β-Nucleosides and their analogs are dominant clinically-used antiviral and antitumor drugs. α-Nucleosides, the anomers of β-nucleosides, exist in nature and have significant potential as drugs or drug carriers. Currently, the most widely used methods for synthesizing β- and α-nucleosides are via N-glycosylation and pentose aminooxazoline, respectively. However, the stereoselectivities of both methods highly depend on the assisting group at the C2’ position. Herein, we report an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or β-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for β-nucleosides; PPh₃S for α-nucleosides). A series of β- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (β:α up to 66:1, α:β up to 70:1). Notably, the introduced iodine at the C2’ position of the nucleoside is readily functionalized, leading to multiple structurally diverse nucleoside analogs, including stavudine, an FDA-approved anti-HIV agent, and molnupiravir, an FDA-approved anti-SARS-CoV-2 agent.

β-核苷及其类似物是临床上主要使用的抗病毒和抗肿瘤药物。α-核苷是β-核苷的端基异构体，存在于自然界中，具有作为药物或药物载体的巨大潜力。目前，最广泛使用的合成β-和α-核苷的方法分别是通过N-糖基化和戊糖氨基恶唑啉。然而，这两种方法的立体选择性在很大程度上取决于 C2' 位置的辅助基团。在此，我们报告了一种用于选择性合成 α- 或 β- 核苷的添加剂控制的立体发散碘环化方法。异头碳的立体选择性由添加剂控制（β-核苷为 NaI；PPh ₃S 代表 α-核苷）。以高产率（高达 95%）和立体选择性（β:α 高达 66:1，α:β 高达 70:1）制备了一系列 β- 和 α- 核苷。值得注意的是，在核苷 C2' 位置引入的碘很容易被功能化，从而产生多种结构多样的核苷类似物，包括司他夫定（一种 FDA 批准的抗 HIV 药物）和莫努拉韦（一种 FDA 批准的抗 SARS-CoV- 2代理。