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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=645014
• 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.

该研究项目旨在通过新的级联反应开发出有效合成复杂天然产物的原始策略。在这方面，提出的研究分为三个方向（见下文）。这一研究计划将对有机化学家产生重大影响，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，这些方法很难用现有的方法获得。这样的课程非常适合为制药行业和学术界培养高素质人才。******1-顺序Vilsmeier-Haack和有机催化的不对称Mannich环化。***在之前关于Vilsmeier-Haack和Mannich环化级联的项目（已发表）中，我们在最后一步（Mannich）中发现了严重的局限性，例如低反应性的铝离子以及缺乏手性诱导。为了解决这两个问题，我们计划在含有非活性酮或醛的底物上进行初始环化。然后，催化量的仲胺的加入将通过烯胺中间体触发第二次环化（曼尼希）。将研究不对称催化剂的负载、底物范围以及手性诱导。******2-使用活化氨基甲酸酯的新环化序列。***我们最近证明了在第二次（曼尼希）环化中同样的反应性问题可以通过氨基甲酸酯开始解决。在激活和第一次环化之后，快速脱烷基反应产生一种酰胺，这种酰胺在过量活化剂存在的情况下在原位被重新激活。所得到的三氟铝离子实质上比上一序列中常规的最小离子中间体更具反应性。从而大大促进了二次循环，提高了该策略的适用性。将研究底物和亲核试剂范围，以获得结构上不同的氮杂双环和氮杂三环化合物。******3-使用顺序的维斯迈耶-哈克环化和分子内亚甲基环加成完成了复杂的多环生物碱的全合成。***这些合成利用了连续的一锅维斯迈耶-哈克环化和分子内亚甲基酰环加成。我们已经证明了这种策略在合成三种天然产物时是高效的，即daphnanes， aspidospermans和aspidospermatans。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中完成这些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。