| Carbocyclic nucleosides possess potent biological activities as antiviral and anticancer drugs. A number of methods have been reported for the synthesis of simple carbocyclic nucleosides in which an unsubstituted methylene moiety replaces the ring oxygen of ribose. On the other hand, only a few methods to synthesize the carbocyclic nucleoside analogs incorporating functionality at the methylene carbon (the 6′-position of the carbocyclic nucleosides or the 5-position of cyclopentyl amines) have been reported although none of these offer optically pure compounds without the need for resolution of the enantiomers.; Synthetic methodology to synthesize enantiomerically pure 5-substituted cyclopentyl amine intermediates as versatile synthons for producing 6 ′-substituted carbocyclic nucleoside analogs bearing the 2,3-hydroxyls in ribo-, lyxo-, arabino- or xylo-configurations, as well as the corresponding 2′,3′-dideoxy and 2,3′ -didehydro-2′,3-dideoxy nucleoside analogs was developed. Rearrangement of the bicyclic lactam, 2-azabicyclo [2.2.1]hept-5-en-3-one, upon bromination was utilized to place the leaving group bromide at the apical position. It was found that the electron releasing groups on nitrogen facilitate this rearrangement while the electron withdrawing groups prevent it. The presence of base stable alkyl protecting groups on nitrogen was found to be necessary for dehydrohalogenation reaction. The directing effect of sterically bulky mono-methoxytrityl nitrogen protecting group was utilized to direct the catalytic cis-hydroxylation from the more hindered exo-face of the bicyclic molecule.; The key intermediate (1S, 2S, 3 R, 4R, 5S)-1-(tert-Butyloxycarbonyl)amino-5-bromo-2,3-(dimethylmethylene)dioxy-4-hydroxymethyl cyclopentane was synthesized starting from commercially available enantiomerically pure lactam, (1S)-(+)-2-azabicyclo[2.2.1]hept-5-en-3-one, in 7 steps in an overall yield of 21%. The t-BOC protected nitrogen in compound (1S, 2S, 3R, 4 R, 5S)-1-(tert-Butyloxycarbonyl)amino-5-bromo-2,3-(dimethylmethylene)dioxy-4-hydroxymethyl cyclopentane was found to be very reactive resulting in intramolecular nucleophilic displacement reactions. Complete inactivation of the reactivity of nitrogen was achieved by protection as a phthalimide derivative. This intermediate has been elaborated to produce (1S, 2S, 3R, 4R, 5S)-4-acetoxymethyl-5-fluoro-2,3-(dimethylmethylene)dioxy-1-phthalimido cyclopentane in 60% yield. The overall yield of this compound was 12% starting from the lactam. |
