- 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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- 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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p. 685 - 691
(2017/04/11)
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- Finding the Selectivity Switch - A Rational Approach towards Stereocomplementary Variants of the Ene Reductase YqjM
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Ene reductases from the Old Yellow Enzyme family are versatile biocatalysts useful for the synthesis of optically active compounds. One disadvantage of biocatalysts when compared to competing catalysts in chemical syntheses is that often only one stereoisomer of the product is available. Another drawback can be the lack of activity in certain enzyme-substrate combinations. We were able to approach both of these challenges rationally in the case of the enzymatic synthesis of methyl 3-hydroxy-2-methylpropanoate (commonly denoted as the Roche ester) and derivatives thereof using the ene reductase YqjM. By a highly efficient, concept-based approach of designing mutant variants of YqjM and engineering substrates we could alter both the rate constant and the enantioselectivity of the reaction. Preparative scale reactions have been performed with successful mutants. In addition, the iterative modification of the substrate gave experiment-based insights into the binding mode of the Roche ester precursor and its derivatives.
- Rüthlein, Elisabeth,Classen, Thomas,Dobnikar, Lina,Sch?lzel, Melanie,Pietruszka, J?rg
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supporting information
p. 1775 - 1786
(2015/06/02)
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- MaxPHOS ligand: PH/NH tautomerism and rhodium-catalyzed asymmetric hydrogenations
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MaxPHOS is an active and robust P-stereogenic ligand for asymmetric catalysis. The presence of an -NH- bridge between the two phosphine moieties allows the NH/PH tautomerism to take place. The neutral ligand, in which the NH form predominates, is an air-sensitive compound. However, protonation of MaxPHOS leads to the stable PH form of the ligand, in which the overall positive charge is distributed on both P centers. This protonation turns the MaxPHOS×HBF4 salt 3 into an air-stable compound both in the solid state and in solution. The salt 3 is also a convenient precursor for the preparation of rhodium(I) complexes by direct ligand exchange with the complex [Rh(acac)(cod)]. Finally, the corresponding rhodium(I)-MaxPHOS complex was tested in the asymmetric hydrogenation of a wide range of substrates. The complex proved to be a highly selective and robust system in these reactions.
- Cristobal-Lecina, Edgar,Etayo, Pablo,Doran, Sean,Reves, Marc,Martin-Gago, Pablo,Grabulosa, Arnald,Costantino, Andrea R.,Vidal-Ferran, Anton,Riera, Antoni,Verdaguer, Xavier
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p. 795 - 804
(2014/04/03)
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- Metal-organic framework Co(D-cam)1/2(bdc)1/2(tmdpy) for improved enantioseparations on a chiral cyclodextrin stationary phase in gas chromatography
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Initial efforts to combine a chiral metal-organic framework (MOF), Co(D-Cam)1/2(bdc)1/2(tmdpy) (D-Cam=D-camphoric acid, bdc=1,4-benzenedicarboxylic acid, tmdpy=4,4′-trimethylenedipyridine), with peramylated β-cyclodextrins to investigate whether the use of a MOF can enhance enantioseparations on a cyclodextrin stationary phase are reported. Compared with columns of peramylated β-cyclodextrin incorporated in a MOF containing sodium chloride, the column of peramylated β-cyclodextrin+MOF shows excellent selectivity for the recognition of racemates, and higher resolutions are achieved on the peramylated β-cyclodextrin+MOF stationary phase. Experimental results indicate that the use of Co(D-Cam) 1/2(bdc)1/2(tmdpy) can improve enantioseparations on peramylated β-cyclodextrins. This is the first report that chiral MOFs can improve enantioseparations on a chiral stationary phase for chromatography. Copyright
- Liu, Hong,Xie, Sheng-Ming,Ai, Ping,Zhang, Jun-Hui,Zhang, Mei,Yuan, Li-Ming
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p. 1103 - 1108
(2014/11/07)
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- P-CHIROGENIC ORGANOPHOSPHORUS COMPOUNDS
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The present invention relates to novel P-chirogenic organophosphorus compounds of general formula (I). The present invention also provides a process for the synthesis of said compounds of formula (I). The present invention also relates to intermediate products of general formulae (II), (III) and (IV), as shown below, which are involved in the synthesis of compounds (I). Further, the invention relates to metal complexes comprising compounds (I) as ligands. The novel compounds and complexes of the present invention are useful in asymmetric catalysis by transition metal complexes or organocatalysis, especially for asymmetric hydrogenation or allylation. Compounds of general formula (I) may useful as agrochemical and therapeutic substances, or as reagents or intermediates for fine chemistry.
