cas 127852-28-2, (R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol

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Asymmetric Hydrogenation of 3,5-Bistrifluoromethyl Acetophenone in Pilot Scale with Industrially Viable Ru/Diphosphine-Benzimidazole Complexes
A novel efficient asymmetric hydrogenation (AH) process was developed for the preparation of (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol (3), using a catalyst Ru/(4R,5R)-(+)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxoane-(R,R-Diop)-2R-(α-met
Xu, Liang,Huang, Zhi-Hong,Sandoval, Christian A.,Gu, Lian-Quan,Huang, Zhi-Shu
p. 1137 - 1141
(2014)
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A convergent approach to the synthesis of aprepitant: a potent human NK-1 receptor antagonist
A simple and convergent approach to enantiomerically pure 5-[[2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one 1, a potent orally active antagonist of the human neurokinin-1 (NK-1) receptor, is described. The synthetic procedure starts from p-fluorobenzaldehyde to access the racemic morpholinone 2 via a modified Strecker synthesis and utilizes a diastereomeric salt resolution technique to accomplish the synthesis of 1 in enantiomerically pure form and good yield.
Elati, Chandrashekar R.,Kolla, Naveenkumar,Gangula, Srinivas,Naredla, Anitha,Vankawala, Pravinchandra J.,Avinigiri, Muttu L.,Chalamala, Subrahmanyeswararao,Sundaram, Venkatraman,Mathad, Vijayavitthal T.,Bhattacharya, Apurba,Bandichhor, Rakeshwar
p. 8001 - 8004
(2007)
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Efficient synthesis of (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol, a key intermediate for aprepitant, an NK-1 receptor antagonist
Enzyme-catalyzed efficient synthesis of (1R)-[3,5-bis (trifluoromethyl) phenyl] ethanol (R)-(3), a key intermediate for aprepitant, via enantioselective transesterification of racemic 1-[3,5-bis (trifluoromethyl) phenyl] ethanol (RS)-3 using vinyl acetate as the acyl donor in the presence of Candida antarctica lipase-B (CAL-B) in an overall yield of 84% with >99% ee is described. Copyright Taylor & Francis Group, LLC.
Vankawala, Pravinchandra J.,Kolla, Naveenkumar,Elati, Chandrashekar R.,Sreenivasulu,Kumar, K. Arun,Anjaneyulu, Yerrimilli,Venkatraman, Sundaram,Bhattacharya, Apurba,Mathad, Vijayavitthal T.
p. 3439 - 3446
(2007)
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Total production of (R)-3,5-bistrifluoromethylphenyl ethanol by asymmetric reduction of 3,5-bis(trifluoromethyl)-acetophenone in the submerged culture of Penicillium expansum isolate
A total of 82 fungal isolates were screened for their ability to reduce 3,5-bis(trifluoromethyl)-acetophenone 1. Penicillium expansum was found to successfully reduce ketone 1 in the submerged culture. A second screening was performed on the active P. exp
Kurbanoglu, Esabi B.,Zilbeyaz, Kani,Taskin, Mesut,Kurbanoglu, Namudar I.
p. 2759 - 2763
(2009)
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Bioreduction of 3,5-bis(trifluoromethyl)acetophenone using ionic liquid as a co-solvent catalyzed by recombinant Escherichia coli cells
We investigated the asymmetric bioreduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to (R)-[3,5-bis(trifluoromethyl) phenyl] ethanol ((R)-BTPE) in a hydrophilic quaternary ammonium-based ionic liquid (IL)-containing system to improve the efficiency of bioreduction catalyzed by recombinant Escherichia coli cells overexpressing carbonyl reductase. Based on the low toxicity to microbial cells and moderately increased cell membrane permeability, tetramethylammonium cysteine ([N1,1,1,1][Cys]) was selected and employed as co-solvent. Some key reaction parameters involved in the bioreduction were also investigated in the [N1,1,1,1][Cys]-containing system. The optimum conditions for the process were found to be: 3.5% (w/v) [N1,1,1,1][Cys], 20% (v/v) isopropanol, 1. M BTAP, 12.7. g/L of recombinant E. coli cells, pH 6.8, reaction for 12. h at 30. °C. A 98.7% yield (with >99 % of enantiomeric excess (ee)) was obtained under the optimum conditions. The biocatalytic process was scaled up to a 5. L fermentor afforded high reaction yield in IL-containing system. The results demonstrated that the IL [N1,1,1,1][Cys] is a useful co-solvent to improve bioreduction process and may has potential applications in various biocatalytic reactions.
Wang, Nengqiang,Li, Jun,Sun, Jing,Huang, Jin,Wang, Pu
p. 119 - 125
(2015)
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Microbial and homogenous asymmetric catalysis in the reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone
Two complementary approaches for the enantioselective reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone 1 are described and compared: microbial versus asymmetric reduction of ketones through asymmetric hydrogen transfer. Among the various microorgan
Gelo-Pujic, Mirjana,Le Guyader, Frederic,Schlama, Thierry
p. 2000 - 2005
(2006)
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Identification of ketone reductase ChKRED20 from the genome of Chryseobacterium sp. CA49 for highly efficient anti-Prelog reduction of 3,5-bis(trifluoromethyl)acetophenone
A strain of Chryseobacterium sp. CA49 was isolated to perform efficient anti-Prelog reduction of 3,5-bis(trifluoromethyl)acetophenone (1a) to enantiopure (R)-3,5-bis(trifluoromethyl)-1-phenylethanol ((R)-1b), a key intermediate for the chiral drug Aprepit
Liu, Yan,Tang, Tuo-Xian,Pei, Xiao-Qiong,Zhang, Chao,Wu, Zhong-Liu
p. 1 - 8
(2014)
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Scalable, efficient process for the synthesis of (R)-3,5- bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex
(R)-3,5-Bistrifluoromethylphenyl ethanol 2, a key building block in the synthesis of aprepitant, has been synthesized from ketone 5 via catalytic asymmetric transfer hydrogenation using a simplified catalyst generation procedure. The process uses (1S,2R)-
Hansen, Karl B.,Chilenski, Jennifer R.,Desmond, Richard,Devine, Paul N.,Grabowski, Edward J. J.,Heid, Richard,Kubryk, Michele,Mathre, David J.,Varsolona, Richard
p. 3581 - 3587
(2003)
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Effective synthesis of (S)-3,5-bistrifluoromethylphenyl ethanol by asymmetric enzymatic reduction
The synthesis of (S)-3,5-bistrifluoromethylphenyl ethanol, a pharmaceutically important alcohol intermediate for the synthesis of NK-1 receptor antagonists, was demonstrated from a ketone via asymmetric enzymatic reduction. The isolated enzyme alcohol dehydrogenase from Rhodococcus erythropolis reduced the poorly water soluble substrate with excellent ee (>99.9%) and good conversion (>98%). The optimized process was demonstrated up to pilot scale using high substrate concentration (390 mM) using a straightforward isolation process achieving excellent isolation yields (>90%) and effective space time yield (100-110 g/L d). Process improvements, demonstrated at preparative scale, increased the substrate concentration to 580 mM achieving a space time yield of 260 g/L d.
Pollard, David,Truppo, Matthew,Pollard, Jennifer,Chen, Cheng-yi,Moore, Jeffrey
p. 554 - 559
(2006)
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P/S ligands derived from carbohydrates in Rh-catalyzed hydrosilylation of ketones
Reported is the synthesis of a number of diastereomerically pure cationic Rh(i)-complexes I starting from phosphinite thioglycosides. These complexes were used in the asymmetric hydrosilylation of prochiral ketones. The reactivity and enantioselectivity o
Khiar, Noureddine,Leal, Manuel Pernia,Navas, Raquel,Moya, Juan Francisco,Perez, Maria Victoria Garcia,Fernandez, Inmaculada
p. 355 - 360
(2012)
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Influence of cofactor regeneration strategies on preparative-scale, asymmetric carbonyl reductions by engineered escherichia coli
