Copper‐Catalysed Conjugate Addition of Grignard Reagents to 2‐Methylcyclopentenone and Sequential Enolate Alkylation

Calvo, Beatriz C.; Madduri, Ashoka V. R.; Harutyunyan, Syuzanna R.; Minnaard, Adriaan J.

doi:10.1002/adsc.201400085

Cited by 24 publications

(14 citation statements)

References 37 publications

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“…Neither L 7 (Table 1, entry 5, 16 % ee ) nor L 8 (Table 1, entry 6, rac ) showed satisfying results. A complex mixture of compounds was detected with TaniaPhos‐type ligand L 8 (Table 1, entry 7), thus narrowing the path towards an extensive screening of ferrocene‐based ligands 9…”

Section: Resultsmentioning

confidence: 99%

“…The ACA of EtMgBr carried out with carbene ligands L 3 and C 2 -symmetric L 4 furnished ar acemic mixture of the desired saturated ketone 8 ( , thus narrowingt he path towards an extensive screening of ferrocene-based ligands. [9] It should be noted that adduct 8 was obtained as cis/trans mixture in variable amounts. As the enantioselectivity is determined during the conjugate addition step, both diastereomers have the same ee.T his was checked in many instances.…”

Section: Introductionmentioning

confidence: 99%

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Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Germain

Alexakis

2015

Chemistry A European J

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Herein a comprehensive study is provided on the asymmetric conjugate addition (ACA) of Grignard reagents to α-substituted cyclic enones. After the elucidation of the optimal experimental conditions, the scope of Grignard reagents and Michael acceptors was examined. Whereas secondary Grignards gave better enantioselectivities with 2-cyclopentenones, both linear and branched Grignard reagents were tolerated for the ACA to 2-methylcyclohexenone. The sequential ACA-enolate trapping, which leads to quaternary stereocenters, was then studied. Thus, many electrophiles have been tested, thereby giving rise to highly functionalized cyclic ketones with contiguous α-quaternary and β-tertiary centers. The present technique is believed to bring a new approach to versatile terpenoid-like skeletons of bioactive natural products. Straightforward derivatizations of enantioenriched saturated cyclic ketones further support the potential of the present methodology in synthesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Germain

Alexakis

2015

Chemistry A European J

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“…There are many examples in the literature which report enantioselective addition/trapping experiments with cycloalkenones using ionic chemistry to provide 2,3‐disubstituted cycloalkanones. These reactions show selectivities across the spectrum in addition/trapping experiments . Reactions with 2‐substituted cyclohexenones generally proceed with modest enantio‐ and/or diastereoselectivity .…”

Section: Introductionmentioning

confidence: 94%

Asymmetric Synthesis of 2,3‐Disubstituted Cyclic Ketones by Enantioselective Conjugate Radical Additions

Nad

Sibi

2019

Helvetica Chimica Acta

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“…It includes the use of copper/Rev-JosiPhos (L26) for the ECA reaction, followed by in situ trapping of the magnesium enolate with various alkylating reagents, in the presence of DMPU. This strategy provides -quaternary centres contiguous to tertiary centres with very good enantio-and distereoselectivities, especially when cyclopentenones are used as substrates (Scheme 57) [91].…”

Section: Grignard Reagents As Nucleophilesmentioning

confidence: 99%

“…Scheme 57. Tandem copper-diphosphine catalysed ECA of Grignard reagents to -substituted cyclopentenones / enolate trapping by Minnaard [91].…”

Section: Grignard Reagents As Nucleophilesmentioning

confidence: 99%

Formation of Quaternary Stereocentres by Copper-Catalysed Enantioselective Conjugate Addition Reaction

Maciá

2015

Progress in Enantioselective Cu(I)-Catalyzed Formation of Stereogenic Centers

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Remarkable progress in copper catalysed enantioselective conjugate addition (ECA) reactions has been made over the past decade. This enantioselective transformation now allows the challenging formation of chiral quaternary centres by addition of different nucleophiles to trisubstituted ,unsaturated systems. This chapter summarizes the developments in the area.to overcome this barrier and allow the synthesis of quaternary stereogenic centres with very good selectivities [32,33], as it will be presented in the following pages of this chapter. Alternative strategies to facilitate the copper catalysed formation of quaternary chiral centres include the activation of the ,-disubstituted ,-unsaturated systems (by making the β-position more electrophilic) by using Lewis-acidic nucleophiles or by the implementation of additional electronwithdrawing functionalities in the substrate.This chapter is an overview of the copper-based catalytic systems that enable the formation of chiral quaternary centres through conjugate addition reactions. The existing methodologies have been classified in three main sections, according to the nature of the nucleophile that participates in the ECA reaction. Thus, Section 2 covers carbon nucleophiles, including organoaluminium (section 2.1), Grignard (section 2.2), organozinc (section 2.3) and organozirconium reagents (section 2.4). Next, Section 3 reviews the use of organoboron reagents, to form boron containing quaternary centres. And last, Section 4 presents the use of organosilicon reagents, to form silicon containing quaternary centres.After the ECA reaction step, the generated enolate requires protonation to generate the corresponding enol, which rapidly tautomerises to the ketone product. Protonation is typically carried out by addition of water, aqueous NH4Cl or aqueous HCl. For simplicity, this step has been omitted in all schemes, and only the conditions for the ECA have been presented. * Strangely, the use of two equivalents of MeLi gave poor processes -despite the known efficacy of Me2AlCH≡CHR species in related processes. Scheme 14. Copper catalysed ECA of organoaluminium reagents to -aryl cyclohexenones by Alexakis [47,48].Regarding the challenging -substituted cyclopenten-2-one substrates, phosphinamine ligands give moderate, comparable enantioselectivities to phosphoramidites, as shown in Scheme 15.Scheme 15. Copper-phosphinamine catalysed ECA of organoaluminium reagents to -substituted cyclopentenones by Alexakis [47,48].The tandem hydroalumination-ECA process to β-substituted cyclic enones with phosphinamine ligands also works very efficiently (Scheme 16) [49,50]. The best copper source for this catalytic system is copper (II) naphthenate, which is cheaper than the CuTC used in previous methodologies and can be used as a stock solution. A wide range of alkenylaluminium reagents can be added with

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Copper‐Catalysed Conjugate Addition of Grignard Reagents to 2‐Methylcyclopentenone and Sequential Enolate Alkylation

Cited by 24 publications

References 37 publications

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Formation of Contiguous Quaternary and Tertiary Stereocenters by Sequential Asymmetric Conjugate Addition of Grignard Reagents to 2‐Substituted Enones and Mg–Enolate Trapping

Asymmetric Synthesis of 2,3‐Disubstituted Cyclic Ketones by Enantioselective Conjugate Radical Additions

Formation of Quaternary Stereocentres by Copper-Catalysed Enantioselective Conjugate Addition Reaction

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