Spiropentane Mimics of Nucleosides:  Analogues of 2‘-Deoxyadenosine and 2‘-Deoxyguanosine. Synthesis of All Stereoisomers, Isomeric Assignment, and Biological Activity

Synthesis of spirocyclic analogues of 2‘-deoxyadenosine and 2‘-deoxyguanosine (12a−15a and 12b−15b) is described. Rhodium-catalyzed reaction of ethyl diazoacetate with methylenecyclopropane 19, obtained from 2-bromo-2-bromomethylcyclopropane 17 via debromination (16), reduction (18), and acetylation (19), gave a mixture of all four isomeric spiropentanes 20a − 20d. Hydrolysis afforded hydroxy carboxylic acids 21a−21d. Acetylation of separated proximal + medial-syn isomers 21a + 21b and medial anti + distal isomers 21c + 21d furnished acetates 22a + 22b and 22c + 22d. Curtius rearrangement effected by diphenylphosphoryl azide in tert-butyl alcohol performed separately with mixtures 22a + 22b and 22c + 22d led to BOC-amino spiropentanes 23a + 23b and 23c + 23d. After deacetylation all isomers 24a−24d were separated and deprotected to give aminospiropentane hydrochlorides 25a−25d. Free bases were of limited stability. The heterocyclic moieties were introduced into individual isomers 25a−25d via 6-chloropurine derivatives 26a−26d or 30a−30d. Ammonolysis of 26a−26d furnished the adenine isomeric series 12a−15a, whereas guanine derivatives 12b−15b were obtained by hydrolysis of 30a−30d with formic acid. The isomeric assignments followed from IR spectra of BOC-aminospiropentanes 24a−24d and NMR spectra of 12a−15a including NOE and (H,H) COSY. The proximal and medial-syn isomers 12a and 12b were modest inhibitors of human cytomegalovirus (HCMV) and Epstein−Barr virus (EBV) in culture, whereas the medial-anti isomer 12c was a substrate for adenosine deaminase. The distal isomer 15b was an anti-EBV agent. The medial-syn phosphoralaninate 34 was an effective inhibitor of HCMV replication in vitro. It was also active against herpes simplex virus type 1 (HSV-1), varicella zoster virus (VZV), human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), and EBV with a varying degree of cytotoxicity.