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'-deoxyguanosi ne (12a-15a and 12b-15b) is described. Rhodium-catalyzed reaction of ethyl diazoacetate with methylenecyclopropane 19, obtained from 2-bromo-2-bromome thylcyclopropane 17 via debromination (18), reduction (18), and acetylation (19), gave a mixture of all four isomeric spiropentanes 20a-20d. Hydrolysi s afforded hydroxy carboxylic acids 21a-21d. Acetylation of separated proxi mal + medial-syn isomers 21a + 21b and medial anti + distal isomers 21c + 2 1d furnished acetates 22a + 22b and 22c + 22d. Curtius rearrangement effect ed by diphenylphosphoryl azide in tert-butyl alcohol performed separately w ith mixtures 22a + 22b and 22c + 22d led to BOC-amino spiropentanes 23a + 2 3b and 23c + 23d. After deacetylation all isomers 24a-24d were separated an d deprotected to give aminospiropentane hydrochlorides 25a-25d. Free bases were of limited stability, The heterocyclic moieties were introduced into i ndividual isomers 25a-25d via 6-chloropurine derivatives 26a-26d or 30a-30d . Ammonolysis of 26a-26d furnished the adenine isomeric series 12a-15a, whe reas guanine derivatives 12b-15b were obtained by hydrolysis of 30a-30d wit h formic acid. The isomeric assignments followed fi om IR spectra of BOC-am inospiropentanes 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 inhibito rs 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 phosphoralani nate 34 was an effective;re inhibitor of HCMV replication in vitro. It tvas also active against herpes simplex virus type I. (HSV-1), varicella tester virus (VZV), human immunodeficiency virus (HN-I), hepatitis B virus (HBV), and EBV with a varying degree of cytotoxicity.