- -
-
Page/Page column 88; 89; 90
(2013/03/26)
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- Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands
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A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.
- Pignataro, Luca,Boghi, Michele,Civera, Monica,Carboni, Stefano,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 1383 - 1400
(2012/03/27)
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- SIAPhos: Phosphorylated sulfonimidamides and their use in iridium-catalyzed asymmetric hydrogenations of sterically hindered cyclic enamides
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Phosphorylated sulfonimidamides (SIAPhos) undergo ion exchange reactions with cationic complexes, [Rh(cod)2BF4] and [Ir(cod) 2BarF], or neutral complexes [Rh(cod)Cl] 2 and [Ir(cod)Cl] 2, leading to unprecedented neutral complexes with PN- S-N chelates. Use of the resulting neutral iridium complexes in asymmetric hydrogenation reactions of tri- and tetrasubstituted enamides leads to products with high enantioselectivities (up to 92% ee).
- Patureau, Frederic W.,Worch, Christin,Siegler, Maxime A.,Spek, Anthony L.,Bolm, Carsten,Reek, Joost N. H.
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supporting information; experimental part
p. 59 - 64
(2012/04/10)
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- Structural and catalytic characterization of pichia stipitis OYE 2.6, a useful biocatalyst for asymmetric alkene reductions
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We have probed Pichia stipitis CBS 6054 Old Yellow Enzyme 2.6 (OYE 2.6) by several strategies including X-ray crystallography, ligand binding and catalytic assays using the wild-type as well as libraries of site-saturation mutants. The alkene reductase crystallized in space group P 63 2 2 with unit cell dimensions of 127.1×123.4 A and its structure was solved to 1.5 A resolution by molecular replacement. The protein environment surrounding the flavin mononucleotide (FMN) cofactor was very similar to those of other OYE superfamily members; however, differences in the putative substrate binding site were also observed. Substrate analog complexes were analyzed by both UV-Vis titration and X-ray crystallography to provide information on possible substrate binding interactions. In addition, four active site residues were targeted for site saturation mutagenesis (Thr 35, Ile 113, His 188, His 191) and each library was tested against three representative Baylis-Hillman adducts. Thr 35 could be replaced by Ser with no change in activity; other amino acids (Ala, Cys, Leu, Met, Gln and Val) resulted in diminished catalytic efficiency. The Ile 113 replacement library yielded a range of catalytic activities, but had very little impact on stereoselectivity. Finally, the two His residues (188 and 191) were essentially intolerant of substitutions with the exception of the His 191 Asn mutant, which did show significant catalytic ability. Structural comparisons between OYE 2.6 and Saccharomyces pastorianus OYE1 suggest that the key interactions between the substrate hydroxymethyl groups and the side-chain of Thr 35 and/or Tyr 78 play an important role in making OYE 2.6 an (S)-selective alkene reductase. Copyright
- Pompeu, Yuri A.,Sullivan, Bradford,Walton, Adam Z.,Stewart, Jon D.
