An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids
An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids
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DOI：
10.1126/science.adl6163
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发表时间：
2024-02
期刊：
影响因子：
56.9
通讯作者：
Brandon W. Alexander;Noah M. Bartfield;Vaani Gupta;Brandon Q. Mercado;Mark Del Campo;Seth B. Herzon-
中科院分区：
文献类型：
--
作者：
Brandon W. Alexander;Noah M. Bartfield;Vaani Gupta;Brandon Q. Mercado;Mark Del Campo;Seth B. Herzon-
一叶警卫和一叶警卫胺是细胞毒性生物碱，其含有嵌入骨架中的活性烯烃和杂环残基，所述骨架包含4至6个氧化环。这种结构的复杂性赋予了分离物丰富的化学性质，但在分离后的近三十年里，这种结构的合成途径受到阻碍。我们提出了一个灵活的路线，八个分离物的三个骨架类的代谢产物。该路线通过高级叠氮化物38和49的模块化组装（13个步骤，6至10%产率）、连续氧化光环化和后期官能团操作进行。用这种方法，目标物在17至19个步骤中获得，12至13次纯化，总收率为0.5至3.5%。通过微晶电子衍射（MicroED）分析确定了高级中间体的结构。该路线将支持securamines的结构-功能和靶标鉴定研究。由小型海洋无脊椎动物生物合成的securamine和securine生物碱，因其稠合杂环的致密核心以及氯和溴取代基而脱颖而出。亚历山大等人报道了该天然产物家族的八个成员的化学合成。该方法的关键是大环的初始组装，该大环在暴露于无水盐酸时经历显著选择性级联的内部修饰。高级中间体的微调氧化光环化然后提供各种差异化的最终产品。- 杰克·S Yeston连续光环化反应能够合成三种不同类型的海洋生物碱。
Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines. Editor’s summary The securamine and securine alkaloids, which are biosynthesized by small marine invertebrates, stand out for their dense core of fused heterocycles and both chlorine and bromine substituents. Alexander et al. report chemical syntheses of eight members of this natural product family. Key to the approach is the initial assembly of a macrocycle that undergoes a remarkably selective cascade of internal modifications upon exposure to anhydrous hydrochloric acid. Finely tuned oxidative photocyclizations of advanced intermediates then deliver the various differentiated final products. —Jake S. Yeston Sequential photocyclization reactions enable the synthesis of three skeletally distinct classes of marine alkaloids.