Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA.
Nat Chem. 2011 Nov 6;4(1):21-5. doi: 10.1038/nchem.1196.
Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane--taxadiene--which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.
紫杉醇（Taxol）是一种价值数十亿美元的抗癌药物，是一种具有代表性的萜类化合物，属于紫杉烷家族，包含超过 350 个成员。在这里，我们描述了一种通过简洁的 (+)-taxa-4(5),11(12)-dien-2-one 的制备来首次实现这些天然产物的实际和可扩展的合成途径，这种方法具有合适的功能基，可用于制备更多氧化的紫杉烷家族成员。该路线能够实现“母体”紫杉烷——紫杉二烯的克级制备，这是有史以来从天然来源中分离或纯制得到的最大数量的这种天然萜类化合物。紫杉烷家族的特征 6-8-6 三环系统包含桥头烯烃，通过邻位双官能化/Diels-Alder 策略形成。通过对映选择性共轭加成引入不对称性，形成全碳季碳中心，通过底物控制固定所有其他立体中心。这项研究为计划获得最小氧化的紫杉烷类似物以及紫杉醇本身的可扩展实验室制备奠定了关键基础。