This study was designed to determine whether whole cells or crude enzyme extracts are more effective for preparative-scale ketone reductions by dehydrogenases as well as learning which cofactor regeneration scheme is most effective. Based on results from
Dascier, Dimitri,Kambourakis, Spiros,Hua, Ling,David Rozzell,Stewart, Jon D.
p. 793 - 800
(2014)
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Purification and characterization of a new carbonyl reductase from Leifsonia xyli HS0904 involved in stereoselective reduction of 3,5-bis(trifluoromethyl) acetophenone
Leifsonia xyli HS0904 can stereoselectively catalyze the bioreduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to its corresponding alcohol, which is a valuable chiral intermediate in the pharmaceuticals. In this study, a new carbonyl reductase der
Wang, Nengqiang,Huang, Jin,Luo, Hongdou,Wang, Pu,Li, Jun
p. 1 - 6
(2013)
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High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols
Dynamic kinetic resolution (DKR) of various fluorinated aryl alcohols by a combination of lipase-catalyzed enzymatic resolution with in situ ruthenium-catalyzed alcohol racemization is described. (R)-Selective Candida antarctica lipase B (CALB) was employed for transesterification of different fluoroaryl alcohols in DKR reactions delivering the corresponding acetates in high yield (≥97%) with excellent enantiomeric excess (≥98%).
Bogár, Krisztián,B?ckvall, Jan-E.
p. 5471 - 5474
(2007)
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From imine to amine: An unexpected left turn.: Cis -β Iron(II) PNNP′ precatalysts for the asymmetric transfer hydrogenation of acetophenone
A novel PNN ligand bearing an orthophenylene group and a primary amine was synthesized with the aid of a palladium-catalyzed amination and reacted with phosphonium dimers [-PR2CH2CH(OH)-]2[Br]2 R = Et, iPr, Cy,
Demmans, Karl Z.,Seo, Chris S. G.,Lough, Alan J.,Morris, Robert H.
p. 6531 - 6541
(2017)
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Half-sandwich ruthenium catalyst bearing an enantiopure primary amine tethered to an N-heterocyclic carbene for ketone hydrogenation
By using a copper transmetalation reagent [Cu-(Kaibene)2]I, the NHC ligand (S,S)-MeNC3H2NCHPhCHPhNH2 "Kaibene" was transferred to ruthenium to make a precatalyst [RuCp?(Kaibene)(MeCN)](PF6) (Cp? = 1,2,3,4,5-pentamethylcyclopentadienyl), 7, in high yield as a mixture of two diastereomers. Under relatively mild conditions (0.02 mol % Ru, 0.16 mol % KOtBu, iPrOH, 50 °C, 25 bar of H2), this compound catalyzes the hydrogenation of aryl ketones and one alkyl ketone effectively with excellent activity and productivity (TOF up to 48 s-1, TON up to 104). At higher hydrogenation pressure (46 bar), the catalytic hydrogenation of N-phenyl-benzylimine to the corresponding amine is efficiently achieved. The hydrogenation of prochiral ketones resulted in low ee (35% for 4-chloroacetophenone). NMR spectroscopy was used to observe diastereomeric hydrides RuCp?(Kaibene)(H) 13-R/S that were generated by reaction of 7 with H2 and base in THF-d8. Complementary DFT studies suggest that either the heterolytic splitting of dihydrogen to form 13-R/S or the hydride transfer to the substrate can be rate-determining depending on the substrate. Experimental and computational results support mechanisms that involve the heterolytic splitting of dihydrogen to the nitrogen of the amide-ligated form of Kaibene in THF or the heterolytic splitting to an outer-sphere alkoxide derived from the product alcohol or 2-PrOH solvent. An unusual feature is the rapid drop in ee of the product alcohol from as high as 60% (R) to 0% in some cases; this might be due to racemization of the Kaibene ligand in THF caused by the strong base or competitive inhibition of one diastereomer of the catalyst by reaction with the product (R)-alcohol.
Wan, Kai Y.,Sung, Molly M. H.,Lough, Alan J.,Morris, Robert H.
p. 6827 - 6842
(2017)
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Enzymatic preparation of optically pure t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate by a novel alcohol dehydrogenase discovered from Klebsiella oxytoca
Alcohol dehydrogenases can catalyze the inter-conversion of aldehydes and alcohols. The t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate is a key chiral intermediate in the synthesis of statin-type drugs such as Crestor (rosuvastatin calcium) and Lipitor (atorvastatin). Herein, a novel alcohol dehydrogenase (named as KleADH) discovered from Klebsiella oxytoca by a genome mining method was cloned and characterized. The KleADH was functionally overexpressed in Escherichia coli Rosetta (DE3) and the whole cell biocatalyst was able to convert t-butyl 6-chloro-(5S)-hydroxy-3-oxohexanoate to t-butyl 6-chloro-(3R,5S)-dihydroxyhexanoate with more than 99% diastereomeric excess (de) and 99% conversion in 24?h without adding any expensive cofactors. Several factors influencing the whole cell catalyst activity such as temperature, pH, the effects of metal ions and organic solvent were determined. The optimum enzyme activity was achieved at 30?°C and pH 7.0 and it was shown that 1?mM Fe3+ can increase the enzyme activity by 1.2 times. N-hexane/water and n-heptane/water biphasic systems can also increase the activity of KleADH. Substrate specificity studies showed that KleADH also exhibited notable activity towards several aryl ketones with high stereoselectivity. Our investigation on this novel alcohol dehydrogenase KleADH reveals a promising biocatalyst for producing chiral alcohols for preparation of valuable pharmaceuticals.
Xu, Tingting,Wang, Can,Zhu, Shaozhou,Zheng, Guojun
p. 72 - 79
(2017)
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Enantioselective ketone hydrogenation: From R&D to pilot scale with industrially viable Ru/phosphine-oxazoline complexes
The development of a pilot process for the enantioselective hydrogenation of 3,5-bistrifluoromethyl acetophenone (BTMA) using a Ru/phosphine-oxazoline complex in toluene in the presence of aqueous NaOH is described. Various reaction parameters and quality
Naud, Frederic,Spindler, Felix,Rueggeberg, Carsten J.,Schmidt, Andreas T.,Blaser, Hans-Ulrich
p. 519 - 523
(2007)
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Inversion of enantioselectivity in the platinum-catalyzed hydrogenation of substituted acetophenones
The enantioselective hydrogenation of ring-substituted acetophenones that possess no functional group in the α-position to the keto group represents the latest extension of the application range of the Pt-cinchona system. The influence of the type of solv
Hess, Reto,Vargas, Angelo,Mallat, Tamas,Buergi, Thomas,Baiker, Alfons
p. 117 - 128
(2004)
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Dynamic Kinetic Resolution of Alcohols by Enantioselective Silylation Enabled by Two Orthogonal Transition-Metal Catalysts
A nonenzymatic dynamic kinetic resolution of acyclic and cyclic benzylic alcohols is reported. The approach merges rapid transition-metal-catalyzed alcohol racemization and enantioselective Cu-H-catalyzed dehydrogenative Si-O coupling of alcohols and hydrosilanes. The catalytic processes are orthogonal, and the racemization catalyst does not promote any background reactions such as the racemization of the silyl ether and its unselective formation. Often-used ruthenium half-sandwich complexes are not suitable but a bifunctional ruthenium pincer complex perfectly fulfills this purpose. By this, enantioselective silylation of racemic alcohol mixtures is achieved in high yields and with good levels of enantioselection.
Oestreich, Martin,Seliger, Jan
supporting information
p. 247 - 251
(2020/10/29)

