- Highly enantioselective, intermolecular hydroamination of allenyl esters catalyzed by bifunctional phosphinothioureas
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Bifunctional phosphinothiourea catalysts have been developed successfully for the highly regio- and enantioselective γ-hydroamination of allenyl and propargyl esters with N-methoxy carbamate nucleophiles to yield α,β-unsaturated γ-amino acid ester products. In the case of propargyl ester substrates, the reaction proceeds through reversible phosphinothiourea-catalyzed isomerization to the corresponding allenyl ester. The high enantioselectivity of the process is attributed to a cooperative conjugate addition of a thiourea-bound carbamate anion to a vinyl phosphonium ion resulting from covalent activation of the allenyl ester substrate.
- Fang, Yuan-Qing,Tadross, Pamela M.,Jacobsen, Eric N.
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- Asymmetric Transfer Hydrogenation of α-Keto Amides; Highly Enantioselective Formation of Malic Acid Diamides and α-Hydroxyamides
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The asymmetric transfer hydrogenation (ATH) of α-keto-1,4-diamides using a tethered Ru/TsDPEN catalyst was achieved in high ee. Studies on derivatives identified the structural elements which lead to the highest enantioselectivities in the products. The α-keto-amide reduction products have been converted to a range of synthetically valuable derivatives.
- Gediya, Shweta K.,Vyas, Vijyesh K.,Clarkson, Guy J.,Wills, Martin
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supporting information
p. 7803 - 7807
(2021/10/20)
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- Peptide-Catalyzed Fragment Couplings that Form Axially Chiral Non-C2-Symmetric Biaryls
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We have demonstrated that small, modular, tetrameric peptides featuring the Lewis-basic residue β-dimethylaminoalanine (Dmaa) are capable of atroposelectively coupling naphthols and ester-bearing quinones to yield non-C2-symmetric BINOL-type scaffolds with good yields and enantioselectivity. The study culminates in the asymmetric synthesis of backbone-substituted scaffolds similar to 3,3′-disubstituted BINOLs, such as (R)-TRIP, with good (94:6 e.r.) to excellent (>99.9:0.1 e.r.) enantioselectivity after recrystallization, and a diastereoselective net arylation of the minimally modified nonsteroidal anti-inflammatory drug (NSAID) naproxen.
- Coombs, Gavin,Sak, Marcus H.,Miller, Scott J.
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supporting information
p. 2875 - 2880
(2020/01/24)
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- PD(II)-CATALYZED ENANTIOSELECTIVE C-H ARYLATION OF FREE CARBOXYLIC ACIDS
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The invention includes procedures for stereoselective β-arylation of carboxylic acids having a β-carbon atom. For example, stereoselective arylation procedures include the following reactions: (I)
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Page/Page column 16-17
(2019/11/12)
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- Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Free Carboxylic Acids
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A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp3)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.
- Shen, Peng-Xiang,Hu, Liang,Shao, Qian,Hong, Kai,Yu, Jin-Quan
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supporting information
p. 6545 - 6549
(2018/05/23)
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- Diversity of Secondary Structure in Catalytic Peptides with β-Turn-Biased Sequences
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X-ray crystallography has been applied to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in an atroposelective bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop-region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3J-values, and 1H-1H-NOESY contacts. hese findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. These findings implicate the advantages of low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.
- Metrano, Anthony J.,Abascal, Nadia C.,Mercado, Brandon Q.,Paulson, Eric K.,Hurtley, Anna E.,Miller, Scott J.
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supporting information
p. 492 - 516
(2017/02/23)
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- Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination
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We describe herein a crystallographic and NMR study of the secondary structural attributes of a β-turn-containing tetra-peptide, Boc-Dmaa-d-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-d-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I′ β-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well.
