Michael Addition of Amines and Thiols to Dehydroalanine Amides:  A Remarkable Rate Acceleration in Water

Naidu, B. Narasimhulu; Sorenson, Margaret E.; Connolly, Timothy P.; Ueda, Yasutsugu

doi:10.1021/jo034762z

Cited by 65 publications

(37 citation statements)

References 15 publications

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“…23 Importantly, Naidu et al reported a dramatic increase in both the rate and yields in the Michael addition of amines and thiols to dehydroalanine amides upon using THF:water or methanol:water as the solvent. 24 A similar rate enhancement was observed in the aza-Michael addition of cyclam to phenyl vinyl sulfone and phenyl vinyl sulfoxide when water was added to the reaction mixture. 25 However, in the case of vinyl sulfonamides, it was not known if there is any rate acceleration of the aza-Michael addition in the presence of water in the solvent system.…”

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confidence: 53%

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3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: aza-Michael addition reactions and the preparation of poly-HOPO chelators

Martı́nez

Jayanthi

Jacobs

et al. 2013

Tetrahedron Letters

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The HOPO vinyl sulfonamide 3 and the corresponding HOPO acrylamide 10, were easily prepared by short synthetic sequences. Investigation of the aza-Michael reactions of these linkers showed that they proceed at a higher rate in solvent systems containing water. The scope and limits of the aza-Michael reactions of 3 and 10 were examined. Reagents 3 and 10 reacted cleanly with piperazine to give the corresponding adducts which were deprotected to give the di-HOPO ligands 7 and 16. Reaction of HOPO acrylamide 10 with 1,4,7-triazacyclononane gave the tris-adduct 17 which was deprotected to give the desired tris-HOPO ligand 18. Overall, the aza-Michael reactions of 3 and 10 appear to be governed not only by the solvent but also by the nature of the amine and the solubility of the reaction intermediates.

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confidence: 53%

“…24 Indeed, this proved to be correct. In the aza-Michael addition of benzyl amine (1 eq) to vinyl sulfonamide 1 (1 eq) we observed significant increase in the rate of reaction, when the reaction was run in a 2:3 mixture of methanol/water for 18 hours.…”

mentioning

confidence: 90%

3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: aza-Michael addition reactions and the preparation of poly-HOPO chelators

Martı́nez

Jayanthi

Jacobs

et al. 2013

Tetrahedron Letters

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“…Usually, a tertiary amine is selected as catalyst for the conjugate addition, [27] since primary amines are prone to react with a, b-unsaturated compounds, a reaction that decreases the yield of the thiol Michael addition. [28,29] In our procedure, the a, b-unsaturated ester was added in excess, relative to the total thiol concentration, consisting of the two polymer end groups and the 1-isobutylthiol by-product. The low molecular weight Michael addition by-products were removed entirely by reprecipitations of the polymers, as shown by the absence in the NMR spectra of P-2 and P-3 of signals in the region between 0.9 and 1.0 ppm where resonances of the methyl groups of butylthiourea, isobutylthiol and butylamine appear (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Facile and Efficient One‐Pot Transformation of RAFT Polymer End Groups via a Mild Aminolysis/Michael Addition Sequence

Qiu

Winnik

2006

Macromol. Rapid Commun.

207

220

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Summary: The trithiocarbonate end groups of polymers prepared by RAFT polymerization are converted into colorless and stable thioethers in a one‐pot process that combines aminolysis of the trithiocarbonate functions and Michael addition of the resulting thiols to α, β‐unsaturated carbonyl derivatives. This post polymerization procedure, which is carried out under mild conditions to near quantitative conversion, is described in the case of a telechelic poly(N‐isopropylacrylamide) sample bearing isobutylsulfanylthiocarbonylsulfanyl end groups. The chemical composition, purity, and molar masses of the modified polymers are assessed by GPC, 1H NMR spectroscopy and UV‐vis spectroscopy, which together demonstrate the efficiency of the method and confirm that the molecular weight and polydispersity of the precursor RAFT polymer are not affected by the treatment.The facile, one pot synthesis combines the reactions of trithiocarbonate aminolysis and Michael addition of a thiol to an α, β‐unsaturated ester to transform the labile, colored thiocarbonylthio moiety into a stable, colorless thioether.imageThe facile, one pot synthesis combines the reactions of trithiocarbonate aminolysis and Michael addition of a thiol to an α, β‐unsaturated ester to transform the labile, colored thiocarbonylthio moiety into a stable, colorless thioether.

