Synthesis Of 2,2,3-Tris(Hydroxymethyl)Methylenecyclopropane Analogues Of Nucleosides

Synthesis of 2,2,3-tris(hydroxymethyl)methylenecyclopropane analogues 16a, 16b, 17a, and 17b is described. Diethyl ester of Feist's acid 18b was hydroxymethylated via carbanion formation using formaldehyde under simultaneous isomerization to cis diester to give intermediate 19. Reduction followed by acetylation gave triacetate 22. Addition of bromine afforded reagent 23, which was used for alkylation-elimination of adenine and 2-amino-6-chloropurine to provide Z,E-isomeric mixtures of 24a and 24b. Deacetylation and separation furnished the Z-isomers 16a, 16c and E-isomers 17a, 17c. Hydrolytic dechlorination of 16c and 17c gave guanine analogues 16b and 17b. None of the analogues exhibited a significant antiviral activity. Adenosine deaminase is refractory toward adenine analogues 16a and 17a.

Keywords:

• Tris(hydroxymethyl)methylenecyclopropanes
• alkylation-elimination
• nucleoside analogues
• antivirals

We thank L. M. Hrihorczuk from the Central Instrumentation Facility, Department of Chemistry, Wayne State University (D. M. Coleman, Director) for mass spectra. The work described herein was supported by U.S. Public Health Service grants RO1-CA32779 from the National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Notes

^a CD₃SOCD₃ as solvent. For numbering of signals see Table 2. Values for 3a, 4a, 3b, and 4b were taken from Ref.^[ [3] ^]