Synthesis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides and their conformational analysis by 500 MHz 1H-NMR

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° < PS < 131° (C1′-exo-C2′-endo), 28° < Ψm < 32°, rms error ±0.05]. In compounds 35a – 38a, the riboses have a conformation biased toward the North-type [∼90 % N, 20° < PN < 38° (C3′-endo) and 27°< Ψm < 30°, rms error ±0.05]. In compounds 19a – 22a, the pyrrolidine geometry is biased toward the North-type conformation (C2′-exo), with a phase angle of pseudorotation QN ≈ −28° and a puckering amplitude Ψ*m ≈ 40° (rms error ±0.5). In compounds 35a – 37a, the pyrrolidine has a geometry biased toward a South-type conformation (C2′-endo), with QS ≈ 175° and Ψ*m ≈ 39° (rms error ±0.8). The furanose and the pyrrolidine rings share the C2′C3′ bond and have correlated conformations. The pyrrolidine adopts a North-type conformation in 19a – 22a when the ribose is in a South-type conformation. In contrast, the pyrrolidine ring adopts a South-type conformation when the ribose is in a North-type conformation (in 35a – 37a). Compounds 19a – 23a and 35a – 38a show a preference for the γ+ conformation (∼70%). The glycosyl conformation for all pyrrolidine-fused systems was found to be anti.