Zinc Acetate

康龙化成举办第五十期“合成与药物化学前沿”名师线上讲座 2024年10月31日，北京——加拿大多伦多大学的Sophie Rousseaux教授做客康龙化成第五十期“合成与药物化学前沿”名师线上讲座，报告主题为“小环和腈类化合物的合成和官能团化新策略”。报告重点介绍了环丙烷的官能团化策略，包括高烯醇类化合物与亲核试剂合成环丙胺类化合物；镍催化交叉偶联策略合成环丙胺，醇类化合物，以及镍催化体系的氰基化反应。这些合成策略中，大部分的反应条件比较温和，可以实现良好到优秀的产率和选择性，并且能够耐受广泛的官能团。为实现携带环丙胺，醇类，以及腈类砌块药物的合成工作提供了更丰富的方法。 首先，Rousseaux教授介绍了基于官能团化环丙烷砌块尤其是环丙胺类化合物在药物化学中的广泛存在，并根据环丙醇锌盐衍生物具有特殊（亲电&亲核）两性的特点，设计了金属高烯醇酯类化合物与亲核试剂反应，实现一系列环丙胺类化合物的合成策略。此外，Rousseaux教授根据已实现的环丙醇的合成方法，将环丙胺类化合物的合成策略进行延伸，实现了α-氯代醛，烯酮类化合物以及1-芳基取代的环丙醇类化合物对环丙胺类化合物的转化。这一系列对环丙胺类化合物的合成策略基本都具备反应条件温和，产率高，并且非对映选择性高的优点。同时，Rousseaux教授的团队还将这些合成工作应用到多种具有药学意义的环丙胺类化合物的合成工作中。 随后，Rousseaux教授介绍了在Ni催化体系下，与携带有氧化还原活性离去集团的偶联子，在温和的条件下实现一系列环丙胺类化合物合成的策略。尤其在一些特别的方法下，还可以实现与四元以及五元和六元环α-氨基体系反应，实现相应的环胺类化合物的合成。同时，对这一系列环胺类化合物进行衍生化，合成相应的螺环γ‑内酰胺类化合物。除此之外，Rousseaux教授还介绍了N-苯甲酰氨基甲硫酸酯作为最佳离去基团，在Ni催化体系下实现环丙醇芳基化的策略；以及实现了光催化策略在室温下对环丙叔醇衍生物进行有效的脂肪O到S重排反应。 最后，Rousseaux教授介绍了镍催化还原性氰化反应，包括：芳基溴化物的还原氰化，芳基氯化物以及类卤化物（如：烯基对甲苯磺酸酯和三氟甲磺酸酯）的氰化反应和丙二腈经过脱氰-金属化过程，实现的叔腈的α-芳基化反应。特别的，在最后一种氰基化策略中，Rousseaux教授展示了反应的催化循环过程以及腈类化合物作为配体，尤其是在稳定低价金属中心方面的作用。 会后，Rousseaux教授在问答环节中与听众进行了热烈的讨论。 Frontiers in Synthetic and Medicinal Chemistry --The 50th Pharmaron Virtual Lecture Beijing, China, October 31, 2024 - Pharmaron held its 50th virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Prof. Sophie Rousseaux from University of Toronto. The presentation was titled “New Strategies for the Synthesis and Functionalization of Small Rings and Nitriles.” The lecture focused on the functionalization strategies of cyclopropane, including the synthesis of cyclopropylamines from homoenolates and nucleophiles; the synthesis of cyclopropylamines and cyclopropanols by nickel-catalyzed cross-coupling strategy, and the cyanation of nickel-catalyzed system. Most of these syntheses achieved good to excellent yield and selectivity under mild reaction conditions, tolerated a wide range of functional groups, and provided a rich approach for the synthesis of cyclopropylamine, cyclopropanol, and nitrile pharmaceutical building blocks. Prof. Rousseaux introduced the ubiquitous presence of cyclopropane blocks, specifically cyclopropylamines in pharmaceutical chemistry. Her group devised a synthetic strategy of a series of cyclopropylamine preparation by the reaction of metal homoenolates with nucleophiles based on the amphoteric nature of zinc homoenolate derivatives. Prof. Rousseaux’s team extended the synthesis of cyclopropylamines from α-chloroaldehydes, enones and 1-phenyl cyclopropanols. These strategies for cyclopropylamine synthesis possess the advantages of mild reaction conditions, high yield and excellent diastereoselectivity. Prof. Rousseaux's team also applied these synthetic methods to the synthesis of various cyclopropylamines relevant to pharmaceuticals. Subsequently, Prof. Rousseaux presented strategies for achieving a series of cyclopropylamines with the substrates bearing redox-active leaving groups as cross-coupling partners under mild Ni-catalyzed conditions. In some specific methods they could realize the conversions with the strained four-membered and five-, six-membered α-amino ring systems to provide the corresponding cyclic amines. At the same time, the series of cyclopropylamines led to the formation of the corresponding spiro γ-lactams in the presence of  α,β-unsaturated compounds. Prof. Rousseaux also introduced the strategy of Ni-catalyzed arylation of activated cyclopropanol N-benzoyl carbamothioate as the optimal leaving group. The photoredox method was also applied to an aliphatic O- to S-rearrangement of readily available tertiary cyclopropanols at room temperature. Lastly, Prof. Rousseaux described nickel-catalyzed reductive cyanation, of aryl bromides, aryl chlorides and pseudohalides such as alkenyl tosylates, triflates and α-arylation of tertiary nitriles and disubstituted malononitrile through decyanation-metalation. The last cyanationstrategy Prof. Rousseaux presented proposed the catalytic cycle of the reaction and the role of nitrile compounds as ligands, especially about their function in stabilizing low-valent metal centers. After the meeting, Professor Rousseaux had a lively discussion with the audience during the question and answer session.