Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
J Org Chem. 2020 Aug 21;85(16):10293-10320. doi: 10.1021/acs.joc.0c01287. Epub 2020 Aug 2.
This Perspective goes into the fine details of our laboratory's quest to answer a longstanding fundamental question: Could any new approach to terpene synthesis, perhaps one patterned on biosynthesis, enable a divergent synthetic approach to the taxane family of natural products? We targeted Taxol, the flagship taxane, as the upper limit of chemical complexity and employed two-phase terpene synthesis logic as the guiding strategy. The first synthesis target was taxadiene, the lowest oxidized member of the taxane family, followed by three site-selective allylic oxidations at C5, C10, and C13, which led to the two-phase synthesis of taxuyunnanine D. Successful C9 oxidation enabled access to a wider range of taxanes, which was demonstrated by the two-phase synthesis of decinnamoyltaxinine E and taxabaccatin III. The final two sp C-H oxidations at C1 and C7 were attained by dioxirane-mediated C-H oxidation and an oxidation relay based on judicious substrate design, culminating in a two-phase synthesis of Taxol. The purpose of this Perspective is to articulate strategies and tactics developed for the two-phase synthesis of taxanes, whose lessons can be potentially extrapolated to medicinal chemistry endeavors in the taxane family, as well as to the synthesis of other terpene families.
是否可以采用新型萜类化合物合成方法，例如基于生物合成的方法，为紫杉烷类天然产物提供一种不同的合成方法？我们以泰素（Taxol），即紫杉烷类的旗舰药物为目标，作为化学复杂性的上限，并采用两相萜类合成逻辑作为指导策略。第一个合成目标是紫杉烯，这是紫杉烷家族中氧化程度最低的成员，随后在 C5、C10 和 C13 进行了三个选择性的烯丙基氧化，这导致了 taxuyunnanine D 的两相合成。成功的 C9 氧化使更多种类的紫杉烷化合物得以合成，这通过 decinnamoyltaxinine E 和 taxabaccatin III 的两相合成得到了证明。最后两个 sp³ C-H 氧化在 C1 和 C7 上通过双环氧乙烷介导的 C-H 氧化和基于明智的底物设计的氧化接力反应实现，最终完成了泰素的两相合成。本文的目的是阐明为紫杉烷类化合物两相合成开发的策略和战术，这些经验教训可以潜在地推广到紫杉烷类药物化学研究以及其他萜类化合物的合成中。
