Cinchona Organocatalysts Research Articles

Recyclable fluorous cinchona organocatalysts for asymmetric synthesis of biologically interesting compounds.

Organocatalysis has unique modes of activation, mild reaction conditions, and good catalyst structural amenability. The integration of green techniques such as catalyst recovery and one-pot reactions makes organocatalysis more efficient and attractive. Presented in this article are the recyclable cinchona alkaloid-catalyzed reactions including fluorination and Michael addition-initiated cascade reactions in asymmetric synthesis of functionalized compounds of biological interest.

Comparison of Cinchona Catalysts Containing Ethyl or Vinyl or Ethynyl Group at Their Quinuclidine Ring.

Numerous cinchona organocatalysts with different substituents at their quinuclidine unit have been described and tested, but the effect of those saturation has not been examined before. This work presents the synthesis of four widely used cinchona-based organocatalyst classes (hydroxy, amino, squaramide, and thiourea) with different saturation on the quinuclidine unit (ethyl, vinyl, ethynyl) started from quinine, the most easily available cinchona derivative. Big differences were found in basicity of the quinuclidine unit by measuring the pKa values of twelve catalysts in six solvents. The effect of differences was examined by testing the catalysts in Michael addition reaction of pentane-2,4-dione to trans-β-nitrostyrene. The 1.6–1.7 pKa deviation in basicity of the quinuclidine unit did not result in significant differences in yields and enantiomeric excesses. Quantum chemical calculations confirmed that the ethyl, ethynyl, and vinyl substituents affect the acid-base properties of the cinchona-thiourea catalysts only slightly, and the most active neutral thione forms are the most stable tautomers in all cases. Due to the fact that cinchonas with differently saturated quinuclidine substituents have similar catalytic activity in asymmetric Michael addition application of quinine-based catalysts is recommended. Its vinyl group allows further modifications, for instance, recycling the catalyst by immobilization.

Enantioselective electrophilic cyanation of β-keto amides catalysed by a cinchona organocatalyst

An operationally simple protocol for the enantioselective electrophilic α-cyanation of β-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric α-cyanation reaction.

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts.

Cinchona alkaloids with a free 6'-OH functionality are being increasingly used within asymmetric organocatalysis. This fascinating class of bifunctional catalyst offers a genuine alternative to the more commonly used thiourea systems and because of the different spacing between the functional groups, can control enantioselectivity where other organocatalysts have failed. In the main, this review covers the highlights from the last five years and attempts to show the diversity of reactions that these systems can control. It is hoped that chemists developing asymmetric methodologies will see the value in adding these easily accessible, but underused organocatalysts to their screens.

Cinchona‐Derived Picolinamides: Effective Organocatalysts for Stereoselective Imine Hydrosilylation

AbstractPicolinamide–cinchona organocatalysts for the successful enantioselective reduction of ketomines were developed. For the first time, a new type of chiral Lewis base, a cationic species, is reported to efficiently organocatalyze the addition of trichlorosilane to imines. Excellent yields with good to high enantioselectivities (up to 91 %) were obtained in the reduction of differently substituted substrates. Noteworthy, remarkably high turnover frequencies for the hydrosilylation of imines were observed; the catalyst of choice proved to be active even at a loading of only 1 mol‐%. The loading was further reduced to 0.5 mol‐%, and for very short reaction times (15 min) very impressive asymmetric catalyst efficiency speed values were reached.

Asymmetric aldol addition of α-azido ketones to ethyl pyruvate mediated by a cinchona-based bifunctional urea catalyst

The first asymmetric synthesis of ethyl 4-aryl-3-azido-2-hydroxy-2-methyl-4-oxobutanoates via a cinchona organocatalyst induced aldol addition of α-azido ketones to ethyl pyruvate has been developed. The coupling reaction under optimized conditions was carried out to furnish tetrafunctionalized synthons with enantioselectivities of up to 91:9 and enriched diastereoselectivities of up to 95:5 (syn:anti).

Theoretical study on the mechanism and stereochemistry of the cinchona–thiourea organocatalytic hydrophosphonylation of an α-ketoester

The mechanism and stereochemistry of the hydrophosphonylation of an α-ketoester with dimethylphosphonate (DMHP) catalyzed by a thiourea-cinchona organocatalyst have been studied by the ONIOM method. The calculations show that the catalytic cycle is a three-step process, including the deprotonation of DMHP, C-P bond formation via nucleophilic addition and proton transfer with the regeneration of the catalyst. The deprotonation of DMHP mediated by the basicity of the quinuclidine nitrogen atom is the rate-determining step for the entire reaction. The activation of the α-ketoester by the thiourea or protonated cinchona moiety of the bifunctional catalyst is comparatively investigated, and the former is energy-preferred. AIM combined with NBO analysis indicate that the multiple hydrogen bonds play essential roles in activating substrates, facilitating charge transfer and stabilizing transition states and intermediates. The stereochemistry of the reaction is controlled by the C-P bond formation step and originated from the chiral induction of the multiple hydrogen-bonding interactions. The bulkier substituent groups on the chiral scaffold of the catalyst may increase rigidity of the catalyst and the asymmetric induction to the substrates. The calculations predict that alkyl substituted α-ketoesters might also be converted to chiral α-hydroxyl phosphonates with high enantioselectivity.

