- α-Allylation of aryl- or heteroarylketones via the Claisen rearrangement
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A new one-step synthesis of α-allyl or α-(2-haloallyl) aryl- or heteroarylketones from the corresponding ketones via the Claisen rearrangement is described.
- Wu,Kover
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Read Online
- A synthetic approach to 5/5/6-polycyclic tetramate macrolactams of the discodermide type
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A flexible synthetic route to the 16-membered tetramate-embedding macrocyclic scaffold present in various polycyclic tetramate macrolactams (PTMs) was developed which differs from the seminal synthesis of ikarugamycin by Boeckman Jr. in protecting groups and the order of connections. We also devised a short approach to various stereoisomers of the 5/5/6-tricarbocyclic motif found in discodermide and other PTMs, starting from the Weiss’ diketone.
- Bodenschatz, Kevin,St?ckl, Julia,Winterer, Markus,Schobert, Rainer
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- Carbonyl 1,2-transposition through triflate-mediated a-amination
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To date, it remains challenging to selectively migrate a carbonyl oxygen within a given molecular scaffold, especially to an adjacent carbon. In this work, we describe a simple one- or two-pot protocol that transposes a ketone to the vicinal carbon. This approach first converts the ketone to the corresponding alkenyl triflate, which can then undergo the palladium- and norbornene-catalyzed regioselective a-amination and ipso-hydrogenation enabled by a bifunctional hydrogen and nitrogen donor. The resulting "transposed enamine" intermediate can subsequently be hydrolyzed to produce the 1,2-carbonyl-migrated product. This method allows rapid access to unusual bioactive analogs through late-stage functionalization.
- Wu, Zhao,Xu, Xiaolong,Wang, Jianchun,Dong, Guangbin
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p. 734 - 740
(2021/11/16)
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- Atroposelective Synthesis of Axially Chiral N-Arylpyrroles by Chiral-at-Rhodium Catalysis
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A transformation of fluxional into configurationally stable axially chiral N-arylpyrroles was achieved with a highly atroposelective electrophilic aromatic substitution catalyzed by a chiral-at-metal rhodium Lewis acid. Specifically, N-arylpyrroles were alkylated with N-acryloyl-1H-pyrazole electrophiles in up to 93 percent yield and with up to >99.5 percent ee, and follow-up conversions reveal the synthetic utility of this new method. DFT calculations elucidate the origins of the observed excellent atroposelectivity.
- Chen, Shuming,Han, Feng,Houk, K. N.,Ivlev, Sergei,Meggers, Eric,Xie, Xiulan,Ye, Chen-Xi
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p. 13552 - 13556
(2020/06/05)
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- Formation, Alkylation, and Hydrolysis of Chiral Nonracemic N-Amino Cyclic Carbamate Hydrazones: An Approach to the Enantioselective α-Alkylation of Ketones
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The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.
- Huynh, Uyen,McDonald, Stacey L.,Lim, Daniel,Uddin, Md. Nasir,Wengryniuk, Sarah E.,Dey, Sumit,Coltart, Don M.
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p. 12951 - 12964
(2018/11/30)
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- Reactivity of Lithium β-Ketocarboxylates: The Role of Lithium Salts
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Lithium β-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li+) with carbon dioxide, readily undergo decarboxylative disproportionation in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable at room temperature in inert atmosphere. The availability of stable THF solutions of lithium β-ketocarboxylates 1(COOLi) in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give α-alkyl ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing group for the selective monoalkylation of lithium enolates 2(Li+). The roles of lithium salts in preventing the disproportionation of lithium β-ketocarboxylates 1(COOLi) and in determining the course of the reaction with bases and alkyl halides 3 are discussed.
