Direct Trapping of Sterically Encumbered Aluminum Enolates

Bleschke, Christian; Tissot, Matthieu; Müller, Daniel S.; Alexakis, Alexandre

doi:10.1021/ol400642y

Cited by 26 publications

(31 citation statements)

References 36 publications

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“…The enolate 12 was selectively converted into the desired amino intermediate 15 , which was subjected to the subsequent oxidation/elimination step without further purification. The amino function of 15 was easily oxidized upon short treatment at room temperature with meta ‐chloroperoxybenzoic acid, and was thus prone to a spontaneous elimination reaction 12. This oxidation/elimination sequence afforded compound 6 , bearing the required exocyclic enone system, with only minor impurities.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, to control the selective formation of the tetrasubstituted double bond of the natural product, our strategy involved a copper‐mediated conjugate addition of an aryllithium species across the exo ‐methylene bond of enone 6 , followed by an O ‐enolate trapping reaction. Finally, the key intermediate 6 would be prepared through a multistep sequence, as recently reported by our group,12 starting from the Michael acceptor 7 . This procedure was based on a tandem copper‐catalyzed asymmetric conjugate addition of trialkylaluminum reagents to β‐substituted cyclohexenones/ C ‐enolate trapping reaction.…”

Section: Introductionmentioning

confidence: 99%

“…Then, the oxidation of the corresponding amino intermediate led to the formation of an exo ‐methylene bond, which could undergo a subsequent copper‐catalyzed conjugate addition of Grignard reagents. Interestingly, a single purification step was required to isolate the final highly functionalized cyclohexanone derivatives in good overall yields with excellent enantioselectivities 12…”

Section: Introductionmentioning

confidence: 99%

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Catalytic Enantioselective Total Synthesis of Riccardiphenol B

et al. 2016

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The first catalytic enantioselective total synthesis of riccardiphenol B, a sesquiterpene derivative isolated from a Japanese collection of the liverwort Riccardia crassa, has been achieved. A copper-catalyzed asymmetric conjugate addition of trimethylaluminum was used at an early stage to generate the quaternary stereogenic center with high enantiomeric excess. The corresponding sterically encumbered aluminum enolate was directly trapped with an α-amino ether, allowing after oxidation, the release of a key intermediate in the total synthesis of the target natural product

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Catalytic Enantioselective Total Synthesis of Riccardiphenol B

et al. 2016

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“…Reaction of in situ formed enolates has been reported a number of times, [20,[30][31][32][33] however, unlike lithium enolates, magnesium enolates react only sluggishly and additives or co-solvents are mostly used to accelerate the reaction. none, the conjugate addition resulted in very poor conversions.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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The copper/Rev-JosiPhos-catalysed asymmetric conjugate addition of Grignard reagents to 2methylcyclopentenone (1) provides 2,3-disubstituted cyclopentanones in high yields and enantioselectivities, and good diastereoselectivities. Reaction of the in situ formed enolate with various alkylating reagents in the presence of 1,3-dimethyltetrahydropyrimidine-2(1H)-one (DMPU) affords the correspond-ing products in a one-pot reaction. This procedure creates two vicinal stereocentres, one of them quaternary.

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“…Phosphinamide ligands have also been applied to the formation of chiral and sterically congested cyclohexanone derivatives through a multistep sequence using (n-butoxymethyl)-diethylamine for the direct trapping of the aluminium enolate (Scheme 20) [57]. As mentioned before, aluminium enolates (and those adjacent to an all-carbon quaternary stereocentre in particular) are not very reactive towards most electrophilic species.…”

Section: Organoaluminium 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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Direct Trapping of Sterically Encumbered Aluminum Enolates

Cited by 26 publications

References 36 publications

Catalytic Enantioselective Total Synthesis of Riccardiphenol B

Catalytic Enantioselective Total Synthesis of Riccardiphenol B

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

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

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