- Synthesis of optically active α-phenylpyridylmethanols by immobilized cell cultures of Catharanthus roseus
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We have synthesized optically active α-phenylpyridylmethanols by reduction or hydrolysis with calcium alginate immobilized cells of Catharanthus roseus.
- Takemoto, Masumi,Achiwa, Kazuo,Stoynov, Nikolay,Chen, David,Kutney, James Peter
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- Laboratory scale-up synthesis of chiral carbinols using Rhizopus arrhizus
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Rhizopus arrhizus mediated bioreduction was optimized using acetophenone as a model substrate. Various parameters such as bio-processing conditions, reaction time, substrate concentration, temperature, and solvent carrier were studied. This optimized protocol was further exploited for scaled up bioreductions of various prochiral ketones. This study demonstrates the versatility of the fungus Rhizopus arrhizus as a biocatalyst to obtain chiral carbinols in good to excellent yields and selectivities.
- Salvi, Neeta A.,Chattopadhyay, Subrata
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- Production of enantiomerically pure (S)-phenyl(pyridin-2-yl)methanol with Lactobacillus paracasei BD101
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Asymmetric reduction studies of heteroaryl ketones, including phenyl(pyridin-2-yl)methanone in enantioselective form with biocatalysts are very few, and chiral heteroaryl alcohols have been synthesized generally in the small scale. In this study, seven bacterial strains have been used to produce the (S)-phenyl(pyridin-2-yl)methanol in high enantiomeric excess and yield. Among the tested strains, Lactobacillus paracasei BD101, was found to be the best biocatalyst for the reducing phenyl(pyridin-2-yl)methanone to the (S)-phenyl(pyridin-2-yl)methanol at gram scale. The asymmetric bioreduction conditions were systematically optimized using L. paracasei BD101, which demonstrated excellent enantioselectivity and high level of conversion for the bioreduction reaction. (S)-phenyl(pyridin-2-yl)methanol, which is an analgesic, was produced enantiomerically pure form in the first time on gram scale using a biocatalyst. In total, 5.857 g of (S)-phenyl(pyridin-2-yl)methanol in enantiomerically pure form (>99% enantiomeric excess) was obtained in 52 h with 93% yield using whole cells of L. paracasei BD101. Enantiomerically pure (S)-phenyl (pyridin-2-yl)methanol, which is an analgesic, was first produced in the gram scale using a biocatalyst with excellent ee (>99%) and yield (93%).
- ?ahin, Engin,Serencam, Hüseyin,Dertli, Enes
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- Synthesis, Crystal Structure of Chiral Ferrocenyl Amino Alcohols, and Its Use for Asymmetric Transfer Hydrogenation
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Abstract: Two chiral ferrocenyl amino alcohols (IIIa and IIIb) have been synthesized for the iridium catalyzed asymmetric transfer hydrogenation of aromatic ketones. The structures of two chiral ferrocenyl amino alcohols have been determined by single crystal X-ray diffraction (CIF files CCDC nos. 1056737 (IIIa) and 1056734 (IIIb)). The results show that the activity and enantioselectivity of the chiral iridium catalyst are very sensitive to the substrate structure. Ir(I)-catalyzed asymmetric transfer hydrogenation of acetophenone resulted in moderate to good yield and lower enantioselectivity; asymmetric transfer hydrogenation of proopiophenone and 2-benzoylpyridine resulted in lower yield and lower enantioselectivity; as for 4-benzoylpyridine, good results have been achieved.
- Zhang,Li,Liu
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- Electronic Effect-Guided Rational Design of Candida antarctica Lipase B for Kinetic Resolution Towards Diarylmethanols
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Herein, we developed an electronic effect-guided rational design strategy to enhance the enantioselectivity of Candida antarctica lipase B (CALB) mutants towards bulky pyridyl(phenyl)methanols. Compared to W104A mutant previously reported with reversed S-stereoselectivity toward sec-alcohols, three mutants (W104C, W104S and W104T) displayed significant improvement of S-enantioselectivity in the kinetic resolution (KR) of various phenyl pyridyl methyl acetates due to the increased electronic effects between pyridyl and polar residues. The electronic effects were also observed when mutating other residues surrounding the stereospecificity pocket of CALB, such as T42A, S47A, A281S or A281C, and can be used to manipulate the stereoselectivity. A series of bulky pyridyl(phenyl) methanols, including S-(4-chlorophenyl)(pyridin-2-yl) methanol (S-CPMA), the intermediate of bepotastine, were obtained in good yields and ee values. (Figure presented.).
- Li, Dan-Yang,Lou, Yu-Jiao,Xu, Jian,Chen, Xiao-Yang,Lin, Xian-Fu,Wu, Qi
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p. 1867 - 1872
(2021/02/12)
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- Amino alcohols using the optically active amino alcohol derivative bi- Nord complex boron - -
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Disclosed are an amino alcohol-boron-binol complex as an intermediate, including Complex 3-1-1 shown below, and a method for preparing an optically active amino alcohol by using the same, wherein a racemic amino alcohol is resolved in an enationselective manner using a boron compound and a (R)- or (S)-binol, whereby an amino alcohol derivative with high optical purity can be prepared at high yield.
