The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2’-O positions of the viral RNA cap (GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA), using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.
Acetophenone can be selectively hydrogenated in isopentane solution to a 70% yield of cyclo-hexylmethylcarbinol1 but the conditions must be controlled carefully.
L-Selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active α-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting α,α-dimethyl-β-hydroxy ketones are inherent to a variety of biologically active natural products.Asymmetric aldol reactions leading to the stereocontrolled generation of β-hydroxy carbonyl derivatives are among the most important reactions in organic synthesis. 1 Consequently, a number of effective methodologies have been developed over the years. In a series of elegant studies, Stork and co-workers have shown that lithium-ammonia reduction of enones leads to stoichiometric generation of enolates. 2 Since then, reductive aldol reactions in which conjugate reduction followed by aldol reaction of the resulting enolates led to the development of a wide variety of methodologies for the synthesis of β-hydroxy carbonyl derivatives. 3 In recent years, impressive progress has been made in both catalytic 4 and enantioselective 5 reductive aldol processes. In the context of our enantioselective synthesis of (+)-peloruside A, we recently carried out a L-selectride mediated reductive aldol coupling of enone 1 and aldehyde 2 to provide aldol product 3 and its diastereomer as a 4:1 mixture in 92% yield at −78 °C for 1 h. 6,7 The major aldolate 3 was subsequently converted to peloruside A. The overall process is quite practical and offers significant improvement over the direct aldol reaction of related ketone enolate and aldehyde reported recently. 8 Of particular importance, these α,α-dimethyl β-hydroxy carbonyl derivatives are structural features of numerous bioactive natural products like epothilones, 9 mycalamide A 10 and peloruside A. 6 Encouraged by the reasonable diastereoselectivity of the L-selectride mediated reductive aldol process, we have now examined the stereochemical outcome with a variety of chiral and achiral enones and aldehydes bearing an α-β-alkoxy stereocenter. Herein, we report the results of our investigations. Excellent levels of diastereoselectivity are attainable when the enolate from L-selectride reduction is reacted with aldehydes containing an α-chiral center.Our preliminary investigations focused on reactions with model 5 and optically active isopropylidene glyceraldehyde 4. As shown in Scheme 1, enone 5 was prepared in a two stepakghosh@purdue.edu . Supporting Information Available: Experimental procedures and 1 H-and 13 C-NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 September 22. (1) reaction of isopropenyl magnesium bromide in diethyl ether followed by Dess-Martin oxidation 11 of the resulting diastereomeric alcohols to enone 5 in 63% yield in 2-steps. Enone 5 was treated with 1·1 equiv of L-selectride at −78 °C for 10 min to form the corresponding lithium enolate. To the resulting enolate, 2 equiv of isopropylidene-Dglyceraldehyde...
In contrast to the extensive investigation of the elaidinization of oleic acid,2,3 very little work appears to have been done on the similar isomerization of the biologically important linoleic acid.4 Green and Hilditch5 treated linoleic acid with Poutet's reagent for one hour and obtained on the partial oxidation of the resulting product, the iodine number of which had fallen to 137.5, a small quantity of a new sativic acid, m. p. 140-141°, in addition to the known a-and ¡S-sativic acids corresponding to ordinary linoleic acid. Noller and Girvin6 stated that linoleic acid treated with this reagent loses its characteristic ability to form the ligroin-insoluble tetrabromide.As a part of the larger study of the nutritive value of all fatty adds and their isomers, the elaidinization of linoleic acid was reinvestigated and the following isomers of this acid were prepared and described. Their nutritive value will be reported elsewhere. ExperimentalElaidinization with Nitrogen Oxides.-Ten cc. of pure methyl linoleate7 in a glass-stoppered flask was mixed with 4 cc. of 1:1 nitric acid at 0°; 0.5 g. of finely powdered sodium nitrite was added gradually with rapid shaking. The flask was then immersed momentarily in a boiling water-bath and allowed to stand at room temperature overnight. The dark brown ester layer was extracted with ligroin, which precipitated much tarry material, the extract washed with water, dried over sodium sulfate, and the ligroin evaporated under partial vacuum.The residue was distilled at 150-160°at 3 mm.8 The distillate, a yellowish oil weighing 1 g., was saponified and the fatty acids isolated in the usual manner.
We have developed a practical synthesis of unique nucleoside derivatives via TiCl4 promoted multicomponent reaction of optically active dihydrofuran, ethyl pyruvate/glyoxylate, and a TMS protected nucleobase in a single-pot operation.
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