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.

Improvements, Variations and Biomedical Applications of the Michaelis–Arbuzov Reaction

“…The synthesis of these compounds is carried out according to Scheme 49 [ 81 ]. The importance of this study is based on the generation of the methylenecyclopropylphosphonate backbone that can also be used in other biomedical applications.…”

Synthesis of Methylene‐ and Alkylidenecyclopropane Derivatives

“…[60] Indeed, this dibromoacetate was converted into the corresponding bromocyclopropyl phosphonate 63 by a Michaelis-Arbuzov reaction with triisopropyl phosphite. Subsequent base-catalyzed b-elimination and deacetylation led to a mixture of the corresponding Z-and E-hydroxymethylcyclopropyl phosphonates 64, which were separated by chromatography.…”