- Berton, Mateo,Mello, Rossella,Williard, Paul G.,González-Nú?ez, María Elena
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supporting information
p. 17414 - 17420
(2017/12/15)
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- Chemoenzymatic route to optically active dihydroxy cyclopenta[b]naphthalenones; precursors for decalin-based bioactive natural products
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The development of an efficient chemoenzymatic route for the synthesis of optically active dihydroxy cyclopenta[b]naphthalenones; (+)-1,4a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-10 and (+)-1,8a-dihydroxy-4a,5,6,7,8,8a,9,9a-octahydro-1H-cyclopenta[b]naphthalen-2(4H)-one (+)-11 is described. Different lipases and esterases were tested in the enzymatic hydrolysis of the corresponding acetates (±)-4a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-8, (±)-8a-hydroxy-2-oxo-2,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-cyclopenta[b]naphthalen-1-yl acetate (±)-9, CRL (Candida Rugosa Lipase) and PLE (Pig Liver Esterase) were found to be the most effectual enzymes; for (?)-8 by 47% ee with the corresponding dihydroxy; (+)-10 by 98% ee in the presence of CRL; whereas, (?)-8 was obtained with 40% ee with the corresponding dihydroxy, (+)-10 with 58% ee in the PLE hydrolysis. It was concluded that CRL was the best biocatalyst for the substrate (±)-8. Moreover, enzymatic resolution in the presence of CRL yields, (?)-9 with 46% ee with the corresponding dihydroxy derivative; (+)-11 with 98% ee; however, in the presence of PLE, yields (?)-9 with 36% ee as well as the related dihydroxy derivative; (+)-11 with 49% ee respectively. The study concluded that CRL is the best biocatalyst for compounds (±)-8 and (±)-9.
- ?zdemirhan, Devrim,Sar??elik, ?zlem
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p. 118 - 124
(2017/01/12)
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- Direct palladium-catalyzed allylic alkylations of alcohols with enamines: Synthesis of homoallyl ketones
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An efficient, direct nucleophilic allylic substitution of α-, β- and γ-substituted alcohols with enamines, using the Pd(OAc)2/PPh3 catalyst system and ZnBr2 as a promoter in CH2Cl2 at reflux, is reported. The reaction course was dependent on the steric hindrance at the α- or γ-positions with respect to the functionalized α-carbon, selectively affording in moderate to good yields, α- or γ-homoallyl ketones, the so-called “linear” and “branched” products, respectively.
- Bouhalleb, Ghalia,Mhasni, Olfa,Poli, Giovanni,Rezgui, Farhat
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p. 2525 - 2529
(2017/06/13)
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- First chemo-enzymatic synthesis of the (R)-Taniguchi lactone and substrate profiles of CAMO and OTEMO, two new Baeyer–Villiger monooxygenases
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Abstract: This study investigates the substrate profile of cycloalkanone monooxygenase and 2-oxo-Δ3-4,5,5-trimethylcyclopentenylacetyl-coenzyme A monooxygenase, two recently discovered enzymes of the Baeyer–Villiger monooxygenase family, used as whole-cell biocatalysts. Biooxidations of a diverse set of ketones were performed on analytical scale: desymmetrization of substituted prochiral cyclobutanones and cyclohexanones, regiodivergent oxidation of terpenones and bicyclic ketones, as well as kinetic resolution of racemic cycloketones. We demonstrated the applicability of the title enzymes in the enantioselective synthesis of (R)-(?)-Taniguchi lactone, a building block for the preparation of various natural product analogs such as ent-quinine. Graphical abstract: [Figure not available: see fulltext.]
- Rudroff, Florian,Fink, Michael J.,Pydi, Ramana,Bornscheuer, Uwe T.,Mihovilovic, Marko D.
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p. 157 - 165
(2017/01/17)
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- Selective Synthesis of Cyclooctanoids by Radical Cyclization of Seven-Membered Lactones: Neutron Diffraction Study of the Stereoselective Deuteration of a Chiral Organosamarium Intermediate
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Seven-membered lactones undergo selective SmI2–H2O-promoted radical cyclization to form substituted cyclooctanols. The products arise from an exo-mode of cyclization rather than the usual endo-attack employed in the few radical syntheses of cyclooctanes. The process is terminated by the quenching of a chiral benzylic samarium. A labeling experiment and neutron diffraction study have been used for the first time to probe the configuration and highly diastereoselective deuteration of a chiral organosamarium intermediate.
- Just-Baringo, Xavier,Clark, Jemma,Gutmann, Matthias J.,Procter, David J.
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p. 12499 - 12502
(2016/10/13)
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- Platinum(IV)-Catalyzed Synthesis of Unsymmetrical Polysubstituted Benzenes via Intramolecular Cycloaromatization Reaction
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A one-pot synthesis of polysubstituted benzene derivatives was achieved via a platinum(IV)-catalyzed intramolecular cycloaromatization reaction. The reaction proceeds via a tandem skeletal rearrangment, dehydration and double bond isomerization, which proved to be very useful for the syntheses of a range of interesting polyalkyl-substituted benzenes.
- Zheng, Shuyan,Zhang, Jinghua,Shen, Zhengwu
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supporting information
p. 2803 - 2808
(2015/09/28)
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- Palladium-catalyzed allylic alkylation of simple ketones with allylic alcohols and its mechanistic study
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Allylic alcohols were directly used in Pd-catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20°C by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier. Concerted action: Allylic alcohols were directly used in the title reaction under mild conditions. The reaction smoothly proceeds by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π-allylpalladium complex by lowering the activation barrier.
