Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science. 2013 Aug 23;341(6148):878-82. doi: 10.1126/science.1241606. Epub 2013 Aug 1.
Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently Food and Drug Administration-approved Picato, a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Currently, that compound is sourced inefficiently from Euphorbia peplus. Here, we detail an efficient, highly stereocontrolled synthesis of (+)-ingenol proceeding in only 14 steps from inexpensive (+)-3-carene and using a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and provides a strategic blueprint for chemical production. These results validate two-phase terpene total synthesis as not only an academic curiosity but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.
艾杜醇是一种具有独特结构的二萜类化合物，其衍生物具有重要的抗癌活性，包括最近获得美国食品和药物管理局批准的 Picato，这是一种用于治疗癌前皮肤状况光化性角化病的首创药物。目前，该化合物是从大戟属植物中低效获得的。在这里，我们详细介绍了一种从廉价的 (+)-3-蒈烯出发，仅通过 14 步反应，以高效、高度立体选择性的方式合成 (+)-艾杜醇的方法，采用两相设计。该合成方法将允许创建生物活性艾杜烷的全合成类似物，以解决药理学限制，并为化学生产提供战略蓝图。这些结果验证了两相萜类全合成不仅是学术上的好奇心，而且是一种可行的替代方法，可用于在化学复杂性的极限下高效制备多氧化萜类化合物，而无需进行分离或生物工程。
