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

Oliva, Cristina Gómez de la; Silva, Artur M. S.; Resende, Diana I. S. P.; Paz, Filipe A. A.; Cavaleiro, José A. S.

doi:10.1002/ejoc.201000273

Cited by 49 publications

(5 citation statements)

References 68 publications

(34 reference statements)

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“…However, a single diastereomer was formed. Usually, the asymmetric Michael addition of nitromethane involves the use of complex organocatalysts [ 23 , 24 , 25 ], however, in our particular case, their use was not required, since the observed diastereoselectivity was inducted by the defined stereochemistry of the triterpene scaffold.…”

Section: Resultsmentioning

confidence: 99%

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles

et al. 2022

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Betulinic acid (BA) was used as starting building block to create a library of novel BA-derived compounds containing O- and N-heterocycles. Firstly, BA was converted into methyl betulonate (BoOMe), which was used as intermediate in the developed methodologies. 1,2-Oxazine-fused BoOMe compounds were obtained in 12–25% global yields through a Michael addition of nitromethane to methyl (E)-2-benzylidenebetulonate derivatives, followed by nitro group reduction and intramolecular cyclization. Remarkably, the triterpene acts as a diastereoselective inducer in the conjugate addition of nitromethane, originating only one diastereomer out of four possible ones. Furthermore, other oxygen and nitrogen-containing heterocycles were installed at the A-ring of BoOMe, affording 2-amino-3-cyano-4H-pyran-fused BoOMe, diarylpyridine-fused BoOMe and 1,2,3-triazole–BoOMe compounds, using simple and straightforward synthetic methodologies. Finally, BA was revealed to be a versatile starting material, allowing the creation of a molecular diversification of compounds containing a triterpenic scaffold and O- and N-heterocycles.

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Section: Resultsmentioning

confidence: 99%

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles

et al. 2022

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“…Compared with traditional metal‐based catalysts, chiral organic molecules as catalysts exhibit distinctive and competitive potency in Michael addition reactions. In particular, organocatalysts based on primary amines have proven to be effective catalytic systems for the activation of carbonyl compounds 7,8…”

Section: Introductionmentioning

confidence: 99%

“…As typical primary amine organocatalysts, the derivatives of 9‐ epi ‐amino‐cinchona alkaloids have been successfully used in asymmetric Michael addition reactions7,8g,9 to gain access to chiral building blocks of high enantiopurity. It is now generally accepted that such condensation is facilitated by the formation of iminium intermediates between the primary amine moiety of the cinchona alkaloids and the carbonyl substrates.…”

Section: Introductionmentioning

confidence: 99%

“…Silva and co‐workers reported the 1,4‐Michael addition of malononitrile to unsaturated aryl ketones catalyzed by the 9‐amino‐(9‐deoxy)‐ epi ‐cinchona alkaloids. The use of trifluoroacetic acid (TFA) as the acid additive increased the ee values of the reactions 7. List and co‐workers reported that an acid co‐catalyst significantly affected both the reactivity and enantioselectivity of intramolecular aldolizations of ketones 11.…”

Section: Introductionmentioning

confidence: 99%

“…For Michael addition reactions catalyzed by a primary amine derived from the cinchona alkaloid under acidic conditions, a bifunctional activation model was proposed based on experimental observations in which the primary amine and quinuclidine moieties promote the reaction by simultaneously activating electrophiles and nucleophiles through an iminium mechanism 7,9a. In comparison with experimental investigations, there have been few theoretical studies on the reaction mechanism and enantioselectivity of asymmetric 1,4‐Michael addition reactions of malononitrile15 and the important role of the acidic proton from the co‐catalyst in the asymmetric transformation requires further study.…”

Section: Introductionmentioning

confidence: 99%

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Asymmetric 1,4‐Michael Addition Reactions Catalyzed by a Cinchona Alkaloid Derived Primary Amine: A Theoretical Investigation of the Reaction Mechanism and Enantioselectivity

Lee

Kim

2013

Eur J Org Chem

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The mechanism and enantioselectivity of the asymmetric 1,4‐Michael addition of malononitrile to unsaturated aryl ketones catalyzed by a cinchona alkaloid derived primary amine have been investigated by DFT and ONIOM methods. The calculations indicated that three continuous stages are involved in the overall reaction: 1) The formation of a (ket)iminium intermediate, 2) an addition reaction between the iminium and malononitrile, and 3 ) hydrolysis and regeneration of the catalyst. The proton from an acidic additive plays an important role in the formation of the key ketiminium ion intermediate in which the protonated tertiary amine of the alkaloid not only activates the carbonyl substrate through hydrogen bonding, but also facilitates the condensation of the primary amine catalyst by participating in the formation of water molecules. The calculations also indicated that steric interactions between the aromatic substituent, the quinoline ring, and the alkene moiety of the unsaturated ketone force the key ketiminium ion intermediate to adopt a preferred conformation to achieve more accessible Re‐face attack of the substrate. These results are in good agreement with experimental observations.

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The Catalytic, Enantioselective Michael Reaction

et al. 2016

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The catalytic enantioselective Michael reaction is the conjugate addition of a resonance‐stabilized carbanion to an electron‐poor olefin (an αβ‐unsaturated carbonyl compound or a related derivative) mediated by substoichiometric amounts of a chiral catalyst that enables stereocontrol in the newly generated stereocenter(s). This reaction allows the direct enantioselective construction of substituted 1,5‐dicarbonyl compounds or related architectures through the appropriate selection of the enolizable carbonyl compound employed as pronucleophile and the Michael acceptor. A variety of catalyst architectures have been described that make it possible to carry out this reaction with superior levels of chemical efficiency and high enantio‐ and stereocontrol, and also under conditions that tolerate a wide variety of functional groups. Both transition metal catalysis and organocatalysis have been employed as methodological approaches for carrying out this reaction in an enantioselective manner. This chapter describes different catalytic systems and methods developed for achieving enantioselective Michael reactions through the end of 2012, including a detailed mechanistic explanation of the different generic modes of substrate activation operating with each type of catalyst and their associated stereochemical aspects. The intention is to provide researchers interested in applying this methodology to their own synthetic strategies with a suitable starting point for identifying an efficient synthetic approach. In addition, the preparation of selected catalysts that are excellent for a particular pairing of substrates in this reaction, together with practical experimental protocols are described and some examples in which these methodologies have been applied to total synthesis have been included. This chapter is limited exclusively to those examples in which the final Michael addition product is obtained after protonation of the conjugate addition intermediate and therefore, tandem, domino, or cascade processes initiated by Michael reactions lie outside the scope of this work. Supplemental references are provided for articles published after the 2012 cut‐off date through the first half of 2015.

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

Cited by 49 publications

References 68 publications

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles

Decoration of A-Ring of a Lupane-Type Triterpenoid with Different Oxygen and Nitrogen Heterocycles

Asymmetric 1,4‐Michael Addition Reactions Catalyzed by a Cinchona Alkaloid Derived Primary Amine: A Theoretical Investigation of the Reaction Mechanism and Enantioselectivity

The Catalytic, Enantioselective Michael Reaction

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