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 / Développement de cyclations séquentielles monotopes et applications à la Synèse dalcaloïdes 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710830
• 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合成复杂的天然产物。在这方面，所提出的研究分为三个方向（见下文）。这项拟议的研究计划将对有机化学家界产生重大影响，因为它将提供创新且有效的方法来获取使用当前可用方法难以获得的复杂生物碱和基序。这样的项目非常适合培养面向制药行业和学术界的高素质人才。 1- 顺序 Vilsmeier-Haack 和有机催化的不对称曼尼希环化。 在之前关于 Vilsmeier-Haack 和曼尼希环化级联的项目​​（已发表）中，我们发现最后一步（曼尼希）存在严重局限性，例如亚胺离子的低反应性以及缺乏手性诱导。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。添加催化量的仲胺将通过烯胺中间体引发第二次环化（曼尼希）。将研究催化剂负载、底物范围以及使用不对称催化剂的手性诱导。 2-使用活化氨基甲酸酯的新环化序列。 我们最近证明，第二次（曼尼希）环化中的相同反应性问题可以通过从氨基甲酸酯开始解决。活化和首次环化后，快速脱烷基化生成酰胺，该酰胺在过量活化剂存在下原位重新活化。所得的三氟亚胺离子比之前序列中的常规亚胺离子中间体更具反应性。因此极大地促进了第二次环化，从而提高了该策略的适用性。将研究底物和亲核试剂范围，以获取结构上不同的氮杂双环和氮杂三环化合物。 3-使用顺序Vilsmeier-Haack环化和分子内偶氮甲碱叶立德环加成完成复杂的多环生物碱的全合成。 这些合成利用了顺序一锅 Vilsmeier-Haack 环化和分子内偶氮甲碱叶立德环加成。我们已经证明，该策略在应用于三类天然产物（即瑞香、冬青素和冬青素）的合成时是非常有效的。在所有情况下，关键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每个家族中一系列目标生物碱的合成，以证明我们的顺序环化对复杂天然产物的适用性。