A Catalyst‐Directed Remote Stereogenic Center Switch During the Site‐Selective Aldol Desymmetrization of Cyclohexanone‐Based Diketones

Nugent, Thomas C.; Spiteller, Peter; Hussain, Ishtiaq; Hussein, Hussein Ali El Damrany; Najafian, Foad Tehrani

doi:10.1002/adsc.201600833

Cited by 7 publications

(4 citation statements)

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“…[9] The technique is both relevant to our work and appealing because we often recovered starting material. [15] Gong was the first to report enamine based desymmetrizations of 4-substituted cyclohexanones exemplified by 1 a-d. [17][18][19] But, our demonstrations are the first to move beyond simple 4-alkyl or 4-phenyl substituted cyclohexanones, and so should increase the application utility. Remarkably, aldol product formation supersedes Knoevenagel and enaminone formation.…”

Section: Resultsmentioning

confidence: 98%

Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

et al. 2021

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Aldol reaction chemoselectivity, racemic or enantioselective, has not been previously demonstrated in the presence of Knoevenagel active functional groups. Here, we show that unhindered β-diketones remain unreacted while a ketone moiety undergoes a highly enantioselective aldol desymmetrization resulting in three new stereogenic centers using in water reaction conditions. A mechanistic hypothesis for the chemoselective formation of either aldol or Knoevenagel products is presented. It elucidates how these amino acid catalyzed reactions completely suppress formation of the expected Knoevenagel product under in water (heterogeneous) reaction conditions, but not when water is present as a dissolved cosolvent (homogeneous). Finally, the developed hypothesis reinforces and expands the role of water at an organic-water interface.

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Section: Resultsmentioning

confidence: 98%

Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

et al. 2021

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“… Regioselective mono‐aldol reaction of diketones [48c,d] . [a] Isolated yields of a single diastereomer.…”

Section: Regioselective Mono‐aldol Reactions Of Di‐ or Higher‐ketonesmentioning

confidence: 99%

“…Miss assigned structures have occasionally followed [137] . Interestingly, chiral amine catalyst tuning has shown that diastereomer III (Scheme 10) can be formed in high ee and mediocre yield, albeit with approximately equal quantities of diastereomer I concomitantly forming [48d] …”

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

confidence: 99%

“…For example, an achiral diketone could undergo enantioselective mono‐aldol functionalization, wherein high regioselectivity occurs. Some examples are shown in Scheme 6 [48c,d] . This approach avoids ketone protection‐deprotection protocols, and becomes synthetically relevant when the synthesis of the diketone, the resulting mono‐aldol product, and a set of further reaction steps, results in a more step efficient synthesis of a target molecule.…”

Section: Regioselective Mono‐aldol Reactions Of Di‐ or Higher‐ketonesmentioning

confidence: 99%

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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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Highly Enantioselective Synthesis of (R)‐3‐Alkyl‐3‐hydroxyindolin‐2‐ones Including Natural Product (R)‐Convolutamydine A Catalyzed by A Primary Amine

et al. 2017

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An efficient strategy for constructing (R)‐3‐alkyl‐3‐hydroxyindolin‐2‐one derivatives catalyzed by a structurally simple and easily prepared primary amine catalyst under mild conditions has been developed. Various isatins and ketones were tolerated, and the desired products were obtained in up to 99 % yield and up to 99 % ee. The biologically active natural product (R)‐convolutamydine A was synthesized in 96 % yield and 95 % ee.

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A Catalyst‐Directed Remote Stereogenic Center Switch During the Site‐Selective Aldol Desymmetrization of Cyclohexanone‐Based Diketones

Cited by 7 publications

References 43 publications

Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity

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.

Highly Enantioselective Synthesis of (R)‐3‐Alkyl‐3‐hydroxyindolin‐2‐ones Including Natural Product (R)‐Convolutamydine A Catalyzed by A Primary Amine

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