Theory of Asymmetric Organocatalysis of Aldol and Related Reactions:  Rationalizations and Predictions

Allemann, Christophe; Gordillo, Ruth; Clemente, Fernando R.; Cheong, Paul Ha Yeon; Houk, K. N.

doi:10.1021/ar0300524

Cited by 462 publications

(183 citation statements)

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“…1, and has inspired the development of many other catalysts for a myriad of selective transformations [2]. Computational studies [3] have suggested a mechanistic analogy to reactions of aldolase enzymes [4]. Our recent work provided the first kinetic support for the enamine mechanism in aldol reactions and clarified the role of water on and off the catalytic cycle [5,6].…”

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confidence: 96%

A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

et al. 2009

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Abstract. Differences in the kinetic behavior of aldol reactions compared to aminoxylation and amination reactions are rationalized by consideration of the ratedetermining step in each case. Both autoinductive behavior and the rate-enhancing effect of additives are attributed to an effect on the enamine formation step.Keywords: organocatalysis · kinetics · autoinduction · amino acid catalysis · reaction mechanism Proline catalysis, elegantly revived by List, Lerner and Barbas in 2000 [1], has demonstrated efficient and enantioselective carbon-carbon and carbonheteroatom bond-forming reactions, including those shown in eq. 1, and has inspired the development of many other catalysts for a myriad of selective transformations [2]. Computational studies [3] have suggested a mechanistic analogy to reactions of aldolase enzymes [4]. Our recent work provided the first kinetic support for the enamine mechanism in aldol reactions and clarified the role of water on and off the catalytic cycle [5,6].(1a) (1b) (1c)A number of intriguing experimental observations have yet to be rationalized for these reactions. One unusual feature is a striking temporal increase in reaction rate that is observed in the α-aminoxylation [7,8] (eq 1a) and α-amination of aldehydes [9,10] (eq 1b), but is not observed in aldol reactions (eq 1c). In addition, additives including acids and bases have been observed to influence reactions employing proline as well as other pyrrolidine-based catalysts [11,12]. Here we present kinetic results that offer a coherent mechanistic rationalization for both the role of additives and the autoinductive behavior in proline-mediated reactions. These findings suggest an important role for detailed kinetic analysis in understanding and improving catalyst efficiency.The autoinductive behavior observed in the reactions of eqs 1a and 1b suggests that the product plays a role in accelerating rate, as is confirmed in Figure 1 for addition of product 3b to the α-amination reaction of eq 1b. The figure also shows that addition of aldol product 7 to the aldol reaction of eq 1c has no influence on the rate of this reaction. 2The two reactions exhibit distinctly different kinetic profiles, with the aldol reaction characterized by well-behaved positive order kinetics while the reactions of eqs 1a-1b show the sigmoidal conversion profile characteristic of an autoinductive process. Product ee is unaffected by added product in either reaction. The reactions of eqs. 1a and 1b do not proceed in the in the presence of product and absence of proline, confirming that the reactions are productaccelerated, or autoinductive, but not truly autocatalytic [14]. Careful studies, including those using fully soluble proline derivatives, showed that the effect could not be attributed to increasing solubilization of proline as the reaction proceeds [13].Interestingly, however, our further studies show that the source of the rate enhancement in the reactions of eqs 1a and 1b is not limited to the product specific to that reaction: Figure 2 show...

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A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

et al. 2009

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“…However, only a few studies [1][2][3][4][5][6][7][8][9][10][11] of synthetic reactions using unprotected (free) amino acids have been reported. Most of the synthetic transformations to natural products, pharmaceuticals, and chiral auxiliaries have been performed [12][13][14][15] with protected amino acids to increase solubility in organic solvents and avoid side reactions.…”

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Chemistry of Unprotected Amino Acids in Aqueous Solution: Direct Bromination of Aromatic Amino Acids with Bromoisocyanuric Acid Sodium Salt under Strong Acidic Condition

et al. 2006

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Brominations of unprotected aromatic amino acids such as phenylalanine, tyrosine, and glycine, with bromoisocyanuric acid mono sodium salt (BICA-Na) were conducted in 60% aq. H 2 SO 4 at 0°C to give a mixture of mono-brominated products in good yield. Unexpectedly, meta-bromophenylglycine was obtained as main product accompanied by ortho-and para-substituted products, while phenylalanine gave only ortho-and para-substituted products. Bromination of 2-phenylethylamine or benzylamine showed a tendency similar to the corresponding amino acids.

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“…18 Whilst a universally accepted mechanism for the HPESW reaction remains elusive, the most widely cited mechanistic pathway for conversion of 1 into 2 involves the carboxylic acid-facilitated formation of an enamine intermediate, the initial step of which involves the nucleophilic attack of the carbonyl of 1 by the nitrogen lone pair of electrons in proline. 19 In addition, proline possesses both acidic and basic properties and can consequently influence the propensity of dehydration of the ketal into the ketone. Therefore, the precise balance between nucleophilicelectrophilic and acid-base properties of proline are essential in order to control the HPESW reaction, with the conversion of 1 into 2 being determined by nucleophilicity of the nitrogen and 2 into 3 being controlled by the availability of the proton (i.e.…”

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The effects of interactions between proline and carbon nanostructures on organocatalysis in the Hajos–Parrish–Eder–Sauer–Wiechert reaction

Rance

Khlobystov

2014

Nanoscale

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. The non-covalent interactions of S-(-)-proline with the surfaces of carbon nanostructures (fullerene, nanotubes and graphite) change the nucleophilic-electrophilic and acid-base properties of the amino acid, thus tuning its activity and selectivity in the organocatalytic HajosParrish-Eder-Sauer-Wiechert (HPESW) reaction. Whilst our spectroscopy and microscopy measurements show no permanent covalent bonding between S-(-)-proline and carbon nanostructures, a systematic investigation of the catalytic activity and selectivity of the organocatalyst in the HPESW reaction demonstrates a clear correlation between the pyramidalisation angle of carbon nanostructures and the catalytic properties of S-(-)-proline. Carbon nanostructures with larger pyramidalisation angles have a stronger interaction wit h the nitrogen atom lone pair of electrons of the organocatalyst, thereby simultaneously decreasing the nucleophilicity and increasing the acidity of the organocatalyst. These translate into lower conversion rates but higher selectivities towards the dehydrated product of Aldol addition.

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Theory of Asymmetric Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions

Cited by 462 publications

References 71 publications

A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

Chemistry of Unprotected Amino Acids in Aqueous Solution: Direct Bromination of Aromatic Amino Acids with Bromoisocyanuric Acid Sodium Salt under Strong Acidic Condition

The effects of interactions between proline and carbon nanostructures on organocatalysis in the Hajos–Parrish–Eder–Sauer–Wiechert reaction

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