- Application of piperazine-derived hydrazone linkers for alkylation of solid-phase immobilized ketones
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The preparation and application of three new solid supports with piperazine-derived hydrazine anchoring groups are described. The supports were used for immobilization of ketones. The ketones: cyclohexanone, 4-tert-butylcyclohexanone, 3-pentanone and tropinone, which were bound to polymers in the form of their hydrazones, were deprotonated with LDA and alkylated with propyl iodide or benzyl bromide. The resulting alkylated products were cleaved off the solid support on treatment with trifluoroacetic acid in dichloromethane. Linkers with 6- and 3-carbon atom spacers gave better results than the simple N-aminopiperazine linker.
- Lazny, Ryszard,Michalak, Michal
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- Indene Derived Phosphorus-Thioether Ligands for the Ir-Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups
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A family of phosphite/phosphinite-thioether ligands have been tested in the Ir-catalyzed asymmetric hydrogenation of a range of olefins (50 substrates in total). The presented ligands are synthesized in three steps from cheap indene and they are air-stable solids. Their modular architecture has been crucial to maximize the catalytic performance for each type of substrate. Improving most Ir-catalysts reported so far, this ligand family presents a broader substrate scope, covering different substitution patterns with different functional groups, ranging from unfunctionalized olefins, through olefins with poorly coordinative groups, to olefins with coordinative functional groups. α,β-Unsaturated acyclic and cyclic esters, ketones and amides werehydrogenated in enantioselectivities ranging from 83 to 99% ee. Enantioselectivities ranging from 91 to 98% ee were also achieved for challenging substrates such as unfunctionalized 1,1′-disubstituted olefins, functionalized tri- and 1,1′-disubstituted vinyl phosphonates, and β-cyclic enamides. The catalytic performance of the Ir-ligand assemblies was maintained when the environmentally benign 1,2-propylene carbonate was used as solvent. (Figure presented.).
- Margalef, Jèssica,Biosca, Maria,de la Cruz-Sánchez, Pol,Caldentey, Xisco,Rodríguez-Escrich, Carles,Pàmies, Oscar,Pericàs, Miquel A.,Diéguez, Montserrat
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supporting information
p. 4561 - 4574
(2021/04/05)
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- Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins
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In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).
- Besora, Maria,Borràs, Carlota,Diéguez, Montserrat,Faiges, Jorge,Pàmies, Oscar,Pastor, Isidro M.
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p. 3424 - 3435
(2021/10/25)
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- Giving a Second Chance to Ir/Sulfoximine-Based Catalysts for the Asymmetric Hydrogenation of Olefins Containing Poorly Coordinative Groups
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This work identifies a family of Ir/phosphite-sulfoximine catalysts that has been successfully used in the asymmetric hydrogenation of olefins with poorly coordinative or noncoordinative groups. In comparison with analogue Ir/phosphine-sulfoximine catalysts previously reported, the presence of a phosphite group extended the range of olefins than can be efficiently hydrogenated. High enantioselectivities, comparable to the best ones reported, have been achieved for a wide range of olefins containing relevant poorly coordinative groups such as α,β-unsaturated enones, esters, lactones, and lactams as well as alkenylboronic esters.
- Biosca, Maria,Pàmies, Oscar,Diéguez, Montserrat
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p. 8259 - 8266
(2019/06/17)
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- Phosphite-thioether/selenoether Ligands from Carbohydrates: An Easily Accessible Ligand Library for the Asymmetric Hydrogenation of Functionalized and Unfunctionalized Olefins
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A large family of phosphite-thioether/selenoether ligands has been easily prepared from accessible L-(+)-tartaric acid and D-(+)-mannitol and applied in the M-catalyzed (M=Ir, Rh) asymmetric hydrogenation of a broad number of substrates (46 in total). Its highly modular architecture has been crucial to maximize the catalytic performance. Improving most of the reported approaches, this ligand family presents a broad substrate scope. By selecting the ligand parameters high enantioselectivities (ee's up to 99 %) have therefore been achieved in a broad range of both, functionalized and unfunctionalized substrates. Interestingly, both enantiomers of the hydrogenation products can be usually achieved by changing the ligand parameters.
