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1.
Bioorg Med Chem Lett ; 28(16): 2697-2700, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29657102

ABSTRACT

ß-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of ß-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of ß-amino difluoromethyl ketones provided the most potent compound across these two series.


Subject(s)
GABA-B Receptor Agonists/pharmacology , Ketones/pharmacology , Propylamines/pharmacology , Binding Sites , GABA-B Receptor Agonists/chemical synthesis , GABA-B Receptor Agonists/chemistry , HEK293 Cells , Humans , Ketones/chemical synthesis , Ketones/chemistry , Molecular Docking Simulation , Propylamines/chemical synthesis , Propylamines/chemistry , Receptors, GABA-B/chemistry , Stereoisomerism , Structure-Activity Relationship
2.
Tetrahedron Lett ; 58(5): 396-400, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28943667

ABSTRACT

Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the "CF2D" group were routinely observed. This strategy is mild and versatile and it can be applied to both ketones and sulfones without additional concerns of over- or under-fluorination. Additional examples address issues of over-deuteration when compounds with other acidic protons are subjected to the reaction conditions. This process not only demonstrates a new method to install a "CF2D" group but also extends the scope of trifluoroacetate release to sulfones.

3.
Tetrahedron Lett ; 57(17): 1906-1908, 2016 Apr 27.
Article in English | MEDLINE | ID: mdl-27182091

ABSTRACT

Pentafluoro-gem-diols are substrates that enable the synthesis of valuable difluoromethylene-containing organic molecules through the release of trifluoroacetate. Currently, only one synthetic strategy is available to assemble these important precursors. Herein, two new synthetic strategies to a complex pentafluoro-gem-diol are compared to the existing route, and an improved synthetic route has completed. Moreover, the first synthesis of a CF2Br-glucopyranose was finished by a tandem trifluoroacetate-release halogenation/cyclization protocol.

4.
J Org Chem ; 76(21): 9163-8, 2011 Nov 04.
Article in English | MEDLINE | ID: mdl-21995668

ABSTRACT

Three series of α-halo-α,α-difluoromethyl ketones are prepared from highly α-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated α,α-difluoroenolate with an electrophilic chlorine, bromine, or iodine source. The products are typically isolated in good yields, even in the case of sensitive, α-iodo-α,α-difluoromethyl ketones. Also, we demonstrate that an α-iodo-α,α-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon-carbon bond.


Subject(s)
Ketones/chemical synthesis , Trifluoroacetic Acid/chemical synthesis , Halogenation , Ketones/chemistry , Molecular Structure , Stereoisomerism , Trifluoroacetic Acid/chemistry
5.
J Org Chem ; 76(10): 3676-83, 2011 May 20.
Article in English | MEDLINE | ID: mdl-21491928

ABSTRACT

An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (-)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of (19)F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (-)-eburnamonine with significant cytotoxicity (LC(50) = 14.12 µM) in drug-resistant MDA-MB-231 breast cancer cells.


Subject(s)
Diterpenes/chemistry , Ketones/chemistry , Methane/analogs & derivatives , Trifluoroacetic Acid/chemistry , Vinca Alkaloids/chemistry , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Methane/chemistry , Vinca Alkaloids/chemical synthesis , Vinca Alkaloids/pharmacology
6.
J Org Chem ; 74(16): 6083-91, 2009 Aug 21.
Article in English | MEDLINE | ID: mdl-19606883

ABSTRACT

Synthesis of plakortethers F and G has been performed by taking advantage of the symmetry in the structure. The structures of the prepared compounds have been confirmed by COSY, 1D NOE, and chemical transformation studies. The synthetic plakortether F was found to match the natural product by all physical data. The synthetic plakortether G exhibited several disagreements in (13)C NMR data with the reported values. However, on the basis of an extremely close match in appearance of its (1)H NMR spectrum to the obtained (1)H NMR spectrum of the natural product, as well as matching optical rotations, the two compounds are believed to be identical.


Subject(s)
Furans/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Furans/chemistry , Magnetic Resonance Spectroscopy
7.
Tetrahedron Lett ; 50(17): 1954-1957, 2009 Apr 29.
Article in English | MEDLINE | ID: mdl-20160855

ABSTRACT

Selectivity of six- vs. five- membered ring formation in C-H insertion on alkylsulfonyl diazoacetates is sensitive to the substrate structure and catalyst used.

8.
Org Lett ; 9(1): 61-3, 2007 Jan 04.
Article in English | MEDLINE | ID: mdl-17192085

ABSTRACT

[reaction: see text] Carbethoxy diazosulfones and sulfonates, easily available from corresponding sulfones and sulfonates, undergo C-H insertion with preferential formation of six membered cyclic sulfones and sulfonates.

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