Manganese-catalyzed homogeneous hydrogenation of ketones and conjugate reduction of α,β-unsaturated carboxylic acid derivatives: A chemoselective, robust, and phosphine-free in situ-protocol
We communicate a user-friendly and glove-box-free catalytic protocol for the manganese-catalyzed hydrogenation of ketones and conjugated C[dbnd]C[sbnd]bonds of esters and nitriles. The respective catalyst is readily assembled in situ from the privileged [Mn(CO)5Br] precursor and cheap 2-picolylamine. The catalytic transformations were performed in the presence of t-BuOK whereby the corresponding hydrogenation products were obtained in good to excellent yields. The described system offers a brisk and atom-efficient access to both secondary alcohols and saturated esters avoiding the use of oxygen-sensitive and expensive phosphine-based ligands.
Topf, Christoph,Vielhaber, Thomas
(2021/07/10)

Copper-catalyzed asymmetric reductions of aryl/heteroaryl ketones under mild aqueous micellar conditions
Enantioselective syntheses of nonracemic secondary alcohols have been achieved in an aqueous micellar medium via copper-catalyzed (Cu(OAc)2·H2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones. This methodology serves as a green protocol to access enantio-enriched alcohols under mild conditions (0-22 °C) using a base metal catalyst, together with an inexpensive, innocuous, and convenient stoichiometric hydride source (PMHS). The secondary alcohol products are formed in good to excellent yields with ee values greater than 90%.
Etemadi-Davan, Elham,Fialho, David M.,Gadakh, Amol,Langner, Olivia C.,Lipshutz, Bruce H.,Sambasivam, Ganesh,Takale, Balaram S.
supporting information
p. 3282 - 3286
(2021/05/29)

Mn(i) phosphine-amino-phosphinites: a highly modular class of pincer complexes for enantioselective transfer hydrogenation of aryl-alkyl ketones
A series of Mn(i) catalysts with readily accessible and more π-accepting phosphine-amino-phosphinite (P′(O)N(H)P) pincer ligands have been explored for the asymmetric transfer hydrogenation of aryl-alkyl ketones which led to good to high enantioselectivities (up to 98%) compared to other reported Mn-based catalysts for such reactions. The easy tunability of the chiral backbone and the phosphine moieties makes P′(O)N(H)P an alternative ligand framework to the well-known PNP-type pincers.
Jayaprakash, Harikrishnan
supporting information
p. 14115 - 14119
(2021/10/25)

Method for refining chiral alcohol
The invention relates to a method for refining chiral alcohol shown as a formula (I). The method comprises the following steps: providing a crude product of the chiral alcohol shown as the formula (I); refining the crude product of chiral alcohol shown in the formula (I) by adopting a refining solvent to prepare a refined product of chiral alcohol shown in the formula (I); wherein the refining solvent is selected from at least one of diethyl ether, n-heptane, methyl tert-butyl ether and isopropyl ether; according to the refining method of the chiral alcohol, on the basis of ensuring the yield of the chiral alcohol, the residual quantity of process impurities can be controlled to be below 0.3%. The refining method is simple, special instruments and equipment are not needed, special operation skills are also not needed, and therefore the refining method is particularly suitable for industrial production and application.
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Paragraph 0102-0143

(2021/04/10)

Cobalt-catalyzed asymmetric hydrogenation of ketones: A remarkable additive effect on enantioselectivity
A chiral cobalt pincer complex, when combined with an achiral electron-rich mono-phosphine ligand, catalyzes efficient asymmetric hydrogenation of a wide range of aryl ketones, affording chiral alcohols with high yields and moderate to excellent enantioselectivities (29 examples, up to 93% ee). Notably, the achiral mono-phosphine ligand shows a remarkable effect on the enantioselectivity of the reaction.
Du, Tian,Wang, Biwen,Wang, Chao,Xiao, Jianliang,Tang, Weijun
supporting information
p. 1241 - 1244
(2020/10/02)

A Cobalt(II) Complex Bearing the Amine(imine)diphosphine PN(H)NP Ligand for Asymmetric Transfer Hydrogenation of Ketones
Novel chiral cobalt complex a containing amine(imine)diphosphine PN(H)NP ligand and complex b containing bis(amine)diphosphine PN(H)N(H)P ligand were synthesized. The structures of two complexes were characterized by X-ray crystallography and high resolution mass spectrometry. The catalytic performances of cobalt complexes a and b for asymmetric transfer hydrogenation (ATH) of ketones under mild conditions were evaluated using 2-propanolisopropanol as solvent and hydrogen source after being activated by 8 equivalents of base. Complex a showed a good reactivity for reduction of ketones, with a turnover number (TON) of up to 555, and a maximum enantiomeric excess (ee) value of up to 91 %. Complex b exhibited inertness for hydrogenation of ketones. Electronic structure studies on a and b were conducted to account for the function of ligands on the catalytic performances.
Huo, Shangfei,Chen, Hong,Zuo, Weiwei
supporting information
p. 37 - 42
(2020/10/21)

Effectiveness and Mechanism of the Ene(amido) Group in Activating Iron for the Catalytic Asymmetric Transfer Hydrogenation of Ketones
I-interacting ligands of the diphosphino amido-ene(amido) type are effective in activating iron to resemble the properties of precious metals in the catalytic asymmetric transfer hydrogenation of ketones. To further verify the effectiveness of the ene(amido) group, we synthesized four amine(imine) diphosphine iron precatalyst complexes with substituents at α and β positions relative to imino groups (1-3) or with enlarged chelate ring sizes (5,5,6-membered rings) (4). In comparison with the parent trans-(R,R)-[Fe(CO)(Cl)(PPh2CH2CHaNCHPhCHPhNHCH2CH2PPh2)]BF4 (I), the introduction of a methyl group in 1 and 2 reduced the catalytic activity but led to undiminished enantioselectivity as reaction proceeded. In comparison to the iron complexes 1-3 with a 5,5,5-coordination geometry, the complex 4 derived from the new (R,R)-P-NH-NH2 tridentate ligand showed high reactivity comparable to that of I but was unfortunately not enantioselective. The catalytic reactivity of 1, 2, and 4 illustrates the effectiveness of the ene(amido) group. An electronic structure study on the important catalytic intermediate amido-ene(amido) complex 1b proved that iron was activated by an additional I-back-donation-interaction ligand to participate in the traditional metal-ligand bifunctional pathway in the asymmetric transfer hydrogenation reactions.
Xue, Qingquan,Wu, Rongliang,Wang, Di,Zhu, Meifang,Zuo, Weiwei
supporting information
p. 134 - 147
(2021/02/05)

Mechanochemical, Water-Assisted Asymmetric Transfer Hydrogenation of Ketones Using Ruthenium Catalyst
Asymmetric catalytic reactions are among the most convenient and environmentally benign methods to obtain optically pure compounds. The aim of this study was to develop a green system for the asymmetric transfer hydrogenation of ketones, applying chiral Ru catalyst in aqueous media and mechanochemical energy transmission. Using a ball mill we have optimized the milling parameters in the transfer hydrogenation of acetophenone followed by reduction of various substituted derivatives. The scope of the method was extended to carbo- and heterocyclic ketones. The scale-up of the developed system was successful, the optically enriched alcohols could be obtained in high yields. The developed mechanochemical system provides TOFs up to 168 h?1. Our present study is the first in which mechanochemically activated enantioselective transfer hydrogenations were carried out, thus, may be a useful guide for the practical synthesis of optically pure chiral secondary alcohols.
Kolcsár, Vanessza Judit,Sz?ll?si, Gy?rgy
(2022/01/04)

