Asymmetric Total Synthesis of Taxol

Abstract

Taxol is one of the most famous natural diterpenoids and an important anticancer medicine. Taxol represents a formidable synthetic challenge and has prompted significant interest from the synthetic community. However, in all the previous syntheses of Taxol, there have been no reports of closing the desired eight-membered ring through C1–C2 bond formation. Furthermore, the existence of Taxol-resistant tumors and side effects of Taxol make the development of new approaches to synthesize Taxol and its derivatives highly desirable. Here, we report the asymmetric total synthesis of Taxol using a concise approach through 19 isolated intermediates. The synthetically challenging eight-membered ring was constructed efficiently by a diastereoselective intramolecular SmI2-mediated pinacol coupling reaction to form the C1–C2 bond. The unique biomimetic oxygen ene reaction and the newly developed facile tandem C2-benzoate formation and C13 side chain installation improved the efficiency of the synthesis. The mild oxygen ene reaction under light conditions would be an alternative reaction involved in Taxol biosynthesis. This new convergent approach will allow the diverse creation of Taxol derivatives to enable further biological research.

Chiral dihydroxytetraphenylene-catalyzed enantioselective conjugate addition of boronic acids to β-enaminones

“…Biologically active molecules containing the β-amino carbonyl skeleton can be found in a wide range of pharmaceutical drugs and natural products, 1 such as the protein phosphatase inhibitor Motuporin, 2 the anticancer medicine Taxol, 3 and the potent aminopeptidase inhibitor Bestatin. 4 Therefore, the development of new procedures for the synthesis of enantioenriched β-amino carbonyl compounds has attracted significant interest from chemists.…”

Total Synthesis of Clovan-2,9-dione via [3 + 2 + 1] Cycloaddition and Hydroformylation/Aldol Reaction

“…First, refluxing 9 with TsNHNH 2 in the presence of concentrated HCl generated tosylhydrazone 10 . Subsequent 1,2-reduction of the unsaturated hydrazone with catecholborane afforded 11 in 42% yield over 2 steps . Then, reduction of the double bond and deprotection of the benzyl group in 11 , using Pd/C/H 2 , provided diol 12 , which can be oxidized by PDC to deliver the natural product of clovan-2,9-dione 1 .…”

The Anti-Cancer Legend of Paclitaxel

“…"全合成方法大致分为三个步骤：骨架的合成；对骨架进行官能团反应，对其进行修饰；加上 侧链苯基异丝氨酸完成全合成。从总体上来看，全合成方法反应步骤太多、反应十分繁琐，而且需 要使用的辅助化学药剂十分昂贵，反应条件很难控制，最重要的是，该种方法的收率非常低，因此 难以用于大规模生产 [5] 。南方科技大学李闯创教授团队报道了一种全合成方法(图2)，该方法总共21 步，高效完成了紫杉醇的全合成，且产率有了较大提升 [6] 。" 图 1 紫杉醇的全合成 "为解决全合成方法繁琐且收率低的问题，科学家们将目光转向紫杉醇的半合成。巴卡亭III (图3)和紫杉醇的结构十分相似，只需在其基础上再引入侧链便可得到紫杉醇 [7] 。巴卡亭III是在提取 紫杉醇的过程中得到的一种副产物，而且天然植物红豆杉中巴卡亭III含量较高 [8] 。与全合成相比， 半合成方法(图4)的原料更易得，且收率相对更高、更适合大规模生产。" 图 2 巴卡亭 III 的结构 图 3 紫杉醇的半合成路线 "以上两种方法都在一定程度上依赖于红豆杉资源，为了打破这个僵局，科学家们还开辟了生 物合成的新道路。目前，参与生物合成的酶的大部分基因已被确定，而且已经通过生物合成成功得 到了紫杉醇的前体物质紫杉烯，这就意味着可以避免对大量红豆杉树皮的提取，但是目前还未解决 如何将中间体转化为产物这一关键问题 [9] 。不过请大家对我们充满信心，相信科学技术的发展终将 使生物合成紫杉醇成为现实。"…”