- Huo, Xiaohong,Yang, Guoqiang,Liu, Delong,Liu, Yangang,Gridnev, Ilya D.,Zhang, Wanbin
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supporting information
p. 6776 - 6780
(2014/07/08)
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- Hydrogen-bond-activated palladium-catalyzed allylic alkylation via allylic alkyl ethers: Challenging leaving groups
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C-O bond cleavage of allylic alkyl ether was realized in a Pd-catalyzed hydrogen-bond-activated allylic alkylation using only alcohol solvents. This procedure does not require any additives and proceeds with high regioselectivity. The applicability of this transformation to a variety of functionalized allylic ether substrates was also investigated. Furthermore, this methodology can be easily extended to the asymmetric synthesis of enantiopure products (99% ee).
- Huo, Xiaohong,Quan, Mao,Yang, Guoqiang,Zhao, Xiaohu,Liu, Delong,Liu, Yangang,Zhang, Wanbin
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supporting information
p. 1570 - 1573
(2014/04/17)
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- Enantioselective oxidation by a cyclohexanone monooxygenase from the xenobiotic-degrading Polaromonas sp. strain JS666
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A cyclohexanone monooxygenase (CHMO) from the xenobiotic-degrading Polaromonas sp. strain JS666 was heterologously expressed in Escherichia coli, and its ability to catalyze enantio- and regiodivergent oxidations of prochiral and racemic ketones was investigated. The expression system was also used to evaluate this enzyme's potential role in the oxidation of cis-1,2-dichloroethene (cDCE), a groundwater pollutant for which strain JS666 is the only known assimilator. The substrate enantiopreference and -selectivity of the strain JS666 CHMO is similar to that of other CHMO-type enzymes; of note is this enzyme's excellent stereodiscrimination of 2-substituted cyclic ketones. The expression system exhibits no activity with ethene or cDCE as substrates under the tested conditions. Phylogenetic analysis shows that sequence variability among cyclohexanone monooxygenases could be a rich source of new enzyme activities and attributes.
- Alexander, Anne K.,Biedermann, David,Fink, Michael J.,Mihovilovic, Marko D.,Mattes, Timothy E.
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experimental part
p. 105 - 110
(2012/07/28)
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- CANNABINOID AGONISTS
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The present disclosure relates to compounds useful as agonists of the cannabinoid receptors. The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders, either alone or in combination therapy. The compounds of the invention have Formula (I).
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Page/Page column 72-73
(2011/09/15)
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- C-N bond cleavage of allylic amines via hydrogen bond activation with alcohol solvents in Pd-catalyzed allylic alkylation of carbonyl compounds
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Hydrogen-bond-activated C-N bond cleavage of allylic amines was realized in Pd-catalyzed allylic alkylation to form the C-C bond product. The method could be expanded to a series of allylic amines and carbonyl compounds with excellent results. It provides a new and convenient access to C-C bond formation based on Pd-catalyzed allylic alkylation of allylic amines by using only inexpensive alcohol solvents.
- Zhao, Xiaohu,Liu, Delong,Guo, Hui,Liu, Yangang,Zhang, Wanbin
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supporting information; experimental part
p. 19354 - 19357
(2012/01/06)
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- An epoxide ring-opening approach for a short and stereoselective synthesis of icetexane diterpenoids
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A new approach for the synthesis of the core skeleton of icetexane diterpenoids is presented and deals with an epoxide ring-opening reaction by metallated aromatic compounds. Employing this strategy, a short synthesis of an icetexane analogue of brussonol was achieved in just four steps from 2-allyl-cyclohexanone.
- Carita, Adriana,Burtoloso, Antonio C.B.
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scheme or table
p. 686 - 688
(2010/04/02)
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- Organic Compounds
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Described are spiroalkyl- and -alkenylketones and esters thereof, a method for their production and fragrance compositions comprising them.
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Page/Page column 26
(2010/12/18)
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- Direct and enantioselective a-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis
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The first enantioselective organocatalytic a-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated ena
- Mastracchio, Anthony,Warkentin, Alexander A.,Walji, Abbas M.,MacMillan, David W. C.
