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

多环生物碱的经典合成通常很长，并且主要由于分子的每个环的顺序制备而涉及大量步骤。众所周知，一锅多反应（反应级联和反应顺序）提供了优于分步方法的不可否认的优点，例如节省时间、资源管理、劳动力和废物产生。在这方面，我们将使用我们最近开发的序列Vilsmeier-Haack环合和甲亚胺叶立德环加成（V-H/3+2），在一次转化中产生3个C-C键和3个环，并使用该策略合成瑞香内酯B型和尤珠利明型生物碱（以前从未合成过），以及Aspidosperma和Strychnos生物碱（比公开的非外消旋合成少33 - 40%的步骤）。有了这样一种快速的方法，这些家族的许多成员将很容易获得，这无疑将引起几位合成化学家的注意，用于设计，以及药物化学家在药物开发中使用这些核心。 我们还将开发Vilsmeier-Haack反应的不对称版本，以生成含有全碳季中心的分子，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策略以获得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无法获得的各种非外消旋非天然氨基酸提供入口，这当然会引起制药行业和学术研究的最大兴趣。

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.