Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions

Bahmanyar, Sogole; Houk, K. N.; Martin, Harry J.; List, Benjamin

doi:10.1021/ja028812d

Cited by 548 publications

(344 citation statements)

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“…Due to the lack of directing hydrogen bonds and electrostatic interactions between the participating aldehyde and the enamine intermediate, the selectivities were very poor. The hydrogen bonding with proline is believed to stabilize the transition state [50][51][52]. The recyclability of IL immobilized catalyst 1a was also examined by using cyclopentenone as donor for the aldol reaction; the catalyst could be easily recovered and reused up to six times with only a slight decrease in activity.…”

Section: Imidazolium Immobilized Organocatalystsmentioning

confidence: 99%

Ionic Liquid Immobilized Organocatalysts for Asymmetric Reactions in Aqueous Media

Qiao

Headley

2013

Catalysts

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Ionic liquids are organic salts with melting points typically below ambient or reaction temperature. The unique combination of physical properties of ionic liquids, such as lack of measurable vapor pressure, high thermal and chemical stability, make them ideal to be used as reusable homogenous support for catalysts. In addition, the solubility of ionic liquids in various reaction media can be controlled and easily fine-tuned by modification of the structures of their cations and anions. As a result, ionic liquid immobilized organocatalysts are very effective in aqueous media and can be separated easily from organic solvents, as well as aqueous phases by simply adjusting the polarity of the media. Ionic liquid immobilized organocatalysts are not only very versatile compounds that are effective catalysts for a wide spectrum of reactions, but are also environmentally friendly and recyclable organocatalysts. Herein, we provide a summary of the past decade in the area of asymmetric catalysis in aqueous media for a wide variety of reactions in which ionic liquid and related ammonium salt immobilized organocatalysts are used.

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Section: Imidazolium Immobilized Organocatalystsmentioning

confidence: 99%

Ionic Liquid Immobilized Organocatalysts for Asymmetric Reactions in Aqueous Media

Qiao

Headley

2013

Catalysts

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“…Agami's widely accepted twoproline mechanism was recently challenged when we proposed a homogenous one-proline enamine mechanism for the intermolecular variant in which the various proton transfers are mediated by proline's carboxylic acid functionality (9). On the basis of density functional theory calculations, Houk et al (23)(24)(25) subsequently proposed a very similar mechanism for the intramolecular variant (D of Scheme 1). Surprisingly, despite the apparent interest, very limited experimental data in support of either of the several mechanistic proposals has been accumulated.…”

mentioning

confidence: 99%

New mechanistic studies on the proline-catalyzed aldol reaction

List

Hoang

Martin

2004

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

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The mechanism of the proline-catalyzed aldol reaction has stimulated considerable debate, and despite limited experimental data, at least five different mechanisms have been proposed. Complementary to recent theoretical studies we have initiated an experimental program with the goal of clarifying some of the basic mechanistic questions concerning the proline-catalyzed aldol reaction. Here we summarize our discoveries in this area and provide further evidence for the involvement of enamine intermediates. D iscovered in the early 1970s, the Hajos-Parrish-EderSauer-Wiechert reaction (1, 2), a proline-catalyzed intramolecular aldol reaction, represents not only the first asymmetric aldol reaction invented by chemists but also the first highly enantioselective organocatalytic transformation [1(4) 3 2(5) 3 3(6)] (Eq. 1 of Scheme 1) (3-6). Inspired by Nature's phenomenal enzymes, which catalyze direct asymmetric aldolizations of unmodified carbonyl compounds (7, 8), we have recently extended the Hajos-Parrish-Eder-Sauer-Wiechert reaction to the first intermolecular variant (7 ϩ 8 3 9) (Eq. 2 of Scheme 1) (9), and to several other reactions including prolinecatalyzed asymmetric Mannich (10), Michael (11), ␣-amination (12), and intramolecular enolexo aldolization reactions (10 3 11) (13) (Eq. 3 of Scheme 1) (14-18).Similar to the aldolase enzymes, proline catalyzes direct asymmetric aldol reactions between two different carbonyl compounds to provide aldol products in excellent yields and enantioselectivities. Early on it has been speculated that in addition to operating on related substrates, both class I aldolases and proline may also share a similar enamine mechanism (19,20). However, there has been some debate over several mechanistic aspects of the reaction, and a number of alternative models have been proposed. For example, Hajos (1) suggested a mechanism that involves the ''activation'' of one of the enantiotopic acceptor carbonyl groups as a carbinol amine (A of Scheme 1). At least the stereochemistry of this model was questioned by Jung (19) soon after its initial proposal. An enamine mechanism was suggested by various groups already in the 1970s and 1980s (19-21). Nonlinearity studies by Agami and colleagues (21) have led to the proposal of a side-chain enamine mechanism that involves two proline molecules in the C-C-bondforming transition state, one engaged in enamine formation and the other as a proton transfer mediator (B of Scheme 1). Swaminathan et al. (22) favor a heterogeneous aldolization mechanism on the surface of crystalline proline (C of Scheme 1), despite the fact that many proline-catalyzed aldolizations are completely homogenous. Agami's widely accepted twoproline mechanism was recently challenged when we proposed a homogenous one-proline enamine mechanism for the intermolecular variant in which the various proton transfers are mediated by proline's carboxylic acid functionality (9). On the basis of density functional theory calculations, subsequently proposed a very similar mechanism for the in...

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“…Among the many different primary and secondary amine catalysts that have been developed in this field, the amino acid proline remains a privileged motif and there are literally dozens of reaction types that are catalyzed with this wonderful natural product (5). Proline-derived enamines of aldehydes and ketones are key intermediates in the catalytic cycles of these reactions (Scheme 1) (6)(7)(8)(9)(10)(11)(12)(13). Surprisingly though, such enamines have remained entirely hypothetical and resisted attempts at their structural characterization.…”

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confidence: 99%

Crystal structures of proline-derived enamines

Bock

Lehmann

List

2010

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

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The isolation and structural characterization of both aldehyde-and ketone-derived proline enaminones are reported and discussed. Crystal structures of 10 proline enamines provide information on stereochemical aspects, i.e., double bond configuration and synvs. anti-positioning of the carboxylate relative to the enamine double bond. Furthermore, the obtained crystal structures are compared with the density functional theory-calculated structures of the ground and transition state and the postulated SeebachEschenmoser transition state.enamine catalysis | mechanism | organocatalysis

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Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions

Cited by 548 publications

References 19 publications

Ionic Liquid Immobilized Organocatalysts for Asymmetric Reactions in Aqueous Media

Ionic Liquid Immobilized Organocatalysts for Asymmetric Reactions in Aqueous Media

New mechanistic studies on the proline-catalyzed aldol reaction

Crystal structures of proline-derived enamines

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