- Highly enantioselective copper(I)-phosphoramidite-catalysed additions of organoaluminium reagents to enones
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Simple phosphoramidite ligands afford good to excellent levels of enantioselectivity in 1,4-additions of AIR3 species to enones; sequential carboalumination-ACA cascades are possible. The Royal Society of Chemistry 2005.
- Alexakis, Alexandre,Albrow, Victoria,Biswas, Kallolmay,D'Augustin, Magali,Prieto, Oscar,Woodward, Simon
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- New Chiral Selectors Derived from Lactic Acid. Cocrystalline and Sorptive Optical Resolutions, and the Crystal Structure of an Inclusion Complex with 3-Methylcyclohexanone
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A new type of optically active clathrate formers derived from lactic acid, 1, is described, enabling useful enantiomer separations of different chiral compounds via cocrystalliation and, for the first time, via sorption; the X-ray structure of the 2:1 inc
- Weber, Edwin,Wimmer, Claus,Llamas-Saiz, Antonio L.,Foces-Foces, Concepcion
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- Asymmetric hydrogenation of substituted 2-pyrones
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Various substituted 2-pyrones have been hydrogenated with high enantioselectivity (up to 97% ee) to the corresponding 5,6-dihydropyrones using cationic ruthenium catalysts containing the (6,6'-dimethoxybiphenyl- 2,2'diyl)bis[3,5-di(tert-butyl)phenylphosphine] ligand. When substituents at position 3 are absent, 5,6-dihydropyrones are further hydrogenated to the fully saturated δ-lactones. In the case of 4,6-dimethyl-2H-pyran-2-one, the diastereoselectivity of the second hydrogenation step was determined by the chirality of the applied catalyst, while for the 4,5,6-trimethyl-2H-pyran2- one a double asymmetric induction effect was observed. Other cyclic substrates with endo- or exocyclic double bonds were hydrogenated, although with substantially lower enantioselectivity with respect to the 2-pyrones.
- Fehr, Matthias J.,Consiglio, Giambattista,Scalone, Michelangelo,Schmid, Rudolf
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- Revealing Additional Stereocomplementary Pairs of Old Yellow Enzymes by Rational Transfer of Engineered Residues
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Every year numerous protein engineering and directed evolution studies are published, increasing the knowledge that could be used by protein engineers. Here we test a protein engineering strategy that allows quick access to improved biocatalysts with very little screening effort. Conceptually it is assumed that engineered residues previously identified by rational and random methods induce similar improvements when transferred to family members. In an application to ene-reductases from the Old Yellow Enzyme (OYE) family, the newly created variants were tested with three compounds, revealing more stereocomplementary OYE pairs with potent turnover frequencies (up to 660 h?1) and excellent stereoselectivities (up to >99 %). Although systematic prediction of absolute enantioselectivity of OYE variants remains a challenge, “scaffold sampling” was confirmed as a promising addition to protein engineers' collection of strategies.
- Nett, Nathalie,Duewel, Sabine,Richter, Alexandra Annelis,Hoebenreich, Sabrina
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- Scalemic β-amino sulfide ligands: Use in enantioselective conjugate additions and X-ray analysis of a dimeric copper(I) complex
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The enantioselective conjugate addition using a number of scalemic β-amino sulfide ligands to achieve enantiomeric excesses of up to 64% are described together with the X-ray absolute structure analysis of a dimeric copper(I) complex.
- Cran, Graeme A.,Gibson, Colin L.,Handa, Sheetal,Kennedy, Alan R.
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- Aryl ferrophites - A new class of ligands for asymmetric catalysis
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Enantiopure lithiated 1,2-ferrocenes, [CpFe{1,2-η5-C 5H3(Ar)-(Li)}] (Ar = Ph, 4-CF3C 6H4, 1-C10H7), react readily with PhOP(OR)2 to yield [CpFe{1,2-η5-C5H 3(Ar)P(OR)2}] (R = Ph, 1,1′-biphenyl-based, 1,1′-binaphthyl-based) efficiently. Traditional routes to these species, involving the use of chlorophosphites CIP(OR)2 were found to be ineffective. These "ferrophite" ligands have been characterised by X-ray crystallography (4 examples) and shown to be effective in both nickel-catalysed addition of AlMe3 to PhCHO (up to 77 % ee) and copper(I)-catalysed additions of organoaluminium reagents to enones (up to 92 % ee). Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Albrow, Victoria E.,Blake, Alexander J.,Fryatt, Ross,Wilson, Claire,Woodward, Simon
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- Total Synthesis of (+)-Sarcophytin
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A total synthesis of the cembranoid (+)-sarcophytin is presented, featuring a Diels–Alder cycloaddition of an enone as the dienophile with an ester-derived dienoate. The study highlights a peculiar geometric preference for the Z dienoate to furnish the cy
- Nannini, Leonardo J.,Nemat, Suren J.,Carreira, Erick M.
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- Electroenzymatic asymmetric reduction of rac-3-methylcyclo-hexanone to (1S,3S)-3-methyleyclohexanol in organic/aqueous media catalyzed by a thermophilic alcohol dehydrogenase
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Electrochemical regeneration of nicotinamide cofactors has been discussed as a promising, clean, and sustainable technology since the 1980s. However, most concepts for the coupling of this technology to enzymes suffer from low productivities, insufficient
- Hoellrigl, Volker,Otto, Katja,Schmid, Andreas
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- CATALYTIC ASYMMETRIC SYNTHESES II. HYDROGENATION OF α,β-UNSATURATED KETONES USING CHIRAL RUTHENIUM COMPLEXES
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α,β-Unsaturated ketones have been hydrogenated in the presence of HRuCl(TBPC)2 (TBPC) = (-)-trans-1,2-bis(diphenylphosphinomethyl)cyclobutane) to give ketones with a maximum optical purity of 62percent.Factors affecting the stereoselectivity of the catalytic reaction are discussed.
