Enamine versus Oxazolidinone: What Controls Stereoselectivity in Proline‐Catalyzed Asymmetric Aldol Reactions?

Sharma, Akhilesh K.; Sunoj, Raghavan B.

doi:10.1002/anie.201001588

Cited by 101 publications

(45 citation statements)

References 49 publications

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“…This is in contrast to proline which is known to preferentially form anti-enamine. [8,[32][33][34] It is also speculated that under the catalytic influence of 9, the reaction could proceed predominantly through syn-enamine formation between β-amino site of 9 and acetone 2.…”

Section: Esi-ms Studies and Proposal Of Catalytic Cyclementioning

confidence: 99%

“…Although the formation of an oxazolidinone species is often reported as a rationale towards appropriate enamine formation primarily with secondary amines [6,8,20,31] (while L-leucinol was also shown to form oxazolidinone species [31] ), additional studies are required to support such hypothesis.…”

Section: Esi-ms Studies and Proposal Of Catalytic Cyclementioning

confidence: 99%

“…[4] Aminocatalysis is a covalent catalytic process, where the substrate initially becomes attached to the catalyst via an imine, enamine or oxazolidine linkage, forming an activated intermittent species which helps to lower the activation energy of later transition state (TS) responsible for asymmetric bond formation. [5][6][7][8] This field, dominated by proline derivatives and related secondary amine organocatalysts (with some examples given in Figure 1), has received, extensive consideration over the last two decades. [4,[9][10][11][12][13][14][15][16] Despite its catalytic success, there are still several challenges, such as low efficiency, requirement of high catalyst loading, long reaction times, limited substrate scope, contribu-…”

Section: Introductionmentioning

confidence: 99%

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Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

et al. 2019

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In this work, a series of novel organocatalysts derived from unique unnatural β-amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossedaldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)-2-amino-N-((R)-1-phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3-hydroxy-3-alkyl-2-oxindole in excellent yield (> 99%) and distereoselectivity (> 99% dr) with good enantioselective control (up to 52% ee) in the presence of p-nitrophenol and EtOH in < 24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β-amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI-MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.

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Section: Esi-ms Studies and Proposal Of Catalytic Cyclementioning

confidence: 99%

Section: Esi-ms Studies and Proposal Of Catalytic Cyclementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

et al. 2019

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“…Pertinent to this particular discussion is the recent computational analysis of the proline-catalyzed propanal self-aldol reaction by Sharma and Sunoj. [69] In reconciling the differences between the Houk-List and Seebach-Eschenmoser models to rationalize stereoselectivity,t he authors demonstrate that convergence of both the enamine and oxazolidinone pathways (Figure 3) is likely under the reaction conditions,underscoring the value of synergy between experiment and theory.Inarecent analysis of the List-Houk model, Armstrong,R zepa et al note that ten years after the initial report, seemingly small systems such as this one continue to be challenging,e specially in understanding the role of dispersion interactions in rationalizing selectivity. [70] Thec onceptually related organocatalytic addition of linear aldehydes to nitroolefins has become an excellent platform for evaluating new catalyst architectures for enamine activation.…”

Section: Methodsmentioning

confidence: 99%

Deconstructing Covalent Organocatalysis

2015

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Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy.

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“…In passing, we note that oxazolidinones, [42] which have been observed to be in equilibrium with the enamine intermediate, [26] cannot account for the observed high facial selectivity. [43] Given the importance of aldol reactions, extensive research is going on to design organocatalysts which can promote the asymmetric aldol reaction in aqueous media. [16-18, 23, 24, 44-47] Water can exert a very complex influence on the stereoselectivity of enamine-based organocatalytic aldol reactions.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Role of Water in the Stereoselective Step of Aqueous Proline‐Catalyzed Aldol Reactions

Ribas‐Ariño¹,

Carvajal²,

Chaumont³

et al. 2012

Chemistry A European J

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A multiscale computational study was performed with the aim of tracing the source of stereoselectivity and disclosing the role of water in the stereoselective step of propionaldehyde aldol self-condensation catalyzed by proline amide in water, a reaction that serves as a model for aqueous organocatalytic aldol condensations. Solvent mixing and hydration behavior were assessed by classical molecular dynamics simulations, which show that the reaction between propanal and the corresponding enamine takes place in a fully hydrated environment. First-principles molecular dynamics simulations were used to study the free-energy profile of four possible reaction paths, each of which yields a different stereoisomer, and high-level static first-principles calculations were employed to characterize the transition states for microsolvated species. The first solvation shell of the oxygen atom of the electrophilic aldehyde at the transition states contains two water molecules, each of which donates one hydrogen bond to the nascent alkoxide and thereby largely stabilizes its excess electron density. The stereoselectivity originates in an extra hydrogen bond donated by the amido group of proline amide in two reaction paths.

show abstract

Enamine versus Oxazolidinone: What Controls Stereoselectivity in Proline‐Catalyzed Asymmetric Aldol Reactions?

Cited by 101 publications

References 49 publications

Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

Deconstructing Covalent Organocatalysis

Unraveling the Role of Water in the Stereoselective Step of Aqueous Proline‐Catalyzed Aldol Reactions

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