Tridentate nitrogen phosphine ligand containing arylamine NH as well as preparation method and application thereof
The invention discloses a tridentate nitrogen phosphine ligand containing arylamine NH as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The tridentate nitrogen phosphine ligand disclosed by the invention is the first case of tridentate nitrogen phosphine ligand containing not only a quinoline amine structure but also chiral ferrocene at present, a noble metal complex of the type of ligand shows good selectivity and extremely high catalytic activity in an asymmetric hydrogenation reaction, meanwhile, a cheap metal complex of the ligand can also show good selectivity and catalytic activity in the asymmetric hydrogenation reaction, and is very easy to modify in the aspects of electronic effect and space structure, so that the ligand has huge potential application value. A catalyst formed by the ligand and a transition metal complex can be used for catalyzing various reactions, can be used for synthesizing various drugs, and has important industrial application value.
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Paragraph 0095-0102; 0105-0109

(2021/06/26)

Efficient Transfer Hydrogenation of Ketones using Methanol as Liquid Organic Hydrogen Carrier
Herein, we demonstrate an efficient protocol for transfer hydrogenation of ketones using methanol as practical and useful liquid organic hydrogen carrier (LOHC) under Ir(III) catalysis. Various ketones, including electron-rich/electron-poor aromatic ketones, heteroaromatic and aliphatic ketones, have been efficiently reduced into their corresponding alcohols. Chemoselective reduction of ketones was established in the presence of various other reducible functional groups under mild conditions.
Garg, Nidhi,Paira, Soumen,Sundararaju, Basker
p. 3472 - 3476
(2020/05/29)

Porous Organic Frameworks Featured by Distinct Confining Fields for the Selective Hydrogenation of Biomass-Derived Ketones
The asymmetric hydrogenation of biomass-derived molecules for the preparation of single enantiomer compounds is an effective method to reduce the rapid consumption of fossil resources. Porous organic frameworks (POFs) with pure organic surfaces may provide unusual confinement effects for organic substrates in chiral catalysis. Here, a series of POF catalysts are designed with chiral active centers decorated into sharply defined one-dimensional channels with diameters in the range of 1.2–2.9 nm. Due to the synergistic effect originating from the conjugated inner wall, the POF material (aperture size 2.4 nm) concentrates over 90% of aromatic species into the porous architecture, and its affinity is one or two orders of magnitude higher than those of classical porous solids. As determined by PBE+D3 calculation, the phenyl fragment reveals strong π–π interaction for steric hindrance around the metal active site to achieve stronger asymmetric induction. Therefore, this POF catalyst achieves high conversion (>99% yield) and enantioselectivity (>99% ee) for various substrates. The advantages of using the POF platform as a chiral catalyst can provide new perspectives on POF-based solid-state host–guest chemistry and asymmetric heterogeneous catalysis.
Yang, Yajie,Deng, Dan,Zhang, Shenli,Meng, Qinghao,Li, Zhangnan,Wang, Zeyu,Sha, Haoyan,Faller, Roland,Bian, Zheng,Zou, Xiaoqin,Zhu, Guangshan,Yuan, Ye
(2020/04/30)

Ketone Reductase Biocatalysis in the Synthesis of Chiral Intermediates Toward Generic Active Pharmaceutical Ingredients
A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to reduction by >400 commercially available ketone reductases from different suppliers. Positive screening results were achieved for five ketones screened, with multiple ketone reductases available for each successful ketone. Selectivity was typically >99.5% ee in most cases, including for the opposite enantiomer. The three best examples were then optimized and quickly scaled up to 1 L scale in high conversion and isolated yield while retaining selectivity of >99.5% ee for the desired chiral alcohol enantiomer. This work illustrates that where a wide range of enzymes are available, productive enzymes to give either alcohol enantiomer can be readily identified for many ketones and rapidly scaled up to produce chiral alcohols. This approach is particularly applicable to generating chiral API intermediates.
Forsyth, Sian M.,Moseley, Jonathan D.,Raynbird, Marina Y.,Sampson, Joanne B.,Smith, Dan A.,Wells, Andrew S.
supporting information

(2020/06/29)

RETRACTED ARTICLE: The Manganese(I)-Catalyzed Asymmetric Transfer Hydrogenation of Ketones: Disclosing the Macrocylic Privilege
The bis(carbonyl) manganese(I) complex [Mn(CO)2(1)]Br (2) with a chiral (NH)2P2 macrocyclic ligand (1) catalyzes the asymmetric transfer hydrogenation of polar double bonds with 2-propanol as the hydrogen source. Ketones (43 substrates) are reduced to alcohols in high yields (up to >99 %) and with excellent enantioselectivities (90–99 % ee). A stereochemical model based on attractive CH–π interactions is proposed.
Passera, Alessandro,Mezzetti, Antonio
supporting information
p. 187 - 191
(2019/12/11)

Stereoselective synthesis of the key intermediate of ticagrelor and its diverse analogs using a new alcohol dehydrogenase from Rhodococcus kyotonensis
Bioreduction catalyzed by alcohol dehydrogenase/reductase is one of the most valuable biotransformation processes widely used in industry. The (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol is a key chiral synthon for synthesizing the antithrombotic agent ticagrelor. Herein, a new alcohol dehydrogenase (named Rhky-ADH) identified from Rhodococcus kyotonensis by an enzyme promiscuity-based genome mining method was successfully cloned and functionally expressed in Escherichia coli. The whole cell biocatalyst harboring Rhky-ADH was biochemically characterized and was shown to be able to convert 2-Chloro-1-(3, 4-difluorophenyl) ethanone to (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol with more than 99 % enantiomeric excess (ee) and 99 % conversion. Our data showed that the optimum temperature and pH for Rhky-ADH were 25 °C and pH 8.0, respectively. The addition of NADH and an appropriate concentration of isopropanol enhanced the activity of Rhky-ADH, and 1 mM Mn2+ increased the enzyme activity by about 8 %. Substrate specificity experiments showed that Rhky-ADH had notable enzyme promiscuity and could reduce several ketones with high stereoselectivity. Our investigation on this novel enzyme adds another rare biocatalyst to the toolbox for producing chiral alcohols, which are widely used in the pharmaceutical industry.
Hu, Junmei,Li, Gudong,Liang, Chaoqun,Shams, Saira,Zheng, Guojun,Zhu, Shaozhou
(2020/02/05)

An iron variant of the Noyori hydrogenation catalyst for the asymmetric transfer hydrogenation of ketones
We report the design of a new iron catalyst for the asymmetric transfer hydrogenation of ketones. This type of iron catalyst combines the structural characteristics of the Noyori hydrogenation catalyst (an axially chiral 2,2′-bis(phosphino)-1,1′-binaphthyl fragment and the metal-ligand bifunctional motif) and an ene(amido) group that can activate the iron center. After activation by 8 equivalents of potassiumtert-butoxide, (SA,RP,SS)-7aand (SA,RP,SS)-7bare active but nonenantioselective catalysts for the transfer hydrogenation of acetophenone and α,β-unsaturated aldehydes at room temperature in isopropanol. A maximum turnover number of 14480 was observed for (SA,RP,SS)-7ain the reduction of acetophenone. The right combination of the stereochemistry of the axially chiral 2,2′-bis(phosphino)-1,1′-binaphthyl group and the carbon-centered chiral amine-imine moiety in (SA,RP,RR)-7b′afforded an enantioselective catalyst for the preparation of chiral alcohols with moderate to good yields and a broad functional group tolerance.
Huo, Shangfei,Wang, Qingwei,Zuo, Weiwei
supporting information
p. 7959 - 7967
(2020/06/26)