- Massonneau, Viviane,Maux, Paul Le,Simonneaux, Gerard
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- A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation
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We report an engineered panel of ene-reductases (ERs) from Thermus scotoductus SA-01 (TsER) that combines control over facial selectivity in the reduction of electron deficient C[dbnd]C double bonds with thermostability (up to 70 °C), organic solvent tolerance (up to 40 % v/v) and a broad substrate scope (23 compounds, three new to literature). Substrate acceptance and facial selectivity of 3-methylcyclohexenone was rationalized by crystallisation of TsER C25D/I67T and in silico docking. The TsER variant panel shows excellent enantiomeric excess (ee) and yields during bi-phasic preparative scale synthesis, with isolated yield of up to 93 % for 2R,5S-dihydrocarvone (3.6 g). Turnover frequencies (TOF) of approximately 40 000 h?1 were achieved, which are comparable to rates in hetero- and homogeneous metal catalysed hydrogenations. Preliminary batch reactions also demonstrated the reusability of the reaction system by consecutively removing the organic phase (n-pentane) for product removal and replacing with fresh substrate. Four consecutive batches yielded ca. 27 g L?1 R-levodione from a 45 mL aqueous reaction, containing less than 17 mg (10 μM) enzyme and the reaction only stopping because of acidification. The TsER variant panel provides a robust, highly active and stereocomplementary base for further exploitation as a tool in preparative organic synthesis.
- Nett, Nathalie,Duewel, Sabine,Schmermund, Luca,Benary, Gerrit E.,Ranaghan, Kara,Mulholland, Adrian,Opperman, Diederik J.,Hoebenreich, Sabrina
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- Counterion Enhanced Organocatalysis: A Novel Approach for the Asymmetric Transfer Hydrogenation of Enones
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We present a novel strategy for organocatalytic transfer hydrogenations relying on an ion-paired catalyst of natural l-amino acids as main source of chirality in combination with racemic, atropisomeric phosphoric acids as counteranion. The combination of a chiral cation with a structurally flexible anion resulted in a novel chiral framework for asymmetric transfer hydrogenations with enhanced selectivity through synergistic effects. The optimized catalytic system, in combination with a Hantzsch ester as hydrogen source for biomimetic transfer hydrogenation, enabled high enantioselectivity and excellent yields for a series of α,β-unsaturated cyclohexenones under mild conditions. Moreover, owing to the use of readily available and chiral pool-derived building blocks, it could be prepared in a straightforward and significantly cheaper way compared to the current state of the art.
- Scharinger, Fabian,Márk Pálv?lgyi, ádám,Zeindlhofer, Veronika,Schnürch, Michael,Schr?der, Christian,Bica-Schr?der, Katharina
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p. 3776 - 3782
(2020/06/22)
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- Mechanistic-Insight-Driven Rate Enhancement of Asymmetric Copper-Catalyzed 1,4-Addition of Dialkylzinc Reagents to Enones
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The combination of [Cu(MeCN)4]TFA·TFAH (TFA = O2CCF3) with Feringa's phosphoramidite ligand (LA) provides an exceptionally active (0.75 mol %) catalyst for asymmetric conjugate additions of ZnR2 (R = Et and Me at -40 to -80 °C) to enones. Kinetic and other studies of the addition of ZnEt2 to cyclohex-2-en-1-one indicate a transition state stoichiometry composition of (ZnEt2)3(enone)4Cu2(LA)3 that is generated by transmetalation from Et2Zn(enone)2. Catalyst genesis is significantly slower than turnover (which has limited previous attempts to attain useful kinetic data); in the initial stages, varying populations of catalytically inactive, off-cycle, species are present. These issues are overcome by a double-dose kinetic analysis protocol. A rest state of [LACu(Et)(μ-TFA)(μ-{(enone)(ZnEt)2(enolate)})CuLA2]+ (through the equivalence of enolate = enone + ZnEt2) is supported by DFT studies (ωB97X-D/SRSC). Rate-determining ZnEt2(enone)2 transmetalation drives the exceptionally high catalytic activity of this system.
- Lewis, William,Nouch, Ryan,Robinson, David,Willcox, Darren,Woodward, Simon
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supporting information
(2020/03/13)
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- Asymmetric Baeyer-Villiger oxidation: Classical and parallel kinetic resolution of 3-substituted cyclohexanones and desymmetrization of: Meso -disubstituted cycloketones
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Regioselectivity is a crucial issue in Baeyer-Villiger (BV) oxidation. To date, few reports have addressed asymmetric BV oxidation of 3-substituted cycloketones due to the high difficulty of controlling regio- and stereoselectivity. Herein, we report the asymmetric BV oxidation of 3-substituted and meso-disubstituted cycloketones with chiral N,N′-dioxide/Sc(iii) catalysts performed in three ways: classical kinetic resolution, parallel kinetic resolution and desymmetrization. The methodology was applied in the total and formal synthesis of bioactive compounds and natural products. Control experiments and calculations demonstrated that flexible and adjustable catalysts played a significant role in the chiral recognition of substrates.
