Enantioselective Mannich Reaction of β-Keto Esters with Aromatic and Aliphatic Imines Using a Cooperatively Assisted Bifunctional Catalyst

Neuvonen, Antti; Pihko, Petri M.

doi:10.1021/ol5025025

Cited by 22 publications

(23 citation statements)

References 32 publications

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“…Further X‐ray structures and computational studies supported that the cooperative intramolecular hydrogen bonds and the overall fold of the catalysts are maintained intact during the whole process. Later, the same research group has extended this work including a new catalyst structure 15g to promote the same Mannich reaction (Figure ) . However, an extensive computational study with additional control experiments suggested that the enhanced activity of this family of catalysts may not be due to cooperative effects of intramolecular hydrogen bonds but simply due to the inherent structural conformation.…”

Section: Internal Hydrogen Bonding Assisted (Thio)urea Catalystsmentioning

confidence: 98%

“…Later, the same research group has extended this work including a new catalyst structure 15g to promote the same Mannich reaction (Figure 11). [45] However, an extensive computational study with additional control experi- ments suggested that the enhanced activity of this family of catalysts may not be due to cooperative effects of intramolecular hydrogen bonds but simply due to the inherent structural conformation. This folded structure would provide an active site pocket, accommodating the substrates and, at the same time, impeding undesirable side reactions.…”

Section: Internal Hydrogen Bonding Assisted (Thio)urea Catalystsmentioning

confidence: 99%

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Hydrogen Bonding and Internal or External Lewis or Brønsted Acid Assisted (Thio)urea Catalysts

Gimeno

Herrera

2019

Eur J Org Chem

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The obtainment of more active organocatalysts has promoted the search for new modes of activation and new organocatalytic systems. Inspired on the mode of activation of enzymes, organocatalysis has recently focused on the challenge to create an enzyme‐like “active site” giving access to hydrogen‐bond donors (HBDs) with enhanced activity. Therefore, the assembly of catalytic species, connected through multiple weak inter‐ or intramolecular interactions, is a young and emerging topic of research which could become in the future a powerful tool for asymmetric catalysis. In the area of (thio)ureas, different alternatives such as internal hydrogen bonds or the use of an internal or an external Lewis or Brønsted acid assisted catalysts have been developed. The pivotal publications recently reported covering this family of organocatalysts are proof of this importance. This review treats to illustrate these important and scarce examples and to show a plausible mode of activation for each one.

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Section: Internal Hydrogen Bonding Assisted (Thio)urea Catalystsmentioning

confidence: 98%

Section: Internal Hydrogen Bonding Assisted (Thio)urea Catalystsmentioning

confidence: 99%

Hydrogen Bonding and Internal or External Lewis or Brønsted Acid Assisted (Thio)urea Catalysts

Gimeno

Herrera

2019

Eur J Org Chem

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“…Ethyl 3-Oxo-3-(p-tolyl)propanoate (5c): 4 Compound 3c prepared following General Procedure C from the corresponding aldehyde (1.0 g, 8.33 mmol) to give 5c (1.1 g, 69%)…”

Section: S8mentioning

confidence: 99%

“…4Ethyl 3-(4-Bromophenyl)-3-oxopropanoate (5d):4 Compound 3d was prepared by following General Procedure B from the corresponding aldehyde (1.0 g, 5.54 mmol) to afford 5d (945 mg, S9 63%) as 2H), 5.62 (s, 0.15 x 2H, keto), 4.27 (q, J = 7.4 Hz, 0.15 x 2H, enol), 4.22 (q, J = 7.1 Hz, 0.85 x 2H, keto), 3.97 (s, 0.85 x 2H, keto), 1.34 (t, J = 7.1 Hz, 0.15 x 3H, enol), 1.26 (t, J = 7.1 Hz, 0.85 x 3H).13 C NMR (100 MHz, CDCl3) δ 191.04, 173.24, 171.80 (d, 280 Hz) , 164.93, 164.75 (d, J = 251 Hz, 132.60 (d, J = 3.0 Hz), 131.37 (d, J = 9.5 Hz), 129.74 ( d, J = 3.4 Hz), 128.34 (d, J = 8.8 Hz), 116.06 (d, J = 22 Hz), 115.75 (s), 87.28, 61.67, 60.50, 46.06 (s), 14.39 , 14.16. 68%) as an oil after SiO2 flash chromatography [EtOAc:hexane (1:9)].…”