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experimental part
p. 20648 - 20651
(2011/09/16)
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- Induced allostery in the directed evolution of an enantioselective Baeyer-Villiger monooxygenase
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The molecular basis of allosteric effects, known to be caused by an effector docking to an enzyme at a site distal from the binding pocket, has been studied recently by applying directed evolution. Here, we utilize laboratory evolution in a different way, namely to induce allostery by introducing appropriate distal mutations that cause domain movements with concomitant reshaping of the binding pocket in the absence of an effector. To test this concept, the thermostable Baeyer-Villiger monooxygenase, phenylacetone monooxygenase (PAMO), was chosen as the enzyme to be employed in asymmetric Baeyer-Villiger reactions of substrates that are not accepted by the wild type. By using the known X-ray structure of PAMO, a decision was made regarding an appropriate site at which saturation mutagenesis is most likely to generate mutants capable of inducing allostery without any effector compound being present. After screening only 400 transformants, a double mutant was discovered that catalyzes the asymmetric oxidative kinetic resolution of a set of structurally different 2-substituted cyclohexanone derivatives as well as the desymmetrization of three different 4-substituted cyclohexanones, all with high enantioselectivity. Molecular dynamics (MD) simulations and covariance maps unveiled the origin of increased substrate scope as being due to allostery. Large domain movements occur that expose and reshape the binding pocket. This type of focused library production, aimed at inducing significant allosteric effects, is a viable alternative to traditional approaches to designed directed evolution that address the binding site directly.
- Wu, Sheng,Acevedo, Juan Pablo,Reetz, Manfred T.
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experimental part
p. 2775 - 2780
(2010/10/03)
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- A facile and practical method of preparing optically active α-monosubstituted cycloalkanones by thermodynamically controlled deracemization
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Racemic 2-monosubstituted cycloalkanones were converted to R-isomers when TADDOLs (e.g., 1a, b) were used as host molecules in alkaline aqueous MeOH. The efficiency of this thermodynamically controlled deracemization was strongly influenced by the mixture ratio of the solvent, H2O/MeOH. Based on this finding, an improved method of preparing (R)-2-monosubstituted cycloalkanones with higher optical purity was developed. For example, (R)-2-(4-methylbenzyl)cyclohexanone (5) was obtained in 85% yield with 98% ee, when a 1:1 mixture of H2O/MeOH was used as the solvent in the presence of 1a.
- Kaku, Hiroto,Nakamaru, Aya,Inai, Makoto,Nishii, Takeshi,Horikawa, Mitsuyo,Tsunoda, Tetsuto
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experimental part
p. 9450 - 9455
(2011/01/12)
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- ASYMMETRIC ALPHA FUNCTIONALIZATION AND ALPHA, ALPHA BISFUNCTIONALIZATION OF ALDEHYDES AND KETONES
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The present invention relates, generally, to asymmetric α-functionalization and to asymmetric α,α-bisfunctionalization of ketones and aldehydes and, in particular, to chiral auxiliaries suitable for use in effecting such functionalizations and to methods
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Page/Page column 19
(2009/12/05)
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- Dual palladium-and proline-catalyzed allylic alkylation of enolizable ketones and aldehydes with allylic alcohols
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The dual Pd/proline-catalyzed α-allylation reaction of a variety of enolizable ketones and aldehydes with allylic alcohols is described. In this reaction, the choice of a large-bite angle ligand Xantphos and proline as the organocatalyst was essential for generation of the crucial π-allyl Pd intermediate from allylic alcohol, followed by nucleophilic attack of the enamine formed in situ from the corresponding enolizable carbonyl substrate and proline.
- Usui, Ippei,Schmidt, Stefan,Breit, Bernhard
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supporting information; experimental part
p. 1453 - 1456
(2009/09/30)
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- Synthesis of 2,6-dioxo-1,2,3,4,5,6-hexahydroindoles by acid-catalyzed cyclization of acetal-protected (2,4-dioxocyclohex-l-yl)acetamides and their transformation into 5,8,9,10-tetrahydro-6H-indolo[2,1-a]isoquinolin-9-ones
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Acetal-protected (2,4-dioxocyclohex-1-yl)-acetic acids were prepared by allylation of dilithiated 1,3-cyclohexane-1,3-diones, protection of the carbon-yl groups and oxidation of the alkene moiety. Their reaction with amines afforded the corresponding amides which were transformed, by acid-catalyzed cyclization, into various 2,6-dioxo-1,2,3,4,5,6-hexahy-droindoles. The reaction of the latter with triflic acid resulted in the formation of novel 5,8,9,10-tetrahy-dro-6H-indolo[2,1-a]isoquinolin-9-ones.
