Chiral Secondary Alcohols Research Articles

Synthesis and characterization of novel chiral derivatizing agents containing β-keto-anthracene adducts (KAAs) by 1H-NMR: aromatic influence and chiral alcohol absolute configuration determination.

New alternative chiral derivatizing agents, β-keto-anthracene adducts (KAAs), were accomplished and the influence of aromatic moieties at the α-carbon position for elucidation of the absolute configuration of chiral secondary alcohols via NMR was studied. The α-benzoyl substituted KAAs strongly enhance the anisotropic effect which produced greater ΔδRS values than other conventional reagents. We propose a simplified model to describe the conformations and to assign the absolute configuration in several chiral alcohol samples.

Kinetic Resolution of Allylic Alcohol with Chiral BINOL-Based Alkoxides: A Combination of Experimental and Theoretical Studies.

The development and characterization of enantioselective catalytic kinetic resolution of allylic alcohols through asymmetric isomerization with chiral BINOL derivatives-based alkoxides as bifunctional Brønsted base catalysts were described in the study. A number of chiral BINOL derivatives-based alkoxides were synthesized, and their structure-enantioselectivity correlation study in asymmetric isomerization identified a promising chiral Brønsted base catalyst, which afforded various chiral secondary allylic alcohols (ee up to 99%, S factor up to >200). In the mechanistic study, alkoxide species were identified as active species and the phenol group of BINOL largely affected the high reactivity and enantioselectivity via hydrogen bonding between the chiral Brønsted base catalyst and substrates. The strategy is the first successful synthesis strategy of various chiral secondary allylic alcohols through enantioselective transition-metal-free base-catalyzed isomerization. The applicability of the strategy had been demonstrated by the synthesis of the bioactive natural product (+)-veraguensin.

Asymmetric Catalysis Using Aromatic Aldehydes as Chiral α-Alkoxyalkyl Anions.

We have developed a new umpolung strategy for catalytically forming a chiral α-alkoxyalkyl anion from an aromatic aldehyde for use in asymmetric synthesis. The reaction between aromatic aldehydes and aryl or allyl electrophiles with a silylboronate utilizing a chiral copper-N-heterocyclic carbene catalyst and a palladium-bisphosphine catalyst in a synergistic manner occurred with high enantioselectivities to deliver the three-component coupling products, chiral silyl-protected secondary alcohol derivatives. Our method features the catalytic generation of enantioenriched chiral α-alkoxyalkylcopper(I) intermediates from aldehydes and their subsequent palladium-catalyzed stereospecific cross-coupling.

Synthesis, characterization and aggregation properties of non-peripherally (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol substituted optically active zinc phthalocyanine and its catalytic application in enantioselective ethylation of aldehydes

The novel optically active zinc(II) phthalocyanine having four (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol 1 at non-peripheral positions has been synthesized in a condensation using optically active phthalonitrile 2, and characterized by 1H NMR, IR, UV–Vis, Circular Dichroism (CD) and HRMS-TOF spectral data. The spectral and aggregation properties of novel optically active zinc(II) phthalocyanine 3 were investigated. The aggregation behavior of phthalocyanine 3 was investigated at different concentrations in N,N-dimethylformamide and tetrahydrofuran. No aggregation behavior was observed in both solvents at concentrations between 10 × 10−6 and 2 × 10−6 mol dm−3. The applicability of these chiral ligands 1–3 was evaluated in the enantioselective diethyl zinc addition of aldehydes. The addition of diethylzinc to 2-methoxybenzaldehyde was achieved with excellent enantioselectivity (87% ee, 80% yield) under catalysis with (1R,2R)-1,2-di(naphthalen-1-yl)ethane-1,2-diol 1. At the same condition, optically active zinc(II) phthalocyanine 3 afforded the corresponding chiral secondary alcohol with the enantiomeric excess of 11%.