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Paragraph 0064; 0071-0076; 0108-0109
(2021/04/16)
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- Asymmetric reduction of aromatic heterocyclic ketones with bio-based catalyst Lactobacillus kefiri P2
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Abstract: Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical intermediates. In this study, Lactobacillus kefiri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asymmetric bioreduction of different prochiral substrates with results up to > 99% enantiomeric excess (ee). (R)-1-(benzofuran-2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale, high yield and enantiomerically pure form using L. kefiri P2 biocatalysts. The gram-scale production was carried out, and 9.70?g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-effective, clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an environmental and economic perspective, this biocatalytic method has great application potential, making it a green and sustainable way of synthesis. Graphical Abstract: [Figure not available: see fulltext.]
- Bayda?, Yasemin,Kalay, Erbay,?ahin, Engin
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p. 1147 - 1155
(2020/10/06)
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- Production of enantiopure chiral aryl heteroaryl carbinols using whole‐cell Lactobacillus paracasei biotransformation
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Aryl and heteroaryl chiral carbinols are useful precursors in the synthesis of drugs. Lactobacillus paracasei BD87E6, which is obtained from a cereal based fermented beverage, was investigated as whole cell biocatalyst for the bioreduction of different ketones (including aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbinols, which can be used as a pharmaceutical intermediate. The study shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone (1–5) to their corresponding chiral carbinols (1a–5a) in excellent enantioselectivity (>99%) with high yields. This study gave the first example for an enantiopure production of (S)-6-chlorochroman-4-ol (3a), which has many antioxidant activity, by a biological method. For asymmetric bioreduction of other prochiral ketones, these results open way to use of L. paracasei BD87E6 as biocatalysts. Also, the present process shows a hopeful and alternative green synthesis for the production of enantiopure carbinols in a mild, inexpensive and environmentally friendly process.
- ?ahin, Engin
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p. 549 - 557
(2020/01/08)
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- Molecular switch manipulating Prelog priority of an alcohol dehydrogenase toward bulky-bulky ketones
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Structure-guided rational design revealed the molecular switch manipulating the Prelog and anti-Prelog priorities of an NADPH-dependent alcohol dehydrogenase toward prochiral ketones with bulky and similar substituents. Synergistic effects of unconserved residues at 214 and 237 in small and large substrate binding pockets were proven to be vital in governing the stereoselectivity. The ee values of E214Y/S237A and E214C/S237 G toward (4-chlorophenyl)-(pyridin-2-yl)-methanone were 99.3% (R) and 78.8% (S) respectively. Substrate specificity analysis revealed that similar patterns were also found with (4’-chlorophenyl)-phenylmethanone, (4’-bromophenyl)-phenylmethanone and (4’-nitrophenyl)-phenylmethanone. This study provides valuable evidence for understanding the molecular mechanism on enantioselective recognition of prochiral ketones by alcohol dehydrogenase.
- Xu, Guochao,Dai, Wei,Wang, Yue,Zhang, Lu,Sun, Zewen,Zhou, Jieyu,Ni, Ye
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- Engineering an alcohol dehydrogenase with enhanced activity and stereoselectivity toward diaryl ketones: Reduction of steric hindrance and change of the stereocontrol element
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Steric hindrance in the binding pocket of an alcohol dehydrogenase (ADH) has a great impact on its activity and stereoselectivity simultaneously. Due to the subtle structural difference between two bulky phenyl substituents, the asymmetric synthesis of diaryl alcohols by bioreduction of diaryl ketones is often hindered by the low activity and stereoselectivity of ADHs. To engineer an ADH with practical properties and to investigate the molecular mechanism behind the asymmetric biocatalysis of diaryl ketones, we engineered an ADH from Lactobacillus kefiri (LkADH) to asymmetrically catalyse the reduction of 4-chlorodiphenylketones (CPPK), which are not catalysed by the wild type (WT) enzyme. Mutants seq1-seq5 with gradually increased activity and stereoselectivity were obtained through iterative "shrinking mutagenesis." The final mutant seq5 (Y190P/I144V/L199V/E145C/M206F) demonstrated the highest activity and excellent stereoselectivity of >99% ee. Molecular simulation analyses revealed that mutations may enhance the activity by eliminating steric hindrance, inducing a more open binding loop and constructing more noncovalent interactions. The pro-R pose of CPPK with a halogen bond formed a pre-reaction conformation more easily than the pro-S pose, resulting in the high ee of (R)-CPPO in seq5. Moreover, different halogen bonds formed due to the different positions of chlorine substituents, resulting in opposite substrate binding orientation and stereoselectivity. Therefore, the stereoselectivity of seq5 was inverted toward ortho- rather than para-chlorine substituted ketones. These results indicate that the stereocontrol element of LkADH was changed to recognise diaryl ketones after steric hindrance was eliminated. This study provides novel insights into the role of steric hindrance and noncovalent bonds in the determination of the activity and stereoselectivity of enzymes, and presents an approach producing key intermediates of chiral drugs with practical potential.
