Synthesis of Carbocyclic 2',3'-Dideoxy-2'-C-hydroxymethyl Nucleosides as Potential Inhibitors of HIV

Abstract

The synthesis of the enantiomerically pure carbocyclic 2',3'-dideoxy-2'-C-hydroxymethyl derivatives of adenosine and guanosine is described. trans-(1R,2R)-1,2-Bis(methoxycarbonyl)-4-oxocyclopentane (4) was reacted with the zinc-dibromomethane-titanium tetrachloride mixed reagent to give an exocyclic olefin. Hydroboration followed by oxidation gave the C-2 symmetric hydroxymethyl diester 6. The two ester groups in 6 were differentiated by lactonization to give lactone 7. The lactone 7 was opened with ammonia, and the remaining carboxylic acid group was reduced. Hofmann rearrangement of the amide gave (1R,2R,4R)-2,4-bis(acetoxymethyl)-1-[(tert-butoxycarbonyl)amino]-cyclopentane (9), which after deprotection was converted to the adenosine derivative 12 and the guanosine derivative 15. Compounds 12 and 15 were evaluated for activity against human immunodeficiency virus(HIV)