Asymmetric Total Synthesis of Vindorosine, Vindoline, and Key Vinblastine Analogues

Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels−Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C−C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ6,7-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6−C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ6,7-double bond.

本研究基于受天然产物结构启发的1,3,4-恶二唑（1,3,4-oxadiazoles）独特分子内[4+2]/[3+2]环加成级联反应，详细阐述了文多灵（vindoline）(1)与文多洛辛（vindorosine）(2)的简洁不对称全合成路线。连接亲双烯体（dienophile）与恶二唑的连接臂（tether）上的手性取代基，可用于调控起始狄尔斯-阿尔德（Diels−Alder）反应的面选择性，并确定级联环加成产物（cascade cycloadduct）中剩余6个手性中心（stereocenters）的绝对立体构型。该关键反应一步构建了五环骨架（pentacyclic ring system）核心的3个环与4个碳-碳键，同时确立了全部6个手性中心，并几乎同时引入了天然产物中存在的所有功能基团。为实现化合物1与2的合成，本研究开发了一种扩环反应（ring expansion），以得到可精准引入天然产物核心结构中Δ6,7双键的六元官能化环。我们开发了两种独特策略，确立了以保护羟甲基作为取代基来调控环加成级联反应立体化学进程的方法。在本研究过程中，我们制备了多种文多灵类似物，其包含目前仅能通过全合成获得的深层结构修饰。这些在C6-C8位带有关键修饰的类似物被引入长春碱（vinblastine）类似物中，用于探究长春碱Δ6,7双键非同寻常的重要性（100倍差异），并明确其潜在作用。