- Wu, Wangbin,Cao, Weidi,Hu, Linfeng,Su, Zhishan,Liu, Xiaohua,Feng, Xiaoming
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p. 7003 - 7008
(2019/07/31)
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- Enantio- A nd regioselective: Ene-reductions using F420H2-dependent enzymes
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In the past decade it has become clear that many microbes harbor enzymes that employ an unusual flavin cofactor, the F420 deazaflavin cofactor. Herein we show that F420-dependent reductases (FDRs) can successfully perform enantio-, regio- A nd chemoselective ene-reductions. For the first time, we have demonstrated that F420H2-driven reductases can be used as biocatalysts for the reduction of α,β-unsaturated ketones and aldehydes with good conversions (>99%) and excellent regioselectivities and enantiomeric excesses (>99% ee). Noteworthily, FDRs typically display an opposite enantioselectivity when compared to the well established FMN-dependent Old Yellow Enzymes (OYEs).
- Mathew, Sam,Trajkovic, Milos,Kumar, Hemant,Nguyen, Quoc-Thai,Fraaije, Marco W.
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supporting information
p. 11208 - 11211
(2018/10/15)
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- Total synthesis of TMS-ent-bisabolangelone
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The absolute configuration of bisabolangelone has been established by an eleven step total synthesis of the corresponding TMS protected antipode starting from (R)-(+)-pulegone. Comparison of the TMS-derivatives by GC on a chiral column, allowed us to assign the absolute configuration of the synthetic compound and thus of the corresponding natural product. The latter has been confirmed by the Mosher's ester analysis of the known secondary carbinol derivative.
- Riss, Bernard,Garreau, Marion,Fricero, Prisca,Podsiadly, Patricia,Berton, Nicolas,Buchter, Sophie
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p. 3202 - 3212
(2017/05/12)
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- The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands derived from D-(-)-tartaric acid
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A series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition of organozincs to enones. There was a synergic effect between the stereogenic ce
- Pang, Zeng-Bo,Tian, Mi,Li, Hai-Feng,Wang, Lai-Lai
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supporting information
p. 618 - 627
(2017/03/15)
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- Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones
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A series of novel chiral diphosphite ligands have been synthesized from (1R,2R)-trans-1,2-cyclohexanediol, (1S,2S)-trans-1,2-cyclohexanediol, racemic trans-1,2-cyclohexanediol and chlorophosphoric acid diary ester, and were successfully employed in the Cu
- Pang, Zeng-Bo,Li, Hai-Feng,Wang, Lai-Lai
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supporting information
p. 271 - 276
(2018/03/22)
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- Chiral ferrocene-based P,S ligands for Ir-catalyzed hydrogenation of minimally functionalized olefins. Scope and limitations
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A family of 12 modular ferrocenyl planar chiral phosphine-thioethers (P,S) has been studied in the asymmetric hydrogenation of minimally functionalized alkenes. These ligands differ by the substituent on sulfur or by the linker between the ferrocene moiety and the sulfur atom (no linker, methylene or methyl substituted methylene linker bearing an additional element of chirality). The cationic iridium(cod) complexes of the different P,S ligands have been efficiently synthesized. For the majority of the ligands, coordination yielded only a single diastereoisomer with full control of the absolute configuration on sulfur. The different iridium complexes have been used in the hydrogenation of various di, tri, and tetrasubstituted minimally functionalized olefins. Conversions and enantioselectivities are highly dependent on the ligand and substrate structure. Full conversions and low-to-excellent enantioselectivities could be obtained (maximum ee from 14 to 94% for 1,1-disubsituted alkenes, from 17 to 99% for trisubstituted olefins, and 34% for the tetrasubstituted alkene).
- Biosca, Maria,Coll, Mercè,Lagarde, Florian,Brémond, Emma,Routaboul, Lucie,Manoury, Eric,Pàmies, Oscar,Poli, Rinaldo,Diéguez, Montserrat
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p. 2623 - 2631
(2015/03/30)
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- Cp2ZrMeCl: A Reagent for Asymmetric Methyl Addition
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The use of Cp2ZrMeCl is described as a source of nucleophilic methyl in asymmetric catalysis. This easily prepared reagent is bench stable, weighable in air, and generally useful in highly enantioselective copper-catalyzed addition reactions at room temperature. Methyl is successfully (generally >90% ee) added in 1,4-additions to cyclic and acyclic α,β-unsaturated ketones to provide tertiary and quaternary centers. Examples of catalyst controlled diastereoselective 1,6-addition and dynamic kinetic asymmetric allylic alkylation reactions are also reported. The reagent is used in the catalytic asymmetric synthesis of naturally occurring fragrance (R)-(-)-muscone (82% yield, 91% ee).
- Garrec, Kilian,Fletcher, Stephen P.
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supporting information
p. 3814 - 3817
(2016/08/16)
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- Synthesis of (1R,3R)-1-amino-3-methylcyclohexane by an enzyme cascade reaction
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Amine transaminases (ATAs) are powerful enzymes for the synthesis of chiral amines. Although the request for amines with more than one chiral center is increasing, their synthesis is still challenging. Here we show a casacde reaction combining an enoate r
- Skalden, Lilly,Peters, Christin,Ratz, Lukas,Bornscheuer, Uwe T.
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p. 7207 - 7211
(2016/10/26)
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- Broadening the scope of Baeyer-Villiger monooxygenase activities toward α,β-unsaturated ketones: A promising route to chiral enol-lactones and ene-lactones
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Three regiodivergent Baeyer-Villiger mono-oxygenases (enantioselectively) oxidized a series of cyclic α,β-unsaturated ketones into (chiral) either enol-lactones or ene-lactones. An easy-to-use and efficient biocatalytic process based on a host-microorganism deprived of unwanted activities (knock-out mutant) was developed to enable the exclusive synthesis of unsaturated lactones. This journal is the Partner Organisations 2014.
