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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=678659
• 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.

该研究计划旨在制定原始策略，以通过新的反应级联反应有效地合成复杂的天然产品。在这种情况下，提出的研究分为三个方向（见下文）。该提出的研究计划将对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访问复杂的生物碱和图案，而这些生物碱和图案很难使用当前可用的方法获得。这样的计划非常适合形成注定要进行制药行业和学术界的高素质的人员。****** 1-顺序的vilsmeier-haack和有机催化的不对称的Mannich Cyclization。亚米群离子的反应性以及缺乏手性诱导。为了解决这两个问题，我们计划在带有无反应性酮或醛的底物上运行最初的环化。然后，添加催化量的二级胺将通过磁氨氨酸中间体触发第二环（Mannich）。将研究使用非对称催化剂的催化剂负载，底物范围以及手性诱导。****** 2-使用活性氨基甲酸酯的新循环序列。激活和第一次环化后，快速脱甲化会产生一个酰胺，该酰胺在存在过量激活剂的情况下被原位重新激活。所得的三级离子比上一个序列中的常规亚米尼离子中间体更具反应性。因此，第二个环化得到了极大的促进，从而提高了该策略的适用性。将研究底物和亲核试剂范围，以获取建筑型不同的AZA-BICICLIC和AZA-TRICYCLIC化合物。一锅vilsmeier-haack环化和分子内偶氮蛋白Ylide Cyclation。我们已经证明，当将这种策略应用于三类天然产品，即达芙妮，aspidospermans和aspidospermatans时，这种策略非常有效。在所有情况下，密钥转换都会产生高级中间体。现在，我们需要从关键步骤加合物中完成一系列靶向生物碱的一系列目标生物碱的合成，以证明我们对复杂天然产物的顺序循环的适用性。