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 β-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 H_4′). Significant differences of the chemical shifts of the cyclopropane C_3(3’) carbons and coupling constants ³J_P,C2(2’) or ³J_P,C3(3’) selective for the Z- or E-isomers were also noted. Phosphonates 6a, 7a, 6b, and 7b are devoid of significant antiviral activity.

Keywords:

• Methylenecyclopropane phosphonates
• Nucleotide analogues
• michaelis-arbuzov reaction
• Mitsunobu alkylation
• Antivirals

We thank A. Ambrose for preparation of the starting material 8 and L. M. Hrihorczuk from the Central Instrumentation Facility (D.M. Coleman, Director), Department of Chemistry, Wayne State University, for mass spectra. The work described herein was supported by grant RO1-CA32779 from the National Cancer Institute.

Notes

^a CDCl₃.

^b AB system.

^c D₂O, sodium salt.

^a CDCl₃.

^b D₂O, sodium salt.