- Reignier,De Berardinis,Petit,Mariage,Hamze,Duquesne,Alphand
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supporting information
p. 7793 - 7796
(2014/07/08)
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- Chiral phosphite ligands derived from l-(+)-tartaric acid: Synthesis and application in the Cu-catalyzed 1,4-conjugate addition of organozincs to cyclic enones
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A new series of chiral phosphite ligands derived from readily available l-(+)-tartaric acid and binaphthol derivatives were designed and prepared in convenient synthetic routes. These ligands were successfully employed in the Cu-catalyzed asymmetric conju
- Xing, Ai-Ping,Bai, Cui-Bing,Wang, Lai-Lai
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supporting information
p. 455 - 459
(2013/02/23)
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- Functionalized BINOL-mono-PHOS for multinuclear Cu-catalysts in asymmetric conjugate addition of organozinc reagents
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Functionalization of BINOL-mono-PHOS achieved the Cucatalyzed highly asymmetric conjugate addition of organozinc reagents to enones. The incorporation of a bulky hydroxy group at the 3'-position of BINOL-mono-PHOS dramatically improved the yield and enantioselectivity. The present novel BINOL-mono-PHOS ligands are effective in the Cu-catalyzed asymmetric conjugate addition of organozinc reagents in both acyclic enones and cyclohexenone.
- Endo, Kohei,Yakeishi, Sayuri,Hamada, Daisuke,Shibata, Takanori
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supporting information
p. 547 - 549
(2013/06/05)
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- CYCLIC AMINE-1-CARBOXYLIC ACID ESTER DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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Provided is a compound useful as a therapeutic drug for pain and inflammation caused by various pathological conditions such as neuropathic pain and rheumatoid arthritis. The compound of the formula (I) or a salt thereof [wherein R1 is a methyl group or a hydrogen atom, R2 represents a hydrogen atom, an alkyl group, an alkylcarbonyl group or an aryl carbonyl group, A represents a cycloalkyl group, a cycloalkenyl group, an aryl group or a heteroaryl group (each group may be substituted with a substituent selected from the group consisting of alkyl, alkenyl, cycloalkyl and halogen), n and m each represent an integer of 1, 2 or 3, and p represents an integer of 0, 1, 2 or 3].
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Page/Page column 21
(2012/02/06)
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- Hydroxy-amide functionalized azolium salts for Cu-catalyzed asymmetric conjugate addition: Stereocontrol based on ligand structure and copper precatalyst
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A series of hydroxy-amide functionalized azolium salts have been designed and synthesized for Cu-catalyzed asymmetric conjugate addition reaction. The (CH2)2-bridged hydroxy-amide functionalized azolium ligand precursors 2, in addition to the previously reported CH2-bridged azolium salts 1, have been prepared from readily available enantiopure β-amino alcohols. The combination of a Cu species with 1 or 2 efficiently promoted the 1,4-addition reaction of cyclic enones with dialkylzincs. For example, the reaction of 2-cyclohepten-1-one (17) with Bu2Zn in the presence of catalytic amounts of Cu(OTf)2 and 1 gave (S)-3-butylcycloheptanone (20) in 99% yield and 96% ee. On the other hand, when the reaction was carried out under the influence of Cu(OTf)2 combined with 2, (R)-20 in preference to (S)-20 was obtained in 98% yield and 80% ee. In this manner, the enantioselecvity was switched by controlling the structure of chiral ligand. Additionally, the reversal of enantioselectivity was also achieved by changing the Cu precatalyst from Cu(OTf)2 to Cu(acac)2 with the same ligand. The combination of Cu(acac) 2 with CH2-bridged azolium salt 1 in the reaction of 17 with Bu2Zn led to formation of (R)-20 as a major product in 55% yield and 80% ee. This result was in contrast to the Cu(OTf)2/1 catalytic system, where the 1,4-adduct with opposite configuration was obtained. Moreover, use of the Cu(acac)2/2 catalytic system produced (S)-20, while (R)-20 was formed by the Cu(OTf)2/2 catalytic system. Thus, it was found that either varying the linker of the chiral ligands or changing the counterion of Cu species between a OTf and acac ligand initially on the metal led to dual enantioselective control in the 1,4-addition reaction.
- Shibata, Naoatsu,Yoshimura, Misato,Yamada, Haruka,Arakawa, Ryuichi,Sakaguchi, Satoshi
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experimental part
p. 4079 - 4086
(2012/06/04)
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- Retro-aldol reactions in micellar media
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Convenient methods for retro-aldol reactions of a, β-unsaturated ketones in micellar media under acidic or basic conditions are proposed that enable obtaining optically pure (3R)-methylcyclohexanone and (1R,4R)-4- methylmenthone in high yields. Springer-V
- Vashchenko, Elena V.,Knyazeva, Irina V.,Krivoshey, Alexander I.,Vashchenko, Valerii V.
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p. 1545 - 1549
(2013/02/21)
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- Preparation and characterization of new C2- and C 1-symmetric nitrogen, oxygen, phosphorous, and sulfur derivatives and analogs of TADDOL. part i
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The chloro alcohols 4-6 derived from TADDOLs (=α,α, α′,α′-tetraaryl-1,3-dioxolan-4,5-dimethanols) are used to prepare corresponding sulfanyl alcohols, ethers, and amines (Scheme 1 and Table 1). The dithiol analog of TADDOL and derivatives thereof, 45-49,
- Pichota, Arkadius,Gramlich, Volker,Beck, Albert K.,Seebach, Dieter
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experimental part
p. 1239 - 1272
(2012/09/21)
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- CYCLIC AMINE-1-CARBOXYLIC ACID ESTER DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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Provided is a compound useful as a therapeutic drug for pain and inflammation caused by various pathological conditions such as neuropathic pain and rheumatoid arthritis. The compound of the formula (I) or a salt thereof [wherein R1 is a methyl group or a hydrogen atom, R2 represents a hydrogen atom, an alkyl group, an alkylcarbonyl group or an aryl carbonyl group, A represents a cycloalkyl group, a cycloalkenyl group, an aryl group or a heteroaryl group (each group may be substituted with a substituent selected from the group consisting of alkyl, alkenyl, cycloalkyl and halogen), n and m each represent an integer of 1, 2 or 3, and p represents an integer of 0, 1, 2 or 3].