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experimental part
p. 1949 - 1960
(2012/09/25)
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- A library approach to the development of BenzaPhos: Highly efficient chiral supramolecular ligands for asymmetric hydrogenation
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A library of chiral supramolecular ligands, named BenzaPhos, of straightforward preparation (two steps from commercially or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search for new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter library showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins, such as enamide S4 and β-dehydroamino ester S5 (>99 % ee: best value ever reported in both cases). A series of control experiments were undertaken to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen atom and the substrate amide NH atom. As simple as selective: BenzaPhos ligands, benzamide-containing chiral monophosphites of modular structure and trivial synthesis, have been screened in the Rh-catalyzed hydrogenation of olefins (see scheme), giving excellent enantioselectivities with three benchmark and two industrially relevant substrates. Control experiments and computational studies suggest an important role of ligand-substrate hydrogen bonding in the stereodiscriminating step of the catalytic cycle. Copyright
- Pignataro, Luca,Bovio, Chiara,Civera, Monica,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 10368 - 10381
(2012/10/08)
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- Nicotinamide-dependent Ene reductases as alternative biocatalysts for the reduction of activated alkenes
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Four NAD(P)H-dependent non-flavin ene reductases have been investigated for their ability to reduce activated C=C bonds in an asymmetric fashion by using 20 structurally diverse substrates. In comparison with flavin-dependent Old Yellow Enzyme homologues, a higher degree of electronic activation was required, because the best activities were obtained with enals and nitroalkenes rather than enones and carboxylic esters. Although FaEO from Fragaria x ananassa (strawberry) and its homologue SlEO from Solanum lycopersicum (tomato) exhibited a narrow substrate spectrum, progesterone 5β-reductase (At5β-StR) from Arabidopsis thaliana (thale cress) and leukotriene B4 12-hydroxydehydrogenase (LTB4DH/PGR) from Rattus norvegicus (rat) appear to be promising candidates, in particular for the asymmetric bioreduction of open-chain enals, nitroalkenes and α,β-unsaturated γ-butyrolactones. Competing nitro reduction and non-enzymatic Weitz-Scheffer epoxidation were largely suppressed. Electronically activated alkenes have been stereoselectively reduced by using a single-enzyme-cofactor system employing nicotinamide-dependent non-flavin ene reductases. Copyright
- Durchschein, Katharina,Wallner, Silvia,MacHeroux, Peter,Schwab, Wilfried,Winkler, Thorsten,Kreis, Wolfgang,Faber, Kurt
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p. 4963 - 4968
(2013/01/14)
-
- Supramolecular hybrid bidentate ligands in asymmetric hydrogenation
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In this study we introduce a novel class of supramolecular bidentate hybrid ligands and their application in the rhodium-catalysed asymmetric hydrogenation of prochiral olefins. A new supramolecular strategy is reported in which the two nonequivalent phosphorus atoms are linked covalently to a chiral scaffold, and the supramolecular interactions are used to control the second coordination sphere of the transition-metal catalyst. The supramolecular assembly is formed in situ by selective interaction between the nitrogen-donor atoms and the zinc(II) template, which is essential for obtaining high activity and selectivity. The investigations of the different zinc(II) and ruthenium(II) templates on the reaction parameters revealed a dependence of the activity and selectivity on the association constant between the supramolecular template and the pyridyl ligands. The scope of the supramolecular assemblies was explored in the Rh-catalysed asymmetric hydrogenation of α-dehydroamino acid esters and Roche ester derivatives. High activities and good to excellent enantioselectivities up to 99 % ee were obtained with the supramolecular ligands. Application of the supramolecular strategy on the basis of variations of the steric and electronic properties of zinc(II) templates demonstrate that these changes can influence key reaction parameters such as activity and selectivity. Copyright
- Bellini, Rosalba,Reek, Joost N. H.
