Silylated Pyrrolidines as Catalysts for Asymmetric Michael Additions of Aldehydes to Nitroolefins

The design of efficient catalysts with new structural motifs [1] is one of the major challenges in the growing field of asymmetric organocatalysis. [2] Inspired by the dramatic effect of subtle steric and electronic modifications on catalyst activity, [2f] we set out to investigate the performance of silicon-based, enantiomerically pure pyrrolidines in organocatalytic reactions.[3] A remarkable feature of silicon is its tolerance of sterically demanding substituents, thus allowing straightforward access to quaternary silicon centers by nucleophilic substitution reactions of trialkylchlorosilanes (Scheme 1). [3, 4] Hence, a diverse array of novel catalyst scaffolds should be accessible, which are hitherto unknown for carbon-based pyrrolidine catalysts. Recently, Maruoka et al. reported the asymmetric a-benzyloxylation of aldehydes using (S)-2-tritylpyrrolidine [(S)-1] as organocatalyst.[5] The synthesis of (S)-1 involves a nucleophilic addition to a nitrone followed by hydrogenolysis and resolution of (AE )-1.These results prompted us to render the corresponding silicon analogue (S)-2 and related derivatives available for a direct comparison of their catalytic performance in enamine catalysis (Scheme 1). [6] In an accompanying quantum-chemical study, we aimed to rationalize silicon effects on the new catalytic systems by studying electronic as well as steric differences between the carbon and silicon analogues 1 and 2. For this purpose DFT calculations were performed at the B3LYP/6-31 + G(d) level. Based on the energy-optimized structures A1 and B1 of a meaningful conformer for both catalysts, we studied the NBO charge (Figure 1) and calculated the electrostatic potential (Figure 2).The comparison of the decisive bond length between pyrrolidine C-2 and silicon or carbon, respectively, revealed a significant elongation of this bond changing from carbon (A) to silicon (B), which is clearly visible in the space-filling models A2 and B2 (Figure 2) and may have an effect on the stereochemical outcome in catalytic asymmetric reactions. [7] Due to the overcrowded substitution sphere, the respective C À C distance (1.589 ) is slightly longer than endocyclic C À C bonds, while the C À Si length (1.915 ) lies in the normal range for carbon À silicon bonds in aminoalkyl silanes.[8] Furthermore, the NBO analysis of B1 indicates a high positive charge of 1.818 at the silicon center and a definite negative charge at the carbon atoms (À0.516 to À0.542) directly attached to silicon (Figure 1). By contrast, the carbon analogue A1 shows a well-balanced negative charge distribution across the carbon-atom backbone. Consequently, the electronic structure causes a more negatively charged electrostatic potential around the phenyl-substituted silyl moiety when compared to 2-tritylpyrrolidine, shown at the fast surface models A3 and B3 (Figure 2). In view of polar transition states in enamine and iminium catalysis, these electronic features possibly contribute to a deeper insight into the activity of novel catalytic systems. [9] As p...

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“…Finally, we would like to express our gratitude to Prof. Dr. Carsten Bolm for sharing his unpublished results with us. [26]…”

Section: Acknowledgementsmentioning

confidence: 99%

Silyl‐Modified Analogues of 2‐Tritylpyrrolidine: Synthesis and Applications in Asymmetric Organocatalysis

Bauer

Stiller

Marqués‐López

et al. 2010

Chemistry A European J

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“…have already been structurally characterized in the form of their hydrochloride [1,2] and their hydrobromide salts [3] (Figure 1). …”

Section: (S)-2-(triphenylsilyl)pyrrolidine [(S)-1] and (S)-2-(methyldmentioning

confidence: 99%

“…In 2010, we and others reported on the enantioselective synthesis of 2-silylpyrrolidines as organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefines [1,2]. Since then, some impressive developments in the catalyst design have been achieved, overcoming synthetic challenges and introducing pyrrolidinylsilanols as bifunctional hydrogen bond-directing organocatalysts [3,4].…”

Section: Introductionmentioning

confidence: 99%

Molecular Structures of Enantiomerically-Pure (S)-2-(Triphenylsilyl)- and (S)-2-(Methyldiphenylsilyl)pyrrolidinium Salts

Bauer

Strohmann

2017

Inorganics

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Silyl-substituted pyrrolidines have gained increased interest for the design of new catalyst scaffolds. The molecular structures of four enantiomerically-pure 2-silylpyrrolidinium salts are reported.The perchlorate salts of (S)-2-(triphenylsilyl)pyrrolidine [(S)-1·HClO 4 ] and (S)-2-(methyldiphenylsilyl)pyrrolidine [(S)-2·HClO 4 ], the trifluoroacetate (S)-2·TFA, and the methanol-including hydrochloride (S)-1·HCl·MeOH were elucidated by X-ray crystallography and discussed in terms of hydrogen-bond interactions.

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“…Decades-long, asymmetric organocatalytic transformations have witnessed historic advancements to attain enantiomerenriched products without purification of the intermediates and protection or deprotection manipulation. [1][2][3][4][5][6][7][8][9][10][11] Along with, the organocatalysis [12][13][14] has prodigiously modified the outline of many asymmetric reactions such as Diels-Alder reaction, [15] aldol reaction, [16][17] Mannich reaction, [18] Michael addition reactions, [19] hetero-Michael addition reactions, [20] Shi Epoxidation [21] and organocatalytic transfer hydrogenation. [22] Among all these above organocatalytic reactions, Michael addition reactions are quite significant in the field of modern organic synthesis since these reactions produce the key precursors of natural products by constructing carbon-carbon and carbon-heteroatom bonds.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Organocatalytic Asymmetric Michael Addition Reactions to α, β‐Unsaturated Nitroolefins

et al. 2021

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An organocatalyzed asymmetric Michael addition reaction has been established as the most relevant and dynamic research area for the construction of chiral carbon‐carbon and carbon‐heteroatom bond. In the current scenario, rapid revolutions on asymmetric Michael addition to nitroolefins have been explored by taking advantage of newly developed chiral organocatalysts. Moreover, nitroolefins have proven as well‐known Michael acceptors for providing various structurally essential nitro‐functionalized frameworks. In addition to this, remarkable stereoselectivity has been achieved in this asymmetric process by following different mechanistic pathways that involve enamine, iminium ion intermediate formation and bifunctional H‐bonding interaction. So, we have discussed the recent advancements of organocatalytic Michael addition reactions to α, β‐unsaturated nitroolefins from the year 2016 to 2020.

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Silylated Pyrrolidines as Catalysts for Asymmetric Michael Additions of Aldehydes to Nitroolefins

Cited by 46 publications

References 75 publications

Silyl‐Modified Analogues of 2‐Tritylpyrrolidine: Synthesis and Applications in Asymmetric Organocatalysis

Silyl‐Modified Analogues of 2‐Tritylpyrrolidine: Synthesis and Applications in Asymmetric Organocatalysis

Molecular Structures of Enantiomerically-Pure (S)-2-(Triphenylsilyl)- and (S)-2-(Methyldiphenylsilyl)pyrrolidinium Salts

Recent Advances in Organocatalytic Asymmetric Michael Addition Reactions to α, β‐Unsaturated Nitroolefins

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