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Page/Page column 24
(2011/02/19)
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- Synthesis of novel chiral bidentatephosphite ligands derived from the pyranoside backbone of monosaccharides and their application in the Cu-catalyzed conjugate addition of dialkylzinc to enones
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A series of novel bidentatephosphite ligands, derived from methyl 3,6-anhydro-α-d-glucopyranoside and chlorophosphoric acid diaryl ester, were easily synthesized. These ligands were successfully employed in the Cu-catalyzed asymmetric conjugate 1,4-additi
- Zhao, Qing-Lu,Wang, Lai-Lai
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experimental part
p. 1885 - 1890
(2012/02/05)
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- Miniaturizing biocatalysis: Enzyme-catalyzed reactions in an aqueous/organic segmented flow capillary microreactor
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A segmented flow capillary microreactor was used to perform the enzyme-catalyzed conversion of 1-heptaldehyde to 1-heptanol in a two liquid-liquid phase system. These reactor formats are established for chemical reactions but so far data describing the relevant system parameters for enzymatic catalysis are lacking. This work now addresses the impact of important parameters such as capillary diameter, flow velocity, phase ratio, and enzyme as well as substrate concentration on the performance of the enzymatic reaction under segmented flow conditions. All key parameters governing reaction performance have been correlated in a novel operational window for an easy assessment of the various system constraints. Such systems are characterized by high productivities and easy phase separation facilitating downstream processing. This work underscores the importance of segmented flow systems as a promising tool to perform multiphasic enzymatic catalysis. Abbreviations/ Nomenclature: Da: Damkoehler number; kcat: turnover number (s-1); eo: enzyme concentration (mM); I?: phase ratio; kL: mass transfer coefficient (m s-1); a: interfacial area per volume (m-1); CAe: equilibrium substrate concentration in the aqueous phase (mM); CAL: substrate concentration in the bulk aqueous phase (mM); rA: rate of reaction in the aqueous phase; mA: substrate mass transfer into the aqueous phase; STY: space time yield. Copyright
- Karande, Rohan,Schmid, Andreas,Buehler, Katja
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experimental part
p. 2511 - 2521
(2011/11/07)
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- Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones
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This work describes the enantioselective synthesis of a new series of terpenic chiral 9-aminotetrahydroacridine analogues. Several chiral ketones were synthesized from natural monoterpenes in an optically active form and subjected to the cyclodehydration reactions with anthranilonitrile in the presence of BF3·Et2O as catalyst. The 9-aminotetrahydroacridine analogues were tested as acetylcholinesterase (AChE) inhibitors. Based on qualitative structure-activity relationship some trends are suggested.
- Santos Pisoni, Diego dos,Sobieski da Costa, Jessé,Gamba, Douglas,Petzhold, Cesar Liberato,César de Amorim Borges, Antonio,Ceschi, Marco Antonio,Lunardi, Paula,Saraiva Gon?alves, Carlos Alberto
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body text
p. 526 - 535
(2010/04/06)
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- Copper-catalyzed asymmetric 1,4-conjugate addition of dialkylzinc to enones
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Asymmetric 1,4-conjugation addition of dialkylzinc (diethylzinc and dimethylzinc) to cyclic enones, chalcone and nitroalkenes was achieved by a 25 mol% (R)-6,6'-Br2-BINOL(1f), 25 mol% CuSPh and 100 mol% dicyclohexylmethylamin(Cy2NMe) catalyst system. The Cu(I) catalyst system enables the cyclic enone, chalcone and nitroalkene generality with high enantioselectivity (up to84%ee) and isolated yield (up to 94%) under mild reaction conditions.
- Gou, Shaohua,Ye, Zhongbin,Shi, Leiting,Qing, Dayong,Zhang, Wen,Wang, Yuliang
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experimental part
p. 517 - 522
(2010/10/18)
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- Synthesis of diphosphite ligands derived from glucopyranoside and their application in the Cu-catalyzed asymmetric 1,4-addition of organozinc to enones
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Novel chiral diphosphite ligands derived from glucopyranoside and H 8-binaphthol were synthesized, and successfully employed in the Cu-catalyzed asymmetric 1,4-addition of organozinc reagents dimethylzinc, diethylzinc, and diphenylzinc to cycli
- Zhao, Qing-Lu,Tse, Man Kin,Wang, Lai-Lai,Xing, Ai-Ping,Jiang, Xianxing
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experimental part
p. 2788 - 2793
(2011/03/18)
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- Synthesis of novel diphosphite ligands derived from d-mannitol and their application in Cu-catalyzed enantioselective conjugate addition of organozinc to enones
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A series of novel chiral diphosphite ligands have been synthesized from d-mannitol derivatives and chlorophosphoric acid diary ester, and were successfully employed in the copper catalyzed enantioselective conjugate addition of organozinc reagents diethyl
- Zhao, Qing-Lu,Wang, Lai-Lai,Xing, Ai-Ping
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experimental part
p. 2993 - 2998
(2011/03/22)
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- Nitroreductase from Salmonella typhimurium: Characterization and catalytic activity
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The biocatalytic activity of nitroreductase from Salmonella typhimurium (NRSal) was investigated for the reduction of α,β-unsaturated carbonyl compounds, nitroalkenes, and nitroaromatics. The synthesized gene was subcloned into a pET28 overexpression system in E.coli BL21 strain, and the corresponding expressed protein was purified to homogeneity with 15% protein mass yield and 41% of total activity recovery. NRSal showed broad substrate acceptance for various nitro compounds such as 1-nitrocyclohexene and aliphatic nitroalkenes (alkene reductase activity), as well as nitrobenzene (nitroreductase activity), with substrate conversion efficiency of > 95%. However, the reduction of enones was generally low, proceeding albeit with high stereoselectivity. The efficient biocatalytic reduction of substituted nitroalkenes provides a route for the preparation of the corresponding nitroalkanes. NRSal also demonstrated the first single isolated enzyme-catalyzed reduction of nitrobenzene to aniline through the formation of nitrosobenzene and phenylhydroxylamine as intermediates. However, chemical condensation of the two intermediates to produce azoxybenzene currently limits the yield of aniline.
