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

Article abstract of DOI:10.1016/S0040-4020(01)87228-8

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 percent S, 126 degS<131 deg (C1'-exo-C2'-endo), 28 deg <Ψ_m<32 deg, rms error +/-0.05>.In compounds 35a-38a, the riboses have a conformation biased toward the North-type N<38 deg (C3'-endo) and 27 deg<Ψ_m<30 deg, 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 Q_N ca. -28 deg and a puckering amplitude Ψ*_m ca. 40 deg (rms error +/-0.5).In compounds 35a-37a, the pyrrolidine has a geometry biased toward a South-type conformation (C2'-endo), with Q_S ca. 175 deg and Ψ*_m ca. 39 deg (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 (ca. 70 percent).The glycosyl conformation for all pyrrolidine-fused systems was found to be anti.