- Metrano,Abascal,Mercado,Paulson,Miller
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supporting information
p. 4816 - 4819
(2016/04/09)
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- Enantioselective Synthesis of 3-Arylquinazolin-4(3H)-ones via Peptide-Catalyzed Atroposelective Bromination
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We report the development of a tertiary amine-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope. The structure of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and 2D-NOESY experiments. Quinazolinone rotational barriers about the chiral anilide axis were also studied using density functional theory calculations and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. The observation of stereoisomerically stable monobromides stimulated the conversion of the tribromide products to other atropisomerically defined products of interest. For example, (1) a dehalogenation Suzuki-Miyaura cross-coupling sequence delivers ortho-arylated derivatives, and (2) a regioselective Buchwald-Hartwig amination procedure installs para-amine functionality. Stereochemical information was retained during these subsequent transformations.
- Diener, Matthew E.,Metrano, Anthony J.,Kusano, Shuhei,Miller, Scott J.
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supporting information
p. 12369 - 12377
(2015/10/12)
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- Peptide-catalyzed conversion of racemic oxazol-5(4 H)-ones into enantiomerically enriched α-amino acid derivatives
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We report the development and optimization of a tetrapeptide that catalyzes the methanolytic dynamic kinetic resolution of oxazol-5(4H)-ones (azlactones) with high levels of enantioinduction. Oxazolones possessing benzylic-type substituents were found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis.
- Metrano, Anthony J.,Miller, Scott J.
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p. 1542 - 1554
(2014/03/21)
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- NITROGEN-CONTAINING HETEROCYCLIC COMPOUND
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The present invention provides a novel compound having a superior activity as an ERR-alpha modulator and useful as an agent for the prophylaxis or treatment of ERR-alpha associated diseases. The present invention relates to a compound represented by the formula (1) wherein each symbol is as defined in the specification, or a salt thereof
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Paragraph 0654
(2013/03/26)
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- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDE INHIBITORS OF GLYCOGEN PHOSHORYLASE
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Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
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- Process for the preparation of substituted N-(indole-2-carbonyl)- glycinamides
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Processes and intermediates for preparing compounds of Formula (I).
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- Epoxysuccinamide derivative or salt thereof
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PCT No. PCT/JP98/01778 Sec. 371 Date Dec. 17, 1998 Sec. 102(e) Date Dec. 17, 1998 PCT Filed Apr. 17, 1998 PCT Pub. No. WO98/47887 PCT Pub. Date Oct. 29, 1998The invention relates an epoxysuccinamide derivative represented by a formula (I): wherein R1 represents a hydrogen atom, an alkyl or aminoalkyl group, R2 represents an aminoalkyl group which May be substituted, an aryl group which may be substituted, a heterocyclic group which may be substituted, an aralkyl group which may be substituted, or an alkyl group substituted by a heterocyclic ring which may be substituted, or R1 and R2 may form a nitrogen-containing heterocyclic ring, which may be substituted, together with the adjacent nitrogen atoms, and R3 and R4 are the same or different from each other and independently represent a hydrogen atom, or an alkyl or aralkyl group, or a salt thereof, a preparation process thereof, and a medicine comprising such a derivative or salt as an active ingredient. This compound has a specific inhibitory activity for cathepsin L and family enzymes thereof, and is useful as an agent for preventing and treating metabolic osteopathy such as osteoporosis and hypercalcemia.
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- Substituted n-(indole-2-carbonyl)-glycinamides and derivatives as glycogen phosphorylase inhibitors
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PCT No. PCT/IB95/00442 Sec. 371 Date Dec. 2, 1997 Sec. 102(e) Date Dec. 2, 1997 PCT Filed Jun. 6, 1995 PCT Pub. No. WO96/39384 PCT Pub. Date Dec. 12, 1996Compounds of Formula (1) wherein R6 is carboxy, (C1-C8)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR8R9 or C(O)R12 as glucogen phosphorylase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia in mammals.
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- Anti-ulcer composition
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An anti-peptic ulcer composition containing, as an active ingredient, a therapeutically effective amount of a compound having the formula (I): STR1 wherein A represents H2 NCH2 --, STR2 B represents STR3 D and E each independently re
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