A Practical Synthesis of (-)-Swainsonine.
A Practical Synthesis of (-)-Swainsonine.
复制标题
(-)-苦马豆素的实际合成。
DOI：
10.1021/jo961101b
复制
发表时间：
1996
影响因子：
3.6
通讯作者：
E. Hembre
中科院分区：
文献类型：
--
作者：
W. Pearson;E. Hembre
吲哚里西定生物碱(-)-苦马豆素(1)因其多种生物活性而备受关注。1，2它可以被认为是甘露糖的氮杂糖类似物，确实是许多甘露糖苷酶的有效抑制剂，包括糖蛋白加工酶甘露糖苷酶II。3-7苦马豆素是第一个作为抗癌药物选择用于临床试验的糖蛋白加工抑制剂，8，9，但其高昂的成本阻碍了临床试验。10显然，无论是从天然来源中分离苦马豆素还是合成制备苦马豆素，都还没有经济有效的方法。虽然已经在开发苦马豆素的合成路线上花费了大量的努力，11但仍然需要对这种重要的生物碱进行实用的合成。也许到目前为止开发的最实用的路线是由Fleet11m、r和Cha研究小组报告的路线。11N我们小组开发的最短合成路线已被证明不适合扩大规模。我们实验室最近在制备苦马豆素类似物方面的努力导致了一条获得这种重要生物碱的实用路线的发展。我们在这里报道了一种(-)-苦马豆素的合成，它相对较短和有效，并且使用简单的反应，允许良好的重复性和材料产量。我们合成苦马豆素的策略如图1所示。内酰胺A可能来自叠氮内酯B的还原双环化反应，这应该是通过C的二羟基化反应得到的。γ，δ不饱和羧酸衍生物C是通过烯丙醇D的克莱森重排反应得到的
The indolizidine alkaloid (-)-swainsonine (1) is of longstanding interest due to its diverse biological activity. 1, 2 It may be considered an azasugar analog of mannose and is indeed a potent inhibitor of many mannosidases including the glycoprotein-processing enzyme mannosidase II. 3-7 Swainsonine is the first glycoprotein-processing inhibitor to be selected for clinical testing as an anticancer drug, 8, 9 but its high cost has hindered clinical trials. 10 Apparently, there is still no cost-effective way to either isolate swainsonine from natural sources or to prepare it synthetically. While a great deal of effort has been expended on developing synthetic routes to swainsonine, 11 there is still a need for a practical synthesis of this important alkaloid. Perhaps the most practical routes developed to date are those reported by the research groups of Fleet11m, r and Cha. 11n The shortest synthetic route, developed in our group, has not proven amenable to scale-up. 11o Recent efforts in our laboratories directed toward preparing analogs of swainsonine have led to the development of a practical route to this important alkaloid. We report herein a synthesis of (-)-swainsonine that is relatively short and efficient and uses simple reactions that allow good reproducibility and material throughput. Multigram quantities of the pure alkaloid were easily prepared using small-scale laboratory equipment.Our strategy for the synthesis of swainsonine is shown in Scheme 1. The lactam A may arise from a reductive double-cyclization of the azido lactone B, which should be available by dihydroxylation of C. The γ, δ-unsaturated carboxylic acid derivative C was proposed to be available by a Claisen rearrangement of the allylic alcohol D derived by addition of a vinyl organometallic