP turnover. Through the use of chemically synthesized MEsP and its phosphate-truncated analogue, 2-C-methyl-d-glyceraldehyde, the current study revealed a loss of 6.1 kcal/mol of kinetic barrier stabilization upon truncation, of which 4.4 kcal/mol was regained in the presence of phosphite dianion. The activating effect of phosphite was accompanied by apparent tightening of its interactions within the active site at the intermediate stage of the reaction, suggesting a role of the phosphodianion in disfavoring intermediate release and in modulation of the on-enzyme isomerization equilibrium. The results of kinetic isotope effect and structural studies indicate rate limitation by physical steps when the covalent linkage is severed. These striking differences in the energetics of the natural reaction and the reactions in pieces provide a deeper insight into the contribution of enzyme-phosphodianion interactions to the reaction coordinate.
- Kholodar, Svetlana A.,Allen, C. Leigh,Gulick, Andrew M.,Murkin, Andrew S.
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- An efficient synthesis of the 1,6-dioxaspiro[4.4]nonan-2-one motif of the immunosuppressive triterpenoid Phainanoid F
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We describe an efficient synthesis of the 1,6-dioxaspiro[4.4]nonan-2-one motif of the immunosuppressive triterpenoid Phainanoid F and its C4 epimer. A furan oxidative spirocyclization for constructing the spiro center was used as the key step. Other important reactions involved Sharpless asymmetric dihydroxylation, Weinreb ketone synthesis and Yamaguchi esterfication. The synthesis was achieved in 11 linear steps with 17.3% overall yield.
- Zhang, Chen-Lu,Nan, Fa-Jun
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- Total Synthesis of the Death Cap Toxin Phalloidin: Atropoisomer Selectivity Explained by Molecular-Dynamics Simulations
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Phallotoxins and amatoxins are a group of prominent peptide toxins produced by the death cap mushroom Amanita phalloides. Phalloidin is a bicyclic cyclopeptide with an unusual tryptathionin thioether bridge. It is a potent stabilizer of filamentous actin and in a fluorescently labeled form widely used as a probe for actin binding. Herein, we report the enantioselective synthesis of the key amino acid (2S,4R)-4,5-dihydroxy-leucine as a basis for the first total synthesis of phalloidin, which was accomplished by two different synthesis strategies. Molecular-dynamics simulations provided insights into the conformational flexibility of peptide intermediates of different reaction strategies and showed that this flexibility is critical for the formation of atropoisomers. By simulating the intermediates, rather than the final product, molecular-dynamics simulations will become a decisive tool in orchestrating the sequence of ring formation reactions of complex cyclic peptides.
- Yao, Guiyang,Joswig, Jan-Oliver,Keller, Bettina G.,Süssmuth, Roderich D.
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- Asymmetric dihydroxylation of esters and amides of methacrylic, tiglic, and angelic acid: No exception to the sharpless mnemonic!
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Literature findings on the facial selectivity of the Sharpless asymmetric dihydroxylation (SAD) of isobutyl angelate are contradictory and partly in conflict with the Sharpless mnemonic. We systematically screened the SAD of esters and amides of angelic, tiglic, and methacrylic acid. Enantiocontrol arose in 14 of the 15 reactions, culminating at 99 % ee for the Weinreb amide of tiglic acid. The absolute configurations of all the nonracemic products were established by (stereo)chemical correlations. Without exception, they conform to the Sharpless mnemonic.
- Weber, Fabian,Brückner, Reinhard
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- Rhodium(III)-Catalyzed Aerobic Oxidative C-H Olefination of Unsaturated Acrylamides with Unactivated Olefins
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A rhodium(III)-catalyzed aerobic oxidative cross-coupling of acrylamides with unactivated alkenes via vinylic C-H activation has been developed. The present cross-coupling reaction was examined with a variety of differently functionalized acrylamides and unactivated olefins. In these reactions, highly valuable amide-functionalized butadienes were prepared in good to excellent yields. This protocol was also compatible with Weinreb amides. A possible reaction mechanism involving the chelation-assisted vinylic C-H activation via a carboxylate-assisted deprotonation pathway is proposed.
- Logeswaran, Ravichandran,Jeganmohan, Masilamani
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supporting information
p. 767 - 771
(2021/02/06)
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- An iron-catalyzed hydroalkylation reaction of α,β-unsaturated ketones with ethers
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A general strategy for the hydroalkylation of vinyl ketones using ethers catalyzed by an iron catalyst is described. This catalytic method permits direct transformation of easily accessible and abundant precursors into highly substituted, structurally diverse and functionally concentrated products.
- Lan, Yun,Fan, Pei,Liu, Xiao-Wei,Meng, Fei-Fan,Ahmad, Tanveer,Xu, Yun-He,Loh, Teck-Peng
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supporting information
p. 12353 - 12356
(2017/11/20)
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- Enantioselective enolate protonation in sulfamichael addition to r-substituted n-acryloyloxazolidin-2-ones with bifunctional organocatalyst
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Organocatalytic conjugate addition of thiols to R-substituted N-acryloyloxazolidin-2-ones followed by asymmetric protonation has been studied in the presence of cinchona alkaloid derived thioureas. Both of the enantiomers are accessible with the same level of enantioselectivity using pseudoenantiomeric quinine/quinidine derived catalysts. The addition/protonation products have been converted to useful biologically active molecules. 2011 American Chemical Society.
- Rana, Nirmal K.,Singh, Vinod K.
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supporting information; experimental part
p. 6520 - 6523
(2012/02/01)
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- A Practical synthesis of 3-Acyl cyclobutanones by [2 〈 2] annulation. Mechanism and utility of the zn(II)-Catalyzed condensation of r-Chloroenamines with electron-deficient alkenes
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New conditions for the conversion of simple tertiary amides to R-chloroenamines and their use in Zn(II)-catalyzed cycloaddition reactions with commercial α,β-unsaturated carbonyl compounds allows rapid, regiocontrolled access to 3-acyl cyclobutanones. Rea
- O'Brien, Jeannette M.,Kingsbury, Jason S.
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experimental part
p. 1662 - 1672
(2011/05/12)
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- PYRIDIN-2-YL-AMINO-1,2,4-THIADIAZOLE DERIVATIVES AS GLUCOKINASE ACTIVATORS FOR THE TREATMENT OF DIABETES MELLITUS
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Provided are compounds of Formula (I): wherein R2, R3, R13, L and D2 are as defined in the specification, which are useful in the treatment and/or prevention of diseases or disorders mediated by deficient levels of glucokinase activity or which can be treated by activating glucokinase including, but not limited to, diabetes mellitus, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glycemia), as well as other diseases and disorders such as those discussed herein
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Page/Page column 127; 131
(2009/05/29)
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- Enantioselective synthesis of α-methyl-D-cysteine and lanthionine building blocks via α-methyl-d-serine-β-lactone
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(Matrix presented) We report here the enantioselective synthesis of Boc-α-methyl-D-cysteine(PMB)-OH and lanthionine building blocks through the regioselective ring opening of key intermediate Boc-α -methyl-D-serine-β-lactone.
- Smith, Nicole D.,Goodman, Murray
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p. 1035 - 1037
(2007/10/03)
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