Syntheses of D- and L-cyclopentenone derivatives using ring-closing metathesis: versatile intermediates for the synthesis of D- and L-carbocyclic nucleosides.

Neplanocin A (1)1 and aristeromycin (2)2 are representatives of naturally occurring carbocyclic nucleosides, which exhibit interesting biological activity3 (Figure 1). These compounds act as potent inhibitors of S-adenosylhomocysteine (SAH) hydrolase, which catalyzes the hydrolysis of S-adenosylhomocysteine into adenosine and homocysteine.4 Inhibition of the SAH hydrolase accumulates S-adenosylhomocysteine in the cell, which in turn inhibits S-adenosylmethionine (SAM) transferase, resulting in the inhibition of viral mRNA capping.5 Thus, SAH hydrolase inhibitors such as neplanocin A and aristeromycin have received great attention in the development of broad spectrum antiviral agents. Although neplanocin A and aristeromycin act as good inhibitors of SAH hydrolase, they were too cytotoxic to be clinically useful agents.6 Thus, in the search of less toxic and more potent inhibitors of SAH hydrolase than these compounds, many D-carbocyclic analogues have been synthesized and evaluated for SAH hydrolase inhibitory activity. As a result, compounds 37 and 48 have been discovered as potent SAH hydrolase inhibitors, but additional efforts should be still made to find clinically useful SAH hydrolase inhibitor. On the other hand, since the discovery of (-)-3TC (lamivudine)9 as a potent anti-HIV and anti-HBV agent, nucleoside chemists turned their attention to the development of L-nucleosides. Several L-nucleosides10 were found to be less cytotoxic than the corresponding Dnucleosides while maintaining more potent antiviral activity such as (-)-3TC. Recently, on the basis of these findings, L-carbocyclic nucleosides11 such as L-aristeromycin and L-carbovir analogues have been synthesized to search for less toxic and more potent antiviral agents than the counterpart D-nucleosides. Although most of the synthesized nucleosides did not exhibit significant antiviral activities, systematic structure-activity relationship study of L-carbocyclic nucleosides should be continued to find novel antiviral agents. Since carbocyclic nucleosides 1-4 could be synthesized from the same intermediate (-)-512 as shown in Figure 1, a short and efficient synthesis of the key intermediate (-)-5 is highly demanded for the thorough structureactivity relationship study of these classes of carbocyclic † College of Pharmacy, Ewha Womans University. ‡ Division of Chemistry and Molecular Engineering, Seoul National University. § College of Pharmacy, Seoul National University. | College of Pharmacy, Sungkyunkwan University. 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