- Sn/Li exchange reactions in 1,ω-distannylated conjugated trienes and tetraenes: An enabling step for polyene synthesis
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Successive treatments of (1E,3E,5E)- or (1E,3Z,5E)-1,6-bis(tributylstannyl) hexa-1,3,5-triene with nBuLi and butanal rendered polyenyl alcohols resulting from one Sn/Li exchange reaction and exhibiting complete retention of the configuration of all C=C bonds. Mono- or dimethylated all-E-configured 1,6-distannylated conjugated trienes as well as all-E-1,8-bis(tributylstannyl) octa-1,3,5,7-tetraene and dimethylated congeners thereof reacted similarly. The respective Sn/Li exchange reactions affected the substructure Bu 3Sn-CH=CH with a 93-94:7-6 preference over Bu3Sn-CMe=CH and with a 90:10 preference over Bu3Sn-CH=CMe. all-E-1-Lithio-6- (tributylstannyl)hexa-1,3,5-triene was incorporated into navenone B after Negishi coupling and into (-)-cicutoxin after acylation. NMR spectroscopy of our navenone B specimen revealed that certain resonances were misassigned previously. Molecular tinkertoy: all-E-1,6-(Tributylstannyl)hexa-1,3,5-triene, all-E-1,8-(tributylstannyl)octa-1,3,5,7-tetraene, and related bis(tributylstannylated) polyenes undergomono-Sn/Li exchange reactions. They set the stage for terminus-differentiating functionalizations, which provide inter alianavenone B and (-)-cicutoxin.
- Burghart, Jochen,Brueckner, Reinhard
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- Chiral silver phosphate catalyzed transformation of ortho-alkynylaryl ketones into 1H-isochromene derivatives through an intramolecular-cyclization/ enantioselective-reduction sequence
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The transformation of ortho-alkynylaryl ketones through a cyclization/enantioselective-reduction sequence in the presence of a chiral silver phosphate catalyst afforded 1H-isochromene derivatives in high yield with fairly good to high enantioselectivity. An asymmetric synthesis of the 9-oxabicyclo[3.3.1]nona-2,6-diene framework, which has been found in some biologically active molecules, is presented as a demonstration of the synthetic utility of this method. Dependent on its other half: The title reaction of ortho-alkynylaryl ketones in the presence of a silver catalyst with a chiral counteranion afforded 1H-isochromene derivatives in high yield with good to high enantioselectivity (see scheme; R1=alkyl, aryl; R2=aryl; R3=H, F). An asymmetric synthesis of the 9-oxabicyclo[3.3.1]nona-2,6- diene framework found in biologically active molecules highlights the synthetic utility of this method. Copyright
- Terada, Masahiro,Li, Feng,Toda, Yasunori
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- Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation
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This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.
- Zhang, Chenhao,Gao, Anthony Z.,Nie, Xin,Ye, Chen-Xi,Ivlev, Sergei I.,Chen, Shuming,Meggers, Eric
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supporting information
p. 13393 - 13400
(2021/09/03)
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- Iridium-Catalyzed Asymmetric Hydrogenation of α-Fluoro Ketones via a Dynamic Kinetic Resolution Strategy
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The discrimination of a fluorine atom from a hydrogen atom has been challenging in asymmetric catalysis. We herein report iridium-catalyzed hydrogenation of α-fluoro ketones using a strategy of dynamic kinetic resolution. Both enantiomeric and diastereomeric selectivities were satisfactory in the preparation of β-fluoro alcohols. The DFT calculation revealed a C-F···Na charge-dipole interaction in the transition state of hydride transfer. This noncovalent interaction would be responsible for the diastereomeric control.
- Tan, Xuefeng,Wen, Jialin,Zeng, Weijun,Zhang, Xumu
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supporting information
p. 7230 - 7233
(2020/10/02)
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- Enantioselective Mannich Reaction Employing 1,3,5-Triaryl-1,3,5-triazinanes Catalyzed by Chiral-at-Metal Rhodium Complexes
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Chiral-at-metal RhIII complexes catalyze the efficient enantioselective Mannich reaction of 2-acyl imidazoles with 1,3,5-triazinanes, affording the corresponding adducts in 81–99 % yield with up to >99 % enantioselectivity. This protocol performs with 0.1 mol-% of RhIII complex on gram scale without any loss in enantioselectivity.
- Gong, Jun,Li, Shi-Wu,Qurban, Saira,Kang, Qiang
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supporting information
p. 3584 - 3593
(2017/07/22)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 000458; 000459
(2018/01/17)
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- Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides
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The synthesis of α-amino carbonyl/carboxyl compounds is a contemporary challenge in organic synthesis. Herein, we present a stereoselective α-amination of amides employing simple azides that proceeds under mild conditions with release of nitrogen gas. The
- Tona, Veronica,De La Torre, Aurélien,Padmanaban, Mohan,Ruider, Stefan,González, Leticia,Maulide, Nuno
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supporting information
p. 8348 - 8351
(2016/07/26)
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- Differential induction of cytoplasmic vacuolization and methuosis by novel 2-indolyl-substituted pyridinylpropenones
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Because many cancers harbor mutations that confer resistance to apoptosis, there is a need for therapeutic agents that can trigger alternative forms of cell death. Methuosis is a novel form of nonapoptotic cell death characterized by accumulation of vacuo
- Trabbic, Christopher J.,Dietsch, Heather M.,Alexander, Evan M.,Nagy, Peter I.,Robinson, Michael W.,Overmeyer, Jean H.,Maltese, William A.,Erhardt, Paul W.
