Synthesis of Novel Conformationally Locked Carbocyclic Nucleosides Derived from 5,5- and 6,6-Bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol
(1 R *,2 R *,3 R *,4 S *)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol ( 13 ) was prepared from (bicyclo[2.2.1]hept-5-ene-2,2-diyl)dimethyl dibenzoate ( 7 ) via cis -diol 8 , cyclic sulfate 10 , and azide 12 . (1 R *,2 R *,3 S *,4 S *)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]-heptan-2-ol ( 18 ) and (1 R *,2 S *,3 S *,4 S *)-3-amino-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol ( 19 ) were obtained by addition of chromyl azide to double bond of 7 , chromatographic separation, debenzoylation and hydrogenation of resulting azides 14 and 16 . The amines 13 , 18 , and 19 were used to build (1 R *,2 R *,3 R *,4 S *)- ( 21a ), (1 R *,2 R *,3 S *,4 S *)-3-(6-chloro-9 H -purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol ( 21b ), and (1 R *,2 S *,3 S *,4 S *)-3-(6-chloro-9 H -purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol ( 21c ), respectively. Ammonolysis of these compounds led to 6-amino-9 H -purine derivatives 22a - 22c . 6-(Dimethylamino)-9 H -purine analogues 23a - 23c and 6-(cyclopropylamino)-9 H -purine analogues 24a - 24c were prepared by aminolysis of 21a - 21c . Reaction of amines 13 , 18 , and 19 with ethyl N -((2 E )-3-ethoxymethacryloyl)carbamate afforded thymine derivatives 28a - 28c .