Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings

Abstract

6-Oxopurine derivatives containing a northern (N) methanocarba modification (i.e., fused cyclopropane and cyclopentane rings in place of the ribose) were synthesized and the adenosine receptor affinity measured. Guanine or hypoxanthine was coupled at the 7-position, or 1,3-dibutylxanthine was coupled at the 9-position. The pseudoribose ring was also substituted at the 5'-position with an N-methyluronamide or with phosphate groups.

Scheme 1

(a) HSCH₂CH₂OH, NaOMe, MeOH, reflux; (b) RuCl₃, NaIO₄, CH₃CN/CHCl₃/H₂O=2:2:3; (c) BOP-Cl, Et₃N, MeNH₂ (2 M/THF), CH₂Cl₂/DMF=1:1; (d) CF₃CO₂H, wet MeOH, 60 °C; (e) (i) 1H-tetrazole, di-t-butyl N,N-diethylphosphoramidite, THF; (ii) mCPBA, CH₂Cl₂; (f) DOWEX 50×8–200, MeOH/H₂O=2:1; (g) (i) 1,1′-carbonyldiimidazole, DMF; (ii) 5% Et₃N/MeOH; (iii) tetrabutylammonium pyrophosphate.

Scheme 2

(a) 2-Amino-6-chloropurine, DIAD, Ph₃P, THF; (b) 2N NaOH, dioxane; (c) Pd black, 10% HCO₂H in MeOH; (d) TFA/MeOH/H₂O; (e) (i) tetrazole, di-t-butyl-N,N-diethylphosphoramidite, THF; (ii) mCPBA, CH₂Cl₂; (f) TFA/MeOH/H₂O (g) (i) 1,1′-carbonyldiimidazole, DMF; (ii) 5% Et₃N/MeOH; (iii) tetrabutylammonium pyrophosphate.

Scheme 3

(a) 1,3-Dibutylxanthine, DEAD, Ph₃P, THF; (b) BCl₃, CH₂Cl₂; (c) Pd black, 10% HCO₂H in MeOH; (d) (i) tetrazole, di-t-butyl-N,N-diethylphosphoramidite, THF; (ii) mCPBA, CH₂Cl₂; (e) DOWEX 50×8–200, MeOH/H₂O=1:1; (f) (i) 1,1′-carbonyldiimidazole, DMF; (ii) 5% Et₃N/MeOH; (iii) tetrabutylammonium pyrophosphate; (g) RuO₂, NaIO₄, K₂CO₃, H₂O/CH₃CN/CHCl₃; (h) CH₃NH₂^• HCl, Et₃N, BOP-Cl; (i) BCl₃/CH₂Cl₂