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confidence: 99%

A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis

Kudalkar¹,

Tiwari²,

Lee³

et al. 2020

Synlett

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Described is a physical organic study of the reduction of three sets of carbonyl compounds by the NADPH-dependent enzyme Clostridium acetobutylicum alcohol dehydrogenase (CaADH). Previous studies in our group have shown this enzyme to display broad substrate promiscuity, yet remarkable stereochemical fidelity, in the reduction of carbonyl compounds, including α-, β- and γ-keto esters (d-stereochemistry), as well as α,α-difluorinated-β-keto phosphonate esters (l-stereochemistry). To better mechanistically characterize this promising dehydrogenase enzyme, we report here the results of a Hammett linear free-energy relationship (LFER) study across three distinct classes of carbonyl substrates; namely aryl aldehydes, aryl β-keto esters and aryl trifluoromethyl ketones. Rates are measured by monitoring the decrease in NADPH fluorescence at 460 nm with time across a range of substrate concentrations for each member of each carbonyl compound class. The resulting v 0 versus [S] data are subjected to least-squares hyperbolic fitting to the Michaelis–Menton equation. Hammett plots of log(V max) versus σX yield the following Hammett parameters: (i) for p-substituted aldehydes, ρ = 0.99 ± 0.10, ρ = 0.40 ± 0.09; two domains observed, (ii) for p-substituted β-keto esters ρ = 1.02 ± 0.31, and (iii) for p-substituted aryl trifluoromethyl ketones ρ = –0.97 ± 0.12. The positive sign of ρ indicated for the first two compound classes suggests that the hydride transfer from the nicotinamide cofactor is at least partially rate-limiting, whereas the negative sign of ρ for the aryl trifluoromethyl ketone class suggests that dehydration of the ketone hydrate may be rate-limiting for this compound class. Consistent with this notion, examination of the 13C NMR spectra for the set of p-substituted aryl trifluoromethyl ketones in 2% aqueous DMSO reveals significant formation of the hydrate (gem-diol) for this compound family, with compounds bearing the more electron-withdrawing groups showing greater degrees of hydration. This work also presents the first examples of the CaADH-mediated reduction of aryl trifluoromethyl ketones, and chiral HPLC analysis indicates that the parent compound α,α,α-trifluoroacetophenone is enzymatically reduced in 99% ee and 95% yield, providing the (S)-stereoisomer, suggesting yet another compound class for which this enzyme displays high enantioselectivity.

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“…1,2 Foldamers are generally considered as artificial models for molecular folding, 3 but they may also find use in enzyme-like functions, for example as biomimetic receptors 4 and catalysts 5,6,7 . The most common bond type in foldamers is the amide bond with directional and relatively stable hydrogen bonding properties.…”

Section: Introductionmentioning

confidence: 99%

Conformational properties and folding analysis of a series of seven oligoamide foldamers

et al. 2016

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33 crystal structures (11 unsolvated and 22 solvates) of a series of seven oligoamide foldamers were analysed. The crystal structures revealed that despite the structural and environmental differences the series of foldamers prefer only two general conformations, a protohelical @-conformation and a sigmoidal S-conformation. Both conformations also have preferred crystal packing motifs and solvate forming tendencies. Hydrogen bonding was found to be the most decisive factor in conformational preference, but steric properties, the type of the peripheral substituents, as well as solvent and aromatic interactions were also found to have an effect on the conformational details and crystal form.

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Enantioselective Mannich Reaction of β-Keto Esters with Aromatic and Aliphatic Imines Using a Cooperatively Assisted Bifunctional Catalyst

Cited by 22 publications

References 32 publications

Hydrogen Bonding and Internal or External Lewis or Brønsted Acid Assisted (Thio)urea Catalysts

Hydrogen Bonding and Internal or External Lewis or Brønsted Acid Assisted (Thio)urea Catalysts

A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis

Conformational properties and folding analysis of a series of seven oligoamide foldamers

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