- Chen, Rong,Huang, Jiankun,Meng, Xiangguo,Shao, Lei,Wu, Kai,Yang, Zhijun
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p. 1650 - 1660
(2020/04/09)
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- Iridium-Catalyzed Enantioselective Transfer Hydrogenation of Ketones Controlled by Alcohol Hydrogen-Bonding and sp3-C?H Noncovalent Interactions
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Iridium-catalyzed enantioselective transfer hydrogenation of ketones with formic acid was developed using a prolinol-phosphine chiral ligand. Cooperative action of the iridium atom and the ligand through alcohol-alkoxide interconversion is crucial to facilitate the transfer hydrogenation. Various ketones including alkyl aryl ketones, ketoesters, and an aryl heteroaryl ketone were competent substrates. An attractive feature of this catalysis is efficient discrimination between the alkyl and aryl substituents of the ketones, promoting hydrogenation with the identical sense of enantioselection regardless of steric demand of the alkyl substituent and thus resulting in a rare case of highly enantioselective transfer hydrogenation of tert-alkyl aryl ketones. Quantum chemical calculations revealed that the sp3-C?H/π interaction between an sp3-C?H bond of the prolinol-phosphine ligand and the aryl substituent of the ketone is crucial for the enantioselection in combination with O?H???O/sp3-C?H???O two-point hydrogen-bonding between the chiral ligand and carbonyl group. (Figure presented.).
- Murayama, Hiroaki,Heike, Yoshito,Higashida, Kosuke,Shimizu, Yohei,Yodsin, Nuttapon,Wongnongwa, Yutthana,Jungsuttiwong, Siriporn,Mori, Seiji,Sawamura, Masaya
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supporting information
p. 4655 - 4661
(2020/07/13)
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- Highly Enantioselective Hydrogenation of Non- ortho-Substituted 2-Pyridyl Aryl Ketones via Iridium- f-Diaphos Catalysis
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This work disclosed a highly enantioselective hydrogenation of non-ortho-substituted 2-pyridyl aryl ketones via Ir/f-diaphos catalysis. This catalytic system allows for full control over the configuration of the stereocenter, affording two enantiomers of the desired products with extremely high enantioselectivity (up to >99% ee in most cases) and excellent reactivity (TON of up to 19600, TOF of 1633 h-1) under mild conditions. Density functional theory calculations and control experiments revealed that the relay hydrogen bonding among the solvent isopropanol, substrate, and ligand is crucial for high ee's.
- Nian, Sanfei,Ling, Fei,Chen, Jiachen,Wang, Ze,Shen, Haiwei,Yi, Xiao,Yang, Yun-Fang,She, Yuanbin,Zhong, Weihui
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supporting information
p. 5392 - 5396
(2019/08/01)
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- A (S)- phenyl (pyridine -2 - yl) methanol derivative preparation method (by machine translation)
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The invention discloses a (S)- (pyridine - 2 - yl) phenyl methanol derivatives of the preparation method, the process is: in the argon atmosphere and 10 - 40 °C temperature, metal M complex with a chiral ligand L* In A added to the solvent, stirring the reaction 0.5 - 6 hours, to obtain the catalyst [M]/ L* ; The metal M in the complex metal M is Ru, Rh, Pd Ir or in any of the a; to the autoclave is sequentially added in the phenyl (pyridin - 2 - yl) methanone derivatives, the obtained catalyst [M]/ L* , Solvent B and alkali, for 0 - 100 °C temperature and 0.1 - 10.0 mpa of reaction under a hydrogen pressure of 2 - 24 hours, after the reaction, the reaction solution concentrated under reduced pressure to recover solvent B, add water, extracted with ethyl acetate, the organic phase and aqueous phase liquid, drying of the organic phase, desolvation prepared (S)- (pyridine - 2 - yl) phenyl methanol derivatives. The catalyst of the present invention asymmetric hydrogenation reaction, a reaction product of high yield, high enantio-selectively generating (S)- (pyridine - 2 - yl) phenyl methanol derivatives, in the ee value of 99% or more. (by machine translation)
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Page/Page column 8-12
(2019/07/04)
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- Conformational Dynamics-Guided Loop Engineering of an Alcohol Dehydrogenase: Capture, Turnover and Enantioselective Transformation of Difficult-to-Reduce Ketones
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Directed evolution of enzymes for the asymmetric reduction of prochiral ketones to produce enantio-pure secondary alcohols is particularly attractive in organic synthesis. Loops located at the active pocket of enzymes often participate in conformational changes required to fine-tune residues for substrate binding and catalysis. It is therefore of great interest to control the substrate specificity and stereochemistry of enzymatic reactions by manipulating the conformational dynamics. Herein, a secondary alcohol dehydrogenase was chosen to enantioselectively catalyze the transformation of difficult-to-reduce bulky ketones, which are not accepted by the wildtype enzyme. Guided by previous work and particularly by structural analysis and molecular dynamics (MD) simulations, two key residues alanine 85 (A85) and isoleucine 86 (I86) situated at the binding pocket were thought to increase the fluctuation of a loop region, thereby yielding a larger volume of the binding pocket to accommodate bulky substrates. Subsequently, site-directed saturation mutagenesis was performed at the two sites. The best mutant, where residue alanine 85 was mutated to glycine and isoleucine 86 to leucine (A85G/I86L), can efficiently reduce bulky ketones to the corresponding pharmaceutically interesting alcohols with high enantioselectivities (～99% ee). Taken together, this study demonstrates that introducing appropriate mutations at key residues can induce a higher flexibility of the active site loop, resulting in the improvement of substrate specificity and enantioselectivity. (Figure presented.).
