This manuscript describes a concise synthesis of cinobufagin, a natural steroid of the bufadienolide family, from readily available dehydroepiandrosterone (DHEA), as well as its α5-epimer derived from 3-epi-andosterone. This synthesis features expedient installation of the 17β-pyrone moiety with the 14β,15β-epoxide and the 16β-acetoxy group using a photochemical regioselective singlet oxygen [4 + 2] cycloaddition followed by CoTPP-promoted in situ endoperoxide rearrangement to provide a 14β,16β-bis-epoxide in 64% yield with a 1.6:1 d.r. This β,β-bis-epoxide intermediate was subsequently subjected to a regioselective scandium(III) trifluoromethanesulfonate catalyzed House–Meinwald rearrangement to establish the 17β-configuration. The synthesis of cinobufagin is achieved in 12 steps (LLS) and 7.6% overall yield, and we demonstrate that it could be used as a platform for the subsequent medicinal chemistry exploration of cinobufagin analogs such as cinobufagin 5α-epimer.

中文翻译：

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通过后期单线态氧氧化/重排方法合成蟾蜍二烯内酯华蟾素精

该手稿描述了华蟾蜍精（蟾蜍二烯内酯家族的一种天然类固醇）的简明合成，其由容易获得的脱氢表雄酮（DHEA）及其衍生自 3-表雄酮的 α5-差向异构体组成。该合成的特点是使用光化学区域选择性单线态氧 [4 + 2] 环加成，将 17β-吡喃酮部分与 14β,15β-环氧化物和 16β-乙酰氧基方便地安装在一起，然后通过 CoTPP 促进的原位内过氧化物重排来提供 14β， 16β-双环氧化物，产率 64%，dr 为 1.6:1 这种 β,β-双环氧化物中间体随后进行区域选择性三氟甲磺酸钪 (III) 催化的 House-Meinwald 重排，以建立 17β-构型。华蟾素的合成经过12步（LLS）实现，总产率为7.6%，我们证明它可以作为华蟾素类似物（如华蟾素5α-差向异构体）后续药物化学探索的平台。