Preparation of enantioenriched quaternary centers and synthesis of complex alkaloids - Préparation de carbones quaternaires énantioenrichis et synthèse d'alcaloides complexes

对映体富集的四元中心的制备和复杂生物碱的合成 - Preparation de Carbones quaternaires énantioenrichis et Synsè dalcaloides Complexes

• 批准号: 249564-2012
• 负责人: Bélanger, Guillaume
• 金额: $ 3.28万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=570648
• 关键词: Preparation; enantioenriched; quaternary; centers; synthesis

Classical syntheses of polycyclic alkaloids are often long and involve a large number of steps principally due to a sequential preparation of every cycle of the molecule. It is well established that one-pot multi-reactions (reaction cascades and reaction sequences) provide undeniable advantages over stepwise processes, such as economy of time, resource management, labor, and waste generation. In this vein, we will use a sequence Vilsmeier-Haack cyclization and azomethine ylide cycloaddition (V-H/3+2) that we developed recently to create 3 C-C bonds and 3 cycles in a single transformation, and use this strategy to synthesize daphnilactone B-type and yuzurimine-type alkaloids (never synthesized before), as well as Aspidosperma and Strychnos alkaloids (in 33 to 40% less steps than published non racemic syntheses). With such a rapid approach, many members of these families will be readily accessible, which will undoubtedly catch the attention of several synthetic chemists for the design, and of medicinal chemists for using these cores in drug development. We will also develop an asymmetric version of the Vilsmeier-Haack reaction to generate molecules containing all-carbon quaternary centers such as alpha,alpha-disubstituted beta-amino acids and beta dicarbonyls. This method will be used in the V-H/3+2 strategy to access enantioenriched polycyclic alkaloids as well. The success of this project will provide an entry to a wide variety of non-racemic unnatural amino acids that are not yet accessible through existing methods, and this will of course be of the greatest interest for the pharmaceutical industry and academic research.

多环生物碱的经典合成通常很长并且涉及大量步骤，主要是由于分子的每个循环的顺序制备。众所周知，一锅多反应（级联反应和反应序列）比逐步过程具有不可否认的优势，例如时间经济、资源管理、劳动力和废物产生。本着这种精神，我们将使用我们最近开发的 Vilsmeier-Haack 环化和偶氮甲碱叶立德环加成 (V-H/3+2) 序列，在一次转化中创建 3 个 C-C 键和 3 个循环，并使用该策略合成瑞香内酯 B-型和 yuzurimine 型生物碱（以前从未合成过），以及 Aspidosperma 和 Strychnos 生物碱（在比已发表的非外消旋合成步骤少 33% 至 40%）。通过如此快速的方法，这些家族的许多成员将很容易获得，这无疑会引起一些合成化学家的设计以及在药物开发中使用这些核心的药物化学家的注意。 我们还将开发 Vilsmeier-Haack 反应的不对称版本，以生成含有全碳四元中心的分子，例如 α,α-二取代的 β-氨基酸和 β 二羰基。该方法也将用于 V-H/3+2 策略中以获取对映体富集的多环生物碱。该项目的成功将为通过现有方法尚未获得的多种非外消旋非天然氨基酸提供一个入口，这当然将引起制药行业和学术研究的最大兴趣。