-
p. 4684 - 4693
(2013/01/15)
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- Modular P-OP ligands in rhodium-mediated asymmetric hydrogenation: A comparative catalysis study
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Highly efficient and enantioselective hydrogenation reactions for α-(acylamino)acrylates, itaconic acid derivatives and analogues, α-substituted enol ester derivatives, and α-arylenamides (25 substrates) catalyzed by chiral cationic rhodium complexes of a set of P-OP ligands have been developed. The catalytic systems derived from these P-OP ligands provided a straightforward access to enantiomerically enriched α-amino acid, carboxylic acid, amine, and alcohol derivatives that are valuable chiral building blocks. Excellent efficiencies (full conversion in all cases) and extremely high enantiomeric excesses (94-99% ee) were achieved for a wide range of α-substituted enol ester derivatives, regardless of the substitution pattern. The R-oxy group of the ligand (methoxy or triphenylmethoxy) strongly influences the enantioselectivity and catalytic activity. Greater steric bulk around the metal centre correlated to greater (or similar) enantioselectivity, but also to slower hydrogenation. Furthermore, the hydrogenation rates observed with the four model substrates follow the same trend, independently of the R-oxy group of the ligand: methyl 2-acetamidoacrylate>dimethyl itaconate>1-phenylvinyl acetate>N-(1- phenylvinyl)acetamide. A substrate-to-catalyst ratio (S/C) of up to 10,000:1 was sufficient for total hydrogenation of a model substrate of intermediate reactivity (dimethyl itaconate), and did not imply any loss in conversion or enantioselectivity. Copyright
- Nunez-Rico, Jose L.,Etayo, Pablo,Fernandez-Perez, Hector,Vidal-Ferran, Anton
-
supporting information
p. 3025 - 3035
(2013/01/15)
-
- Chiral rhodium complexes derived from electron-rich phosphine-phosphites as asymmetric hydrogenation catalysts
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Two new chiral cationic rhodium(I) complexes derived from electron-rich dicyclohexylphosphine-phosphite ligands were prepared from enantiopure Sharpless epoxy ethers. The best-performing catalyst system, which bears a less bulky methyl ether moiety, exhibited remarkably high enantioselectivity (up to 99% ee) and reactivity (up to >2500 TON) in asymmetric hydrogenation reactions of various functionalized alkenes (α-(acylamino)acrylates, itaconic acid derivatives, α-substituted enol esters and α-arylenamides). Our synthetic methodology has been successfully applied to the enantioselective synthesis of the antiepileptic drug (R)-lacosamide (Vimpat).
- Etayo, Pablo,Nunez-Rico, Jose L.,Vidal-Ferran, Anton
-
experimental part
p. 6718 - 6725
(2012/02/05)
-
- Asymmetric synthesis of (R)-3-hydroxy-2-methylpropanoate ('Roche Ester') and derivatives via biocatalytic C=C-bond reduction
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Enoate reductases from the 'old yellow enzyme' family were employed for the asymmetric bioreduction of methyl 2-hydroxymethylacrylate and its O-allyl, O-benzyl and O-TBDMS derivatives to furnish (R)-configurated methyl 3-hydroxy-2-methylpropionate products in up to >99% ee Variation of the O-protective group had little influence on the stereoselectivity, but a major impact on the reaction rate.
- Stueckler, Clemens,Winkler, Christoph K.,Bonnekessel, Melanie,Faber, Kurt
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experimental part
p. 2663 - 2666
(2010/12/25)
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- Phenol-derived chiral phosphine-phosphite ligands in the rhodium-catalyzed enantioselective hydrogenation of functionalized olefins
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A set of 15 chiral Taddol- and Binol-based phosphine-phosphite ligands were tested in the Rh-catalyzed asymmetric hydrogenation of three olefins, methyl 2-hydroxymethyl-acrylate, 1-phenylvinyl acetate, and α-methyl cinnamic acid. The best enantioselectivities (up to 92% ee) were observed in the hydrogenation of methyl 2-hydroxymethyl-acrylate using Binol-based ligands. As previously observed in other applications of this class of modular chiral ligand in enantioselective catalysis, the stereochemical outcome of the reactions greatly depended on the substituents at the ligand aryl backbone in the ortho-position to the chiral phosphite unit.
- Robert, Tobias,Abiri, Zohar,Sandee, Albertus J.,Schmalz, Hans-Guenther,Reek, Joost N.H.
