9-[1-(Phosphonomethoxycyclopropyl)methyl]guanine (PMCG, 1), representative of a novel class of phosphonate nucleosides, blocks HBV replication with excellent potency (EC(50) = 0.5 microM) in a primary culture of HepG2 2.2.15 cells. It exhibits no significant cytotoxicity in several human cell lines up to 1.0 mM. It does not inhibit replication of human immunodeficiency virus (HIV-1) or herpes simplex virus (HSV-1) at 30 microM. Many purine base analogues of 1 also exhibit inhibitory activity against HBV, but at 30 microM, pyrimidine analogues do not. 1 is 4 times more potent than 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), which was used as a positive control (EC(50) = 2.0 microM). The characteristic cyclopropyl moiety at the 2'-position of 1 was prepared by titanium-mediated Kulinkovich cyclopropanation. 1 was modified to give the orally available drug candidate, PMCDG Dipivoxil (2). Compound 2 exhibited excellent efficacy when administered at 5 mg per kg per day in a study with woodchucks infected with woodchuck hepatitis B virus (WHBV). Drug candidate 2 has successfully completed phase I clinical trials and is currently undergoing phase II clinical studies for evaluation of efficacy.
The azaallyl cation-mediated [4 + 3] cycloaddition with spiro[2.4]hepta-4,6-diene by the procedure of Schmid provides the tricyclic cycloadducts of general type 3. The keto bridge of the cycloadducts 17c, 21, and 22 has been cleaved by PhI(OAc)2-l2 (Suárez cleavage), which involves ^-fragmentation of an alkoxy radical, to furnish iodo lactones 19,32, and 30a,b, respectively. Subsequent oxidation of these alkyl iodides has been investigated to develop a new synthetic route for bridgehead olefins (i.e., 33) of medium-sized carbocycles.
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