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

Germain, Nicolas; Alexakis, Alexandre

doi:10.1002/chem.201500292

Cited by 25 publications

(12 citation statements)

References 70 publications

(60 reference statements)

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“…13,14,15 We sought to implement a short synthesis of (+)- 4 by using an asymmetric conjugate addition developed by Quinkert in his synthesis of confertin 16,17 and showcased by Danishefsky in the synthesis of guanacastepene A. 18 This sequence, while allowing access to enantioenriched (+)- 4 , requires the use of excess amounts of a chiral additive derived from L-proline.…”

Section: Resultsmentioning

confidence: 99%

A total synthesis of (−)-hortonone C

et al. 2017

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A total synthesis of the cytotoxic terpenoid hortonone C was accomplished and its absolute stereochemistry confirmed. Intermediate (+)-4 was synthesized using either an asymmetric conjugate addition strategy, or by elaboration of the Hajos-Parrish ketone. Reduction of (+)-4 under dissolving-metal conditions and trapping the enolate intermediate served to control the cis-stereochemistry at the ring fusion and provide a silyl enol ether necessary for ring expansion. Comparison of optical rotation data confirmed that the absolute configuration of natural hortonone C is (6S,7S,10S).

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Section: Resultsmentioning

confidence: 99%

A total synthesis of (−)-hortonone C

et al. 2017

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“…The asymmetric conjugate addition is a fundamental carbon–carbon bond transformation, which has been used to access enantioenriched building blocks . In recent years, the number of reports describing ACA reaction using alkylzirconium as nucleophile has increased .…”

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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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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“…In this case, the quaternary centre is generated at the α position of the carbonyl, contiguous to a β-tertiary centre. The imidazolium ligand L25 is able to catalyse such a transformation, using Grignard reagents as nucleophiles in the presence of Cu(OTf)2, giving very good enantio-and diastereoselectivities with both α-substituted cyclopentanones and cyclohexanones (Scheme 52) [89,90]. Alkyl, propargyl, allyl and benzyl halides have been used as electrophiles, all providing ketones 30 in high diastereoselectivity and good enantioselectivity when the secondary and bulky Grignard reagent iPrMgBr, is used as nucleophile.…”

Section: Grignard Reagents As Nucleophilesmentioning

confidence: 99%

“…Scheme 52. Tandem copper-NHC catalysed ECA of Grignard reagents to -substituted cyclic enones / enolate trapping by Alexakis [89,90] (all ee measured after recrystallisation).…”

Section: Grignard Reagents As Nucleophilesmentioning

confidence: 99%

“…Other electrophiles, such as derivative 31 (Scheme 53), ‡ triphenylvinylphosphonium bromide 32 (Scheme 54), N-halosuccinimides (Scheme 55) and tosyl cyanide (Scheme 56) have been also evaluated in this tandem ECA-enolate trapping methodology [90]. Lower regio-and enantioselectivities are obtained in these cases than when the trapping is carried out with alkyl, propargyl, allyl or benzyl halides.…”

Section: Grignard Reagents As Nucleophilesmentioning

confidence: 99%

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

Cited by 25 publications

References 70 publications

A total synthesis of (−)-hortonone C

A total synthesis of (−)-hortonone C

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

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

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