Synthesis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides and their conformational analysis by 500 MHz1H-NMR

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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 using1H-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. © 1993.

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Xi, Z., Glemarec, C., & Chattopadhyaya, J. (1993). Synthesis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides and their conformational analysis by 500 MHz1H-NMR. Tetrahedron, 49(34), 7525–7546. https://doi.org/10.1016/S0040-4020(01)87228-8

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