- Liu, Beibei,Qu, Ge,Li, Jun-Kuan,Fan, Wenchao,Ma, Jun-An,Xu, Yan,Nie, Yao,Sun, Zhoutong
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p. 3182 - 3190
(2019/05/15)
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- Preparation method of (R)-phenyl (pyridine-2-base) methanol derivative
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The invention discloses a preparation method of a (R)-phenyl (pyridine-2-base) methanol derivative. The process comprises the following steps: - adding metal M complex and chiral ligand L * to solventA for 0.5-6 hours in argon atmosphere and at 10-40 DEG C to prepare catalyst [M]/ L *. The metal M in the metal M complex is any one of Ru, Rh, Ir or Pd, adding phenyl (pyridine-2-base) methyl ketonederivative, the prepared catalyst [M]/ L *, solvent B into a autoclave to perform an unsymmetrical hydrogenation reaction at 0-100 DEG C and hydrogen pressure of 0.1-10.0 MPa for 2-24 hours. After the reaction, the reaction solution is reduced pressure, concentrated and recovered solvent B, adding water, extracting by ethyl acetate, and separating into organic phase and water phase. The organic phase is dried and dissolved to obtain phenyl (pyridine-2-base) methanol derivative. According to the preparation method of the (R)-phenyl (pyridine-2-base) methanol derivative, in the asymmetric hydrogenation on phenyl (pyridine-2-base) methanol derivative, the yield is high, and (R)-phenyl (pyridine-2-base) methanol derivative is produced with high enantioselectivity and an e value above 99%.
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Page/Page column 8; 9; 11; 12
(2019/06/07)
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- Substituent Position-Controlled Stereoselectivity in Enzymatic Reduction of Diaryl- and Aryl(heteroaryl)methanones
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We report here the discovery of a novel ketoreductase (KRED), named KmCR2, with a broad substrate spectrum on bioreduction of sterically bulky diaryl- and aryl(heteroaryl)methanones. The position of the substituent on aromatic rings (meta versus para or ortho) was revealed to control the stereospecificity of KmCR2. The stereoselective preparation of both enantiomers of diaryl- or aryl(heteroaryl)methanols using strategically engineered substrates with a traceless directing group (bromo group) showcased the potential application of this substrate-controlled bioreduction reaction. The combined use of substrate engineering and protein engineering, was demonstrated to be a useful strategy in efficiently improving stereoselectivity or switching stereopreference of enzymatic processes. (Figure presented.).
- Li, Zhining,Wang, Zexu,Wang, Yuhan,Wu, Xiaofan,Lu, Hong,Huang, Zedu,Chen, Fener
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supporting information
p. 1859 - 1865
(2019/03/07)
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- Two enantiocomplementary ephedrine dehydrogenases from arthrobacter sp. TS-15 with broad substrate specificity
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The recently identified pseudoephedrine and ephedrine dehydrogenases (PseDH and EDH, respectively) from Arthrobacter sp. TS-15 are NADH-dependent members of the oxidoreductase superfamily of short-chain dehydrogenases/reductases (SDRs). They are specific for the enantioselective oxidation of (+)-(S) N-(pseudo)ephedrine and (-)-(R) N-(pseudo)ephedrine, respectively. Anti-Prelog stereospecific PseDH and Prelog-specific EDH catalyze the regio- A nd enantiospecific reduction of 1-phenyl-1,2-propanedione to (S)-phenylacetylcarbinol and (R)-phenylacetylcarbinol with full conversion and enantiomeric excess of >99%. Moreover, they perform the reduction of a wide range of aryl-aliphatic carbonyl compounds, including ketoamines, ketoesters, and haloketones, to the corresponding enantiopure alcohols. The highest stability of PseDH and EDH was determined to be at a pH range of 6.0-8.0 and 7.5-8.5, respectively. PseDH was more stable than EDH at 25 °C with half-lives of 279 and 38 h, respectively. However, EDH is more stable at 40 °C with a 2-fold greater half-life than at 25 °C. The crystal structure of the PseDH-NAD+ complex, refined to a resolution of 1.83 ?, revealed a tetrameric structure, which was confirmed by solution studies. A model of the active site in complex with NAD+ and 1-phenyl-1,2-propanedione suggested key roles for S143 and W152 in recognition of the substrate and positioning for the reduction reaction. The wide substrate spectrum of these dehydrogenases, combined with their regio- A nd enantioselectivity, suggests a high potential for the industrial production of valuable chiral compounds.
- Shanati, Tarek,Lockie, Cameron,Beloti, Lilian,Grogan, Gideon,Ansorge-Schumacher, Marion B.
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p. 6202 - 6211
(2019/08/15)
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- Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of Aryl N-Heteroaryl Ketones with N-Oxide as a Removable ortho-Substituent
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A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric synthesis of bepotastine besilate in 51% total yield and 99.9% ee.
