Zinc‐Catalyzed Amide Cleavage and Esterification of β‐Hydroxyethylamides

Kita, Yusuke; Nishii, Yuji; Higuchi, T.; Mashima, Kazushi

doi:10.1002/ange.201201789

Cited by 19 publications

(8 citation statements)

References 28 publications

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“…likely because of oxidation at the Met and/or Tyr residues. Although we could not detect the UQ(66-76) fragment, predominant production of the three expected fragments (UQ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), UQ , and UQ(58-64)) clearly demonstrated that the Ser selectivity of the present method was reliable when using native protein as the substrate.…”

Section: Methodsmentioning

confidence: 72%

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Serine‐Selective Aerobic Cleavage of Peptides and a Protein Using a Water‐Soluble Copper–Organoradical Conjugate

et al. 2014

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The site-specific cleavage of peptide bonds is an important chemical modification of biologically relevant macromolecules. The reaction is not only used for routine structural determination of peptides, but is also a potential artificial modulator of protein function. Realizing the substrate scope beyond the conventional chemical or enzymatic cleavage of peptide bonds is, however, a formidable challenge. Here we report a serine-selective peptide-cleavage protocol that proceeds at room temperature and near neutral pH value, through mild aerobic oxidation promoted by a water-soluble copperorganoradical conjugate. The method is applicable to the siteselective cleavage of polypeptides that possess various functional groups. Peptides comprising d-amino acids or sensitive disulfide pairs are competent substrates. The system is extendable to the site-selective cleavage of a native protein, ubiquitin, which comprises more than 70 amino acid residues.Chemical modifications of proteins [1,2] have a great impact on a broad range of research fields, such as chemical biology, [3] chemical genetics, [4] protein engineering, [5] proteomics, [6] and drug discovery. [7] Site-specific cleaving reactions of peptide bond are among such important chemical modifications. The method is routinely used when structural determination or fragmentation of peptides plays a pivotal role, [8] and it is also regarded as a new strategy for modulating the physiological functions of proteins for medical applications. [9,10] Although peptidases hydrolyze peptide bonds at specific sites under mild conditions with high fidelity, [11] the scope of the scissile substrates is restricted in principle to genetically encoded amino acid sequences. Unnatural or structurally modified peptides and proteins are out of the scope of peptidase digestion. Metal-catalyzed site-selective hydrolysis of pep-tides [12] has been intensively studied as a potential alternative to the enzymatic method. The establishment of practical protocols and generalization to protein cleavage, however, remain challenging because of the chemical robustness of amides. [13] Herein we report a serine (Ser)-selective cleavage of peptides (including a native protein) through mild aerobic oxidation of the hydroxymethyl group of Ser, promoted by a water-soluble Cu/N-oxyl radical system.We envisioned a Ser-selective cleavage of the peptide bond initiated by aerobic chemoselective oxidation of its hydroxymethyl moiety (see Scheme 1). [8c,d] Oxidation of the hydroxymethyl moiety of a Ser residue (A) to a formyl group would produce an a-formylglycineamide intermediate B.Further oxidation of B would produce oxalimide C through oxidative deformylation. Hydrolysis of the latent precursor C under mild conditions should then be possible, because the carbonyl groups of the oxalimide are more electrophilic than those of simple amides, giving peptide bond cleaved fragments D and D'. Using molecular oxygen as a terminal oxidant, water and a C 1 molecule (possibly HCO 2 H) are stoichiometric side product...

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Section: Methodsmentioning

confidence: 72%

“…This strategy is distinct from Lewis acid promoted Ser-selective peptide hydrolysis through N-to-O rearrangement. [14] To realize the designed reaction, we focused on an oxidation of a Ser hydroxymethyl moiety with molecular oxygen catalyzed by a Cu/N-oxyl radical. [15][16][17] This catalysis is tolerant to water and Lewis basic functionalities.…”

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confidence: 99%

Serine‐Selective Aerobic Cleavage of Peptides and a Protein Using a Water‐Soluble Copper–Organoradical Conjugate

et al. 2014

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“…Amide alcoholysis under mild conditions can be classified into three categories: (i) transformation using activated acyl compounds,4 (ii) directing group‐assisted reactions,5 and (iii) usage of twisted amides for minimizing the amide resonance6 (Scheme ). We recently reported the selective cleavage of β‐hydroxyethylamides catalyzed by a simple zinc triflate, achieving a catalytic serine sequence‐selective peptide bond cleavage 7. In these reports, however, stoichiometric amounts of the activator or specific substituents were required and thus more atom‐economical and general systems are in high demand.…”

