Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation
Laboratory of Medicinal Chemistry, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.Bioorganic & medicinal chemistry (Impact Factor: 2.79). 07/2011; 19(13):3945-55. DOI: 10.1016/j.bmc.2011.05.026
Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, γ-lactonization, a chemoselective reduction of ester in the presence of γ-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti-AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L-2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L-nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity.
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ABSTRACT: Reported herein is a novel and versatile strategy for the stereoselective synthesis of unnatural β-l-arabinofuranosyl nucleoside analogues from acyclic N,OTMS-acetals bearing pyrimidine and purine bases. These unusual acetals undergo a C1' to C4' cyclization where the OTMS of the acetal serves as the nucleophile to generate 2'-oxynucleosides with complete retention of configuration at the C1' acetal center. N,OTMS-acetals are obtained diastereoselectively from additions of silylated nucleobases onto acyclic polyalkoxyaldehydes in the presence of MgBr(2)·OEt(2). The strategy reported is addressing important synthetic challenges by providing stereoselective access to unnatural l-nucleosides starting from easily accessible pools of d-sugars and, as importantly, by allowing the formation of the sterically challenging 1',2'-cis nucleosides. A wide variety of nucleoside analogues were synthesized in 7-8 steps from easily accessible d-xylose.The Journal of Organic Chemistry 08/2012; 77(17):7176-86. DOI:10.1021/jo3012754 · 4.72 Impact Factor
Article: Epihalohydrins in Organic Synthesis[Show abstract] [Hide abstract]
ABSTRACT: Unsymmetrical substitution of the epoxide moiety in epihalohydrins allows the introduction of chirality, making these molecules valuable substrates in enantioselective synthesis as well. As the concept of chirality has become an important issue and challenge in organic and medicinal chemistry, chiral epihalohydrins provide a convenient entry into a wide range of enantiomerically pure target molecules, including complex natural products. The hydrolytic kinetic resolution of terminal oxiranes has been reported for the first time using a Cosalen complex. A major and characteristic property of epihalohydrins is their high reactivity toward a wide variety of nucleophilic reagents, an effect undoubtedly resulting from the presence of three electrophilic carbon centers and the strain associated with the three-membered ring system.Chemical Reviews 12/2012; 113(3). DOI:10.1021/cr3003455 · 46.57 Impact Factor
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ABSTRACT: This chapter focuses on the asymmetric chemical synthesis of carbocyclic analogues of nucleosides, especially on five-membered ring derivatives, even if the preparation of analogues based on other ring sizes is summarized. Although the key synthetic methods developed before 1998 are described, the work reported since the last review on the topic is highlighted. Current methods used for the introduction of the heterocyclic base on the carbasugar, including unusual or C-linked bases, are reported first. The asymmetric synthesis of cyclopentyl carbocyclic analogues of nucleosides is reviewed second. From methods using a resolved cyclopentene building block as the starting material to catalytic enantioselective syntheses, various leading strategies are reported. Finally, the synthesis of fluorinated, cyclohexylic, cyclobutylic, and cyclopropylic carbanucleosides is summarized. Many examples of palladium-catalyzed introduction of nucleobases to functionalized cyclopentenes are described in this chapter.
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