Preparation methods of aprepitant impurity
The invention discloses preparation methods of an aprepitant impurity, which comprise isomer impurity synthesis method of six aprepitant key intermediates (2R, 3S)-2-[(1R)-1-[3, 5-bis (trifluoromethyl)-phenyl] ethoxy]-3-(4-fluorophenyl) morpholine, respectively, synthesis of four diastereomer impurities, synthesis of one enantiomer impurity and synthesis of one by-product impurity. The methods have the beneficial effects that the five synthesis methods are simple and feasible, the raw materials are easy to obtain, the conditions are mild, the cost is low, the production is facilitated, and meanwhile, the isomer impurities of the synthesized aprepitant key intermediate provide a new intermediate raw material for the preparation of aprepitant.
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Paragraph 0118; 0120

(2020/07/13)

Asymmetric Hydrogenation of Ketones and Enones with Chiral Lewis Base Derived Frustrated Lewis Pairs
The concept of frustrated Lewis pairs (FLPs) has been widely applied in various research areas, and metal-free hydrogenation undoubtedly belongs to the most significant and successful ones. In the past decade, great efforts have been devoted to the synthesis of chiral boron Lewis acids. In a sharp contrast, chiral Lewis base derived FLPs have rarely been disclosed for the asymmetric hydrogenation. In this work, a novel type of chiral FLP was developed by simple combination of chiral oxazoline Lewis bases with achiral boron Lewis acids, thus providing a promising new direction for the development of chiral FLPs in the future. These chiral FLPs proved to be highly effective for the asymmetric hydrogenation of ketones, enones, and chromones, giving the corresponding products in high yields with up to 95 % ee. Mechanistic studies suggest that the hydrogen transfer to simple ketones likely proceeds in a concerted manner.
Du, Haifeng,Feng, Xiangqing,Gao, Bochao,Meng, Wei
supporting information
p. 4498 - 4504
(2020/02/05)

Chiral amino-pyridine-phosphine tridentate ligand, manganese complex, and preparation method and application thereof
The invention discloses a chiral amino-pyridine-phosphine tridentate ligand, a manganese complex, and a preparation method and application thereof. The chiral amino-pyridine-phosphine tridentate ligand is shown as a formula II, and the manganese complex of the chiral amino-pyridine-phosphine tridentate ligand can be used for efficiently catalyzing and hydrogenating ketone compounds to prepare chiral alcohol compounds in a high enantioselectivity mode. The chiral amino-pyridine-phosphine tridentate ligand and the manganese complex are simple in synthesis process, good in stability, high in catalytic activity and mild in reaction conditions.
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Paragraph 0597-0599; 0601

(2020/07/13)

One-pot kinetic resolution-Mitsunobu reaction to access optically pure compounds, using silver salts in the substitution protocol
A practical method is developed to access chiral arylalkyl carbinols with a high yield from racemic alcohols. A one-pot enzyme mediated Kinetic Resolution followed by Mitsunobu esterification of the unreacted enantiomer of alcohol with metal acetate results in a nearly complete formation of chiral acetate. Substitution with AgOAc was found to be the most efficient, and the use of sub stoichiometric amounts of AgNO3 and excess of NaOAc affords comparable results; the protocol was further extended to introduce azide as a nucleophile.
Raval, Hiten B.,Bedekar, Ashutosh V.
p. 21238 - 21243
(2020/12/31)

Asymmetric Transfer Hydrogenation with a Bifunctional Iron(II) Hydride: Experiment Meets Computation
Hydride cis-β-[FeH(CNCEt3)(1)]BF4 (5) (1 is a chiral N2P2 macrocycle) is the catalytically active species in the asymmetric transfer hydrogenation of ketones formed upon reaction of [Fe(CNCEt3)2(1)](BF4)2 (3) with base. Stoichiometric reactions show that hydride 5 is formed by H-elimination from the 2-propoxo complex [Fe(OiPr)(CNCEt3)(1)]BF4 (8a) and inserts the C=O bond of acetophenone to give the diastereoisomeric alcoholato complexes [Fe(OCH(Me)Ph)(CNCEt3)(1)]BF4 (10R and 10S). Complexes 5, 8a, and 10 were characterized by NMR spectroscopy, and their structures were calculated by DFT. The DFT study supports a bifunctional mechanism with the alkoxo complexes 8a and 10 as resting species. The stereochemical model reproduces the high enantioselectivity with acetophenone, which results from the combination of the rigid macrocyclic scaffold with the bulky, yet conformationally flexible isonitrile.
De Luca, Lorena,Passera, Alessandro,Mezzetti, Antonio
supporting information

(2019/02/14)

Highly Enantioselective Transfer Hydrogenation of Prochiral Ketones Using Ru(II)-Chitosan Catalyst in Aqueous Media
Unprecedentedly high enantioselectivities are obtained in the transfer hydrogenation of prochiral ketones catalyzed by a Ru complex formed in situ with chitosan chiral ligand. This biocompatible, biodegradable chiral polymer obtained from the natural chitin afforded good, up to 86 % enantioselectivities, in the aqueous-phase transfer hydrogenation of acetophenone derivatives using HCOONa as hydrogen donor. Cyclic ketones were transformed in even higher, over 90 %, enantioselectivities, whereas further increase, up to 97 %, was obtained in the transfer hydrogenations of heterocyclic ketones. The chiral catalyst precursor prepared ex situ was examined by scanning electron microscopy, FT-mid- and -far-IR spectroscopy. The structure of the in situ formed catalyst was investigated by 1H NMR spectroscopy and using various chitosan derivatives. It was shown that a Ru pre-catalyst is formed by coordination of the biopolymer to the metal by amino groups. This precursor is transformed in water insoluble Ru-hydride complex following hydrogen donor addition. The practical value of the developed method was verified by preparing over twenty chiral alcohols in good yields and optical purities. The catalyst was applied for obtaining optically pure chiral alcohols at gram scale following a single crystallization.
Sz?ll?si, Gy?rgy,Kolcsár, Vanessza Judit
p. 820 - 830
(2018/12/13)

Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones
A series of MnI complexes containing lutidine-based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; TON=turnover number), broad substrate scope (81 examples), good functional-group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth-abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer-sphere mode of substrate–catalyst interactions probably dominates the catalysis.
Zhang, Linli,Tang, Yitian,Han, Zhaobin,Ding, Kuiling
supporting information
p. 4973 - 4977
(2019/03/17)

Mn(I) and Fe(II)/PN(H)P Catalysts for the Hydrogenation of Ketones: A Comparison by Experiment and Calculation
The P-stereogenic PN(H)P tridentate ligand HN(CH2CH2)2P(Me)R (R=Cy, 1 a; R=tBu, 1 b) gives the Mn(I) complexes [Mn(CO)3(PN(H)P)]Br, which were tested in the asymmetric H2 hydrogenation of ketones. The amido species [Mn(CO)2(PNP)], hydrides [MnH(CO)2(PN(H)P)], and the alkoxide complex (Formula presented.) were detected by NMR spectroscopy. The manganese(I) derivative [Mn(CO)3(1 a)]Br was compared to its iron(II) analogue [FeHBr(CO)(1 a)] by kinetic and DFT studies. The DFT study suggests that both Mn(I) and Fe(II) operate via a bifunctional mechanism for H+/H? transfer with structurally similar enantiodetermining transition states and hence comparable enantioselectivity. The Mn(I) catalyst is less active than its Fe(II) analogue (k(Fe)/k(Mn)=ca. 30), which we attribute to the higher stability of the Mn(I) resting species, the off-cycle alkoxo complex [Mn(OCH(Me)Ph))(CO)2(1 a)] that follows from the larger π delocalization onto the additional CO ligand as compared to [FeH(OCH(Me)Ph))(CO)(1 a)]. (Figure presented.).
Passera, Alessandro,Mezzetti, Antonio
supporting information
p. 4691 - 4706
(2019/08/26)