- Juma, Benard,Adeel, Muhammad,Villinger, Alexander,Reinke, Helmut,Spannenberg, Anke,Fischer, Christine,Langer, Peter
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supporting information; experimental part
p. 1073 - 1079
(2009/12/05)
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- Laboratory evolution of robust and enantioselective Baeyer-Villiger monooxygenases for asymmetric catalysis
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The Baeyer-Villiger Monooxygenase, Phenylacetone Monooxygenase (PAMO), recently discovered by Fraaije, Janssen, and co-workers, is unusually thermostable, which makes it a promising candidate for catalyzing enantioselective Baeyer-Villiger reactions in organic chemistry. Unfortunately, however, its substrate scope is very limited, reasonable reaction rates being observed essentially only with phenylacetone and similar linear phenyl-substituted analogs. Previous protein engineering attempts to broaden the range of substrate acceptance and to control enantioselectivity have been met with limited success, including rational design and directed evolution based on saturation mutagenesis with formation of focused mutant libraries, which may have to do with complex domain movements. In the present study, a new approach to laboratory evolution is described which has led to mutants showing unusually high activity and enantioselectivity in the oxidative kinetic resolution of a variety of 2-aryl and 2-alkylcyclohexanones which are not accepted by the wild-type (WT) PAMO and of a structurally very different bicyclic ketone. The new strategy exploits bioinformatics data derived from sequence alignment of eight different Baeyer-Villiger Monooxygenases, which in conjunction with the known X-ray structure of PAMO and induced fit docking suggests potential randomization sites, different from all previous approaches to focused library generation. Sites harboring highly conserved proline in a loop of the WT are targeted. The most active and enantioselective mutants retain the high thermostability of the parent WT PAMO. The success of the "proline" hypothesis in the present system calls for further testing in future laboratory evolution studies.
- Reetz, Manfred T.,Wu, Sheng
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supporting information; experimental part
p. 15424 - 15432
(2010/02/16)
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- Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates
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Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of allyl enol carbonates as a highly chemo-, regio-, and enantioselective process for the synthesis of ketones bearing either a quaternary or a tertiary R-stereogenic center has been investigated in detail. Chiral ligand L4 was found to be optimal in the DAAA of a broad scope of cyclic and acyclic ketones including simple aliphatic ketones with more than one enolizable proton. The allyl moiety of the carbonates has been extended to a variety of cyclic or acyclic disubstituted allyl groups. Our mechanistic studies reveal that, similar to the direct allylation of lithium enolates, the DAAA reaction proceeds through an "outer sphere" S N2 type of attack on the π-allylpalladium complex by the enolate. An important difference between the DAAA reaction and the direct allylation of lithium enolates is that in the DAAA reaction, the nucleophile and the electrophile were generated simultaneously. Since the π-allylpalladium cation must serve as the counterion for the enolate, the enolate probably exists as a tight-ion-pair. This largely prevents the common side reactions of enolates associated with the equilibrium between different enolates. The much milder reaction conditions as well as the much broader substrate scope also represent the advantages of the DAAA reaction over the direct allylation of preformed metal enolates.
- Trost, Barry M.,Xu, Jiayi,Schmidt, Thomas
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supporting information; experimental part
p. 18343 - 18357
(2010/04/25)
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- Palladium-catalyzed diastereoselective and enantioselective allylic alkylations of ketone enolates
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Lithium and magnesium enolates of cyclohexanone undergo palladium-catalyzed allylic alkylations under mild conditions. Diastereoselectivity and enantioselectivity are observed when the diphenyl- and dimethyl-substituted allylic substrates 1a and 1b are re
- Braun, Manfred,Meier, Thorsten,Laicher, Frank,Meletis, Panos,Fidan, Mesut
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scheme or table
p. 303 - 314
(2009/04/10)
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- Dioxime oxalates; new iminyl radical precursors for syntheses of N-heterocycles
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Symmetrical and unsymmetrical dioxime oxalates were prepared by treatment of oximes with oxalyl chloride. UV photolysis of these precursors was found to be an atom-efficient way of generating iminyl radicals. The process was most efficient for dioxime oxalates having aryl substituents attached to their C{double bond, long}N bonds. The method was useful for EPR spectroscopic study of iminyl and iminoxyl radicals. Photolyses in toluene solution, of dioxime oxalates containing alkenyl acceptor groups, yielded unsaturated iminyl radicals that ring closed to afford 3,4-dihydro-2H-pyrroles in good yields. Dioxime oxalates with biphenyl substituents also released iminyl radicals that ring closed onto the aromatic acceptor groups and, in acetonitrile solution, this approach provided a useful and atom-efficient method of making substituted phenanthridines.