Section: Methodsmentioning

confidence: 99%

Combined Catalytic System of Scandium Triflate and Boronic Ester for Amide Bond Cleavage

Kita¹,

Nishii²,

Onoue³

et al. 2013

Adv Synth Catal

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We have found that the combination of scandium with boronic ester enables the cleavage of amide bonds. Primary amides were converted to the corresponding esters in the presence of catalytic amounts of scandium triflate and boronic ester under mild and neutral conditions. This unique catalytic system can be applied to the deprotection of acetylaniline derivatives. In addition, control NMR experiments were carried out to examine the effect of the boronic esters.Keywords: amides; boron; scandium; solvolysis The amide bond is a ubiquitous and thermodynamically stable entity due to amide resonance where the lone pair of electrons on the nitrogen is delocalized into the carbonyl. [1,2] Although amide-directed C À H bond functionalization is an attractive topic of interest, [3] cleavage of the amide bond is difficult owing to the inert nature of amides and thus its application is limited. Among amide transformations, amide alcoholysis has attracted widespread attention from synthetic chemists because the resulting esters can be subjected to further transformations. Amide alcoholysis under mild conditions can be classified into three categories: (i) transformation using activated acyl compounds, [4] (ii) directing group-assisted reactions, [5] and (iii) usage of twisted amides for minimizing the amide resonance [6] (Scheme 1). We recently reported the selective cleavage of b-hydroxyethylamides catalyzed by a simple zinc triflate, achieving a catalytic serine sequence-selective peptide bond cleavage. [7] In these reports, however, stoichiometric amounts of the activator or specific substituents were required and thus more atom-economical and general systems are in high demand.In the course of our continued research interest in the transformation of carboxylic acid derivatives, we previously developed oxo-bridged clusters with high catalytic activity and unique chemoselectivity for transesterification.[8] Herein, we have designed a new cooperative catalyst system by combining two different Lewis acidic atoms. Our findings indicate that the Scheme 1. Alcoholysis of amides.

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“…In most cases these take advantage of primary amides using either high temperatures (100 to 160°C) or added metals as essential activating reagents. 19,20 Herein, we present a new activatable acyl donor which in the "off-state" is stable towards nucleophilic attack by e.g. [14][15][16][17][18] The strategy resulted in either the free acid or a new ester bond.…”

Section: Introductionmentioning

confidence: 99%

“…Also, tertiary and secondary amides, activated by Tf 2 O and Zn(OTf ) 2 respectively, have resulted in clever ways of creating intra-and inter-molecular ester bonds from amide bonds. 19,20 Herein, we present a new activatable acyl donor which in the "off-state" is stable towards nucleophilic attack by e.g. amines, whereas in the "on-state" it reacts with nucleophiles such as amines, alcohols, and thiols.…”

Section: Introductionmentioning

confidence: 99%

Oxidative activation of dihydropyridine amides to reactive acyl donors

2015

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Amides of 1,4-dihydropyridine (DHP) are activated by oxidation for acyl transfer to amines, alcohols and thiols. In the reduced form the DHP amide is stable towards reaction with amines at room temperature. However, upon oxidation with DDQ the acyl donor is activated via a proposed pyridinium intermediate. The activated intermediate reacts with various nucleophiles to give amides, esters, and thio-esters in moderate to high yields.

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Zinc‐Catalyzed Amide Cleavage and Esterification of β‐Hydroxyethylamides

Cited by 19 publications

References 28 publications

Serine‐Selective Aerobic Cleavage of Peptides and a Protein Using a Water‐Soluble Copper–Organoradical Conjugate

Serine‐Selective Aerobic Cleavage of Peptides and a Protein Using a Water‐Soluble Copper–Organoradical Conjugate

Combined Catalytic System of Scandium Triflate and Boronic Ester for Amide Bond Cleavage

Oxidative activation of dihydropyridine amides to reactive acyl donors

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