- Liu, Qixing,Wang, Chunqin,Zhou, Haifeng,Wang, Baigui,Lv, Jinliang,Cao, Lu,Fu, Yigang
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p. 971 - 974
(2018/02/23)
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- Fine tuning the enantioselectivity and substrate specificity of alcohol dehydrogenase from Kluyveromyces polysporus by single residue at 237
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Here, S237 was identified to be important in fine tuning the substrate specificity and enantioselectivity of alcohol dehydrogenase from Kluyveromyces polysporus (KpADH). In the reduction of a diaryl ketone, (4-chlorophenyl)-(pyridin-2-yl)-methanone (1a), the highest and lowest enantioselectivity of 96.1% and 27.0% e.e. (R) were obtained with S237A and S237C. Kinetic parameters analysis revealed that S237G, S237A, S237H and S237D displayed improved kcat/Km toward 1a. Various prochiral ketones, including acetophenone, 4-chloroacetophenone and ethyl 2-oxo-4-phenylbutyrate could be asymmetrically reduced by S237C, S237G and S237E with > 99% e.e. This study provides guidance for the application of KpADH in the preparation of chiral secondary alcohols.
- Wang, Yue,Dai, Wei,Liu, Yongmei,Zhang, Zhongwei,Zhou, Jieyu,Xu, Guochao,Ni, Ye
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- Hydroclassified Combinatorial Saturation Mutagenesis: Reshaping Substrate Binding Pockets of KpADH for Enantioselective Reduction of Bulky-Bulky Ketones
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A hydroclassified combinatorial saturation mutagenesis (HCSM) strategy was proposed for reshaping the substrate binding pocket by dividing 20 amino acids into four groups based on their hydrophobicity and size. These smart HCSM libraries could significantly reduce screening effort especially for the simultaneous mutagenesis of three or more residues and lacking high throughput screening methods. Employing HCSM strategy, the stereoselectivity of KpADH, an alcohol dehydrogenase from Kluyveromyces polysporus, was efficiently improved to 99.4% ee. (4-Chlorophenyl)(pyridin-2-yl)methanone (CPMK), generally regarded as a "hard-to-reduce" ketone, was used as a model substrate, and its corresponding chiral alcohol products could be utilized as antihistamine precursors. The best variant 50C10 displayed higher binding affinity and catalytic efficiency toward CPMK with KM/kcat of 59.3 s-1·mM-1, 3.51-fold that of KpADH. Based on MD simulations, increased difference between two binding pockets, enhanced hydrophobicity, and π-π and halogen-alkyl interactions were proposed to favor the enantioselective recognition and substrate binding in 50C10. Substrate spectrum analysis revealed that 50C10 exhibited improved enantioselectivity toward diaryl ketones especially with halo- or other electron-withdrawing groups. As much as 500 mM CPMK could be asymmetrically reduced into chiral diaryl alcohols with ee of 99.4% and a space-time yield of 194 g·L-1·d-1 without addition of external NADP+. This study provides an effective mutagenesis strategy for the protein engineering of substrate specificity and enantioselectivity.
- Xu, Guo-Chao,Wang, Yue,Tang, Ming-Hui,Zhou, Jie-Yu,Zhao, Jing,Han, Rui-Zhi,Ni, Ye
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p. 8336 - 8345
(2018/09/18)
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- Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a "polar Gate" in Stereorecognition of Diaryl Ketones
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Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as "difficult-to-reduce" ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora (KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2-yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a "polarity scanning" strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2-CPMKProR and Mu-S5-CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a "polar gate" for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro-S orientation of CPMK is defined when it passes through the "polar gate" in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion.
- Zhou, Jieyu,Wang, Yue,Xu, Guochao,Wu, Lian,Han, Ruizhi,Schwaneberg, Ulrich,Rao, Yijian,Zhao, Yi-Lei,Zhou, Jiahai,Ni, Ye
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supporting information
p. 12645 - 12654
(2018/10/05)
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- Bifunctional Oxo-Tethered Ruthenium Complex Catalyzed Asymmetric Transfer Hydrogenation of Aryl N-Heteroaryl Ketones
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A facile asymmetric transfer hydrogenation of ortho-substituted aryl N-heteroaryl ketones and non-ortho-substituted N-oxide of aryl N-heteroaryl ketones using a readily available oxo-tethered ruthenium complex as a catalyst and sodium formate as a hydrogen source in an aqueous solution has been discovered. A variety of chiral aryl N-heteroaryl methanols were obtained with up to 99.9% ee.
- Wang, Baigui,Zhou, Haifeng,Lu, Guoren,Liu, Qixing,Jiang, Xiaolan
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p. 2094 - 2097
(2017/04/28)
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- Enantioselective reduction of aryl and hetero aryl methyl ketones using plant cell suspension cultures of Vigna radiata
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Vigna radiata was investigated as whole cell catalyst for the bioreduction of aryl and heteroaryl prochiral ketones into optically active alcohols. The study indicates selective bioreduction of different substituted aryl and heteroaryl ketones (1a–12a) to their respective (S)–chiral alcohols (1b–12b) in good to high enantioselectivity (77.7–97.5%) with very good yields (73–82%). The results obtained confirm that the keto reductase has broad substrate specificity and selectivity in catalyzing both six and five-membered heteroaryl methyl ketones. The current methodology substantiates a promising and alternative green approach for the synthesis of secondary chiral alcohols of biological importance in a mild, cheap and environmentally benign process.
