Lambert Kyle M, Cox Joshua B, Liu Lin, Jackson Amy C, Yruegas Sam, Wiberg Kenneth B, Wood John L
Department of Chemistry and Biochemistry, Baylor University, One Bear Place 97348, Waco, TX, 76798, USA.
Department of Chemistry, Yale University, New Haven, CT, 06520, USA.
Angew Chem Int Ed Engl. 2020 Jun 8;59(24):9757-9766. doi: 10.1002/anie.202003829. Epub 2020 May 8.
The development of a concise total synthesis of (±)-phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen-oxygen (N-O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early-stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N-O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.
本文描述了(±)-叶下珠碱(1)的简洁全合成方法,(±)-叶下珠碱(1)是一种含不寻常的氮杂双环[3.3.1]壬烷核心的叶下珠生物碱家族成员。该合成采用了独特的合成策略,其关键步骤是将取代的环戊酮扩环为环状异羟肟酸,这一步骤能够方便地构建嵌入的氮-氧(N-O)键。通过计算和实验评估了该反应序列的优化,以实现所需的区域化学结果及其机理基础。这种合成方法还具有早期非对映选择性羟醛反应以构建取代的环戊酮、温和还原酰胺中间体而不发生N-O键断裂,以及通过使用贝斯特曼叶立德快速构建(1)中发现的丁烯内酯结构。