- Yanto, Yanto,Hall, Melanie,Bommarius, Andreas S.
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scheme or table
p. 1826 - 1832
(2010/08/06)
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- Focused Directed Evolution of Pentaerythritol Tetranitrate Reductase by Using Automated Anaerobic Kinetic Screening of Site-Saturated Libraries
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This work describes the development of an automated robotic platform for the rapid screening of enzyme variants generated from directed evolution studies of pentraerythritol tetranitrate (PETN) reductase, a target for industrial biocatalysis. By using a 96-well format, near pure enzyme was recovered and was suitable for high throughput kinetic assays; this enabled rapid screening for improved and new activities from libraries of enzyme variants. Initial characterisation of several single site-saturation libraries targeted at active site residues of PETN reductase, are described. Two mutants (T26S and W102F) were shown to have switched in substrate enantiopreference against substrates (E)-2-aryl-1-nitropropene and α-methyl-trans-cinnamaldehyde, respectively, with an increase in ee (62 % (R) for W102F). In addition, the detection of mutants with weak activity against α,β-unsaturated carboxylic acid substrates showed progress in the expansion of the substrate range of PETN reductase. These methods can readily be adapted for rapid evolution of enzyme variants with other oxidoreductase enzymes.
- Hulley, Martyn E.,Toogood, Helen S.,Fryszkowska, Anna,Mansell, David,Stephens, Gill M.,Gardiner, John M.,Scrutton, Nigel S.
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experimental part
p. 2433 - 2447
(2011/07/08)
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- Enders SAMP-hydrazone as traceless auxiliary in the asymmetric 1,4-addition of cuprates to enones
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Conjugate additions of Gilman cyanocuprates to (5)-N-amino-2- (methoxymethyl)pyrrolidine (SAMP)-hydrazones 4, 5 derived from cyclic and acyclic α,β-unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)-1 under the hydrolysis and work-up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP-hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP-hydrazones 5, however, by the nature of the aryl substituent. Electron-donating substituents gave poor enantiomeric excesses, whereas electron-withdrawing groups provided excellent ee values of 98-99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4-addition/ methylation and traceless hydrolytic cleavage of the auxiliary (S)-1 in a one-pot reaction, resulting in enantiomerically pure methyl ketones 11-13, each of them with > 99% ee.
- Sammet, Karsten,Gastl, Christoph,Baro, Angelika,Laschat, Sabine,Fischer, Peter,Fettig, Ina
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supporting information; experimental part
p. 2281 - 2290
(2010/12/29)
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- Characterization of xenobiotic reductase A (XenA): Study of active site residues, substrate spectrum and stability
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Xenobiotic reductase A (XenA) has broad catalytic activity and reduces various α,β-unsaturated and nitro compounds with moderate to excellent stereoselectivity. Single mutants C25G and C25V are able to reduce nitrobenzene, a non-active substrate for the wild type, to produce aniline. Total turnover is dominated by chemical rather than thermal instability. The Royal Society of Chemistry 2010.
- Yanto, Yanto,Yu, Hua-Hsiang,Hall, Melanie,Bommarius, Andreas S.
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scheme or table
p. 8809 - 8811
(2011/02/28)
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- Design of chiral hydroxyalkyl- and hydroxyarylazolinium salts as new chelating diaminocarbene ligand precursors devoted to asymmetric copper-catalyzed conjugate addition
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The design and the synthesis of a set of new chiral hy- droxyalkyl- and hydroxyaryl-chelating diaminocarbene ligands is reported. Comparative catalytic studies show the importance of the scaffold design around the NHC unit to obtain a high enantiocontrol in Cu-catalyzed asymmetric conjugate addition (ACA). Whereas low selectivities are observed when the stereogenic centre is placed within the N-heterocyclic ring, an interesting match effect can be observed when central chirality is located within both of the two side chains, which enables up to 92 % ee in the catalysis reaction. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.
- Rix, Diane,Labat, Stephane,Toupet, Loic,Crevisy, Christophe,Mauduit, Marc
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scheme or table
p. 1989 - 1999
(2009/10/30)
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- ORGANIC SALTS AND METHOD FOR PRODUCING CHIRAL ORGANIC COMPOUNDS
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The invention relates to a method for producing chiral organic compounds by asymmetric catalysis, using ionic catalysts comprising a chiral catalyst anion. The claimed method is suitable for reactions which are carried out over cationic intermediate stages, such as iminium ions or acyl pyridinium ions. The invention enables the production of chiral compounds with high ee values, that until now could only be obtained by means of costly purification methods.
