Synthesis of Polyalkylphenyl Prop-2-ynoates and Their Flash Vacuum Pyrolysis to Polyalkylcyclohepta[b]furan-2(2H)-ones

Nagel, Matthias; Hansen, Hans‐Jürǵen

doi:10.1002/(sici)1522-2675(20000510)83:5<1022::aid-hlca1022>3.0.co;2-y

Cited by 17 publications

(11 citation statements)

References 24 publications

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“…Chloroformates, where not commercially available, were readily obtained from the reaction of a desired alcohol with phosgene in the presence of base (12). N-Hydroxycarbamates could be prepared from the corresponding chloroformates by the method of Defoin et al (13).…”

Section: Methodsmentioning

confidence: 99%

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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The class C serine β-lactamase of Enterobacter cloacae P99 is irreversibly inhibited by Oaryloxycarbonyl hydroxamates. A series of these new inhibitors has been prepared to investigate the kinetics and mechanism of the inactivation reaction. A pH-rate profile for the reaction indicated that the reactive form of the inhibitor is neutral rather than anionic. The reaction rate is enhanced by electron-withdrawing aryloxy substituents and by hydrophobic substitution on both aryloxy and hydroxamate groups. Kinetics studies show that the rates of loss of the two possible leaving groups, aryloxide and hydroxamate are essentially the same as the rate of enzyme inactivation. Nucleophilic trapping experiments prove, however, that the aryloxide is the first to leave. It is likely, therefore, that the rate-determining step of inactivation is the initial acylation reaction, most likely of the active site serine, yielding a hydroxamoyl-enzyme intermediate. This then partitions between hydrolysis and aminolysis by Lys 315, the latter to form an inactive, cross-linked active site. A previously described crystal structure of the inactivated enzyme shows a carbamate cross-link of Ser 64 and Lys 315. Structure-activity studies of the reported compounds suggest that they do not react at the enzyme active site in the same way as normal substrates. In particular, it appears that the initial acylation by these compounds does not involve the oxyanion hole, an unprecedented departure from known and presumed reactivity. Molecular modeling suggests that an alternative oxyanion hole may have been recruited, consisting of the side chain functional groups of Tyr 150 and Lys 315. Such an alternative mode of reaction may lead to the design of novel inhibitors.For decades now, β-lactams have been one of our most effective weapons against bacterial infections (1). These drugs, although still the first line of attack in many clinical situations, have been compromised to a considerable degree by bacterial resistance to them (2). Among various sources of resistance that have arisen in bacteria, the most generally troublesome is the production of β-lactamases. These enzymes very effectively catalyze the hydrolysis and thus destruction of β-lactams before they can reach their cellular targets (3).The threat posed by β-lactamases to the efficacy of β-lactam antibiotics has been tackled by pharmaceutical companies in several ways. One approach that has been quite successful to date is that of including a β-lactamase inhibitor with a β-lactam antibiotic in combination therapies. For many years now, such combinations, using the now-classical β-lactamase inhibitors clavulanic acid, sulbactam and tazobactam, have been used to advantage (4). Since these inhibitors are themselves β-lactams, however, it is perhaps not surprising to find that certain β-lactamase mutants are capable of hydrolyzing them quite effectively. Such mutants have †

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Section: Methodsmentioning

confidence: 99%

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Pelto

Pratt

2008

Biochemistry

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“…Phenyl Propiolate (56). Compound 56 43 (278 mg, 64%) (R f = 0.9 in 1:4 v/v diethyl ether/hexane) was prepared using General Procedure A and isolated as clear, colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.32 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 2.99 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 151.1, 149.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Compound 56 (278 mg, 64%) ( R f = 0.9 in 1:4 v/v diethyl ether/hexane) was prepared using General Procedure A and isolated as clear, colorless oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.32 (t, J = 7.7 Hz, 2H), 7.19 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 2H), 2.99 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 151.1, 149.9, 129.8, 126.7, 121.4, 76.9, 74.4; IR ν max (KBr): 3444, 3278, 3065, 2934, 2857, 2386, 2126, 1947, 1854, 1733, 1649, 1591, 1492, 1456, 1416, 1289, 1202, 1106, 1072, 1024, 1006, 929 cm –1 ; MS (ESI, +ve) m / z : 169 [(M + Na) + , 100%], 147 [(M + H) + , 40]; HRMS (ESI) m / z : [M + Na] + calcd for C 9 H 6 O 2 Na, 169.0265; found, 169.0262.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…Compound 92 43 (260 mg, 96%) (R f = 0.5 in 1:4 v/v diethyl ether/hexane) was prepared using General Procedure B and isolated as a colorless, crystalline solid, mp 52−53 °C (lit. 43 mp 51−53 °C). 1 H NMR (400 MHz, CDCl 3 ): δ 7.90−7.75 (complex m, 3H), 7.64 (d,J = 2.3 Hz,1H),2H), 7.28 (dd, J = 8.9 and 2.3 Hz, 1H), 3.10 (s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 151.…”

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confidence: 99%

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Gold(I)-Catalyzed Intramolecular Hydroarylation of Phenol-Derived Propiolates and Certain Related Ethers as a Route to Selectively Functionalized Coumarins and 2H-Chromenes

Cervi

Chai

et al. 2020

J. Org. Chem.

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Methods are reported for the efficient assembly of a series of phenol-derived propiolates, including the parent system 56, and their Au(I)-catalyzed cyclization (intramolecular hydroarylation) to give the corresponding coumarins (e.g., 1). Simple syntheses of natural products such as ayapin (144) and scoparone (145) have been realized by such means, and the first of these subject to single-crystal X-ray analysis. A related process is described for the conversion of propargyl ethers such as 156 into the isomeric 2H-chromene precocene I (159), a naturally occurring inhibitor of juvenile hormone biosynthesis.

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“…However, acetylenic ketones, aldehydes and alkyl propiolates and can be rather difficult to functionalize. 15 Most importantly, these substrates, particularly in the terminal alkyne form required for CuAAC, are too reactive as Michael acceptors 16 to be bioorthogonal. We regarded propiolamides as having a good combination of synthetic accessibility, electronic activation of the CuAAC process, and attenuated Michael reactivity.…”

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confidence: 99%

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

et al. 2013

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Copper-catalyzed azide–alkyne cycloaddition (CuAAC) has found numerous applications in a variety of fields. We report here only modest differences in the reactivity of various classes of terminal alkynes under typical bioconjugative and preparative organic conditions. Propargyl compounds represent an excellent combination of azide reactivity, ease of installation, and cost. Electronically activated propiolamides are slightly more reactive, at the expense of increased propensity for Michael addition. Certain alkynes, including tertiary propargyl carbamates, are not suitable for bioconjugation due to copper-induced fragmentation. A fluorogenic probe based on such reactivity is available in one step from rhodamine 110 and can be useful for optimization of CuAAC conditions.

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Synthesis of Polyalkylphenyl Prop-2-ynoates and Their Flash Vacuum Pyrolysis to Polyalkylcyclohepta[b]furan-2(2H)-ones

Cited by 17 publications

References 24 publications

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Kinetics and Mechanism of Inhibition of a Serine β-Lactamase by O-Aryloxycarbonyl Hydroxamates

Gold(I)-Catalyzed Intramolecular Hydroarylation of Phenol-Derived Propiolates and Certain Related Ethers as a Route to Selectively Functionalized Coumarins and 2H-Chromenes

Relative Performance of Alkynes in Copper-Catalyzed Azide–Alkyne Cycloaddition

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