Total Synthesis of (−)- and <i>ent</i>-(+)-Vindoline and Related Alkaloids

A concise 11-step total synthesis of (−)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C−C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).本文详细报道了一条简洁的11步全合成路线，用于制备(-)-文多灵（vindoline）及其对映体(+)-文多灵（3），其设计基于受天然产物结构启发的1,3,4-噁二唑独特串联分子内[4+2]/[3+2]环加成级联反应。该反应可一步构建特征性五环骨架所需的三个环与四个碳-碳键，同时确立全部六个手性中心，并引入天然产物中几乎所有官能团。 在明确该反应的适用范围与立体化学特征后，研究团队通过全合成制备了一系列复杂度逐步提升的相关天然产物，包括密诺文（minovine，4）、4-脱乙酰氧基-6,7-二氢文多洛辛（5）、4-脱乙酰氧基文多洛辛（6）、文多洛辛（7）以及N-甲基白坚木精（N-methylaspidospermidine，11）的两种对映异构体。后续对该合成策略的拓展，又分别制备了6,7-二氢文多灵（8）、4-脱乙酰氧基文多灵（9）与4-脱乙酰氧基-6,7-二氢文多灵（10）的两种对映异构体。