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scheme or table
p. 2671 - 2674
(2011/02/25)
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- Asymmetric hydrogenation with highly active IndolPhos-Rh catalysts: Kinetics and reaction mechanism
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The mechanism of the IndolPhos-Rh-catalyzed asymmetric hydrogenation of prochiral olefins has been investigated by means of X-ray crystal structure determination, kinetic measurements, high-pressure NMR spectroscopy, and DFT calculations. The mechanistic study indicates that the reaction follows an unsaturate/dihydride mechanism according to Michaelis Menten kinetics. A large value of KM (KM = 5.01 ± 0.16 M) is obtained, which indicates that the Rh-solvate complex is the catalyst resting state, which has been observed by high-pressure NMR spectroscopy. DFT calculations on the substrate-catalyst complexes, which are undetectable by experimental means, suggest that the major substrate-catalyst complex leads to the product. Such a mechanism is in accordance with previous studies on the mechanism of asymmetric hydrogenation reactions with C1-symmetric heteroditopic and monodentate ligands.
- Wassenaar, Jeroen,Kuil, Mark,Lutz, Martin,Spek, Anthony L.,Reek, Joost N. H.
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scheme or table
p. 6509 - 6517
(2010/09/11)
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- Highly modular P-OP ligands for asymmetric hydrogenation: Synthesis, catalytic activity, and mechanism
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A library of enantiomerically pure P-OP ligands (phosphine-phosphite), straightforwardly available in two synthetic steps from enantiopure Sharpless epoxy ethers is reported. Both the alkyloxy and phosphite groups can be optimized for maximum enantioselectivity and catalytic activity. Their excellent performance in the Rhcatalyzed asymmetric hydrogenation of a wide variety of functionalized alkenes (26 examples) and modular design makes them attractive for future applications. The lead catalyst incorporates an (S)-BINOL-derived (BINOL= 1,1'bi-2-naphthol) phosphite group with computational studies revealing that this moiety has a dual effect on the behavior of our P-OP ligands. On one hand, the electronic properties of phosphite hinder the binding and reaction of the substrate in two out of the four possible manifolds. On the other hand, the steric effects of the BINOL allow for discrimination between the two remaining manifolds, thereby elucidating the high efficiency of these catalysts.
- Fernandez-Perez, Hector,Donald, Steven M. A.,Munslow, Ian J.,Benet-Buchholz, Jordi,Maseras, Feliu,Vidal-Ferran, Anton
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supporting information; experimental part
p. 6495 - 6508
(2010/10/02)
-
- Asymmetric synthesis of chiral Roche ester and its derivatives via Rh-catalyzed enantioselective hydrogenation with chiral phosphine-phosphoramidite ligands
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Methyl 3-hydroxy-2-methylpropionate, known as the Roche ester, was prepared with high enantioselectivity (up to 96.7% ee) via the Rh-catalyzed asymmetric hydrogenation of methyl 2-hydroxymethylacrylate with a chiral 1,2,3,4-tetrahydro-1-naphthylamine-deri
- Qiu, Min,Wang, Dao-Yong,Hu, Xiang-Ping,Huang, Jia-Di,Yu, Sai-Bo,Deng, Jun,Duan, Zheng-Chao,Zheng, Zhuo
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experimental part
p. 210 - 213
(2009/06/20)
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- Singly hydrogen bonded supramolecular ligands for highly selective rhodium-catalyzed hydrogenation reactions
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(Chemical Presented) H bonds make the catalyst! A single hydrogen bond between ligands coordinated to a rhodium center is critical for the formation of pure supramolecular catalyst for asymmmetric hydrogenation reactions. The ester group of the amidite ligand (see scheme) also forms a hydrogen bond with the coordinated substrate. Use of the herecomplex afforded the highest enantioselectivity reported to date for the hydrogenation of several ester substrates.
- Breuil, Pierre-Alain R.,Patureau, Frederic W.,Reek, Joost N. H.