Novel peripherally and non-peripherally hydrobenzoin substituted optically active phthalocyanines: Synthesis, characterization, aggregation, electrochemical properties and catalytic applications

The novel optically active two zinc(II)phthalocyanines and two cobalt(II)phthalocyanines with four chiral hydrobenzoin moieties at the non-peripheral (4 and 5) and peripheral positions (6 and 7) of the phthalocyanine ring have been synthesized. The structures of the synthesized compounds are characterized by 1H NMR, IR, UV–Vis, circular dichroism (CD) and MALDI-TOF MS spectral data. The comparative studies of the spectral, aggregation properties, voltammetry and catalytic applications of novel zinc(II) and cobalt(II)phthalocyanines, tetra-substituted with hydrobenzoin at peripheral and non-peripheral positions, were investigated. All synthesized phthalocyanines are highly soluble in most common organic solvents. In the enantioselective addition of diethylzinc to aldehydes, the best catalytic activity was obtained with 3-methoxybenzaldehyde in the presence of non-peripherally hydrobenzoin substituted zinc(II)phthalocyanine 4 and afforded the corresponding chiral secondary alcohol with the yield of 38% and the enantiomeric excess of 33%. In the oxidation of benzyl alcohol, the highest conversion of benzyl alcohol to benzaldehyde was obtained with non-peripherally substituted cobalt(II)phthalocyanine 5 as 91% with the highest selectivity of 83%.

Scope and Mechanism on Iridium‐f‐Amphamide Catalyzed Asymmetric Hydrogenation of Ketones

AbstractA series of novel and easily accessed ferrocene‐based amino‐phosphine‐sulfonamide (f‐Amphamide) ligands have been developed and applied in Ir‐catalyzed asymmetric hydrogenation of aryl ketones, affording the corresponding chiral secondary alcohols with excellent results (up to >99% conversion, >99% ee and TON up to 200 000). DFT calculations suggest an activating model involving an alkali cation Li+.

Utilization of deep-sea microbial esterase PHE21 to generate chiral sec-butyl acetate through kinetic resolutions.

We previously identified and characterized 1 novel deep-sea microbial esterase PHE21 and used PHE21 as a green biocatalyst to generate chiral ethyl (S)-3-hydroxybutyrate, 1 key chiral chemical, with high enantiomeric excess and yield through kinetic resolution. Herein, we further explored the potential of esterase PHE21 in the enantioselective preparation of secondary butanol, which was hard to be resolved by lipases/esterases. Despite the fact that chiral secondary butanols and their ester derivatives were hard to prepare, esterase PHE21 was used as a green biocatalyst in the generation of (S)-sec-butyl acetate through hydrolytic reactions and the enantiomeric excess, and the conversion of (S)-sec-butyl acetate reached 98% and 52%, respectively, after process optimization. Esterase PHE21 was also used to generate (R)-sec-butyl acetate through asymmetric transesterification reactions, and the enantiomeric excess and conversion of (R)-sec-butyl acetate reached 64% and 43%, respectively, after process optimization. Deep-sea microbial esterase PHE21 was characterized to be a useful biocatalyst in the kinetic resolution of secondary butanol and other valuable chiral secondary alcohols.

Method for Catalytic Enantioselective Alkylation of Aldehydes Using Grignard Reagents as Alkyl Sources.

Alkyltitanium reagents, generated in situ from Grignard reagents and ClTi(O iPr)3, can be employed without further manipulation in the enantioselective alkylation of aldehyde by the catalysis of a chiral titanium complex derived from DTBP-H8-BINOL. The reaction is performed with good stoichiometry [1.5 equiv each of Grignard reagents and ClTi(O iPr)3] at a low catalyst loading (2 mol %), affording a variety of chiral secondary alcohols in high enantioselectivity and yields and, hence, realizing an asymmetric version of the Grignard reaction in an indirect manner.

A Practical and Efficient Stereoselective Synthesis of (S)‐Rivastigmine and (R)‐Rivastigmine

AbstractA stereoselective synthesis of (S)‐rivastigmine and (R)‐rivastigmine was developed. The key steps were stereoselective chlorination of a chiral secondary benzylic alcohol intermediate and amination of the corresponding chloride. Based on this method, both stereoisomers of rivastigmine were obtained stereoselectively in high yields.

Fine tuning the enantioselectivity and substrate specificity of alcohol dehydrogenase from Kluyveromyces polysporus by single residue at 237

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.

