title: Synthesis of "reversed" methylenecyclopropane analogues of antiviral phosphonates.
abstract: Synthesis of "reversed" methylenecyclopropane analogues of nucleoside phosphonates 6a,7a, 6b, and 7b is described. 1-Bromo-1-bromomethylcyclopropane 8 was converted to the bromocyclopropyl phosphonate 9 by Michaelis-Arbuzov reaction with triisopropyl phosphite. Base-catalyzed beta-elimination and deacetylation gave the key Z- and E-hydroxymethylcyclopropyl phosphonates 10 and 11 separated by chromatography. The Mitsunobu type of alkylation of 10 or 11 with adenine or 2-amino-6-chloropurine afforded phosphonates 12a, 12b, 13a, and 13b. Acid hydrolysis furnished the adenine and guanine analogues 6a, 7a, 6b, and 7b. The E and Z configuration was assigned on the basis of NOE experiments with phosphonates 6b and 7b. All Z- and E-isomers were also distinguished by different chemical shifts of CH2O or CH2N (H4 or H4'). Significant differences of the chemical shifts of the cyclopropane C3(3') carbons and coupling constants 3JP,C2(2') or 3JP,C3(3') selective for the Z- or E-isomers were also noted. Phosphonates 6a, 7a, 6b, and 7b are devoid of significant antiviral activity.
authors.affiliation: Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201-1379, USA.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Li
authors.forename: Jiri
authors.initials: J
authors.lastname: Zemlicka
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes / Q000737:chemistry*; D003641:Deamination; D014645:Herpesvirus 3, Human / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D009705:Nucleosides; D063065:Organophosphonates; C508672:methylenecyclopropane