Formation of Quaternary Centers by Copper‐Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Sidera, Mireia; Roth, Philippe M. C.; Maksymowicz, Rebecca M.; Fletcher, Stephen P.

doi:10.1002/anie.201303202

Cited by 70 publications

(26 citation statements)

References 51 publications

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“…In order to increase the applicability of this methodology, a single experiment was performed in gram scale. By reacting the alkene 27 and the enone 28 under the optimized reaction conditions, the desired compound ( 29 ) was isolated in an excellent yield and ee (respectively 94 and 92 %), indicating that this procedure is suitable for scale‐up production (Scheme ) …”

Section: Asymmetric Conjugate Addition (Aca)mentioning

confidence: 96%

“…In addition to these elegant contributions in ACA, Fletcher and co‐workers also developed approaches to form quaternary centers in high yields and excellent enantiomeric excess, using alkylzirconium reagents generated from terminal alkenes ( 20 ) , . After optimization of the reaction conditions concerning the copper source, ligands, additives, and solvents; the best reaction conditions were established (Scheme ).…”

Section: Asymmetric Conjugate Addition (Aca)mentioning

confidence: 99%

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Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

2018

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Organozirconium chemistry has been widely employed in organic synthesis since its discovery in the last century. In this context, Schwartz's reagent stands out as a powerful tool that has been applied in several chemical transformations. This chemistry has attracted considerable attention due to its versatility, allowing chemoselective C–C, C–N, and C–X bond formation, as well as hydrozirconation. The reagent is in fact a zirconium‐containing metallocene, which is compatible with the presence of various metals in cross‐coupling reactions. Enantioselective transformations of organozirconium are described here, which have recently found wide applications in total synthesis. Furthermore, aspects covering ring‐closure reactions, affording complex stereoenriched cycles and heterocycles, such as substituted cyclopropanes and pyrrolidines, are hereby disclosed.

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Section: Asymmetric Conjugate Addition (Aca)mentioning

confidence: 96%

Section: Asymmetric Conjugate Addition (Aca)mentioning

confidence: 99%

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

2018

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“…e , The addition of an alkylzirconium intermediate generated by hydrozirconation of 3,3-dimethyl-1-butene to 54 to form 3,3-dialkylcyclohexanone 58 . 46 Tf, trifluorosulfonyl; Cp, cyclopentadienyl; t -Bu, tert -butyl; Me, methyl. The lower segment of the Figure shows the use of two of these methods to form methyl-containing quaternary stereocenters in syntheses of a potential taxane terpenoid precursor and a dolabellane diterpenoid: f , The enantioselective copper-catalyzed conjugate addition/enolate trapping to introduce a quaternary methyl group in the construction of a taxadienone.…”

Section: Figurementioning

confidence: 99%

Catalytic enantioselective synthesis of quaternary carbon stereocentres

Quasdorf

Overman

2014

Nature

812

327

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Preface Quaternary carbon stereocenters–carbon atoms to which four distinct carbon substituents are attached–are common features of molecules found in nature. However, prior to recent advances in chemical catalysis, there were few methods available for constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for synthesizing organic molecules containing such carbon atoms. This progress now makes it possible to selectively incorporate quaternary stereocenters in many high-value organic molecules for use in medicine, agriculture, and other areas.

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“…Recently, Fletcher et al have demonstrated that the formation of all-carbon quaternary centres can be carried out by copper catalysed ECA of alkylzirconium reagents to -substituted cyclic enones (Scheme 66) [102,103].…”

Section: Zirconiummentioning

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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Formation of Quaternary Centers by Copper‐Catalyzed Asymmetric Conjugate Addition of Alkylzirconium Reagents

Cited by 70 publications

References 51 publications

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

Catalytic enantioselective synthesis of quaternary carbon stereocentres

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

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