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supporting information; experimental part
p. 2162 - 2165
(2009/08/14)
-
- Application of a Supramolecular-Ligand Library for the Automated Search for Catalysts for the Asymmetric Hydrogenation of Industrially Relevant Substrates
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A procedure is described for the automated screening and lead optimization of a supramolecular-ligand library for the rhodium-catalyzed asymmetric hydrogenation of five challenging substrates relevant to industry. Each catalyst is (self-) assembled from two urea-functionalized ligands and a transition-metal center through hydrogen-bonding interactions. The modular ligand structure consists of three distinctive fragments: the urea binding motif, the spacer, and the ligand backbone, which carries the phosphorus donor atom. The building blocks for the ligand synthesis are widely available on a commercial basis, thus ena-bling access to a large number of ligands of high structural diversity. The simple synthetic steps enabled the scale-up of the ligand synthesis to multigram quantities. For the catalyst screening, a library of twelve new chiral ligands was prepared that comprised substantial variation in electronic and steric properties. The automated procedures employed ensured the fast catalyst assembly, screening, and direct acquisition of samples for analysis. It appeared that the most selective catalyst was different for every substrate investigated and that small variations in the building blocks had a major impact on the catalyst performance. For two substrates, a catalyst was found that provided the product with outstanding enantioselectivity. The subsequent automated optimization of these two leads showed that an increase of catalyst loading, dihydrogen pressure, and temperature had a positive effect on the catalyst activity without affecting the catalyst selectivity.
- Meeuwissen, Jurjen,Kuil, Mark,Van Der Burg, Alida M.,Sandee, Albertus J.,Reek, Joost N. H.
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scheme or table
p. 10272 - 10279
(2010/04/05)
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- New strategies for protecting group chemistry: Synthesis, reactivity, and indirect oxidative cleavage of para-siletanylbenzyl ethers
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Reported herein is a new entry in the growing arsenal of arylmethyl ether protecting groups. The parasiletanylbenzyl (PSB) ether is electronically similar to the benzyl ether. Cleavage of the PSB ether is accomplished under mild conditions-involving alkaline hydrogen peroxide - that are unique among cleavage protocols for arylmethyl ethers. Furthermore, the PSB group affords the user new flexibility in the implementation of protecting group strategies that revolve around multiple arylmethyl ether protecting groups. In addition to hydrogen peroxide-based cleavage protocols, conversion of a PSB ether into a para-methoxybenzyl (PMB) ether and assembly of a PSB ether from a pre-existing para-bromobenzyl (PBB) ether are described. Finally, a new reagent for installing PSB ethers under neutral "mix and heat" conditions is reported.
- Tlais, Sami F.,Lain, Hubert,House, Sarah E.,Dudley, Gregory B.
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supporting information; experimental part
p. 1876 - 1885
(2009/07/01)
-
- Asymmetric synthesis of the Roche ester and its derivatives by rhodium-INDOLPHOS-catalyzed hydrogenation
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(S)-3-Hydroxy-2-methylpropionate, known as the Roche ester, and several of its derivatives were successfully synthesized through asymmetric rhodium-catalyzed hydrogenation, using INDOLPHOS (diisopropyl{1-[(S)-3,5-dioxa- 4-phosphacyclohepta[ 2,1-a;3,4-a′]dinaphthalen-4-yl]-3-methyl-2-indolyl} phosphine) as the chiral ligand, in excellent yield and the highest ee reported up to now (TOF over 5500 h-1 at 25°C; up to 98% ee at -40°C).
- Wassenaar, Jeroen,Kuil, Mark,Reek, Joost N. H.
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scheme or table
p. 1610 - 1614
(2009/07/18)
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- Convenient general asymmetric synthesis of roche ester derivatives through catalytic asymmetric hydrogenation: Steric and electronic effects of ligands
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An efficient and concise asymmetric hydrogenation of acrylate esters promoted by the cationic ruthenium monohydride complex [Ru(H) (hη6-cot)SYNPHOS]+BF44- is reported. A full investigation of the effects of catalyst precursors, solvents, temperature, hydrogen pressure, substrates as well as steric and electronic properties of ligands was carried out. The corresponding valuable Roche ester derivatives were obtained in good to excellent isolated yields and high enantioselectivities under mild conditions. The robustness and practicability of this highly enantioselective hydrogenation was demonstrated by the synthesis of the 3-hydroxy-2-methylpropanoic acid tert-butyl ester on a multigram scale, resulting in excellent yield and ee up to 94%.