- Santhanam, Srinath,Patil, Swati,Shanmugam, Ramu,Dronamraju V.L, Sarada,Balasundaram, Usha,Baburaj, Baskar
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p. 223 - 229
(2017/06/09)
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- Rhodium Catalyzed Asymmetric Hydrogenation of 2-Pyridine Ketones
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Catalyzed by [Rh(COD)Binapine]BF4, the asymmetric hydrogenation of 2-pyridine ketones has been achieved with excellent enantioselectivities (enantiomeric excesses up to 99%) under mild conditions. This method is suitable for various kinds of 2-pyridine ketones and their derivatives. A number of enantiomerically pure chiral 2-pyridine-aryl/alkyl alcohols were prepared through hydrogenation, which can be used directly in organic synthesis.
- Yang, Hailong,Huo, Ningning,Yang, Ping,Pei, Hao,Lv, Hui,Zhang, Xumu
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supporting information
p. 4144 - 4147
(2015/09/15)
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- Highly efficient oxidation of alcohols catalyzed by a porphyrin-inspired manganese complex
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A novel strategy for catalytic oxidation of a variety of benzylic, allylic, propargylic, and aliphatic alcohols to the corresponding aldehydes or ketones by an in situ formed porphyrin-inspired manganese complex in excellent yields (up to 99%) has been successfully developed.
- Dai, Wen,Lv, Ying,Wang, Lianyue,Shang, Sensen,Chen, Bo,Li, Guosong,Gao, Shuang
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supporting information
p. 11268 - 11271
(2015/07/07)
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- Zn(salen)-catalyzed enantioselective phenyl transfer to aldehydes and ketones with organozinc reagent
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Abstract A chiral zinc complex of salen was found to be an efficient catalyst for the phenyl transfer of organozinc reagent to aromatic aldehydes and ketones. High enantioselectivities were obtained in reactions of both aromatic aldehydes and ketones (up to 97% and 92% ee, respectively).
- Shimizu, Keisuke,Uetsu, Hidenori,Gotanda, Takashi,Ito, Katsuji
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p. 1238 - 1242
(2015/03/31)
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- A new modular phosphite-pyridine ligand library for asymmetric Pd-catalyzed allylic substitution reactions: A study of the key Pd-π-allyl intermediates
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A library of phosphite-pyridine ligands L1-L12 a-g has been successfully applied for the first time in the Pd-catalyzed allylic substitution reactions of several di- and trisubstituted substrates by using a wide range of C, N and O nucleophiles, among which are the little studied α-substituted malonates, β-diketones, and alkyl alcohols. The highly modular nature of this ligand library enables the substituents/configuration at the ligand backbone, and the substituents/configurations at the biaryl phosphite moiety to be easily and systematically varied. We found that the introduction of an enantiopure biaryl phosphite moiety played an essential role in increasing the versatility of the Pd-catalytic systems. Enantioselectivities were therefore high for several hindered and unhindered di- and trisubstituted substrates by using a wide range of C, N and O nucleophiles. Of particular note were the high enantioselectivities (up to>99 % ee) and high activities obtained for the trisubstituted substrates S6 and S7, which compare favorably with the best that have been reported in the literature. We have also extended the use of these new catalytic systems in alternative environmentally friendly solvents such as propylene carbonate and ionic liquids. Studies on the Pd-π-allyl intermediates provide a deeper understanding of the effect of ligand parameters on the origin of enantioselectivity. A library of phosphite-pyridine ligands has been successfully applied in the Pd-catalyzed allylic substitution reactions of several di- and trisubstituted substrates by using a wide range of C, N, and O nucleophiles. By carefully selecting the ligand components, high regio- and enantioselectivities (up to >99 % ee) and good activities have been achieved (see scheme). The NMR studies on the Pd-π-allyl intermediates provide a deeper understanding of the effect of ligand parameters on the origin of enantioselectivity. Copyright
- Mazuela, Javier,Pàmies, Oscar,Diéguez, Montserrat
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p. 2416 - 2432
(2013/04/23)
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- CuII-catalyzed asymmetric hydrosilylation of diaryl- and aryl heteroaryl ketones: Application in the enantioselective synthesis of orphenadrine and neobenodine
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With certain amounts of sodium tert-butoxide and tert-butanol as additives, catalytic amounts of an inexpensive and easy-to-handle copper source Cu(OAc)2·H2O, a commercially available and air-stable non-racemic dipyridylphosphine ligand, as well as the stoichiometric desirable hydride donor polymethylhydrosiloxane (PMHS), formed a versatile in situ catalyst system for the enantioselective reduction of a broad spectrum of prochiral diaryl and aryl heteroarylketones in air, in high yields and with good to excellent enantioselectivities (up to 96 %). In particular, the practical viability of this process was evinced by its successful applications in the asymmetric synthesis of optically enriched potent antihistaminic drugs orphenadrine and neobenodine. Copyright
- Sui, Yao-Zong,Zhang, Xi-Chang,Wu, Jun-Wen,Li, Shijun,Zhou, Ji-Ning,Li, Min,Fang, Wenjun,Chan, Albert S. C.,Wu, Jing
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supporting information; experimental part
p. 7486 - 7492
(2012/07/27)
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- Hydroxyalkyl thiazolines, a new class of highly efficient ligands for carbonyl additions
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Hydroxyalkyl thiazoline ligands can easily be obtained in an isonitrile-based multicomponent reaction. These ligands are significantly more stable than the comparable oxazoline ligands, and give excellent enantiomeric excess in carbonyl additions of alkyl- and arylzinc compounds. Georg Thieme Verlag Stuttgart.
