Acids as Proline Co-catalysts in the Aldol Reaction of 1,3-Dioxan-5-ones

Majewski, Marek; Niewczas, Izabella; Palyam, Nagarjuna

doi:10.1055/s-2006-950421

Cited by 34 publications

(5 citation statements)

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“…Most reports only note the dr for stereoisomers I and II , presumably because the yields of III and IV are too small to quantify. Majewski was the first to demonstrate this concept through amine catalysis, [135] but it was Gong who examined more meaningful substrates that likely invigorated extensive further study [136] . Unfortunately, Gong's initial stereochemical assignment was incorrect, but he soon amended the assignment, through X‐ray structure procurement, to show the major product as stereoisomer I .…”

Section: Specific Ketones and Their Reaction With 4‐nitrobenzaldehyde...mentioning

confidence: 99%

A 2000 to 2020 Practitioner's Guide to Chiral Amine‐Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances.

et al. 2022

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An extensive introduction is provided for the non-expert regarding enantioselective, amine catalyzed, aldol reactions (Sections 1-3). There, a broad perspective is provided regarding: methodology limitations, mechanism, in-water versus on-water definitions and their theoretical basis, small-and large-scale physical-mechanical aspects, solid versus liquid starting material considerations, reproducibility, ball milling, diketone substrates, etc. The thematic emphasis then turns to practical outcomes for the reaction of nineteen aliphatic, cyclic, and aromatic ketones with 4-nitrobenzaldehyde and benzaldehyde prior to 2021. In doing so, 172 catalysts are highlighted. The ketone substrates are listed in the Table of Contents (Section 4) and their structures are shown in Figure 1. Each ketone is summarized by a: (i) schematic, (ii) text summary, (iii) catalyst Figures, and (iv) tabular reaction/ product data. Individual ketone summaries, at times, represent the distillation of over six hundred and fifty research articles, and the data refinement and its tabular reconstitution is not reproducible using a chemical database search with filters. In the review's broadest use, the Figure 1 ketone structures serve as templates to extrapolate to hypothetical substrates holding more functionality, but of related steric and electronic similarity. This pseudo matching permits a rapid answer to, "Does this methodology suit the ketone substrate at hand or not?" In a positive outcome, the best reaction conditions (stoichiometry, catalyst structure and loading, solvent, time, etc.) to affect aldol product formation (yield, dr, and ee) are delineated. A second envisioned use, allows the directed construction of diketone substrates (after viewing the tabularized data of Section 4) capable of undergoing regioselective mono-aldol product formation. This ketone regioselectivity tactic, reacting one carbonyl moiety while the other remains unreacted, avoids ketone protection-deprotection, and is demonstrated for the advantageous synthesis of an Alzheimer drug candidate.

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Section: Specific Ketones and Their Reaction With 4‐nitrobenzaldehyde...mentioning

confidence: 99%

A 2000 to 2020 Practitioner's Guide to Chiral Amine‐Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances.

et al. 2022

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“…Recently, kinetic and spectroscopic studies revealed that the addition of water increased the proline concentration because of the inhibition of the formation of parasitic species such as the oxazolidinone derivative decreasing the relative concentration of key iminium intermediates by Le Châtelier's principle [83]. Moreover, the addition of Brønsted/Lewis acids such as chiral camphorsulfonic acid (CSA) [84], pyridinium p-toluenesulfonate, or lithium chloride [85] or even the combination of water with acetic and trifluoroacetic acid (TFA) or bases, such as 1,8-diazabyciclo [5.4.0]undec-7-ene (DBU) or triethylamine, showed a benefit effect on the reaction rates [86]. Also, the use of chiral diols, such as (R)-BINOL, as cocatalyst improved the obtained results [87], where this effect is explained by the formation of a template from the chiral diol that may activate and order the aldehyde and enamine nucleophile.…”

Section: Aldehydes As Electrophilesmentioning

confidence: 99%

“…The synthesis of products 372 could be accomplished by using the reaction of the corresponding α-isothiocyanates derived from isatins with simple ketones in the presence of thiourea (375, 20 mol%) as catalyst in mesitylene at −40 • C (75-95% yield, 40-80% de, and 64-98% ee) [434]. α-Isothiocyanato imides 371 reacted also with α-keto esters (85) to form β-hydroxy-α-amino acid derivatives in good results (70-99%, 40-70% de, and 79-98% ee) and catalyzed by thiourea (376, 5 mol%) in methyl tert-butyl ether at 25 • C [435].…”

Section: Ketones As Source Of Nucleophilementioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

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“…As further confirmation, 2,2-dimethyl-1,3-dioxan-5-one 1c (Table 5) also displayed good reactivity and stereoselectivity when reacted with less reactive aldehydes 2g and 2d. In particular, our results represent the first examples of organocatalyzed aldol condensation between 2,2-dimethyl-1, 3-dioxan-5-one 1c and 4-Br benzaldehyde 2g or benzaldehyde 2d, promoted by only 10 mol% of proline [129][130][131][132][133].…”

Section: Application Of the Protocol To Other Ketonesmentioning

confidence: 68%

A Simple and Efficient Protocol for Proline-Catalysed Asymmetric Aldol Reaction

et al. 2020

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The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.

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Acids as Proline Co-catalysts in the Aldol Reaction of 1,3-Dioxan-5-ones

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 34 publications

References 2 publications

A 2000 to 2020 Practitioner's Guide to Chiral Amine‐Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances.

A 2000 to 2020 Practitioner's Guide to Chiral Amine‐Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances.

Organocatalyzed Aldol Reactions

A Simple and Efficient Protocol for Proline-Catalysed Asymmetric Aldol Reaction

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