- Pautigny, Cyrielle,Jeulin, Severine,Ayad, Tahar,Zhang, Zhaoguo,Genet, Jean-Pierre,Ratovelomanana-Vidal, Virginie
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scheme or table
p. 2525 - 2532
(2009/09/07)
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- Synthesis of chiral 2-hydroxy-1-methylpropanoates by rhodium-catalyzed stereoselective hydrogenation of α-(hydroxymethyl)-acrylate derivatives
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The synthesis of chiral 3-hydroxy-2-methylpropanoic acid esters (e.g., "Roche ester" 3a) based on the rhodium-catalyzed stereoselective hydrogenation of Baylis-Hillman reaction products was investigated. Full conversions and enantioselectivities of up to 99% at a substrate/catalyst ratio of up to 500/1 were achieved by application of bisphospholanes of the catASium M series as ancillary ligands. An interesting kinetic resolution was observed by the diastereoselective hydroxy-directed hydrogenation of related racemic β-branched precursors affording mainly anti-isomers with up to 96%ee.
- Holz, Jens,Schaeffner, Benjamin,Zayas, Odalys,Spannenberg, Anke,Boerner, Armin
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experimental part
p. 2533 - 2543
(2009/09/25)
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- Highly enantioselective synthesis of 3-hydroxy-2-methylpropanoic acid esters through ruthenium-SYNPHOS-catalyzed hydrogenation: Useful building blocks for the synthetic community
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Both enantiomers of 3-hydroxy-2-methylpropanoic acid tert-butyl ester were prepared with high enantioselectivity (up to 94%) through a ruthenium- SYNPHOS-promoted asymmetric hydrogenation reaction using an atom-economic transformation from simple and inexpensive precursors.
- Jeulin, Severine,Ayad, Tahar,Ratovelomanana-Vidal, Virginie,Genet, Jean-Pierre
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p. 1592 - 1596
(2008/02/11)
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- Synthesis of Novel Chiral Benzophospholanes and Their Application in Asymmetric Hydrogenation
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A new class of chiral ligands bearing one or two benzophospholanes was developed for the purpose of Ru-catalyzed asymmetric hydrogenation. Although results of the Ru catalysis remain insufficient so far, 1,2-bis(2-isopropyl-2,3- dihydro-1H-phosphindol-1-yl)benzene (iPr-BeePHOS: 2b) has been found to provide high enantioselectivity in the Rh-catalyzed asymmetric hydrogenation of an enamide.
- Shimizu, Hideo,Saito, Takao,Kumobayashi, Hidenori
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p. 185 - 189
(2007/10/03)
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- HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE
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A compound represented by the formula: wherein ring M is a heterocyclic ring wherein--X=Yis one of--N=C,--CO--N or--CS--N; Ra and Rb are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, with the proviso that at least one of them is an optionally substituted heterocyclic ring; Ring C is an optionally substituted homocyclic or heterocyclic ring; Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and n is an integer from 1 to 6, or a salt thereof has a tachykinin receptor antagonistic activity in vitro, and is useful for preventing or treating depression, anxiety, manic-depressive illness or psychopathy.
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- Esterase catalyzed regio-and enantio-selective hydrolysis of substituted carboxylates
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Optically active α-substituted carboxylic acid derivatives were obtained with regio-and enantio-selective hydrolysis catalyzed by esterase from Pseudomonas putida MR-2068. Substrate specificities were summarized in empirical rule to predict the enantiopreferences of the esterase. High regio-selectivities were also discussed with binding models.
