(±)-N9-(2-(hydroxymethyl)spiro[3.3]hept-6-yl)adenine. The first biologically active saturated analogue of adenallene with axial dissymmetry

Article abstract of DOI:10.1021/jo00125a011

Synthesis of the title analogue 2 is described. Fecht's acid (3) was esterified with N,N-dimethylformamide dimethyl acetal to give monoester 4 along with diester 5. Compound 4 was transformed to ester amide 6 by the reaction with isobutyl chloroformate and triethylamine followed by ammonolysis. Hoffman rearrangement of 6 effected by lead tetraacetate in tert-butyl alcohol led to the N-tert-butoxycarbonyl ester 7. The latter was reduced with Ca(BH₄)₂ to give the protected amino alcohol 8. Removal of the N-tert-butoxycarbonyl group with 2 M HCl in methanol afforded the hydrochloride of amino alcohol 2. Reaction of 9 with 5-amino-4,6-dichloropyrimidine and triethylamine gave the pyrimidine derivative 10 which, in turn, was cyclized to 6-chloropurine 11a. Ammonolysis of the latter intermediate afforded the title analogue 2. The ¹H NMR spectrnm of Fecht's acid (3) in CD₃COCD₃ showed that four methylene protons were magnetically nonequivalent (two quartets) whereas the other four were equivalent, forming a single doublet. Compound 2 inhibited the replication of human cytomegalovirus (IC₅₀ 32 μM) and growth of murine leukemia L1210 cells (IC₅₀ 30 μM). Zone assays showed inhibition of the following tumor cultures at 0.5 mg/disk: murine leukemia P388, mouse tumors PO3, C38, and M17/Adr as well as human tumors MCF-7 and CX-1.