- Margalef, Jèssica,Borràs, Carlota,Alegre, Sabina,Alberico, Elisabetta,Pàmies, Oscar,Diéguez, Montserrat
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p. 2142 - 2168
(2019/04/13)
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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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- Alternatives to Phosphinooxazoline (t-BuPHOX) Ligands in the Metal-Catalyzed Hydrogenation of Minimally Functionalized Olefins and Cyclic β-Enamides
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This study presents a new series of readily accessible iridium- and rhodium-phosphite/oxazoline catalytic systems that can efficiently hydrogenate, for the first time, both minimally functionalized olefins and functionalized olefins (62 examples in total) in high enantioselectivities (ees up to >99%) and conversions. The phosphite-oxazoline ligands, which are readily available in only two synthetic steps, are derived from previous privileged 4-alkyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline (PHOX) ligands by replacing the phosphine moiety by a biaryl phosphite group and/or the introduction of a methylene spacer between the oxazoline and the phenyl ring. The modular design of the ligands has given us the opportunity not only to overcome the limitations of the iridium-PHOX catalytic systems in the hydrogenation of minimally functionalized Z-olefins and 1,1-disubstituted olefins, but also to expand their use to unfunctionalized olefins containing other challenging scaffolds (e.g., exocyclic benzofused and triaryl-substituted olefins) and also to olefins with poorly coordinative groups (e.g., α,β-unsaturated lactams, lactones, alkenylboronic esters, etc.) with enantioselectivities typically >95% ee. Moreover, both enantiomers of the hydrogenation product could be obtained by simply changing the configuration of the biaryl phosphite moiety. Remarkably, the new catalytic systems also provided excellent enantioselectivities (up to 99% ee) in the asymmetric hydrogenation of another challenging class of olefins – the functionalized cyclic β-enamides. Again, both enantiomers of the reduced amides could be obtained by changing the metal from Ir to Rh. We also demonstrated that environmentally friendly propylene carbonate can be used with no loss of enantioselectivity. Another advantage of the new ligands over the PHOX ligands is that the best ligands are derived from the affordable (S)-phenylglycinol rather than from the expensive (S)-tert-leucinol. (Figure presented.).
- Biosca, Maria,Magre, Marc,Coll, Mercè,Pàmies, Oscar,Diéguez, Montserrat
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p. 2801 - 2814
(2017/08/23)
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- Bioreduction of α-Acetoxymethyl Enones: Proposal for an SN2′ Mechanism Catalyzed by Enereductase
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(Z)-3-Acetoxymethyl-4-R-3-buten-2-ones (R=aryl, alkyl) and (Z)-3-methyl-4-R-3-buten-2-ones (R=aryl) were synthesized and submitted to reduction by the yeast Saccharomyces cerevisiae producing the (R)- and (S)-4-R-3-methybutan-2-ones, respectively. This stereochemistry control strategy was applied in the syntheses of (R)- and (S)-Tropional with moderate to high enantiomeric excesses. Other (Z)-3-acyloxymethyl-4-phenyl-3-buten-2-ones showed similar behavior to the (Z)-3-acetoxymethyl counterpart, and the acylated Morita–Baylis–Hillman adduct 1-acetoxy-2-methylene-1-phenylbutan-3-one produced a mixture of products, with and without the acetoxy group, via three different reaction pathways. In addition to experiments employing whole cells, those in which isolated enereductases were used suggested that the main pathway through which the loss of the acetoxy group occurs during the biocatalytic cascade is an SN2′-type reaction, rather than formal hydrogen addition followed by acetic acid elimination. Finally, related ethyl enones were reduced enantioselectively by the yeast Candida albicans, producing both (R)- and (S)-reduction products, depending on the presence of the acetoxy group in the starting material. (Figure presented.).
- Paula, Bruno R. S.,Zampieri, Davila,Rodrigues, J. Augusto R.,Moran, Paulo J. S.
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p. 3555 - 3571
(2016/11/25)
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- Iridium-Catalyzed Asymmetric Hydrogenation with Simple Cyclohexane-Based P/S Ligands: In Situ HP-NMR and DFT Calculations for the Characterization of Reaction Intermediates
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We report a reduced but structurally valuable phosphite/phosphinite-thioether ligand library for the Ir-hydrogenation of 40 minimally functionalized alkenes, including relevant examples with poorly coordinative groups. We found that enantiomeric excesses are mainly dependent on the substrate structure and on some ligand parameters (i.e., the type of thioether/phosphorus moieties and the configuration of the phosphite group), whereas the substituents of the biaryl phosphite moiety had little impact. By tuning the ligand parameters we were able to find highly selective catalysts for a range of substrates (ees up to 99%). These phosphite/phosphinite-thioether ligands have a simple backbone and thus yield simple NMR spectra that reduce signal overlap and facilitate the identification of relevant intermediates. Therefore, by combining HP-NMR spectroscopy and theoretical studies, we were also able to identify the catalytically competent Ir-dihydride alkene species, which made it possible to explain the enantioselectivity obtained.
