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，并且涉及大量的步骤，这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（反应级联和反应序列）具有不可否认的优势，如时间经济、资源管理、劳动力和废物产生。在这种情况下，我们将使用我们最近开发的序列Vilsmeier-Haack环化和亚甲酰基环加成（V-H/3+2），在一次转化中产生3个C-C键和3个环，并使用这种策略合成水蚤内酯b型和yuzurimine型生物碱（以前从未合成过），以及Aspidosperma和Strychnos生物碱（比已发表的非外消旋合成少33 - 40%的步骤）。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，这无疑会引起一些合成化学家的注意，他们会设计这些核心，也会引起药物化学家的注意，他们会在药物开发中使用这些核心。

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.