Asymmetric conjugate addition

Rossiter, Bryant E.; Swingle, Nicole M.

doi:10.1021/cr00013a002

Cited by 675 publications

(196 citation statements)

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“…In the catalytic conjugate addition, a primary organometallic reagent has to transmetallate to a copper reagent, which, itself, undergoes the reaction [3]. Until 1993, all authors have relied upon the use of Grignard reagents, whereupon we introduced the idea of using diorganozinc reagents instead [4].…”

Section: Conjugate Additionmentioning

confidence: 99%

Copper-mediated asymmetric transformations

Alexakis

2002

Pure and Applied Chemistry

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Section: Conjugate Additionmentioning

confidence: 99%

Copper-mediated asymmetric transformations

Alexakis

2002

Pure and Applied Chemistry

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“…The development of highly enantioselective catalytic versions of this key transformation is of paramount importance (2)(3)(4)(5)(6)(7)(8)(9). In recent years, the design of new chiral ligands and catalysts has led to the realization of asymmetric Michael additions (10,11) and conjugate additions of dialkylzinc reagents (12,13) as well as arylboronic acids (14) with excellent levels of stereocontrol.…”

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confidence: 99%

“…Meanwhile, considerable difficulties have been experienced in attempts to reach high stereoselectivities in transition metalcatalyzed 1,4-addition of other organometallic reagents. Illustrative of this fact is that an effective copper-catalyzed enantioselective conjugate addition of Grignard reagents is lacking despite more than two decades of intensive research (2,(5)(6)(7)(8)(9).…”

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Copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic enones

Feringa

Badorrey²,

Peña³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

139

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It is no longer necessary to use dialkylzinc reagents to obtain enantioselectivities >95% in the copper-catalyzed asymmetric conjugate addition of organometallic compounds to cyclic enones. We now report how this can be accomplished by using inexpensive and readily available Grignard reagents. Screening of bidentate ligands provided outstanding results with copper complexes of commercially available chiral ferrocenyl-based diphosphines, in particular TaniaPhos and JosiPhos derivatives. These catalysts tolerate a range of Grignard reagents and different cyclic enones as substrates, leading to high regioselectivities and unprecedented enantioselectivities. Moreover, the reactions are successful with moderate catalyst loading (5 mol %) under mild conditions and in the absence of additives.

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“…Since the conjugate addition reaction is one of the powerful methodologies in forming a carbon-carbon bond, 1) the mediator-controlled asymmetric conjugate addition of carbonucleophiles to a,b-unsaturated carbonyl compounds has been an area of active investigations. [2][3][4][5][6][7][8][9] However, albeit of its versatility a lithium enolate of an acetate itself has been one of the scarcely investigated nucleophiles in an asymmetric conjugate addition reaction with enones and enoates probably because of its difficulty in the achievement of the chemo-selective reaction. In fact, the reported approach to the conjugate addition of an acetate via its lithium enolate to even enoates has been limited only to the reaction studied by Yamaguchi.…”

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Chiral Ligand-Controlled Asymmetric Conjugate Addition of .ALPHA.-Trimethylsilanylacetate to Acyclic and Cyclic Enones

Iguchi

Doi

Hata

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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We describe herein our approach to the chiral ligand-controlled asymmetric conjugate addition of a-trimethylsilanylacetate via its lithium enolate to acyclic and cyclic enones, giving the corresponding b,b-disubstituted ketones in a good chemo-and enantioselectivity. Since the conjugate addition reaction is one of the powerful methodologies in forming a carbon-carbon bond, 1) the mediator-controlled asymmetric conjugate addition of carbonucleophiles to a,b-unsaturated carbonyl compounds has been an area of active investigations.2-9) However, albeit of its versatility a lithium enolate of an acetate itself has been one of the scarcely investigated nucleophiles in an asymmetric conjugate addition reaction with enones and enoates probably because of its difficulty in the achievement of the chemo-selective reaction. In fact, the reported approach to the conjugate addition of an acetate via its lithium enolate to even enoates has been limited only to the reaction studied by Yamaguchi. 10,11) This situation is very contrasted to the many brilliant successes in the Lewis acidmediated addition reaction of the silylketene acetal of an acetate.12-15) It is also interesting to note that lithium enolates of ketones have been reported as nucleophiles in asymmetric conjugate addition reactions, 16,17) while little effort has been devoted to lithium ester enolates. 18,19) We have been engaged in the chiral ligand-controlled 20) asymmetric conjugate addition reactions of various types of carbon-, nitrogen-, oxygen-, and sulfur-nucleophiles such as organolithiums, [21][22][23] organocoppers, 24,25) organoboranes, 26) lithium amides 27) lithium peroxides 28,29) and arylthiols. [30][31][32][33] We turned our project to a lithium ester-enolate as the next carbonucleophile in the conjugate addition to enones. Combined with the characteristic nature of the Michael donor [34][35][36] and high ability in enantiofacial differentiation in an enantioselective Peterson reaction under control of a chiral aminodiether (Chart 1), 37) we selected a-trimethylsilanylacetate 1 37) as a precursor for a lithium enolate. The challenge is the methodology extension from discrimination of the either face of the enolate 2 to the enantiofacial differentiation of the carbon-carbon double bond of an enone as well as the chemoselective reaction at the olefin double bond not at the carbonyl carbon.We began our studies with the addition of 1 via 2, generated by treatment with lithium diisopropylamide (LDA) in THF, to chalcone 7 in THF at Ϫ78°C and found the formation of the expected adduct 9 in 37% yield together with Peterson product 13 in 49% yield and reduction product 15 38) in 8% yield (Chart 2; The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of a a-trimethylsilanylacetate to acyclic and cyclic a a,b b-unsaturated ketones was mediated by an external chiral ligand to give the correspondin...

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Asymmetric conjugate addition

Cited by 675 publications

References 49 publications

Copper-mediated asymmetric transformations

Copper-mediated asymmetric transformations

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic enones

Chiral Ligand-Controlled Asymmetric Conjugate Addition of .ALPHA.-Trimethylsilanylacetate to Acyclic and Cyclic Enones

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