Development of one-pot sequential cyclizations and applications towards the synthesis of complex alkaloids / Développement de cyclisations séquentielles monotopes et applications à la synthèse d'alcaloïdes complexes

这项研究计划旨在开发独创的策略，通过新的级联反应有效地合成复杂的天然产物。在这方面，拟议的研究分为三个方向(见下文)。这项拟议的研究计划将在有机化学家社区产生重大影响，因为它将提供创新和有效的方法来获取复杂的生物碱和基序，这些生物碱和基序很难用目前可用的方法获得。这样的计划非常适合培养面向制药行业和学术界的高素质人才。 1-序贯Vilsmeier-Haack和有机催化的不对称Mannich环化反应。 在之前发表的关于Vilsmeier-Haack和Mannich环化反应级联的项目中，我们发现最后一步(Mannich)存在严重的局限性，例如Im离子的低反应性以及没有手性诱导。为了解决这两个问题，我们计划在含有非反应酮或醛的底物上进行初始环化反应。然后加入催化量的仲胺将通过烯胺中间体引发第二次环化(Mannich)。将研究催化剂的负载、底物范围以及使用不对称催化剂时的手性诱导。 2-使用活性氨基甲酸酯的环化反应的新顺序。 我们最近证明，在第二次(Mannich)环化中，同样的反应性问题可以通过从氨基甲酸酯开始解决。在活化和第一次环化后，快速脱烷基反应生成酰胺，在存在过量活化剂的情况下，该酰胺可在原位重新活化。由此得到的三氟化锂离子比前一序列中的常规亚胺离子中间体的活性要高得多。从而极大地促进了第二次环化，从而提高了该策略的适用性。将研究底物和亲核范围，以获得结构上不同的氮杂双环和氮杂三环化合物。 3-通过连续的Vilsmeier-Haack环化和分子内亚甲基叶立德环加成完成复杂的多环生物碱的全合成。 这些合成利用了连续的一锅Vilsmeier-Haack环合反应和分子内亚甲基叶立德环加成反应。我们已经证明，当应用于三类天然产物，即瑞香烷、螺虫和螺精虫的合成时，该策略是高效的。在所有情况下，关键转换都会生成高级中级。我们现在需要完成关键步骤加合物中每一个家族中一系列靶向生物碱的合成，以证明我们连续的环化反应对复杂的天然产物的适用性。

This research program is aimed at developing original strategies to efficiently synthesize complex natural products through new cascades of reactions. In this vein, the research proposed is divided into three orientations (see below). This proposed research program will have a significant impact in the community of organic chemists since it will provide innovative and efficient ways to access complex alkaloids and motifs that are hard to obtain using the currently available methods. Such a program is perfectly suited for the formation of highly qualified personnel destined to pharmaceutical industry and academia. 1- Sequential Vilsmeier-Haack and organocatalyzed asymmetric Mannich cyclizations. In a previous project (published) on Vilsmeier-Haack and Mannich cyclizations cascade, we found serious limitations in the last step (Mannich), such as the low reactivity of the iminium ion as well as the absence of chiral induction. To address both of these issues, we plan to run the initial cyclization on substrates bearing an unreactive ketone or aldehyde. The addition of a catalytic amount of secondary amine will then trigger the second cyclization (Mannich) through an enamine intermediate. Catalyst loading, substrate scope as well as chiral induction with the use of asymmetric catalysts will be studied. 2- New sequence of cyclizations using activated carbamates. We recently demonstrated that the same reactivity issue in the second (Mannich) cyclization could be addressed by starting from a carbamate. After activation and first cyclization, a rapid dealkylation generates an amide that is reactivated in situ in the presence of an excess of activating agent. The resulting triflyliminium ion is substantially more reactive than regular iminiums ions intermediates in the previous sequence. The second cyclization is thus greatly facilitated, which improves the applicability of this strategy. Substrate and nucleophile scope will be studied to access architecturally varied aza-bicyclic and aza-tricyclic compounds. 3- Completion of the total synthesis of complex, polycyclic alkaloids using sequential Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition. These syntheses exploit a sequential one-pot Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition. We already proved that this strategy is highly efficient when applied to the synthesis of three classes of natural products, namely daphnanes, aspidospermans and aspidospermatans. In all cases, the key transformation generated an advanced intermediate. We now need to complete the syntheses of a series of targeted alkaloids in each of these families from the key step adducts to demonstrate the applicability our sequential cyclizations towards complex natural products.