- Portela-Cubillo, Fernando,Lymer, James,Scanlan, Eoin M.,Scott, Jackie S.,Walton, John C.
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supporting information; experimental part
p. 11908 - 11916
(2009/04/06)
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- Gold- Vs. platinum-catalyzed polycyclizations by O-acyl migration. solvent-free reactions
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Polycyclic derivatives incorporating a cyclopropyl group have been efficiently synthesized from propargyl acetates using platinum(II), gold(I) and gold(III) catalysis. These reactions which are also viable for the preparation of medium-sized rings, proceed with a complete diastereocontrol and can also be run in neat conditions.
- Moreau, Xavier,Goddard, Jean-Philippe,Bernard, Matthieu,Lemiere, Gilles,Lopez-Romero, Juan Manuel,Mainetti, Emily,Marion, Nicolas,Mouries, Virginie,Thorimbert, Serge,Fensterbank, Louis,Malacria, Max
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scheme or table
p. 43 - 48
(2009/04/08)
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- Simple and efficient asymmetric α-alkylation and α,α- bisalkylation of acyclic ketones by using chiral N-amino cyclic carbamate hydrazones
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(Chemical Equation Presented) Distinguishing left from right: In the title reactions, chiral N-amino cyclic carbamates (ACCs) substantially diminish the drawbacks associated with the use of chiral dialkyl hydrazines, yet provide excellent stereoselectivity and high yields. In addition, ACCs exhibit a unique directing effect that overrides the inherent selectivity of lithium diisopropylamide (LDA) and enables the asymmetric α,α-bisalkylation of ketones (see scheme).
- Lim, Daniel,Coltart, Don M.
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experimental part
p. 5207 - 5210
(2009/04/11)
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- Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides
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Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.
- Pryde, David C.,Maw, Graham N.,Planken, Simon,Platts, Michelle Y.,Sanderson, Vivienne,Corless, Martin,Stobie, Alan,Barber, Christopher G.,Russell, Rachel,Foster, Laura,Barker, Laura,Wayman, Christopher,Van Der Graaf, Piet,Stacey, Peter,Morren, Debbie,Kohl, Christopher,Beaumont, Kevin,Coggon, Sara,Tute, Michael
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p. 4409 - 4424
(2007/10/03)
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- Direct catalytic intermolecular α-allylic alkylation of aldehydes by combination of transition-metal and organocatalysis
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(Chemical Equation Presented) All in the same pot together: The direct catalytic α-allylic alkylation of aldehydes and cyclic ketones is achieved by using a simple, unprecedented one-pot procedure. Transition-metal and enamine catalysis are combined so that α-allylic alkylated aldehydes and cyclic ketones are formed in high yield with a direct catalytic chemo- and regioselective method.
- Ibrahem, Ismail,Cordova, Armando
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p. 1952 - 1956
(2007/10/03)
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- COMBINATION THERAPY WITH INHIBITORS OF INDUCIBLE NITRIC OXIDE SYNTHASE AND ALKYLATING AGENTS
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A combination therapy comprising administration of a carbamoylating chemotherapeutic agent in conjunction with administration of a selective iNOS inhibitor compound is disclosed. Optionally, resection and radiation therapy are provided with the therapeutic combination. A medicament comprising a carbamoylating chemotherapeutic agent and a selective iNOS inhibitor compound together with a pharmaceutically acceptable carrier is further disclosed. A kit comprising a carbamoylating chemotherapeutic agent and a selective iNOS inhibitor compound is further disclosed.
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Page/Page column 113-114
(2010/02/11)
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- Palladium-catalyzed stereoselective allylic alkylation of lithium enolates
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The lithium enolates, generated from cyclohexanone, cyclopentanone, and 1-tetralone, react with allyl acetate 1b or carbonate 1c enantioselectively, when catalyzed by (R)- or (S)-BINAP-derived palladium complexes. The presence of lithium chloride is cruci
- Braun, Manfred,Meier, Thorsten
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p. 2968 - 2972
(2007/10/03)
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- Regio- and enantioselective Pd-catalyzed allylic alkylation of ketones through allyl enol carbonates
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The Pd-catalyzed reorganization of enol allyl carbonates to allylated ketones occurs asymmetrically in the presence of chiral ligands previously developed in this group. With 2-methylcyclohexanone, asymmetric regioselective alkylation occurs at the more s
- Trost, Barry M.,Xu, Jiayi
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p. 2846 - 2847
(2007/10/03)
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- METHODS FOR TREATMENT AND PREVENTION OF GASTROINTESTINAL CONDITIONS
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Therapeutic methods for the prevention ad treatment of conditions and diseases of the gastrointestinal tract involving an overproduction of nitric oxide by inducible nitric oxide synthase are described, the methods including administering to a subject in need thereof a therapeutically effective amount of a selective inhibitor of inducible nitric oxide synthase (iNOS). The methods also include the use of selective inhibitors of iNOs in combination with other therapeutic agents, including antimicrobial agents and antisecretory agents.