- Borràs, Carlota,Biosca, Maria,Pàmies, Oscar,Diéguez, Montserrat
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supporting information
p. 5321 - 5334
(2015/11/18)
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- Investigation of a novel diamine based chiral auxiliary in the asymmetric alkylation of ketones
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A novel chiral auxiliary containing a pyrrolidine ring has been utilised in the preparation of various chiral ketones with good to excellent enantioselectivities (up to 92%). It has been successfully employed in aldol and Michael reactions giving moderate to high selectivity.
- Clarke, Sarah L.,McSweeney, Christina M.,McGlacken, Gerard P.
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p. 356 - 361
(2014/04/03)
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- The asymmetric alkylation of dimethylhydrazones; Intermolecular chirality transfer using sparteine as chiral ligand
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The asymmetric alkylation of ketones represents a fundamental transformation in organic chemistry. Chiral auxiliaries have been used almost exclusively for this transformation. Herein we describe a strategy for the generation of enantiomerically enriched α-alkylated ketones up to an er of 83:17, using a chiral ligand protocol. This journal is
- McSweeney, Christina M.,Foley, Vera M.,McGlacken, Gerard P.
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supporting information
p. 14817 - 14819
(2014/12/11)
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- A theoretically-guided optimization of a new family of modular P,S-ligands for iridium-catalyzed hydrogenation of minimally functionalized olefins
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A library of modular iridium complexes derived from thioether-phosphite/phosphinite ligands has been evaluated in the asymmetric iridium-catalyzed hydrogenation of minimally functionalized olefins. The modular ligand design has been shown to be crucial in finding highly selective catalysts for each substrate. A DFT study of the transition state responsible for the enantiocontrol in the Ir-catalyzed hydrogenation is also described and used for further optimization of the crucial stereodefining moieties. Excellent enantioselectivities (enantiomeric excess (ee) values up to 99%) have been obtained for a range of substrates, including E- and Z-trisubstituted and disubstituted olefins, α,β-unsaturated enones, tri- and disubstituted alkenylboronic esters, and olefins with trifluoromethyl substituents.
- Margalef, Jèssica,Caldentey, Xisco,Karlsson, Erik A.,Coll, Mercè,Mazuela, Javier,Pàmies, Oscar,Diéguez, Montserrat,Pericàs, Miquel A.
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supporting information
p. 12201 - 12214
(2015/03/31)
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- Substrate scope and synthetic applications of the enantioselective reduction of α-alkyl-β-arylenones mediated by Old Yellow Enzymes
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The ene-reductases mediated bioreduction of a selection of open-chain α-alkyl-β-aryl enones afforded the corresponding saturated α-chiral ketones in high yield and optical purity in several cases. The stereo-electronic requirements of the reaction have been investigated, considering the nature and location of substituents on the aromatic ring as well as the steric hindrance at the α-position and adjacent to the carbonyl functionality. The general considerations drawn allow us to guide the design of α,β-unsaturated ketones to be employed as substrates of ene-reductases in future preparative applications. An interesting case of orthogonality between enzyme-based and substrate-based stereocontrol within the highly homologous ene-reductases from Saccharomyces species (OYE1-3) has been reported and rationalized with the help of computational docking studies. Furthermore, to demonstrate the synthetic versatility of the reaction, the key chiral precursors of biologically active compounds such as (2′R)- stenusines and (S)-iopanoic acid were obtained. The very robust protocol allowed us to run the reactions on preparative scale in quantitative yields, with a simple work-up and no chromatographic purification steps. The Royal Society of Chemistry 2013.