- Ozaki, Eiji,Sakashita, Keiichi
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p. 741 - 742
(2007/10/03)
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- SYNTHESIS OF THE (S)-ENANTIOMER OF PANICULIDINE A. ABSOLUTE CONFIGURATION OF NATURAL PANICULIDINES
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The (S)-enantiomer of paniculidine A (an indole alkaloid from the plant Murraya paniculata) was synthesized from (R)-5-acetoxy-4-methylpentanoic acid by its oxidative transformation into (S)-methyl 2-methyl-3-acetoxypropionate, substitution of the acetoxy group by bromine, Wittig reaction of (R)-2-methoxycarbonylpropyltriphenylphosphonium bromide with 1-tosyl-3-formylindole, hydrogenation of the side chain of (Z,S)-3-(3-methoxycarbonyl-1-butenyl)-tosylindole and reductive desulfonylation of (S)-3-(3-methoxycarbonylbutyl)-1-tosylindole.Comparison of the D values of the synthesized (S)-paniculidine A with published data for the natural product showed that the latter has the (R) configuration.Condensation of the (R)-4-(2-tetrahydropyranyloxy)-3-methylbromobutane obtained from (R)-5-acetoxy-4-methylpentanoic acid with β-indolylmagnesium iodide followed by removal of the tetrahydropyranyl protecting group gave the (R)-enantiomer of paniculidinol .Its (S)-enantiomer was prepared by hydride reduction of (S)-paniculidine A.
- Cheskis, B. A.,Alekseev, I. G.,Moiseenkov, A. M.
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p. 364 - 369
(2007/10/02)
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- Synthesis of the S-Enantiomer of Paniculidine A: Absolute R-Configuration of the Natural Paniculidines A and B
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The absolute R-configuration of both the title monochiral indole alkaloids has been established.
- Czeskis, Boris A.,Moissenkov, Alexander M.
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p. 1353 - 1354
(2007/10/02)
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- Enantioselective Processes. Reaction of Optically Active Amines with Photochemically Generated Ketenes
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The diastereoselectivity of the reaction of d- and l-ephedrine with ketenes photochemically generated from 6-(2-oxopropyl)-2,4,6-trimethyl-2,4-cyclohexadien-1-one (1a), 6-(2-oxopropyl)-2,6-dimethyl-2,4-cyclohexadien-1-one (1b), and 6-acetoxy-2,4,6-trimethyl-2,4-cyclohexadien-1-one (3a) is described.Configurational assignments at C(2) in the major products 5a and 6 resulting from irradiation of 1a in the presence of d-ephedrine and l-ephedrine, respectively, were made by chemical degradation and correlation studies with (S)-(+)-3-hydroxy-2-methylpropanoic acid (7a).
- Schultz, Arthur G.,Kulkarni, Yashwant S.
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p. 5202 - 5206
(2007/10/02)
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- Enantiotopically Selective Oxidation of α,ω-Diols with the Enzyme Systems of Microorganisms
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Gluconobacter were found to be capable of oxidizing prochiral diols such as 2-substituted propane-1,3-diols 1 and 3-substituted pentane-1,5-diols 4 with distinction of pro-R and pro-S sites of the molecules, in that (-)-(R)-α-substituted β-hydroxypropionic acids 2 and (+)-(3S)-3-substituted δ-valerolactones 5 were obtained, respectively.Oxidation of 3-methylpentane-1,3,5-triol 11 afforded unnatural (+)-(S)-mevalonolactone 12.The steric bulkiness of the substituents on the prochiral center and the distance from the hydroxy group greatly affected the rate and the enantioselectivity of the reaction.
- Ohta, Hiromichi,Tetsukawa, Hatsuki,Noto, Naoko
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p. 2400 - 2404
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESIS OF β-HYDROXYISOBUTYRIC ACID: A USEFUL SYNTHON IN THE SYNTHESIS OF POLYPROPIONATE-TYPE NATURAL PRODUCTS
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The aldol reaction of formaldehyde with the dicyclopentylborinyl enolate derived from S-(or R-) 1-tert-butyldimethylsilyloxy-1-cyclohexylbutan-2-one, followed by desilylation and sodium meta-periodate oxidation, provides R-(or S-) β-hydroxyisobutyric acid.
- Choy, William,Ma, Philip,Masamune, Satoru
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p. 3555 - 3556
(2007/10/02)
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