Manganese complex and preparation method and application thereof
The invention discloses a manganese complex taking (RC,SP)-N-5,6,7,8-tetrahydroquinoline-1-(2-diphenylphosphino)ferrocene ethyl amine as a ligand, a preparation method and application of the manganesecomplex in catalyst ketone compound asymmetric hydrogen transfer reduction preparing chiral alcohol. The manganese complex is a cheap metal chiral catalyst, the cost is low, the thermal stability isgood, and the preparation method of the manganese complex has the advantages of mild condition, short period, simple operation condition and the like. The catalyst is used for reducing the chiral alcohol for ketone hydrogen transfer, has higher catalytic activity, and a method for preparing the chiral alcohol is simple, less in environment pollution, and high in yield.
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Paragraph 0063-0066; 0069-0083

(2020/01/03)

Asymmetric aerobic oxidation of secondary alcohols catalyzed by poly(: N-vinyl-2-pyrrolidone)-stabilized gold clusters modified with cyclodextrin derivatives
Surface modification of poly(N-vinyl-2-pyrrolidone)-stabilized gold clusters (1.8 ± 0.6 nm) with aminated cyclodextrins induced aerobic oxidative kinetic resolution of racemic secondary alcohols (krel = 1.2).
Hirano, Koto,Takano, Shinjiro,Tsukuda, Tatsuya
supporting information
p. 15033 - 15036
(2020/01/03)

A Straightforward Deracemization of sec-Alcohols Combining Organocatalytic Oxidation and Biocatalytic Reduction
An efficient organocatalytic oxidation of racemic secondary alcohols, mediated by sodium hypochlorite (NaOCl) and 2-azaadamantane N-oxyl (AZADO), has been conveniently coupled with a highly stereoselective bioreduction of the intermediate ketone, catalyzed by ketoreductases, in aqueous medium. The potential of this one-pot two-step deracemization process has been proven by a large set of structurally different secondary alcohols. Reactions were carried out up to 100 mm final concentration enabling the preparation of enantiopure alcohols with very high isolated yields (up to 98 %). When the protocol was applied to the stereoisomeric rac/meso mixture of diols, these were obtained with very high enantiomeric excesses and diastereomeric ratios (95 % yield, >99 % ee, >99: 1 dr).
Liardo, Elisa,Ríos-Lombardía, Nicolás,Morís, Francisco,González-Sabín, Javier,Rebolledo, Francisca
supporting information
p. 3031 - 3035
(2018/06/27)

ANTIDIABETIC SPIROCHROMAN COMPOUNDS
Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
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Page/Page column 119

(2018/07/29)

Method for separating morpholone isomer
The invention discloses a method for separating morpholone isomer. The method comprises the following steps: under the action of a solvent, recrystallizing the morpholone isomer; wherein the solvent is selected from one or more kinds of solvents including an ether solvent, an alcohol solvent and an alkane solvent; the morpholine isomer refers to a mixture containing a compound 1 and a compound 2,the molar ratio of the compound 1 to the compound 2 is 6:4-99.8:0.02. By using the method, the yield of the compound 1 is high, and the purity is good, the operation is simple, the cost is low, the environment-friendly effect is achieved, and the method is more suitable for industrial production.
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Paragraph 0042-0044

(2019/01/04)

Iridium and Rhodium Complexes Containing Enantiopure Primary Amine-Tethered N-Heterocyclic Carbenes: Synthesis, Characterization, Reactivity, and Catalytic Asymmetric Hydrogenation of Ketones
The imidazolium salt [(S,S)-tBuNC3H3NCHPhCHPhNH2]PF6, (S,S)-11·HPF6 is a precursor to the enantiopure "Kaibene" ligand, tBu-Kaibene, (S,S)-11 featuring a tert-butyl group on the N-heterocyclic carbene (NHC) ring-nitrogen atoms. It has been prepared in high yield and purity by refluxing a chiral cyclic sulfamidate with 1-tert-butylimidazole. Similarly (S,S)-12·HPF6 with a mesityl group at the imidazolium ring-nitrogen atom has been prepared in the same fashion and serves as a source of Mes-Kaibene, (S,S)-12. These bidentate Kaibene ligands feature an NHC and a primary amine separated by a chiral linker. Salts (S,S)-11·HPF6 or (S,S)-12·HPF6 react with base and AgI or CuI to give a total of four M(Kaibene)2I compounds (M = Ag or Cu). At 22 °C, the amine-functionalized imidazolium cations undergo oxidative addition to iridium(I) in [IrCl(cod)]2 (cod = 1,5-cyclooctadiene) to generate iridium(III) hydride R-Kaibene compounds [IrHCl(cod)((S,S)-11)](PF6) (17) and [IrHCl(cod)((S,S)-12)](PF6) (18), respectively, each as a mixture of six configurational isomers. In contrast, the salt (S,S)-11·HPF6 reacts with [Ir(OtBu)(cod)]2 to produce a bimetallic iridium compound with (S,S)-11 as the bridging ligand. This compound contains interesting NH···Cl and NH···Ir noncovalent intramolecular interactions. Salt (S,S)-12·HPF6 reacts with silver oxide to yield [Ag2((S,S)-12)2](PF6)2 (20). Reagent 20 serves as an efficient transmetalation reagent to deliver to each rhodium in [RhCl(cod)]2 1 equiv of (S,S)-12 as a bidentate ligand to give [Rh(cod)((S,S)-12)](PF6). In the reaction between [IrCl(cod)]2 and 20, (S,S)-12 ends up coordinated in an iridium(III) hydride complex (22) as a tridentate ligand via the NHC, NH2, and a cyclometalated phenyl group. The two iridium hydride compounds, 18 and 22, are catalysts for the hydrogenation of a range of ketones (turnover number up to 499, turnover frequency up to 249 h-1, with er (enantiomeric ratio) up to 35:65 R:S).
Wan, Kai Y.,Roelfes, Florian,Lough, Alan J.,Hahn, F. Ekkehardt,Morris, Robert H.
supporting information
p. 491 - 504
(2018/02/17)

A Ferrocene-Based NH-Free Phosphine-Oxazoline Ligand for Iridium-Catalyzed Asymmetric Hydrogenation of Ketones
A new type of ferrocene-based phosphine-oxazoline ligand has been prepared over a few simple steps. An iridium complex of this ligand is air stable and exhibits excellent performance for the asymmetric hydrogenation of simple ketones (up to 98% yield, up to 99% ee, and 20?000 S/C). Exo-α,β-unsaturated cyclic ketones could be regiospecifically hydrogenated to give chiral allylic alcohols with good results. This study indicates that P,N-ligands can also efficiently promote Ir-catalyzed asymmetric hydrogenation without NH-hydrogen-bonding assistance.
Wang, Yanzhao,Yang, Guoqiang,Xie, Fang,Zhang, Wanbin
supporting information
p. 6135 - 6139
(2018/09/27)

