Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β‐Disubstituted Nitroalkenes

Chen, Shengwei; Lou, Qin‐Xin; Ding, Yuyang; Zhang, Shasha; Hu, Wenhui; Zhao, Junling

doi:10.1002/adsc.201500079

Cited by 26 publications

(5 citation statements)

References 72 publications

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“…[32] Zhao and coworkers used a Cinchona alkaloidderived bifunctional thiourea catalyst (Cat-15) to promote the asymmetric Michael addition of malononitrile to α-substituted-β-nitroacrylates (95). [33] At a catalyst loading of 10 mol%, various β-(hetero)aryl nitroalkenes were smoothly converted to the desired Michael adducts (97) bearing all-carbon quaternary stereocenter in high yields and enantioselectivities (up to 98% yield and 93% ee, Scheme 26). However, a very low enantioselectivity (97 g, 7% ee) was observed for the β-alkyl nitroalkene under standard catalytic condition (Scheme 26a).…”

Section: Ma Et Al Devised the Enantioselective Michael Addition Of Ma...mentioning

confidence: 99%

“…[5] The β‐nitro compounds with quaternary stereocenters formed via conjugate addition to β,β‐disubstituted nitroalkenes can be easily transformed into several important species such as β 2,2 ‐amino acids and γ‐aminobutyric acids (GABAs) [6,7,8] . Therefore, the past few decades have witnessed the extensive development of catalytic asymmetric conjugate additions to β,β‐disubstituted nitroalkenes and the emergence of the corresponding elegant strategies [9–60] …”

Section: Introductionmentioning

confidence: 99%

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Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

et al. 2023

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Quaternary stereogenic centers are of great importance because of their prevalence in a series of bioactive natural products and pharmaceuticals. Although the catalytic asymmetric construction of these highly congested centers poses a formidable challenge, this field has been extensively explored in the past few decades, and several elegant strategies, such as the asymmetric conjugate addition to β,β‐disubstituted nitroalkenes, have been developed. The resultant β‐nitro quaternary stereocenters can be conveniently transformed into the corresponding β‐amino quaternary stereocenters commonly found in bioactive compounds. This review summarizes the recent advances in the construction of all‐carbon quaternary or hetero‐carbon quaternary stereocenters via metal‐catalyzed and organocatalyzed asymmetric conjugate addition to β,β‐disubstituted nitroalkenes, focusing on the scope, applications, and mechanisms of these reactions.

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Section: Ma Et Al Devised the Enantioselective Michael Addition Of Ma...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

et al. 2023

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“…The scope of nucleophilic addition to electron-deficient double bonds (i.e., Michael addition) has been broadened by the development of asymmetric organocatalysis. − The analogous addition to conjugated alkynes is a potentially useful transformation, yielding a substituted vinylic system that can be further modified . Control of the alkene E / Z -stereochemistry is essential for such a reaction; however, stereoselective organocatalytic examples are relatively scarce.…”

Section: Introductionmentioning

confidence: 99%

Phosphazene Catalyzed Addition to Electron-Deficient Alkynes: The Importance of Nonlinear Allenyl Intermediates upon Stereoselectivity

Simón

Paton

2017

J. Org. Chem.

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An ONIOM(QM/MM) study on the mechanism of the Michael addition to triple bonds catalyzed by chiral diiminophosphorane catalysts has been performed to understand the stereoselectivity of the product olefin. Our results are consistent with the experimental enantioselectivity, but more importantly, reveal that the Z vs E preference depends on the influence of the catalyst upon the geometry of the allenyl enolate formed in the addition step. These intermediates show an innate preference for a (Z)-configuration, although this can be suppressed by steric interactions due to a catalyst. This leads to two distinct mechanisms in which the kinetic basis for (E) or (Z)-stereoselectivity is determined by a different step. Bifunctional iminophosphorane catalysts are found to use steric interactions to override innate stereoelectronic effects of the allenyl enolate reactive intermediate.

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“…Furthermore, while enantioselective intermolecular Michael addition reactions with nitroolefins has been well-established, [28][29][30][31][32] intramolecular desymmetrising variants that concurrently establish a quaternary carbon centre are unreported. [33][34] Methyl-substituted nitroolefin 7 was selected as an ideal model substrate to develop the enantioselective intramolecular Michael addition reaction. An oxidative radical nitration was employed to efficiently construct 7 in 3 steps from commercially available 1,4cyclohexanedione monoethylene acetal (See SI, Scheme S1).…”

Section: Resultsmentioning

confidence: 99%

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

Shiomi

Shennan

Yamazaki

et al. 2021

Preprint

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The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β’-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon stereocenter, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclisation were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidation-lactamisation, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

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Organocatalytic Enantioselective Michael Reaction of Malononitrile with β,β‐Disubstituted Nitroalkenes

Cited by 26 publications

References 72 publications

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

Advances in Catalytic Asymmetric Construction of Quaternary Stereogenic Centers by Conjugate Addition to β,β‐Disubstituted Nitroalkenes

Phosphazene Catalyzed Addition to Electron-Deficient Alkynes: The Importance of Nonlinear Allenyl Intermediates upon Stereoselectivity

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

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