Optimized aqueous Kinugasa reactions for bioorthogonal chemistry applications

Bilodeau, Didier A.; Margison, Kaitlyn D.; Ahmed, Noreen; Strmiskova, Miroslava; Sherratt, Allison R.; Pezacki, John Paul

doi:10.1039/c9cc09473c

Cited by 7 publications

(7 citation statements)

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“…29 We recently reported upon optimized conditions for aqueous Kinugasa reactions with the goal of increasing its bioorthogonal applicability. 100 The choice of alkyne was found to greatly influence the speed and efficiency of the reaction, with traditionally used unactivated terminal and aryl alkynes leading to lower yields of observed β-lactam products, while alkynes bearing electron-withdrawing groups, such as propiolic esters and propiolamides, increased yields. Propiolamides are advantageous for their ease of synthesis through amide bond formation and for their hydrolytic stability in biological environments.…”

Section: Optimization Of the Kinugasa Reaction For Bioorthogonal Appl...mentioning

confidence: 99%

“…102 Therefore, to showcase CuANCR as a bioorthogonal reaction for mammalian cell for the modification of membrane-associated proteins. 100 The isolation and functionalization of membrane proteins can be challenging, requiring hydrophobic environments in order to properly function and to adopt necessary conformation. Micellar conditions allow for the proper solubilization of membrane proteins, mimicking cellular membranes.…”

Section: Bioorthogonal Applications Of the Kinugasa Reactionmentioning

confidence: 99%

“…Similarly to CuAAC, CuANCR reactions face certain challenges when adapting them for bioorthogonal applications, chiefly, the necessity of copper catalysis. Copper toxicity can perturb living cells’ biology; however, this toxicity is highly dependent on the choice of ligand and base and can be greatly attenuated, namely, through the use of natural amino acids as ligands, such as l -histidine and l -proline. ,, The aqueous stability of nitrones must also be considered, with acyclic aryl nitrones readily hydrolyzing to the parent aldehyde and hydroxylamine. This problem can be circumvented by forming the nitrone in situ from condensation with installed aldehydes or by using cyclic nitrones which display much greater aqueous stability .…”

Section: Development Of the Bioorthogonal Kinugasa Reactionmentioning

confidence: 99%

“…This problem can be circumvented by forming the nitrone in situ from condensation with installed aldehydes or by using cyclic nitrones which display much greater aqueous stability . We recently reported upon optimized conditions for aqueous Kinugasa reactions with the goal of increasing its bioorthogonal applicability . The choice of alkyne was found to greatly influence the speed and efficiency of the reaction, with traditionally used unactivated terminal and aryl alkynes leading to lower yields of observed β-lactam products, while alkynes bearing electron-withdrawing groups, such as propiolic esters and propiolamides, increased yields.…”

Section: Development Of the Bioorthogonal Kinugasa Reactionmentioning

confidence: 99%

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Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

et al. 2021

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Bioorthogonal chemical reactions have emerged as convenient and rapid methods for incorporating unnatural functionality into living systems. Different prototype reactions have been optimized for use in biological settings. Optimization of 3 + 2 dipolar cycloadditions involving nitrones has resulted in highly efficient reaction conditions for bioorthogonal chemistry. Through substitution at the nitrone carbon or nitrogen atom, stereoelectronic tuning of the reactivity of the dipole has assisted in optimizing reactivity. Nitrones have been shown to react rapidly with cyclooctynes with bimolecular rate constants approaching k 2 = 102 M–1 s–1, which are among the fastest bioorthogonal reactions reported (McKay et al. Org. Biomol. Chem. 2012, 10, 3066–3070). Nitrones have also been shown to react with trans-cyclooctenes (TCO) in strain-promoted TCO-nitrone cycloadditions reactions. Copper catalyzed reactions involving alkynes and nitrones have also been optimized for applications in biology. This review provides a comprehensive accounting of the different bioorthogonal reactions that have been developed using nitrones as versatile reactants, and provides some recent examples of applications for probing biological systems.

