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

一锅顺序环化的开发及其在复杂生物碱合成中的应用/Däveloppement de cyclations säquentielles monotopes et applications à la synàse dalcaloàdes Complexes

• 批准号: RGPIN-2017-05400
• 负责人: Bélanger, Guillaume
• 金额: $ 1.6万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748651
• 关键词: Development; pot; sequential; cyclizations; applications

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.

该研究计划旨在开发原创策略，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得使用目前可用的方法难以获得的复杂生物碱和基序。这样一个程序是非常适合于形成高素质的人才注定要制药工业和制药厂。1-顺序Vilsmeier-Haack和有机催化的不对称曼尼希cyclizations.In以前的项目（出版）上Vilsmeier-Haack和曼尼希cyclizations级联，我们发现在最后一步（曼尼希）严重的局限性，如亚胺离子的低反应性以及手性诱导的缺乏。为了解决这两个问题，我们计划在带有非反应性酮或醛的底物上进行初始环化。然后加入催化量的仲胺将通过烯胺中间体引发第二环化（曼尼希）。催化剂装载量，底物范围以及手性诱导与使用不对称催化剂将进行研究。2-新的序列的环化使用活化的氨基甲酸酯。我们最近证明，同样的反应性问题，在第二（曼尼希）环化可以解决从氨基甲酸酯。在活化和第一次环化之后，快速脱烷基化生成酰胺，该酰胺在过量活化剂的存在下原位再活化。所得的三氟锂离子比先前序列中的常规亚胺离子中间体反应性更强。因此，极大地促进了第二环化，这提高了该策略的适用性。底物和亲核试剂的范围将被研究，以获得不同的结构氮杂双环和氮杂三环化合物。3-完成复杂的，多环生物碱的全合成使用顺序Vilsmeier-Haack环化和分子内甲亚胺叶立德环加成。这些合成利用顺序一锅Vilsmeier-Haack环化和分子内甲亚胺叶立德环加成。我们已经证明，这种策略是非常有效的，当应用于三个类的天然产物，即瑞香素，aspidospermans和aspidospermans的合成。在所有情况下，密钥转换都会生成高级中间体。我们现在需要从关键步骤加合物完成这些家族中的一系列靶向生物碱的合成，以证明我们对复杂天然产物的顺序环化的适用性。