Substrate-Dependent Dihydroxylation of Substituted Cyclopentenes:  Toward the Syntheses of Carbocyclic Sinefungin and Noraristeromycin

Abstract

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...

The Nitrosocarbonyl Hetero‐Diels–Alder Reaction as a Useful Tool for Organic Syntheses

“…The Miller research group has published a number of reports regarding the use of nitrosocarbonyl HDA reactions to construct carbocyclic nucleoside analogues. [66,[138][139][140][141][142][143] Enantiomerically pure acetate (À)-85, [105] obtained from the kinetic enzymatic resolution process described in Section 6.2, was used to synthesize carbocyclic uracil polyoxin C (129) and its epimer through the intermediate 128 (Scheme 24). [140,144] The opposite enantiomer of acetate (À)-85 was used to synthesize the carbocyclic fragment of nucleoside Q.…”

Enantioselective syntheses of carbocyclic nucleosides 5′-homocarbovir, epi-4′-homocarbovir, and their cyclopropylamine analogs using facially selective Pd-mediated allylations

“…Our research group's continued interest in the syntheses of diverse carbocyclic nucleosides10, 11 has led to the development of a reliable method for the synthesis of cyclopentenol (−)- 7 12. We recently reported the Cp 2 TiCl-catalyzed reduction of Boc cycloadduct (±)- 6 13.…”

Hetero‐Diels‐Alder‐Reaktionen von Nitrosocarbonylverbindungen als nützliches Verfahren in der organischen Synthese

“…Die Arbeitsgruppe von Miller hat mehrere Beiträge zum Aufbau carbocyclischer Nukleosidanaloga unter Verwendung von Nitrosocarbonyl-HDA-Reaktionen publiziert. [66,[138][139][140][141][142][143] Das enantiomerenreine Acetat (À)-85, [105] das durch die in Abschnitt 6.2 beschriebene kinetische enzymatische Racematspaltung erhalten worden war, wurde zur Synthese des carbocyclischen Uracil Polyoxins C (129) und dessen Epimers über das Intermediat 128 verwendet (Schema 24). [140,144] Das Enantiomer des Acetats (À)-85 wurde für die Synthese des carbocyclischen Fragments des Nukleosids Q eingesetzt.…”