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Page/Page column 113-114
(2010/02/06)
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- A modified thermodynamically controlled deracemization of 2-allylcyclohexanone and its application to asymmetric synthesis of (R)-(-)-epilachnene
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The efficiency of thermodynamically controlled deracemization was influenced considerably by the solvent used. Based on this finding, an improved method was developed, by which 2-allylcyclohexanone was converted to the R-isomer of 93% ee in 72% yield. As an application of the method, (R)-(-)-epilachnene, an antipode of the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized in short steps.
- Kaku, Hiroto,Okamoto, Natsuko,Nakamaru, Aya,Tsunoda, Tetsuto
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p. 516 - 517
(2007/10/03)
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- Cross-coupling reaction of α-chloroketones and organotin enolates catalyzed by zinc halides for synthesis of γ-diketones
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The reaction of tin enolates 1 with α-chloro- or bromoketones 2 gave γ-diketones (1,4-diketones) 3 catalyzed by zinc halides. In contrast to the exclusive formation of 1,4-diketones 3 under catalytic conditions, uncatalyzed reaction of 1 with 2 gave aldol-type products 4 through carbonyl attack. NMR study indicates that the catalyzed reaction includes precondensation between tin enolates and α-haloketones providing an aldol-type species and their rearrangement of the oxoalkyl group with leaving halogen to produce 1,4-diketones. The catalyst, zinc halides, plays an important role in each step. The carbonyl attack for precondensation is accelerated by the catalyst as Lewis acid and the intermediate zincate promotes the rearrangement by releasing oxygen and bonding with halogen. Various types of tin enolates and α-chloro and bromoketones were applied to the zinc-catalyzed cross-coupling. On the other hand, the allylic halides, which have no carbonyl moiety, were inert to the zinc-catalyzed coupling with tin enolates. The copper halides showed high catalytic activity for the coupling between tin enolates 1 and organic halides 7 to give γ,δ-unsaturated ketones 8 and/or 9. The reaction with even chlorides proceeded effectively by the catalytic system.
- Yasuda, Makoto,Tsuji, Shoki,Shigeyoshi, Yusuke,Baba, Akio
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p. 7440 - 7447
(2007/10/03)
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- Heterobicyclic and tricyclic nitric oxide synthase inhibitors
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The current invention discloses useful bicyclic and tricyclic amidino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use as nitric oxide synthase inhibitors.
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- Cyclic amidino agents useful as nitric oxide synthase inhibitors
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The current invention discloses useful amidino derivative useful as nitric oxide synthase inhibitors.
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- Amidino derivatives useful as nitric oxide synthase inhibitors
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The current invention discloses useful pharmaceutical compositions containing amidino derivative useful as nitric oxide synthase inhibitors.
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- Azepine derivatives useful as nitric oxide synthase inhibitors
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The current invention discloses azepine derivatives useful as nitric oxide synthase inhibitors.
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- Synthesis of enantiomerically pure bicyclic lactams
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Enantiomerically pure homologous 1-azabicyclo-[x.y.0]alkanones (x = 4-5, y = 4-7) can be synthesized by ring closing olefin metathesis using Grubbs' ruthenium catalyst. By starting from monocyclic lactams, the bicyclic products, even eight- and nine-membered rings, are formed in high yields. The monocyclic lactames can be obtained enantiomerically pure by enzyme-catalyzed kinetic resolution.
- Diedrichs, Nicole,Westermann, Bernhard
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p. 1127 - 1129
(2007/10/03)
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- Dephosphonylation of β-carbonyl phosphonates
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A new methodology has been developed for the P-C bond cleavage of β- carbonyl phosphonates. The α,α-disubstituted β-keto phosphonates and the α-carbamoyl phosphonates have been shown to undergo dephosphonylation by reaction of their lithium enolate with LiAlH4, followed by quenching with aqueous H2SO4, affording regioselectively α,α-disubstituted ketone and α-substituted and α,α-disubstituted secondary amides.