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Page/Page column 7-8
(2009/02/11)
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- Directed evolution of an enantioselective enoate-reductase: Testing the utility of iterative saturation mutagenesis
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Directed evolution utilizing iterative saturation mutagenesis (ISM) has been applied to the old yellow enzyme homologue YqjM in the quest to broaden its substrate scope, while controlling the enantioselectivity in the bioreduction of a set of substituted cyclopentenone and cyclohexenone derivatives. Guided by the known crystal structure of YqjM, 20 residues were selected as sites for saturation mutagenesis, a pooling strategy based on the method of Phizicky [M. R. Martzen, S. M. McCraith, S. L. Spinelli, F. M. Torres, S. Fields, E. J. Grayhack, E. M. Phizicky, Science 1999, 286, 1153-1155] being used in the GC screening process. The genes of some of the hits were subsequently employed as templates for randomization experiments at the other putative hot spots. Both (R)-and (S)-selective variants were evolved using 3-methylcyclohexenone as the model substrate in the asymmetric bioreduction of the olefinic functionality, only small mutant libraries and thus minimal screening effort being necessary. Some of the best mutants also proved to be excellent catalysts when testing other prochiral substrates without resorting to additional mutagenesis/screening experiments. Thus, the results constitute an important step forward in generalizing the utility of ISM as an efficient method in laboratory evolution of enzymes as catalysts in organic chemistry.
- Bougioukou, J. Despina,Kille, Sabrina,Taglieber, Andreas,Reetz, Manfredt.
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experimental part
p. 3287 - 3305
(2010/04/30)
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- Copper-catalyzed asymmetric conjugate addition with Grignard reagents and SimplePhos ligands
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Herein we report the copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic and acyclic enones, with SimplePhos as chiral ligands. A variety of Grignard reagents can be added to a range of cyclic and acyclic enones, with moderate to good enantioselectivities (ee's up to 86%).
- Palais, Laetitia,Alexakis, Alexandre
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experimental part
p. 2866 - 2870
(2010/04/05)
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- Asymmetric hydrogenation of heteroaromatic ketones and cyclic and acyclic enones mediated by Cu(I)-chiral diphosphine catalysts
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Copper(I)-catalyzed asymmetric hydrogenation of heteroaromatic ketones, cyclic and acyclic enones is reported. The choice of the chiral diphosphine ligand highly influenced enantiose-lectivity as well as chemoselectivity. Highly enantioselective hydrogenation of ortho-substituted heteroaromatic ketones was achieved using BDPP as the ligand. In the 1,2-selective hydrogenation of acylic enone, SEGPHOS gave higher enantioselectivity than BDPP. On the other hand, the bulky ligand DTBM-SEGPHOS had a 1,4-selective nature, leading to the first highly 1,4-selective and enantioselective hydrogenation of cyclic enones.
- Shimizu, Hideo,Nagano, Takuto,Sayo, Noboru,Saito, Takao,Ohshima, Takashi,Mashima, Kazushi
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body text
p. 3143 - 3146
(2010/03/24)
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- Asymmetric catalysis: Resin-bound hydroxyprolylthreonine derivatives in enamine-mediated reactions
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Control of stereochemistry is achieved using two TentaGel-bound di-tert-butoxyprotected hydroxyprolyl-threonine catalysts (see picture, sphere represents TentaGel). These catalysts mediate asymmetric tandem enamine/Michael reactions with high enantioselectivity and complete diastereoselectivity; the choice of catalyst depends on the desired absolute configuration. (Chemical Equation Presented).
- Carpenter, Richard D.,Fettinger, James C.,Lam, Kit S.,Kurth, Mark J.
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supporting information; experimental part
p. 6407 - 6410
(2009/03/11)
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- Highly enantio- and s-trans C=C bond selective catalytic hydrogenation of cyclic enones: Alternative synthesis of (-)-menthol
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A highly enantioselective catalytic hydrogenation of cyclic enones was achieved by using the combination of a cationic Rh1 complex, (S)-5,5′-bis{di(3,5-di-tert-butyl-4-methoxyphenylphosphino)}-4, 4′-bi-1,3-benzodioxole (DTBM-SEGPHOS), and (CH2CH 2PPh3Br)2. The presence of an s-cis C=C bond isopropylidene moiety on the cyclic enone influenced the enantioselectivity of the hydrogenation. Thus, the hydrogenation of 3-alkyl-6-isopropylidene-2- cyclohexen-1-one, which contains both s-cis and s-trans enones, proceeded in excellent enantioselectivity (up to 98% ee). To obtain high enantio- and s-trans selectivities, the addition of a halogen source to the cationic Rh complex was the essential step. With the key step of the s-trans selective asymmetric hydrogenation of piperitenone, we demonstrated a new synthetic method for optically pure (-)-menthol via three atom-economical hydrogenations. Moreover, we found that the complete s-trans and s-cis C=C bond selective reactions were also realized by the proper choice of both the chiral ligands and halides.
- Ohshima, Takashi,Tadaoka, Hiroshi,Hori, Kiyoto,Sayo, Noboru,Mashima, Kazushi
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scheme or table
p. 2060 - 2066
(2009/04/07)
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- Enantioselective hydrogenation of enones with a hydroformylation catalyst
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Use of a typical rhodium precatalyst for hydroformylation results in the enantioselective hydrogenation of cyclic enones with up to 90% ee. Extensive screening of chiral ligands reveals the simple ligand Chiraphos as the best ligand, so far. The hydrogenation shows high chemoselectivity. Exclusive formation of saturated, chiral b-branched ketones is observed. It is proposed that the catalyst follows a frustrated hydroformylation pathway ("monohydride-based mechanism") and differs by that from the classical cationic Schrock-Osborn type rhodium precatalysts ("dihydride-based mechanism") for enantioselective hydrogenation. The catalyst operates under neat conditions and is easily recyclable by simply distilling off the reaction mixture and treatment with syn gas prior to hydrogenation.
