该手稿描述了一种前药合成的新策略，其中在合成序列的早期阶段引入相对惰性的醚基团，并在最后一步中进行功能化，以通过化学选择性过程引入前药激活基团。硼基烯丙氧基 (BAO) 醚基通过多种金属介导的过程合成，形成在癌细胞中常见的氧化条件下易于裂解的实体。 BAO基团的高裂解倾向允许醚裂解，使得这些化合物与酰基连接的前药相比具有显着更高的水解稳定性，同时保留释放醇的能力。我们报道了从缩醛前体制备天然产物喜树碱和佩德林的前药类似物，这些前体在其合成序列中充当保护基团。 BAO 缩醛基团在过氧化氢存在下裂解，释放细胞毒性剂。与非癌细胞系相比，基于pederin的前药显示出比阴性对照显着更大的细胞毒性，并且对癌细胞系具有出色的选择性和效力。这种前药合成的后期功能化方法应适用于可通过化学选择性过程访问的众多系统。© 2024 Wiley‐VCH GmbH。

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective  process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.© 2024 Wiley‐VCH GmbH.