- Lee, Shi Yong,Lee, Chi-Wan,Oh, Dong Young
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p. 7017 - 7022
(2007/10/03)
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- Copper(II) chloride mediated racemization-free hydrolysis of α- alkylated ketone SAMP-hydrazones
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Treatment of ketone SAMP-hydrazones 1a-k with an aqueous copper(II) chloride solution yields the corresponding ketones 2a-k in 52-94% yield and with high enantiomeric purities (ee = 89-99%). The cleavage conditions do not affect functionalities sensitive to oxidation and strong acids. The alkylation/cleavage protocol can be carried out in 'one-pot'.
- Enders, Dieter,Hundertmark, Thomas,Lazny, Ryszard
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- Amidino dervatives useful as nitric oxide synthase inhibitors
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The current invention discloses useful pharmaceutical compositions containing azepine derivatives useful as nitric oxide synthase inhibitors.
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- Enantioselective protonation of prochiral enolates with chiral imides
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New chiral proton sources possessing an asymmetric 2-oxazoline ring, (S,S)-imide 1 and related imides, were synthesized from Kemp's triacid and optically active 2-amino alcohols. With these chiral imides, various lithium enolates of α-monoalkylated cycloalkanones were effectively protonated with excellent to moderate enantioselectivity. An increase in enantioselectivity was observed in the asymmetric protonation of prochiral enolates with (S,S)- imide 1 using lithium salt as an additive. For example, (R)-enriched 2-n- pentylcyclopentanone 35 was obtained in high yield with 90% ee when the silyl enol ether 33 was treated with n-BuLi in the presence of 5 equiv of LiBr in Et2O, and the resulting lithium enolate 34 was then protonated by a solution of (S,S)-imide 1 in THF. In contrast, the product 35 obtained without LiBr exhibited a lower enantiomeric excess (74% ee).
- Yanagisawa, Akira,Kikuchi, Tetsuo,Kuribayashi, Takeshi,Yamamoto, Hisashi
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p. 10253 - 10264
(2007/10/03)
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- Stereoselective reactions. 30. Enantioselective alkylation of the lithium enolates of six-membered cyclic ketones using tetradentate chiral amines in the presence of lithium bromide
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An efficient enantioselective alkylation of the lithium enolates of cyclohexanone and 1-tetralone with reactive alkyl halides was realized using a stoichiometric amount of a tetradentate chiral amine as a ligand for the lithium in the presence of lithium bromide in toluene.
- Murakata, Masatoshi,Yasukata, Tatsuro,Aoki, Takumi,Nakajima, Makoto,Koga, Kenji
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p. 2449 - 2458
(2007/10/03)
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- Deracemization of 2-alkylcyclohexanones utilizing host-guest molecular association with optically active host compounds in basic suspension media
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Based on host-guest inclusion complexation in the solid state, α- substituted cyclohexanones 2α-c were deracemized using optically active host compounds in alkaline conditions to optically active 2 in excellent chemical yield with high enantiomeric excess.
- Tsunoda, Tetsuto,Kaku, Hiroto,Nagaku, Miwa,Okuyama, Etsuko
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p. 7759 - 7760
(2007/10/03)
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- α-Allylation of Carbonyl Compounds via Silyl Enol Ethers and Silyl Ketene Acetals using a Hypervalent Iodine Reagent
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Oxidation of allyltrimethylsilane with iodosobenzene and trimethylsilyl trifluoromethanesulfonate followed by treatment with trimethylsilyl enol ethers of ketones or trimethylsilyl ketene acetals of esters/lactones provides a new method for the α-allylation of the corresponding carbonyl compounds.
- Moriarty, Robert M.,Epa, Widanagamage R.,Prakash, Om
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p. 262 - 263
(2007/10/03)
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- Dephosphorylation of α-fully substituted β-keto phosphonates with LiAlH4; regioselective alkylation of ketones employing phosphonate as a temporary activating group
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Alkylation of β-keto phosphonates is performed by treatment of β-keto phosphonates with n-BuLi, followed by addition of alkyl halides. The acquired α-fully substituted β-keto phosphonates are dephosphonylated by treatment of the lithium enolates with LiAlH4, followed by quenching with aqueous H2SO4 solution. This whole procedure represents a new route to regioselective alkylation of ketones.
- Lee, Shi Yong,Hong, Jong Eoun,Jang, Won Bum,Oh, Dong Young
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p. 4567 - 4570
(2007/10/03)
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