Synthesis of 2′,3′-cis-Fused Pyrrolidino-β-D-nucleosides and Their Conformational Analysis by 500 MHz 1H NMR.

Abstract The unique “off-template” stereoselectivity in the intramolecular free radical cyclization of 3-aza-5-hexenyl endocyclic radical has been demonstrated for the first time through the synthesis of 2′,3′- cis-fused pyrrolidino-β-D-nucleosides, 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a, which are not hithertofore available by any known procedures. The 2′-linked chiral carbon (Cc) in 19a, 20a, 21a and 22a has shown 25:1 to 10:1 stereoselectivity depending upon the bulk of its substituent. The 3′-linked chiral carbon (Cc) in 35a, 36a and 37a, on the other hand, has shown only 4:1 to 2:1 stereoselectivity. Finally, a full conformational analysis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a is reported using 1H-NMR at 500 MHz. The solution geometry of the furanose and the pyrrolidine rings were studied on the basis of vicinal proton-proton coupling constants using the concept of pseudorotation. The furanose rings in 19a – 23a have a geometry biased toward a South-type conformation [70 – 81 % S, 126°