- Bauer, Michael,Maurer, Frauke,Hoffmann, Svenja M.,Kazmaier, Uli
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experimental part
p. 3202 - 3207
(2009/06/05)
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- Complexes of Ruthenium with 2-(Aminomethyl)Pyridines and Phosphines, their Preparation and Use as Catalysts
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The invention relates to a new class of ruthenium (II) complexes containing as ligands 2-(aminomethyl)pyridines and phosphines, proven to be extremely active catalysts in the reduction of ketones to alcohols via hydrogen transfer. By using 2-propanol as the hydrogen source with the ruthenium complexes, high yields of the corresponding alcohol can be rapidly obtained starting from linear and cyclic alkyl aryl, dialkyl and diaryl ketones. The conversion of ketones to alcohols can reach 100% if operating in a gaseous hydrogen atmosphere (2-3 atm). Where the phosphines used are optically active, starting from prochiral ketone compounds various types of optically active alcohols can be produced, being important intermediates in the pharmaceutical industry, in the agrochemical industry and for fine chemicals generally.
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Page/Page column 8
(2008/12/08)
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- Preparation of pyridinyl aryl methanol derivatives by enantioselective hydrogenation of ketones using chiral Ru(diphosphine)(diamine) complexes. Attribution of their absolute configuration by 1H NMR spectroscopy using Mosher's reagent
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Ruthenium-diamine-diphosphine complexes provide highly efficient catalysts for enantioselective hydrogenation of a series of pyridinyl aryl ketones. The hydrogenation proceeds under mild conditions providing chiral pyridinyl aryl methanol derivatives with consistently high yields and moderate to excellent enantioselectivities (up to 99% ee) according to the structure of the chiral diphosphine. NMR studies, based on Mosher's ester derivatisation, allowed to determine the configuration of the major alcohol obtained during asymmetric hydrogenation.
- Maerten, Eddy,Agbossou-Niedercorn, Francine,Castanet, Yves,Mortreux, André
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p. 8700 - 8708
(2008/12/21)
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- Synthesis of chiral pyridyl alcohols using a two-step catalytic approach
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Chira l pyridyl alcohols have been prepared by developing a two-step approach that uses the asymmetric cyanation of aldehydes to give cyanohydrins and subsequent [2+2+2]-cyclotrimerization reaction with acetylene. Georg Thieme Verlag Stuttgart.
- Heller, Barbara,Redkin, Dmitry,Gutnov, Andrey,Fischer, Christine,Bonrath, Werner,Karge, Reinhard,Hapke, Marko
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- Enzyme-catalyzed enantioselective diaryl ketone reductions
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(Chemical Equation Presented) The synthesis of diarylmethanols via the reduction of a range of substituted benzophenone and benzoylpyridine derivatives with ketoreductase enzymes (KREDs) has afforded chiral products with high yield (>90%) and ee (up to >99%). Ortho, meta, and para substitutions with a variety of electron-donating, electron-withdrawing, and halogen groups were examined. Substitution at the ortho position and/or highly electronically dissymmetric molecules were not required for good selectivity, as is the case with conventional chemical catalyst reductions.
- Truppo, Matthew D.,Pollard, David,Devine, Paul
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p. 335 - 338
(2007/10/03)
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- COMPLEXES OF RUTHENIUM WITH 2-(AMINOMETHYL)PYRIDINES AND PHOSPHINES, THEIR PREPARATION AND USE AS CATALYSTS
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The patent describes a new class of ruthenium (II) complexes containing as ligands 2-(aminomethyl)pyridines and phosphines, proven to be extremely active catalysts in the reduction of ketones to alcohols via hydrogen transfer. By using 2-propanol as the hydrogen source with said ruthenium complexes, high yields of the corresponding alcohol can be rapidly obtained starting from linear and cyclic alkyl aryl, dialkyl and diaryl ketones. The conversion of ketones to alcohols can reach 100% if operating in a gaseous hydrogen atmosphere (2 - 3 atm). Where the phosphines used are optically active, starting from prochiral ketone compounds various types of optically active alcohols can be produced, being important intermediates in the pharmaceutical industry, in the agrochemical industry and for fine chemicals generally.