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supporting information
p. 73 - 77
(2014/02/14)
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- The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure-activity relationships
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We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3- arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
- Shaghafi, Michael B.,Barrett, David G.,Willard, Francis S.,Overman, Larry E.
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supporting information
p. 1031 - 1036
(2014/03/21)
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- Ru-catalyzed hydrogenation of 3,5-diketo amides: Simultaneous control of chemo- and enantioselectivity
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By modulating the chelating priorities of the different directing groups in 3,5-diketo amides with the assistance from coordinating solvent, highly chemo- and enantioselective hydrogenation of the C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-SunPhos]Cl in THF.
- Li, Wanfang,Fan, Weizheng,Ma, Xin,Tao, Xiaoming,Li, Xiaoming,Xie, Xiaomin,Zhang, Zhaoguo
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supporting information
p. 8976 - 8978
(2012/11/07)
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- Ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides
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A ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides was found to afford corresponding amides in good to high yields. A simple RuCl 3/Zn-Cu/alcohol system, without the addition of any other ligands, exhibited a high catalytic activity, and therefore the present reaction does not require a stoichiometric amount of metals or metal complexes as reductants. When β-substituted-α,β-unsaturated N-methoxyamides were employed as substrates, concurrent hydrogenation of the olefin moiety proceeded slowly with deprotection of the methoxy group. In the reduction of N-hydroxyamides, the alcoholic solvent was found to function as a hydrogen donor.
- Fukuzawa, Hiroko,Ura, Yasuyuki,Kataoka, Yasutaka
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experimental part
p. 3643 - 3648
(2011/12/02)
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- NOVEL COMPOUNDS
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The present invention relates to novel NADPH oxidase II inhibitors and their use in the treatment of diseases mediated by the NADPH oxidase II enzyme.
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Page/Page column 35; 36
(2011/07/07)
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- Methods of using diaminopyrimidine P2X3 and P2X2/3 receptor modulators for treatment of respiratory and gastrointestinal diseases
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Methods for treating respiratory and gastrointestinal diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.
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Page/Page column 120
(2010/11/26)
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- Diaminopyrimidines as P2X3 and P2X2/3 antagonists
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Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.
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Page/Page column 140
(2010/02/14)
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- Dihydroimidazo[2,1-b]thiazole and dihydro-5h-thiazolo[3,2-A]pyrimidines as antidepressant agents
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The present invention relates to certain novel substituted dihydroimidazo[2,1-b]thiazole and dihydro-5H-thiazolo[3,2-a]pyrimidine compounds of Formula (I) including pharmaceutically acceptable salts thereof in which have affinity for 5-HT1A receptors and which inhibits neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.
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- Biocatalytic reduction of β,δ-diketo esters: A highly stereoselective approach to all four stereoisomers of a chlorinated β,δ-dihydroxy hexanoate
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A stereoselective chemoenzymatic synthesis of all four stereoisomers of tert-bulyl 6-chloro-3,5-dihydroxyhexanoate (6a) is presented. The key step of the sequence is a highly regio-and enantioselective single-site reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (1a) by two enantiocomplementary biocatalysts. Alcohol dehydrogenase from Lactobacillus brevis (recLBADH) afforded a 72% yield of enantiopure tert-butyl (5)-6-chloro-5-hydroxy-3-oxohexanoate [(S)-2a]. The enantiomer (R)-2a was prepared with 90-94% ee by Baker's yeast reduction in a biphasic system (50% yield). Both biotransformations were performed on a gram scale. The β-keto group of the enantiomeric δ-hydroxy-β-keto esters 2a thus obtained was reduced by synand anti-selective borohydride reductions. Permutation of the reduction methods yielded all four stereoisomers of the crystalline target compound 6a (≥99.3% ee, dr≥205:1), which is a versatile 1,3-diol building block. recLBADH accepts a variety of β,δ-diketo esters as was determined in a photometric assay. tert-Butyl 3,5-dioxohexanoate (1b) and tert-butyl 3,5-dioxoheptanoate (1c) were reduced on a preparative scale as well to afford the corresponding δ-hydroxy-β-keto esters (R)-2b and (R)-2c with 99.4% ee and 98.1% ee, respectively. Wiley-VCH Verlag GmbH, 2001.
- Wolberg, Michael,Hummel, Werner,Mueller, Michael
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p. 4562 - 4571
(2007/10/03)
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