Asymmetric Transfer Hydrogenation of Ketones with Well-Defined Manganese(I) PNN and PNNP Complexes
Three new manganese complexes trans-[Mn(P-NH-NH-P)(CO)2][Br], (14) P-NH-NH-P = (S,S)-PPh2CH2CH2NH-CHPhCHPhNHCH2CH2PPh2), fac-[Mn(P′-NH-NH2)(CO)3][Br], (15) P′-NH-NH2 = (S,S)-PPh2(C6H4)NHCHPhCHPhNH2, and syn-mer-Mn(P-NH-NH2)(CO)2Br, (16) P-NH-NH2 = (S,S)-PPh2CH2CH2NHCHPhCHPhNH2 were synthesized and tested for the asymmetric transfer hydrogenation (ATH) of acetophenone in 2-PrOH. The ligands have stereogenic centers derived from the starting diamine, (S,S)-DPEN. Complex 16 was shown by NOE NMR experiments to have Mn-Br syn to the N-H of the secondary amine. Only the precatalyst 16, upon reaction with potassium tert-butoxide (KOtBu) in 2-PrOH, generated an active system at 80 °C for the ATH of acetophenone to 1-phenylethanol in an enantiomeric excess (ee) of 42% and thus was selected for further investigation into the mechanism of transfer hydrogenation. The corresponding amido complex Mn(P-N-NH2)(CO)2 (17), a borohydride complex syn-mer-Mn(P-NH-NH2)(CO)2(BH4) (18), and an ethoxide complex anti-mer-Mn(P-NH-NH2)(CO)2(OEt) (19′) were independently synthesized and tested in the ATH of acetophenone. The amido complex 17 and the borohydride complex 18 displayed similar activity to 16 activated in basic 2-PrOH, but the anti NH OEt complex 19′ was completely inactive. This result suggested that the NH effect, as described by Noyori, was required to obtain catalytic activity. The syn NH BH4 manganese complex is one of the most active manganese ATH catalysts to date and can hydrogenate a variety of aromatic ketones, including base-sensitive substrates such as p-acetylbenzoate ethyl ester.
Demmans, Karl Z.,Olson, Maxwell E.,Morris, Robert H.
supporting information
p. 4608 - 4618
(2019/01/04)

Conversion of Olefins into Ketones by an Iron-Catalyzed Wacker-type Oxidation Using Oxygen as the Sole Oxidant
We describe a mild and operationally simple procedure for the oxidation of olefins into ketones. The reaction is catalyzed by the hexadecafluorinated iron–phthalocyanine complex FePcF16 with stoichiometric amounts of triethylsilane as an additive under oxygen atmosphere to give ketones in good to high yields with excellent chemoselectivity and functional group tolerance. Ketone formation proceeds in up to 95 % yield and with 100 % regioselectivity while the corresponding alcohols were observed as side products.
Puls, Florian,Kn?lker, Hans-Joachim
supporting information
p. 1222 - 1226
(2018/01/01)

Selective Late-Stage Hydrodefluorination of Trifluoromethylarenes: A Facile Access to Difluoromethylarenes
A selective reductive monodefluorination reaction of trifluoromethyl arenes was developed. Mediated by magnesium metal, various difluoromethylated aromatics were accessed at room temperature in the presence of acetic acid. This protocol shows tolerance to a wide range of functional groups and it was applicable in late-stage hydrodefluorination of complex pharmaceutical compounds, affording the corresponding CF2H analogues and their deuterated (CF2D) counterparts.
Munoz, Socrates B.,Ni, Chuanfa,Zhang, Zhe,Wang, Fang,Shao, Nan,Mathew, Thomas,Olah, George A.,Prakash, G. K. Surya
supporting information
p. 2322 - 2326
(2017/05/01)

Extreme halophilic alcohol dehydrogenase mediated highly efficient syntheses of enantiopure aromatic alcohols
Enzymatic synthesis of enantiopure aromatic secondary alcohols (including substituted, hetero-aromatic and bicyclic structures) was carried out using halophilic alcohol dehydrogenase ADH2 from Haloferax volcanii (HvADH2). This enzyme showed an unprecedented substrate scope and absolute enatioselectivity. The cofactor NADPH was used catalytically and regenerated in situ by the biocatalyst, in the presence of 5% ethanol. The efficiency of HvADH2 for the conversion of aromatic ketones was markedly influenced by the steric and electronic factors as well as the solubility of ketones in the reaction medium. Furthermore, carbonyl stretching band frequencies ν (CO) have been measured for different ketones to understand the effect of electron withdrawing or donating properties of the ketone substituents on the reaction rate catalyzed by HvADH2. Good correlation was observed between ν (CO) of methyl aryl-ketones and the reaction rate catalyzed by HvADH2. The enzyme catalyzed the reductions of ketone substrates on the preparative scale, demonstrating that HvADH2 would be a valuable biocatalyst for the preparation of chiral aromatic alcohols of pharmaceutical interest.
Alsafadi, Diya,Alsalman, Safaa,Paradisi, Francesca
p. 9169 - 9175
(2017/11/15)

Iridium-Catalyzed Asymmetric Hydrogenation of Ketones with Accessible and Modular Ferrocene-Based Amino-phosphine Acid (f-Ampha) Ligands
A series of tridentate ferrocene-based amino-phosphine acid (f-Ampha) ligands have been successfully developed. The f-Ampha ligands are extremely air stable and exhibited excellent performance in the Ir-catalyzed asymmetric hydrogenation of ketones (full conversions, up to >99% ee, and 500?000 TON). DFT calculations were performed to elucidate the reaction mechanism and the importance of the COOH group. Control experiments also revealed that the COOH group played a key role in this reaction.
Yu, Jianfei,Long, Jiao,Yang, Yuhong,Wu, Weilong,Xue, Peng,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
supporting information
p. 690 - 693
(2017/02/10)

Base-Free Asymmetric Transfer Hydrogenation of 1,2-Di- and Monoketones Catalyzed by a (NH)2P2-Macrocyclic Iron(II) Hydride
The hydride isonitrile complex [FeH(CNCEt3)(1 a)]BF4 (2) containing a chiral P2(NH)2 macrocycle (1 a), in the presence of 2-propanol as hydrogen donor, catalyzes the base-free asymmetric transfer hydrogenation (ATH) of prostereogenic ketones to alcohols and the hemihydrogenation of benzils to benzoins, which contain a base-labile stereocenter. Benzoins are formed in up to 83 % isolated yield with enantioselectivity reaching 95 % ee. Ketones give the same enantioselectivity observed with the parent catalytic system [Fe(CNCEt3)2(1 a)] (3 a) that operates with added NaOtBu.
De Luca, Lorena,Mezzetti, Antonio
supporting information
p. 11949 - 11953
(2017/09/20)

Development of a Practical Enzymatic Process for Preparation of (S)-2-Chloro-1-(3,4-difluorophenyl)ethanol
(S)-2-Chloro-1-(3,4-difluorophenyl)ethanol (1) is a vital chiral intermediate for the synthesis of Ticagrelor - an effective treatment for acute coronary syndromes. A ketoreductase (KRED) KR-01 in our KRED library was screened to transform 2-chloro-1-(3,4
Guo, Xiang,Tang, Jia-Wei,Yang, Jiang-Tao,Ni, Guo-Wei,Zhang, Fu-Li,Chen, Shao-Xin
p. 1595 - 1601
(2017/10/25)

Readily Accessible and Highly Efficient Ferrocene-Based Amino-Phosphine-Alcohol (f-Amphol) Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Simple Ketones
We have successfully developed a series of novel and modular ferrorence-based amino-phosphine-alcohol (f-Amphol) ligands, and applied them to iridium-catalyzed asymmetric hydrogenation of various simple ketones to afford the corresponding chiral alcohols with excellent enantioselectivities and conversions (98–99.9 % ee, >99 % conversion, turnover number up to 200 000). Control experiments and density functional theory (DFT) calculations have shown that the hydroxyl group of our f-Amphol ligands played a key role in this asymmetric hydrogenation.
Yu, Jianfei,Duan, Meng,Wu, Weilong,Qi, Xiaotian,Xue, Peng,Lan, Yu,Dong, Xiu-Qin,Zhang, Xumu
supporting information
p. 970 - 975
(2017/02/05)

