Synthesis of Novel Conformationally Locked Carbocyclic Nucleosides Derived from 5,5- and 6,6-Bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol

Abstract

(1R*,2R*,3R*,4S*)-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) viacis-diol8, cyclic sulfate10, and azide12. (1R*,2R*,3S*,4S*)-3-Amino-6,6-bis(hydroxymethyl)bicyclo[2.2.1]-heptan-2-ol (18) and (1R*,2S*,3S*,4S*)-3-amino-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (19) were obtained by addition of chromyl azide to double bond of7, chromatographic separation, debenzoylation and hydrogenation of resulting azides14and16. The amines13,18, and19were used to build (1R*,2R*,3R*,4S*)- (21a), (1R*,2R*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-6,6-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (21b), and (1R*,2S*,3S*,4S*)-3-(6-chloro-9H-purin-9-yl)-5,5-bis(hydroxymethyl)bicyclo[2.2.1]heptan-2-ol (21c), respectively. Ammonolysis of these compounds led to 6-amino-9H-purine derivatives22a-22c. 6-(Dimethylamino)-9H-purine analogues23a-23cand 6-(cyclopropylamino)-9H-purine analogues24a-24cwere prepared by aminolysis of21a-21c. Reaction of amines13,18, and19with ethylN-((2E)-3-ethoxymethacryloyl)carbamate afforded thymine derivatives28a-28c.