- Scheuermann Nee Taylor, Caroline J.,Jaekel, Christoph
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supporting information; experimental part
p. 2708 - 2714
(2009/10/06)
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- Stereoselective alkylations of chiral nitro imine and nitro hydrazone dianions. Synthesis of enantiomerically enriched 3-substituted 1-nitrocyclohexenes
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(Chemical Equation Presented) Dianions of chiral nitro imines (generated by a combination of LDA and s-BuLi) underwent diastereoselective alkylation with methyl, butyl, isopropyl, allyl, and methallyl iodides. In contrast to the behavior of simple metalloenamines, the most selective auxiliary contained no coordinating groups but did possess a large steric difference between the two substituents. The yield and selectivity of the alkylations were improved by the addition of HMPA or DMPU. The use of (S)-1-naphthylethylamine as the auxiliary afforded the R absolute configuration of the alkylation products. This stereochemical outcome could be rationalized by simple steric approach controlled alkylation in a conformationally fixed, internally coordinated dianion. A SAMP nitro hydrazone gave poorer yields and selectivities.
- Denmark, Scott E.,Ares, Jeffrey J.
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supporting information; experimental part
p. 9647 - 9656
(2009/04/11)
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- Chiral thiophosphoramide and thioamide ligands in catalytic asymmetric carbon-carbon bond-formation reactions
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Metal complexes with organosulfur ligands exist widely in nature. The high polarizability of the electrons on the sulfur atoms is responsible for a variety of structures and the reactivity of metal complexes with sulfur-containing ligands. Organosulfur-containing chiral ligands have various applications in catalytic asymmetric reactions. Our group has been interested in the applications of a series of thiophosphoramide and thioamide ligands in asymmetric carbon-carbon bond-formation reactions. In this account, we describe the synthesis of chiral thiophosphoramide and thioamide ligands and their applications in catalytic asymmetric carbon-carbon bond formation. Georg Thieme Verlag Stuttgart.
- Zhang, Wen,Shi, Min
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- Design and synthesis of new bidentate alkoxy-NHC ligands for enantioselective copper-catalyzed conjugate addition
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A new family of chiral alkoxy-N-heterocyclic carbene (NHC) ligands has been designed for the enantioselective copper-catalyzed conjugate addition of dialkylzincs to enones. These new bidentate NHC ligands were synthesized in high overall yields using a five-step procedure starting from commercially available β-aminoalcohols. Influence of the temperature, base, solvent and copper source were studied in order to optimize the stereoselectivity of the addition. High reactivity and excellent enantioselectivity were obtained at ambient temperature with a range of cyclic enones and dialkylzinc. Addition to acyclic enones has also been studied.
- Clavier, Hervé,Coutable, Ludovic,Toupet, Lo?c,Guillemin, Jean-Claude,Mauduit, Marc
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p. 5237 - 5254
(2007/10/03)
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- Asymmetric conjugate addition of metal alkyl reagents catalyzed by copper complexes with BINPO: A hemilabile P,O-heterobidentate axially chiral ligand
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We herein report the use of a new class of P,O-bidentate arylphosphine ligand for the asymmetric copper catalyzed conjugate addition of dialkylzinc and trialkylaluminium with the enantiomeric excesses reaching 91% while (R)-muscone was obtained with 77% ee.
- Fuchs, Nicolas,D'Augustin, Magali,Humam, Munir,Alexakis, Alexandre,Taras, Rossana,Gladiali, Serafino
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p. 3143 - 3146
(2007/10/03)
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- Stereoselectivity and substrate specificity in the kinetic resolution of methyl-substituted 1-oxaspiro[2.5]octanes by Rhodotorula glutinis epoxide hydrolase
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The kinetic resolution of a range of methyl-substituted 1-oxaspiro[2.5]octanes by yeast epoxide hydrolase (YEH) from Rhodotorula glutinis has been investigated. The structural determinants of substrate specificity and stereoselectivity of YEH toward these
- Weijers, Carel A. G. M.,Meeuwse, Petra,Herpers, Robert L. J. M.,Franssen, Maurice C. R.,Sudhoelter, Ernst J. R.
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p. 6639 - 6646
(2007/10/03)
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- Highly enantioselective copper-catalyzed 1,4-conjugate addition of diethylzinc to cyclic enones and αβ-unsaturated lactones
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A significant improvement in enantioselectivity has been achieved in the 1,4-additions of diethylzinc to 2-cyclopentenone, 2-cyclohexenone and 5,6-hydro-2H-pyran-2-one (up to 93%, 98% and 94% ee, respectively) by using a chiral diphosphite-copper catalyst under suitable reaction conditions.
- Liang, Liang,Yan, Ming,Li, Yue-Ming,Chan, Albert S.C.
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p. 2575 - 2578
(2007/10/03)
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- Enantioselective conjugate addition of dialkylzinc and diphenylzinc to enones catalyzed by a chiral copper(I) binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system
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The enantioselective conjugate addition of dialkylzinc or diphenylzinc to enones was catalyzed by a copper(I)-axially chiral binaphthylthiophosphoramide or binaphthylselenophosphoramide ligand system at room temperature (20°C) or 0°C, affording the Michae
- Shi, Min,Wang, Chun-Jiang,Zhang, Wen
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p. 5507 - 5516
(2007/10/03)
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- Asymmetric 1,4-reductions of hindered β-substituted cycloalkenones using catalytic SEGPHOS-ligated CuH
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The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unpreced
- Lipshutz, Bruce H.,Servesko, Jeff M.,Petersen, Tue B.,Papa, Patrick P.,Lover, Andrew A.
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p. 1273 - 1275
(2007/10/03)
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