Asymmetric Transfer Hydrogenation of Ketones Using New Iron(II) (P-NH-N-P′) Catalysts: Changing the Steric and Electronic Properties at Phosphorus P′
The asymmetric transfer hydrogenation (ATH) of ketones is an efficient method for producing enantio-enriched alcohols which are used as intermediates in a variety of industrial processes. Here we report the synthesis of new iron ATH precatalysts (S,S)-[FeBr(CO)(Ph2PCH2CH2NHCHPhCHPhNC=CHCH2PR′2)][BPh4] (R′=Et, and ortho-tolyl (o-Tol)) where one of the phosphine groups is modified with small alkyl and large aryl substituents to probe the effect of this change on the activity and selectivity of the catalytic system. A simple reversible equilibrium kinetic model is used to obtain the initial TOF and the inherent enantioselectivity S=kR/kS of these catalysts along with those for the previously reported catalysts with R′=Ph and Cy for the ATH of acetophenone. With an increase in the size of the PR′2 group, the TOF goes through a maximum at PPh2 while the S value goes through a maximum of 510 at R′=Cy. The complex with R′=o-Tol starts with a high S value of 200 but is rapidly changed to a second catalyst with an S value of 28. For the reduction of acetophenone to (R)-1-phenylethanol, turnover numbers of up to 5200 and ee up to 98 % were achieved. The chemotherapeutic pharmaceutical precursor (R)-(3′,5′-bis(trifluoromethyl))-1-phenylethanol is synthesized in up to 95 % ee. Several other alcohols can be prepared in greater than 90 % ee by choosing the precatalyst with the correctly matched steric properties. A hydride complex derived from the catalyst with R′=Cy is characterized by NMR spectroscopy. It is proposed that low concentration trans-hydride carbonyl complexes with the FeH parallel to the NH of the ligand are the active catalysts in all of these systems.
Smith, Samantha A. M.,Prokopchuk, Demyan E.,Morris, Robert H.
p. 1204 - 1215
(2017/09/06)

Unsymmetrical Iron P-NH-P′ Catalysts for the Asymmetric Pressure Hydrogenation of Aryl Ketones
The reductive amination of α-dialkylphosphine acetaldehydes with enantiopure β-aminophosphines is a new, versatile route to unsymmetrical tridentate (pincer) ligands P-NH-P′. Four new ligands PR2CH2CH2NHCHR′CHR′′PPh2 (R=iPr, Cy, R′=Ph, CH(CH3)2, R′′=Ph, H) prepared in this way are used to make the iron(II) complexes mer-FeCl2(CO)(P-NH-P′) and mer-FeCl(H)(CO)(P-NH-P′). The hydride complex with the rigid ligand with R′=R′′=Ph is an efficient and highly enantioselective homogeneous asymmetric pressure hydrogenation (APH) catalyst. Prochiral aryl ketones are reduced under mild conditions (THF, 0.1 mol % catalyst, 1 mol % KOtBu, 5–10 bar, 50 °C) to the (S)-alcohols, usually in enantiomeric excess (ee) greater than 90 %. DFT calculations provided transition-state structures for the enantiodetermining hydride-transfer step.
Smith, Samantha A. M.,Lagaditis, Paraskevi O.,Lüpke, Anne,Lough, Alan J.,Morris, Robert H.
p. 7212 - 7216
(2017/05/31)

Use of the Trost Ligand in the Ruthenium-Catalyzed Asymmetric Hydrogenation of Ketones
The Trost ligand, (1S,2S)-1,2-diaminocyclohexane-N,N′-bis(2′-diphenylphosphinobenzoyl) (L), is reported for the first time as a ligand for the asymmetric hydrogenation (AH) of ketones. Ligand (S,S)-L was screened in the presence of several metal salts and was found to form active catalysts if combined with ruthenium sources in the presence of hydrogen and a base. Reaction optimization was performed by screening different Ru sources, solvents, and bases. Under the optimized conditions, the complex formed by the combination of (S,S)-L with RuCl3(H2O)x in the presence of Na2CO3 was able to promote the AH of several ketones at room temperature in good yields with up to 96 % ee. The reaction kinetics measured under the optimized conditions revealed the presence of a long induction period, during which the initially formed Ru species was transformed into the catalytically active complex by reaction with hydrogen. Remarkably, a ketone that is a precursor of the antiemetic drug aprepitant was hydrogenated in excellent yield with a good ee value.
Cettolin, Mattia,Puylaert, Pim,Pignataro, Luca,Hinze, Sandra,Gennari, Cesare,de Vries, Johannes G.
p. 3125 - 3130
(2017/08/29)

Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction
The invention relates to a chiral tridentate phosphonic amine ligand and application thereof in an asymmetric catalytic reaction. The novel chiral tridentate phosphonic amine ligand disclosed by the invention is a first case of tridentate phosphonic amine ligand containing ferrocenyl chiral phosphine at present and is successfully applied to high-efficiency and high-selectivity asymmetric hydrogenation and similar reaction thereof for simple aromatic ketone and aliphatic ketone. The type of ligand has the advantages of simple synthetic route, low cost, easiness in large-scale synthesis and stable air; the chiral tridentate phosphonic amine ligand shows high activity and high selectivity for asymmetric hydrogenation reaction of carbon-oxygen double bond, and has a broad industrial application prospect.
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Paragraph 0080; 0081; 0082

(2017/08/29)

Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol
The invention discloses a method for preparing chiral alpha-phenylethyl alcohol. The method is a preferential crystallization method implemented by taking petroleum ether as a solved, is simple and convenient to operate, is high in product yield and purit
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Paragraph 0071; 0072; 0073; 0074; 0075

(2016/10/10)

Full chirality transfer in the synthesis of hindered tertiary boronic esters under: In situ lithiation-borylation conditions
Hindered tertiary neopentyl glycol boronic esters can be prepared by using in situ lithiation-borylation of enantiopure secondary benzylic carbamates at -20°C with full chirality transfer.
Blair,Zhong,Hesse,Zabaleta,Myers,Aggarwal
supporting information
p. 5289 - 5292
(2016/05/02)

Chiral-at-metal iridium complex for efficient enantioselective transfer hydrogenation of ketones
A bis-cyclometalated iridium(iii) complex with metal-centered chirality catalyzes the enantioselective transfer hydrogenation of ketones with high enantioselectivities at low catalyst loadings down to 0.002 mol%. Importantly, the rate of catalysis and enantioselectivity are markedly improved in the presence of a pyrazole co-ligand. The reaction is proposed to proceed via an iridium-hydride intermediate exploiting metal-ligand cooperativity (bifunctional catalysis).
Tian, Cheng,Gong, Lei,Meggers, Eric
supporting information
p. 4207 - 4210
(2016/03/19)

Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones
A series of modular and rich electronic tridentate ferrocene aminophosphoxazoline ligands (f-amphox) have been successfully developed and used in iridium-catalytic asymmetric hydrogenation of simple ketones to afford corresponding enantiomerically enriched alcohols under mild conditions with superb activities and excellent enantioselectivities (up to 1"000"000 TON, almost all products up to >99% ee, full conversion). The resulting chiral alcohols and their derivatives are important intermediates in pharmaceuticals.
Wu, Weilong,Liu, Shaodong,Duan, Meng,Tan, Xuefeng,Chen, Caiyou,Xie, Yun,Lan, Yu,Dong, Xiu-Qin,Zhang, Xumu
supporting information
p. 2938 - 2941
(2016/07/06)