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，涉及大量的步骤，这主要是由于分子的每个周期都是连续制备的。众所周知，一锅多反应(反应级联和反应序列)与分步反应相比具有不可否认的优势，如节省时间、资源管理、劳动力和产生废物。在这种情况下，我们将使用我们最近开发的序列Vilsmeier-Haack环化和亚甲基亚胺叶立德环加成(V-H/3+2)在一个转化中产生3个C-C键和3个环，并使用这个策略合成瑞香内酯B型和育珠亚胺型生物碱(以前从未合成过)，以及阿司匹林和马钱子碱(步骤比已发表的非外消旋合成少33%到40%)。有了这种快速的方法，这些家族的许多成员将很容易接触到，这无疑会引起几位合成化学家在设计上的注意，以及药物化学家在药物开发中使用这些核心的注意。 我们还将开发不对称版本的Vilsmeier-Haack反应，以生成包含全碳四元中心的分子，如α，α-二取代β-氨基酸和β-二羰基。该方法也将用于V-H/3+2策略中，以获得富含对映体的多环生物碱。该项目的成功将提供一种广泛的非外消旋非天然氨基酸的入口，这些氨基酸还无法通过现有的方法获得，这当然将是制药行业和学术研究的最大兴趣。