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Page/Page column 22-23
(2010/02/14)
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- Synthesis of Versatile Chiral N,P Ligands Derived from Pyridine and Quinoline
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Potent transition-metal complexes for asymmetric catalysis are formed from readily accessible N,P ligands constructed from basic N-heteroaryl building blocks (see structure). Their simple assembly should not be misconstrued: they posses several handles by which to tune both steric and electronic parameters. The potential of these ligands is demonstrated by the high levels of enantioselection they induce in such divergent processes as asymmetric hydrogenation and the Heck reaction.
- Drury III, William J.,Zimmermann, Nicole,Keenan, Martine,Hayashi, Masahiko,Kaiser, Stefan,Goddard, Richard,Pfaltz, Andreas
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- Highly Enantioselective Hydrogenation of Aromatic-Heteroaromatic Ketones
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(Equation presented) Asymmetric hydrogenation of ketone 1 using trans-RuCl2[(R)-xylbinap][(R)-daipen] (3) as a catalyst afforded secondary alcohol 2 quantitatively and in 99.4% ee. Further exploration of the effect of the thiazole ring substitution revealed that the catalyst was highly effective for the enantioselective hydrogenation of 5-benzoyl thiazoles, which afforded corresponding alcohols in 92-99% ee. The same protocol was applicable to a variety of aromatic-heteroaromatic ketones to generate secondary alcohols in excellent enantioselectivities.
- Chen, Cheng-Yi,Reamer, Robert A.,Chilenski, Jennifer R.,McWilliams, Chris J.
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p. 5039 - 5042
(2007/10/03)
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- Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics
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The preparation of a new class of tricyclic models 1 based on a Friedl?nder reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4-87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30-84% ee (R).
- Vasse, Jean-Luc,Levacher, Vincent,Bourguignon, Jean,Dupas, Georges
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p. 4911 - 4921
(2007/10/03)
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- Studies on Rhizopus arrhizus mediated enantioselective reduction of arylalkanones
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The effect of substitution on the biotransformation of various arylalkanones using Rhizopus arrhizus was investigated. The organism was found to be promising for the reduction of phenylalkanones and arylethanones with good to excellent enantioselectivity. The reduction followed Prelog's rule giving the (S)-carbinols in all the cases. The enantioselectivity of the reaction improved with increasing size of the groups flanking the carbonyl function and the electron withdrawing capacity of the substituents in the aromatic ring. However, the yield was dramatically affected with increased hydrophobicity of the substrates.
- Salvi,Chattopadhyay
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p. 2833 - 2839
(2007/10/03)
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- A compact chemical miniature of a holoenzyme, coenzyme NADH linked dehydrogenase. Design and synthesis of bridged NADH models and their highly enantioselective reduction
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An L-lactate dehydrogenase that requires coenzyme NADH catalyzes the enantioselective reduction of pyruvate to L-lactate in anaerobic glycolysis. As the first homochiral ansa-type NADH models, we designed the bridged NADH models 10a-c having a parapyridinophane structure for strictly mimicking the stereospecificity of hydrogen transfer in the biological asymmetric reduction with NADH. These models were synthesized in several steps from the corresponding bridged nicotinate 5 prepared by our novel pyridine-formation reaction of formyl-substituted (vinylimino)phosphorane 4 with methyl propiolate. The bridged NADH models 10a-c effected excellent biomimetic reduction at various temperatures in the presence of magnesium ion to achieve both the enantioselective and stereospecific reduction of the pyruvate analogues 12u-z into chiral lactate analogues 13u-z with 88-99% ee. The high enantioselectivity was almost completely dependent on the planar chirality of 10a-c but not on the nature of the substituents of their carbamoyl groups. The biomimetic reduction proceeded with retention of the planar chirality, showing that the bridged NADH models are useful for being recycled. An isotope experiment with the deuterated model (±)-10d confirmed the stereospecific hydrogen transfer, which is in good accordance with natural coenzyme characteristics. The model (S)-10c also exhibited good enantioselectivity for the reduction of activated ketones 14k-n into the corresponding chiral alcohols 15k-n with 79-89% ee. The simple bridged NADH model (S)-10c having both a primary carbamoyl group and a shielding bridge feigning an enzyme wall suggests a compact chemical miniature of a holoenzyme, coenzyme NADH linked dehydrogenase, in terms of the unique structure, high enantioselectivity, and recyclability.
- Kanomata, Nobuhiro,Nakata, Tadashi
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p. 4563 - 4568
(2007/10/03)
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- Preparation, Absolute Configuration and Conformation of Some α-Aryl-2-pyridylmethanols
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The syntheses of five optically active α-aryl-2-pyridylmethanols 1-5 are described.It is shown by means of chemical correlation with the known (-)-(α-R,2S)-α-phenyl-2-piperidylmethanol 6 that all levo-rotatory isomers 1-4 are of R configuration.It is also found via the relative integral intensities in the infrared spectra of the bands due to free and intramolecularly bonded hydroxyl groups in the compounds 1-4 and the free hydroxyl groups in the model compounds 7-10, that the population of the conformers with an intramolecular OH...N bond in compounds 1-4 exceds 80percent.
- Bojadziev, Stefan E.,Tsankov, Dimiter T.,Ivanov, Petko M.,Berova, Nikolina D.
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p. 2651 - 2656
(2007/10/02)
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