- Brenna, Elisabetta,Cosi, Sara Lucia,Ferrandi, Erica Elisa,Gatti, Francesco G.,Monti, Daniela,Parmeggiani, Fabio,Sacchetti, Alessandro
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p. 2988 - 2996
(2013/07/25)
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- Development of catalysts for the stereoselective hydrogenation of α,β-unsaturated ketones
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Iridium phosphinitoxazoline complexes were found to be new efficient catalysts for the asymmetric hydrogenation of arylated α,β- unsaturated ketones. Linear as well as cyclic substrates are hydrogenated with similar success, giving selectivities of up to 99.7% ee.
- Maurer, Frauke,Huch, Volker,Ullrich, Angelika,Kazmaier, Uli
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experimental part
p. 5139 - 5143
(2012/07/03)
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- Indium-catalyzed coupling reaction between silyl enolates and alkyl chlorides or alkyl ethers
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The coupling reactions of alkyl chlorides with silyl enolates catalyzed by InBr3, and the coupling reactions of alkyl ethers with silyl enolates catalyzed by the combined Lewis acid of InBr3/Me3SiBr are described. In both reaction systems, various types of silyl enolates were used to give corresponding α-alkylated esters, ketones, carboxylic acids, amides, thioesters, and aldehydes.
- Nishimoto, Yoshihiro,Saito, Takahiro,Yasuda, Makoto,Baba, Akio
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experimental part
p. 5462 - 5471
(2009/12/01)
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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 18-19
(2009/12/05)
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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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- A highly enantioselective, moderately anti-selective aldol reaction using a novel hydrazone moiety as stereo director
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The use of novel hydrazones as stereo directors with a view to develop a highly enantioselective, anti-diastereoselective aldol addition procedure has been investigated. A number of proline-derived hydrazones were produced and their effectiveness in direc
- McGlacken, Gerard P.,Breeden, Simon W.
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p. 3615 - 3618
(2007/10/03)
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- Rhodium promoted isomerisation of allylic alkoxides: A new method for enolate anion formation
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Transition metal mediated isomerisation of allylic alkoxides is presented as a new method for enolate anion generation. The scope and limitations of enolate formation with the catalysts [Rh(dppe)(THF)2]+ClO4- and (Ph3P)3RhCl are explored and the synthetic potential of the methodology demonstrated in the stereoselective formation and reactions of certain ketone and aldehyde enolates.
- Gazzard, Lewis J.,Motherwell, William B.,Sandham, David A.
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p. 979 - 993
(2007/10/03)
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- Non-destructive Removal of the Bornanesultam Auxiliary in α-Substituted N-Acylbornane-10,2-sultams under Mild Conditions: An Efficient Synthesis of Enantiomerically Pure Ketones and Aldehydes
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α-Substituted N-acylbornane-10,2-sultams 6, 9, and 10 can be converted into enantiomerically pure ketones 5, 13, and 14, respectively, via a two-step procedure involving a known mercaptolysis reaction followed by an -mediated coupling of the resulting S-benzyl thioesters with Grignard reagents.Furthermore, enantiomerically pure aldehydes 23 can be obtained from α-substituted N-acylbornane-10,2-sultams 6 via a one-step reduction with (i-Bu)2AlH.No epimerization at the α-chiral center is observed during the cleavage reaction whereby the chiral auxiliary, bornane-10,2-sultam 1 or ent-1, was recovered.By using this methodology, several natural products or precursors thereof can be prepared.
- Oppolzer, Wolfgang,Darcel, Christophe,Rochet, Patrick,Rosset, Stephane,Brabander, Jef De
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p. 1319 - 1337
(2007/10/03)
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- Cerium(III) Chloride Mediated Michael Addition of RMgX to Nitroenes: a Very Efficient Access to Complex Nitroalkanes
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Reactions of RMgX-CeCl3 complexes with nitroenes lead to functionalized nitroalkanes in very good yields.
- Bartoli, Giuseppe,Bosco, Marcella,Sambri, Letizia,Marcantoni, Enrico
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p. 8651 - 8654
(2007/10/02)
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- Enzyme-mediated enantioface-differentiating hydrolysis of α-substituted sulfur-containing cyclic ketone enol esters
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An enzymatic method for obtaining optically active α-substituted acyclic ketones is described. Pichia farinosa IAM 4682, a kind of yeast, hydrolyzed enol esters of sulfur-containing cyclic ketone with differentiation of the enantiotopic face. The resultin
- Kume, Yasunari,Ohta, Hiromichi
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p. 6367 - 6370
(2007/10/02)
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