Excited-state proton transfer and ion pair formation in a Cinchona organocatalyst

The excited-state proton transfer and subsequent intramolecular ion pair formation of a cupreidine-derived Cinchona organocatalyst (BnCPD) were studied in THF-water mixtures using picosecond time-resolved fluorescence together with global analysis. Full spectral and kinetic characterization of all the fluorescent species allowed us to monitor the 3-step process for the ion pair dissociation. In the first step, proton transfer occurs through a water "wire" from the 6-hydroxyquinoline unit (excited-state acid) to the covalently bonded basic quinuclidine moiety, resulting in a hydrogen bonded ion pair. This was confirmed by the observed kinetic isotope effect in the presence of heavy water. In the second step, the formed ions are further solvated by a few solvent molecules, producing the solvent separated ion pair. Finally, a fully solvated ion pair is formed. The 5-exponential global model derived from the reaction scheme describes the experimental data very well.

ChemInform Abstract: Organocatalysis: Cinchona Catalysts

AbstractReview: 50 refs.

Organocatalytic enantioselective Michael addition of β-diketones to β-nitrostyrene: the first Michael addition of dipivaloylmethane to an activated olefin.

The addition of a family of β-diketones to β-nitrostyrene was explored using a library of cinchona organocatalysts. A thiourea organocatalyst, under improved reaction conditions, is shown to be much more efficient at catalyzing this reaction than previously reported giving excellent yields and enantioselectivites (up to 95% yield and 97% ee). The same thiourea organocatalyst was employed in the first successful Michael addition of the sterically challenging dipivaloylmethane to β-nitrostyrene (99% ee).

Organocatalysis: Cinchona catalysts

AbstractThe resurgence of asymmetric organocatalysis has been accompanied by the development of countless synthetic methodologies making use of Cinchona alkaloids (or their derivatives) as catalysts. Although important steps have been made in the understanding of the mode of action of this class of compounds, the development of new catalytic methodologies is largely carried out using experiment‐driven approaches. This overview presents a selection of computational results on the behavior of Cinchona alkaloids with respect to their structure, the way they interact with other species, and, ultimately, their catalytic activity. The twofold aim of this contribution is to provide organic chemists with accessible information on computational results as well as to present theoretical chemists an overview of the methods commonly used to model Cinchona organocatalysts, and how they are comparable to experimental results. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 142–152 DOI: 10.1002/wcms.2This article is categorized under: Structure and Mechanism > Molecular Structures Electronic Structure Theory > Density Functional Theory Theoretical and Physical Chemistry > Reaction Dynamics and Kinetics

ChemInform Abstract: Highly Enantioselective and Regioselective Conjugate Addition of Nitromethane to 1,5‐Diarylpenta‐2,4‐dien‐1‐ones Using Bifunctional Cinchona Organocatalysts.

AbstractThe optimized conditions render possible a good to excellent enantioselectivity for the nitro compounds (III).

Highly Enantioselective 1,4‐Michael Additions of Nucleophiles to Unsaturated Aryl Ketones with Organocatalysis by Bifunctional Cinchona Alkaloids

AbstractThe development of general and efficient asymmetricorganocatalytic additions of malononitrile and nitromethane to 1,5‐diarylpenta‐2,4‐dien‐1‐ones (cinnamylideneacetophenones) catalyzed by cinchona organocatalysts is reported. The reactions afforded excellent enantioselectivities (up to 99 %), high yields (up to 97 %), and exclusive 1,4‐addition regioselectivities. The potential of these new enantioselective additions lies in the demonstration that organocatalysts bearing primary amino groups in combination with TFA provide effective catalytic systems for the activation of a broad range of aryl ketones under mild conditions to give compounds with high levels of enantioselectivity and yields.

Highly Enantioselective and Regioselective Conjugate Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones Using Bifunctional Cinchona Organocatalysts

A general and efficient asymmetric organocatalytic 1,4-Michael addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-ones (cinnamylideneacetophenones) catalyzed by 9-thiourea-9-(deoxy)-epi-hydroquinine has been developed. The reactions afforded excellent enantioselectivities (up to 99%), high yields (up to 97%), and exclusive regioselectivity.

Photophysical Properties of Cinchona Organocatalysts in Organic Solvents

The photophysical properties of cinchona organocatalysts 1 (dehydroquinidine) and 2 (9-benzylcupreidine) in several organic solvents have been studied by means of absorption and fluorescence spectr...

A Highly Efficient Asymmetric Michael Addition of Anthrone to Nitroalkenes with Cinchona Organocatalysts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

A highly efficient asymmetric Michael addition of anthrone to nitroalkenes with cinchona organocatalysts

A highly efficient asymmetric Michael addition of anthrone to nitroalkenes catalyzed by cinchona alkaloids was described. Up to 99% ee of the corresponding adduct was obtained.

Cupreines and Cupreidines: An Emerging Class of Bifunctional Cinchona Organocatalysts

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cupreines and Cupreidines: An Emerging Class of Bifunctional Cinchona Organocatalysts

In the steadily expanding field of organocatalysis, cinchona alkaloids play a prominent role. Until the late 1990s, bifunctional catalysts based on this scaffold relied exclusively on the C9-hydroxy group as the hydrogen-bond donor. Recently, new cinchona catalysts have been developed that feature a phenolic OH group in the C6' position-a structural feature that allows a diverse set of reactions to be catalyzed in a highly stereoselective fashion. This Minireview describes the scope and modes of action of this new class of asymmetric bifunctional organocatalysts.

Enantioselective aza‐Henry Reaction Using Cinchona Organocatalysts.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.