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“…Sortase Converts AAEKs to Reactive Olefin IntermediatesWe hypothesized that the ␤-carbon of AAEK1 or AAEK2 may be linked via Michael-type addition by the sortase thiol to an olefin intermediate generated by amine elimination (42,43). If so, addition of exogenous thiol would be expected to "capture" the olefin intermediate, thereby preventing the modification of (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of Inhibitors by Sortase Triggers Irreversible Modification of the Active Site

Maresso

Kern

et al. 2007

Journal of Biological Chemistry

101

106

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Sortases anchor surface proteins to the cell wall of Gram-positive pathogens through recognition of specific motif sequences. Loss of sortase leads to large reductions in virulence, which identifies sortase as a target for the development of antibacterials. By screening 135,625 small molecules for inhibition, we report here that aryl (␤-amino)ethyl ketones inhibit sortase enzymes from staphylococci and bacilli. Inhibition of sortases occurs through an irreversible, covalent modification of their active site cysteine. Sortases specifically activate this class of molecules via ␤-elimination, generating a reactive olefin intermediate that covalently modifies the cysteine thiol. Analysis of the three-dimensional structure of Bacillus anthracis sortase B with and without inhibitor provides insights into the mechanism of inhibition and reveals binding pockets that can be exploited for drug discovery.The emergence of bacterial strains resistant to antibiotic therapy is a major public health threat (1). Of particular concern is Staphylococcus aureus, because this Gram-positive pathogen is the leading cause of infections in the bloodstream, lower respiratory tract, skin, and soft tissue in the United States (2). S. aureus strains exhibiting resistance against multiple antibiotics, such as methicillin-resistant S. aureus, are isolated in 30 -60% of community and Ͼ80% of hospital infections with this pathogen (3). Vancomycin or other glycopeptides are considered last-resort therapies for methicillin-resistant S. aureus; however, S. aureus strains with intermediate or full resistance to vancomycin can cause infections for which antimicrobial treatment may no longer be effective (4).Surface proteins of Gram-positive bacteria play important roles during pathogenesis (5). Sortases anchor these polypeptides to the bacterial cell wall envelope (6). For example, S. aureus sortase A recognizes proteins destined for the cell surface via an LPXTG motif in their C-terminal sorting signal (7). Following cleavage between the threonine and the glycine residues, an acyl-enzyme intermediate captures cleaved substrate at the active site thiol of sortase (8). Nucleophilic attack of the amino group of the peptidoglycan precursor lipid II (at the thioester intermediate resolves the acyl enzyme and forms an amide bond between the C-terminal threonine of surface protein and pentaglycine crossbridges (9). Lipid II-linked polypeptide is subsequently incorporated into the cell wall envelope of staphylococci (10). The final product of this pathway, protein linked to cell wall pentaglycine cross-bridges, is displayed on the bacterial surface and enables interactions between the pathogen and tissues of its host.Surface protein anchoring to the cell wall envelope is thought to be an essential strategy for bacterial survival during infection, because mutants lacking genes for one or more sortase enzymes are attenuated in virulence (11). Inhibition of sortases by small molecules may therefore function as a therapeutic strategy for bacterial infections. ...

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Michael Addition of Amines and Thiols to Dehydroalanine Amides: A Remarkable Rate Acceleration in Water

Cited by 65 publications

References 15 publications

3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: aza-Michael addition reactions and the preparation of poly-HOPO chelators

3,2-Hydroxypyridinone (3,2-HOPO) vinyl sulfonamide and acrylamide linkers: aza-Michael addition reactions and the preparation of poly-HOPO chelators

Facile and Efficient One‐Pot Transformation of RAFT Polymer End Groups via a Mild Aminolysis/Michael Addition Sequence

Activation of Inhibitors by Sortase Triggers Irreversible Modification of the Active Site

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