- Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation
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An extensive range of functionalized aliphatic ketones with good functional-group tolerance has been prepared by a NiI-promoted coupling of either primary or secondary alkyl iodides with NN2 pincer NiII-acyl complexes. The latter were easily accessed from the corresponding NiII-alkyl complexes with stoichiometric CO. This Ni-mediated carbonylative coupling is adaptable to late-stage carbon isotope labeling, as illustrated by the preparation of isotopically labelled pharmaceuticals. Preliminary investigations suggest the intermediacy of carbon-centered radicals.
- Donslund, Aske S.,Pedersen, Simon S.,Gaardbo, Cecilie,Neumann, Karoline T.,Kingston, Lee,Elmore, Charles S.,Skrydstrup, Troels
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supporting information
p. 8099 - 8103
(2020/03/16)
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- Catalytic asymmetric intramolecular homologation of ketones with α-diazoesters: Synthesis of cyclic α-Aryl/Alkyl β-ketoesters
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A catalytic asymmetric intramolecular homologation of simple ketones with α-diazoesters was firstly accomplished with a chiral N,N′-dioxide-Sc(OTf)3 complex. This method provides an efficient access to chiral cyclic α-aryl/alkyl β-ketoesters containing an all-carbon quaternary stereocenter. Under mild conditions, a variety of aryl- and alkyl-substituted ketone groups reacted with α-diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β-ketoesters in high yield and enantiomeric excess.
- Li, Wei,Tan, Fei,Hao, Xiaoyu,Wang, Gang,Tang, Yu,Liu, Xiaohua,Lin, Lili,Feng, Xiaoming
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p. 1608 - 1611
(2015/01/30)
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- D2 ANTAGONISTS, METHODS OF SYNTHESIS AND METHODS OF USE
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Provided are D2 or D3 antagonist compounds and pharmaceutical compositions of formula I and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R1, R2 and R3 are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D2 or D3 receptor from the compounds of the invention.
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Page/Page column 54
(2012/01/06)
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- Synthesis of γ-halogenated ketones via the Ce(IV)-mediated oxidative coupling of cyclobutanols and inorganic halides
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A straightforward method for the synthesis of γ-halo-substituted ketones formed via the CAN-initiated oxidative addition of halides to 1-substituted cyclobutanols has been developed. This method has short reaction times, and provides access to a range of bromo and iodo γ-substituted ketones in good to excellent yields.
- Casey, Brian M.,Eakin, Cynthia A.,Flowers II, Robert A.
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body text
p. 1264 - 1266
(2009/09/05)
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- Irreversible inhibition of the HIV-1 protease: Targeting alkylating agents to the catalytic aspartate groups
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Irreversible inhibition of the HIV-1 protease by agents that specifically alkylate its catalytic aspartate residues is a potentially useful approach for circumventing the evolution of HIV strains that are resistant to protease inhibitors. Five haloperidol- and two FMOC-based epoxides of differing reactivities have been synthesized and tested as irreversible inhibitors of the HIV-1 protease (HIV-1 PR). Of these, two trisubstituted epoxides, a cis-1,2-disubstituted epoxide, a 1,1-disubstituted epoxide, and a monosubstituted epoxide function as irreversible inhibitors, but two trans-1,2-disubstituted epoxides do not. The most effective of the epoxides (6) inactivates HIV-1 PR with K(inact) = 65 μM and V(inact) = 0.009 min-1. 1,2-Epoxy-3-(p-nitrophenoxy)propane (EPNP), a nonspecific inactivating agent for aspartyl proteases, has been used to validate a protocol for establishing the stoichiometry and site of protein alkylation. Mass spectrometric analysis of the inactivated enzyme shows that one molecule of either EPNP or the cyclic 1,2-disubstituted epoxide 6 is covalently bound per HIV-1 PR dimer. Mass spectrometric sequencing of labeled proteolytic peptides shows that both inhibitors are covalently bound to a catalytic aspartate residue. The covalent binding of three α,β-unsaturated ketone derivatives of haloperidol has been similarly examined. Analysis of HIV-1 PR inactivated by these agents establishes that they bind covalently to the two cysteines and the N-terminal amino group but not detectably to the catalytic aspartate residues. The results indicate that aspartate-targeted inactivation of HIV-1 PR depends on (a) matching the reactivity of the alkylating functionality to that of the aspartates, preferably by exploiting the two-aspartate catalytic motif of the protease to activate the alkylating agent, and (b) appropriate positioning of the alkylating functionality within the active site. These requirements are readily met by a monosubstituted, 1,1-disubstituted, or cyclic cis-1,2-disubstituted epoxide but not by trans-1,2-disubstituted epoxides or α,β-unsaturated ketones.
- Yu,Caldera,McPhee,De Voss,Jones,Burlingame,Kuntz,Craik,Ortiz De Montellano
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p. 5846 - 5856
(2007/10/03)
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- Synthesis of Aryl 3-(2-Imidazolyl)propyl Ketones.
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The approach to the title compounds was via lithiation-substitution of N-methyl or N-(triphenylmethyl)imidazole by some iodo ketals. 4-Chloro-4'-halobutyrophenones (halo = F, Cl, Br) were converted by sodium iodide to the corresponding aliphatic iodides which were subsequently ketalized with ethylene glycol to provide the corresponding iodo ketals.Lithiation of either 1-methyl- or 1-(triphenylmethyl)imidazole with n-butyllithium generated the corresponding 2-lithioimidazoles, in situ, which were then reacted with these iodo ketals to form the corresponding C-2 substitute d imidazoles.Dilute aqueous acid hydrolysis released the ketone from the ketal.For N-triphenylmethyl protected imidazoles, the triphenylmethyl group was also hydrolyzed to give triphenylmethanol and 3-(2-imidazolyl)propyl 4-haloaryl ketones.These N-unsubstituted imidazolyl ketones can be alkylated independently with triphenylmethyl chloride to form the corresponding N-triphenylmethyl imidazole derivatives.
- Davis, Frank S.,Huang, Liang-fu,Bauer, Ludwig
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p. 915 - 920
(2007/10/02)
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- N-(isoquinolin-5-ylsulphonyl) azacycloalkanes
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Compounds of formula (I): STR1 wherein R1, R2, U, X, Y, Z, n, m, p and r are as defined in the description, and medicaments containing the same.
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