Design of a Chiral Ionic Liquid System for the Enantioselective Addition of Diethylzinc to Aldehydes

An important contribution to the field of asymmetric catalysis is described in this work, as it merges the search for new ligands that can provide high performance in asymmetric catalysis with the extremely important and increasing need for sustainability. New chiral ionic liquids have been synthesised from the amino acid l‐cysteine by straightforward routes. With these ligands, we have developed a chiral ionic system that includes chiral ionic liquids and their immobilisation in ionic solvents to provide a chiral supramolecular structure. These new catalytic systems were used in the enantioselective addition of alkylzinc to aldehydes and proved to be very efficient, capable of providing chiral secondary alcohols in excellent enantiomeric excesses and yields. This system also enabled the recycling of the ionic media and the ionic ligand, taking into account green chemistry considerations.

Chiral C2-symmetric η6-p-cymene-Ru(II)-phosphinite complexes: Synthesis and catalytic activity in asymmetric reduction of aromatic, methyl alkyl and alkyl/aryl ketones

Abstract Chiral C2-symmetric bis(phosphinite) ligands and their binuclear ruthenium(II) complexes have been synthesized and used as catalysts in the ruthenium-catalyzed asymmetric transfer hydrogenation of aromatic, methyl alkyl and alkyl/aryl ketones using 2-propanol as both the hydrogen source and solvent in the presence of KOH. Under optimized conditions, all complexes showed high catalytic activity as catalysts in the reduction of various ketones to corresponding chiral secondary alcohols. Products were obtained with high conversions (99%) and moderate to good enantioselectivities (82% ee). Furthermore, C2-symmetric bis(phosphinite) ligands and their binuclear ruthenium(II) complexes were characterized by multinuclear NMR spectroscopy, FT-IR spectroscopy, LC/MS-MS and elemental analysis.

Highly Enantioselective Hydrosilylation of Ketones Catalyzed by a Chiral Oxazaborolidinium Ion.

A highly enantioselective hydrosilylation of ketones was developed for the synthesis of a variety of chiral secondary alcohols. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeded with good yields (up to 99%) with excellent enantioselectivities (up to 99% ee).

Highly enantioselective asymmetric reactions involving zinc ions promoted by chiral aziridine alcohols

Enantiomerically pure, chiral secondary and tertiary aziridine alcohols (including the aziridine analogue of ProPhenol—AziPhenol) have proven to be highly effective catalysts for enantioselective asymmetric reactions in the presence of zinc ions, including arylation of aromatic aldehydes, epoxidation of chalcone and addition of diethylzinc to aldehydes, leading to the desired chiral products in high chemical yields (up to 90%) and with ee’s up to 90%. A higher catalytic activity of Prophenol-type bis(aziridine alcohol) in the aforementioned asymmetric transformations has been demonstrated.

Highly Enantioselective Production of Chiral Secondary Alcohols Using Lactobacillus paracasei BD101 as a New Whole Cell Biocatalyst and Evaluation of Their Antimicrobial Effects.

Chiral secondary alcohols are valuable intermediates for many important enantiopure pharmaceuticals and biologically active molecules. In this work, we studied asymmetric reduction of aromatic ketones to produce the corresponding chiral secondary alcohols using lactic acid bacteria (LAB) as new biocatalysts. Seven LAB strains were screened for their ability to reduce acetophenones to their corresponding alcohols. Among these strains, Lactobacillus paracasei BD101 was found to be the most successful at reducing the ketones to the corresponding alcohols. The reaction conditions were further systematically optimized for this strain and high enantioselectivity (99%) and very good yields were obtained. These secondary alcohols were further tested for their antimicrobial activities against important pathogens and significant levels of antimicrobial activities were observed although these activities were altered depending on the secondary alcohols as well as their enantiomeric properties. The current methodology demonstrates a promising and alternative green approach for the synthesis of chiral secondary alcohols of biological importance in a cheap, mild, and environmentally useful process.

Catalytic asymmetric synthesis of Leukotriene B4

Leukotriene B41 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and 14 were constructed by BINOL/Ti(OiPr)4 catalyzed enantioselective alkynylzinc addition to aldehydes.

