Racemic cis-4-aminocyclopent-2-en-1-ols were synthesized in three steps utilizing hetero Diels-Alder chemistry. Starting from suitably protected hydroxylamines, oxidization with sodium periodate and trapping with cyclopentadiene afforded cycloadducts (()-5a-d. The N-O bond of the cycloadducts was reduced with Mo(CO) 6 to afford (()-cis-4-aminocyclopent-2-en-1-ols (()-6ad. These compounds, or their corresponding acetates, were kinetically resolved by enzymatic acetylation or hydrolysis, respectively. Enzymatic acetylation of cis-N-(benzylcarbamoyl)-4aminocyclopent-2-enol [(()-6a] with Candida antarctica B lipase and Pseudomonas species lipase gave the corresponding acetate (-)-7a in 90% and 92% ee, respectively, after 40% conversion. Enzymatic hydrolysis of cis-N-acetyl-4-aminocyclopent-2-enol 1-O-acetate (()-7d with electric eel acetylcholine esterase was successful in providing both cis-N-acetyl-4-aminocyclopent-2-enols (+)-6d and (+)-7d in 92% ee (99% ee after a single recrystallization) after 40% conversion. Further synthetic transformations of these resolved synthetic building blocks and derivatives are also reported.

Carbocyclic uracil polyoxin C (+)-2 and its alpha-epimer (-)-3 were synthesized in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (+/-)-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis of enantiopure aminocyclopentenols, a Pd(0)-catalyzed substitution reaction, and a mild reduction of an alpha-nitro ester by TiCl(3)/sodium borohydride. Significantly, this process demonstrates the synthetic utility of the versatile enantiopure aminocyclopentenol building block (-)-4.

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Carbocyclic nucleosides are of considerable interest for the development of new therapeutic agents. A key reaction in the preparation of many such nucleoside analogs is dihydroxylation of appropriately substituted cyclopentenes. While often considered a routine reaction, in this paper we report the dramatic influence of substituents on the facial selectivity of dihydroxylations. The substituted cyclopentene substrates are derived from acylnitroso cycloaddition reactions of cyclopentadiene, followed by N-O reduction and efficient enzymatic resolution. The results are directly utilized in a very efficient asymmetric synthesis of an antiviral carbocyclic nucleoside, noraristeromycin 5. Extensions towards synthesis of carbocyclic sinefungin 7 document the importance of realizing the substituent dependence of the dihydroxylation reaction.Infectious diseases are posing increasingly severe health risks, as evidenced by the recent SARS flu epidemic and the rapid spread of AIDS in developing countries. Accordingly, extensive research has been directed at finding effective therapeutic agents for the treatment of viral (eq 1)The natural carbocyclic nucleosides, neplanocin A 3 and aristeromycin 4 have potent antiviral activities ( Figure 1). 3 Aristeromycin (-)-4 is a carbocyclic analog of adenosine that terminates viral growth by inhibiting S-adenosyl-L-homocysteine (AdoHcy) hydrolase. 4 However, the high cytotoxicity of aristeromycin, presumably caused by the metabolism of 4 to its 5'-phosphates, has greatly hindered its therapeutic application. 5 In the search for a less toxic analog of aristeromycin, Schneller and coworkers found that the 5'-nor compound (±)-5 had improved antiviral activity with no cytotoxicity. 6 Subsequently, the same workers found the (-)-enantiomer of 5 was more active than the (+)-enantiomer. 7 Sinefungin 6 is a natural nucleoside first isolated from Streptomyces griseolus in 1973 and S. incarnatus in 1976. 8 Since its isolation from natural sources, sinefungin has been synthesized by several groups. 9 Preliminary bioassays showed that it inhibited the growth of several fungi 8 and viruses 10 , and that it showed significant antiparasitic 11 activity in vitro. There are two key features of the biological activity profile of sinefungin that stand out, one of which is its antiviral activity due to inhibition of methyltransferase. 12 Chemotaxis, neurosecretions, membrane receptor interactions, DNA modification-restriction, gene expression and cellular differentiation are among the diverse processes that methylation of biomolecules affects. 13 Sinefungin and derivatives have been tested against both vaccinia-and Newcastle disease virus-(guanine-7) methyltransferases. 10 The elucidation of structure-activity-relationships for sinefungin and its derivatives was attempted with these studies. Several features were found to be necessary in order to retain methyltransferase inhibition: (1) the L configuration of the side chain (2) both terminal amino and carboxyl groups as well as a three-carbon lin...

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