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Section: Optimization Of the Kinugasa Reaction For Bioorthogonal Appl...mentioning

confidence: 99%

Section: Bioorthogonal Applications Of the Kinugasa Reactionmentioning

confidence: 99%

Section: Development Of the Bioorthogonal Kinugasa Reactionmentioning

confidence: 99%

Section: Development Of the Bioorthogonal Kinugasa Reactionmentioning

confidence: 99%

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Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

et al. 2021

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“…Alkynes are attractive building blocks in organic synthesis because of their stability and versatility . The alkyne subunit is featured in pharmaceuticals and undergoes click reactions. , The biological and medicinal relevance of this functional group has driven the development of alkynylation methods . Among those, cost and atom economic C(sp 3 )–H alkynylations have attracted much attention .…”

Section: Introductionmentioning

confidence: 99%

Visible Light-Induced Direct S₀ → T_n Transition of Benzophenone Promotes C(sp³)–H Alkynylation of Ethers and Amides

2020

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Benzophenone has an S 0 → S 1 absorption band at 365 nm. However, the rarely reported S 0 → T n transition occurs upon irradiation at longer wavelengths. Herein, we employed benzophenone as a catalyst and exploited its S 0 → T n transition in C(sp 3 )−H alkynylations with hypervalent iodine reagents. The selective benzophenone excitation prevented alkynylating reagent decomposition, enabling the reaction to proceed under mild conditions. The reaction mechanism was investigated by spectroscopic and computational studies.

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The Kinugasa Reaction

Chmielewski,

Kutaszewicz,

Ulikowski

et al. 2024

Organic Reactions

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Among the methods of synthesizing the β‐lactam ring, the copper(I)‐mediated reaction between a nitrone and a terminal alkyne in the presence of an organic base is a remarkably simple and direct strategy. This transformation, known as the Kinugasa reaction, is a cascade process that involves a 1,3‐dipolar cycloaddition of a copper acetylide onto the nitrone, followed by a rearrangement step. Initially reported in 1972, this reaction stereoselectively allows access to cis ‐substituted β‐lactam products. Achiral, diastereoselective, and catalytic enantioselective versions of the Kinugasa reaction have been described, both in inter‐ and intramolecular contexts. To date, only aldimine‐derived nitrones have been demonstrated in the reaction. This chapter presents a comprehensive overview of the Kinugasa reaction. Mechanistic proposals and the factors involved in the stereochemistry of the reaction are followed by a discussion of the scope of the reaction and its limitations. Specifically, the combinations of aldonitrones and terminal alkynes that can be used in the achiral and diastereoselective Kinugasa reaction are presented. Enantioselective and intramolecular variants of the reaction are discussed in detail, as are successful synthetic applications, with an emphasis on the preparation of β‐lactam antibiotics. The Kinugasa reaction is compared with more classical and well‐established methods of β‐lactam synthesis, and finally, typical experimental conditions and examples of procedures for selected variants of the Kinugasa reaction are provided. The Tabular Survey covers Kinugasa reactions performed through the end of 2021.

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Optimized aqueous Kinugasa reactions for bioorthogonal chemistry applications

Abstract: We present optimized micelle-assisted aqueous copper(i)-catalyzed alkyne–nitrone cycloaddition involving rearrangement (CuANCR) reactions applicable to bioorthogonal applications, namely membrane-associated peptide modification.

Cited by 7 publications

References 51 publications

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Visible Light-Induced Direct S₀ → T_n Transition of Benzophenone Promotes C(sp³)–H Alkynylation of Ethers and Amides

The Kinugasa Reaction

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Optimized aqueous Kinugasa reactions for bioorthogonal chemistry applications

Abstract: We present optimized micelle-assisted aqueous copper(i)-catalyzed alkyne–nitrone cycloaddition involving rearrangement (CuANCR) reactions applicable to bioorthogonal applications, namely membrane-associated peptide modification.

Cited by 7 publications

References 51 publications

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Bioorthogonal Reactions Utilizing Nitrones as Versatile Dipoles in Cycloaddition Reactions

Visible Light-Induced Direct S0 → Tn Transition of Benzophenone Promotes C(sp3)–H Alkynylation of Ethers and Amides

The Kinugasa Reaction

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Product

Resources

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Visible Light-Induced Direct S₀ → T_n Transition of Benzophenone Promotes C(sp³)–H Alkynylation of Ethers and Amides