Genome hunting of carbonyl reductases from Candida glabrata for efficient preparation of chiral secondary alcohols

In this work, genome hunting strategy was adopted in screening for reductases from Candida glabrata. A total of 37 putative reductases were successfully expressed in E. coli BL21(DE3). A substrate library containing 32 substrates was established for characterization of each reductase by average specific activity and Shannon-Wiener index. Among them, Cg26 was identified with the highest efficiency and wider substrate spectrum in the reduction of prochiral ketones, with average activity and Shannon-Wiener index of 8.95U·mg−1 and 2.82. Cg26 is a member of ‘extended’ short chain dehydrogenase/reductase superfamily. Ni2+ could improve its activity. As much as 150g·L−1 ethyl 2-oxo-4-phenylbutyrate could be completely converted by 10g·L−1 Cg26. This study provides evidence for this newly identified Cg26 in the preparation of chiral secondary alcohols.

Highly Enantioselective Production of Chiral Secondary Alcohols with Candida zeylanoides as a New Whole Cell Biocatalyst.

The increasing demand for biocatalysts in synthesizing enantiomerically pure chiral alcohols results from the outstanding characteristics of biocatalysts in reaction, economic, and ecological issues. Herein, fifteen yeast strains belonging to three food originated yeast species Candida zeylanoides, Pichia fermentans, and Saccharomyces uvarum were tested for their capability for asymmetric reduction of acetophenone to 1-phenylethanol as biocatalysts. Of these strains, C.zeylanoides P1 showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high yields. The preparative scale asymmetric bioreduction of 4-nitroacetophenone (1m) by C.zeylanoides P1 gave (S)-1-(4-nitrophenyl)ethanol (2m) with 89% yield and >99% enantiomeric excess. Compound 2m has been obtained in an enantiomerically pure and inexpensive form. Additionally, these results indicate that C.zeylanoides P1 is a promising biocatalyst for the synthesis of chiral alcohols in industry.

Debaryomyces hansenii as a new biocatalyst in the asymmetric reduction of substituted acetophenones

Chiral secondary alcohols are convenient mediator for the synthesis of biologically active compounds and natural products. In this study fifteen yeast strains belonging to three food originated yeast species Debaryomyces hansenii, Saccharomyces cerevisiae and Hanseniaspora guilliermondii were tested for their capability for the asymmetric reduction of acetophenone to 1-phenylethanol as biocatalyst microorganisms. Of these strains, Debaryomyces hansenii P1 strain showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to the corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high conversion rates. This is the first report on the enantioselective reduction of acetophenone by D. hansenii P1 from pastırma, a fermented Turkish meat product. The preparative scale asymmetric bio reduction of 3-methoxy acetophenone 1g by D. hansenii P1 gave (R)-1-(3-methoxyphenyl) ethanol 2g 82% yield, and >99% enantiomeric excess. Compound 2g can be used for the synthesis of (+)-NPS-R-568 [3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenly) ethyl] propan-1-amine] which have a great potential for the treatment of primary and secondary hyper-parathyroidism. In addition, D. hansenii P1 successfully reduced acetophenone derivatives. This study showed that this yeast can be used industrially to produce enantiomerically pure chiral secondary alcohols, which can be easily converted to different functional groups.

Chiral Catalyst Deactivation during the Asymmetric Hydrogenation of Acetophenone

Asymmetric hydrogenation in solution catalyzed by chiral catalysts is a powerful tool to obtain chiral secondary alcohols. It is possible to reach conversions and enantiomeric excesses close to 99%, but that frequently requires the use of non-optimal amounts of catalysts or long reaction times. That is in part caused by the lack of kinetic information needed for the design of large-scale reactors, including few reported details about catalyst deactivation. In this work, we present a kinetic model for the asymmetric hydrogenation in solution of acetophenone, a prochiral substrate, catalyzed by different bisphosphine-diamine Ru complexes. The experimental data was fitted with a first order model that includes first order deactivation of the catalyst and the presence of residual activity. The fit of the experimental data is very good, and an analysis of the kinetic and deactivation parameters gives further insight into the role of each ligand present in the Ru catalysts. This is the first report of a kinetic analysis of homogenous complexes’ catalysis including an analysis of their deactivation.