Cascade Catalysis: A Valuable Strategy for Complex Molecule Synthesis

级联催化：复杂分子合成的一个有价值的策略

• 批准号: 8302438
• 负责人: David W MacMillan
• 金额: $ 31.44万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-07 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302438
• 关键词: Adopted; Alkaloids; Anabolism; Aspidosperma; Benchmarking; Biological Factors; Catalysis; Chemicals; Complex; Coumarins; Development; Family; Generations; Individual; Investigation; Laboratories; Libraries; Medical; Methodology; Methods; Natural Product Drug; One-Step dentin bonding system; Organic Synthesis; Pharmacologic Substance; Process; Reaction; Reporting; Research; Research Project Grants; Research Proposals; Route; Staging; Strychnine; Strychnos; Technology; Translating; adduct; alpha benzopyrone; analog; aspidospermidine; base; chemical synthesis; cytotoxic; design; enantiomer; interest; member; molecular orbital; novel; novel strategies; programs; public health relevance; teleocidin

DESCRIPTION (provided by applicant): This research proposal seeks to establish the capacity of our newly introduced paradigm of organocascade catalysis to accomplish, with unprecedented levels of efficiency, the total synthesis of an array of complex, natural product-based molecules. The current prevailing approach to complex molecule synthesis, generally adopted by both academic and pharmaceutical practitioners of the field, entails a 'stop-and-go' strategy, wherein each individual chemical transformation is executed as a separate process. Because of the requirement for isolation and purification of intermediates at each stage along the synthetic route, this classical approach to multi-step synthesis suffers from a number of serious limitations with regard to efficiency and product selectivity. As an alternative approach, we recently introduced a novel synthetic concept, termed organocascade catalysis, which seeks to translate some of the advantages offered by natural product biosynthesis to the realm of laboratory synthesis. Organocascade catalysis emulates the conceptual blueprint of biosynthesis through the merger of multiple sequential transformations, each governed by an orthogonal mode of organocatalytic activation, into a single cascade sequence. Toward this end, we have demonstrated, in a variety of settings, the remarkable ability of organocascade catalysis to enable the rapid conversion of simple achiral substrates to complex, stereochemically rich, single-enantiomer adducts. This research proposal seeks to demonstrate the unprecedented synthetic capabilities of organocascade catalysis through the total synthesis of a range of high-profile natural products. Due to their complexity, as well as their historical and medical significance, the natural products targeted herein serve as valuable total synthetic benchmark compounds, by which to assess the current state of the field of organic synthesis. It is of note that each of the synthetic routes to the targets proposed herein, if realizable, would represent a significant improvement, in terms of efficiency and selectivity, over previously reported total syntheses. Specifically, Project I outlines the development of an enantioselective triple organocatalytic cascade sequence. The common intermediate arising from this transformation will be rapidly advanced to key members of the Aspidosperma, Kopsia, and Strychnos families of natural products - namely, strychnine, akuammicine, kopsinine, kopsanone, aspidospermidine, and vincadifformine. Projects II and IV envision the development of second generation, quadruple cascade routes to kopsanone and strychnine, respectively. In Project III, we will pursue a rapid organocascade approach to a common intermediate en route to a number of members of the Aspidosperma and Strychnos families. The key organocascade adduct will be advanced to ochrosamine B. Project V will entail the investigation of a new cascade-based strategy toward cytotoxic teleocidin natural products, such as indolactam V, and analogs thereof. Finally, the focus of Project VI will be on the development of a SOMO-catalysis based organocascade platform, as well as the subsequent application of this novel approach to the total syntheses of the natural products, phyllantidine and bruceol. PUBLIC HEALTH RELEVANCE: The objective of this research is to establish a new strategy for chemical synthesis whereby natural products, bioactive compounds and medicinal agents can be generated in a highly accelerated fashion from cheap, inexpensive and readily available starting materials.

描述（由申请人提供）：本研究计划旨在建立我们新引入的有机级联催化范式的能力，以前所未有的效率水平完成一系列复杂的、基于天然产物的分子的全合成。当前流行的复杂分子合成方法，通常被该领域的学术界和制药从业者所采用，需要“走走停停”的策略，其中每个单独的化学转化都是作为单独的过程执行的。由于在合成路线的每个阶段都需要分离和纯化中间体，这种经典的多步合成方法在效率和产物选择性方面受到许多严重的限制。作为一种替代方法，我们最近引入了一种新的合成概念，称为有机级联催化，旨在将天然产物生物合成提供的一些优势转化为实验室合成领域。有机级联催化通过将多个连续转化（每个转化由有机催化激活的正交模式控制）合并成单个级联序列来模拟生物合成的概念蓝图。为此，我们在各种环境下证明了有机级联催化的卓越能力，能够将简单的非手性底物快速转化为复杂的、立体化学丰富的单对映体加合物。该研究计划旨在通过一系列备受瞩目的天然产物的全合成来展示有机级联催化前所未有的合成能力。由于其复杂性以及其历史和医学意义，本文针对的天然产物可作为有价值的总合成基准化合物，通过其评估有机合成领域的现状。值得注意的是，本文提出的目标的每条合成路线，如果可以实现，将在效率和选择性方面比之前报道的全合成有显着的改进。具体来说，项目 I 概述了对映选择性三重有机催化级联序列的开发。这种转化产生的常见中间体将迅速发展为 Aspidosperma、Kopsia 和 Strychnos 天然产物家族的关键成员，即士的宁、akuammicine、kopsinine、kopsanone、aspidospermidine 和 vincadifformine。项目 II 和 IV 设想分别开发高普萨酮和士的宁的第二代四重级联路线。在项目 III 中，我们将采用快速有机级联方法来获得常见的中间体，从而获得许多 Aspidosperma 和 Strychnos 家族的成员。关键的有机级联加合物将被改进为赭胺 B。项目 V 将需要研究针对细胞毒性 teleocidin 天然产物（例如吲哚内酰胺 V 及其类似物）的新的基于级联的策略。最后，项目VI的重点将是开发基于SOMO催化的有机级联平台，以及随后将这种新方法应用于天然产物叶蝉苷和布烯醇的全合成。 公共健康相关性：本研究的目的是建立一种新的化学合成策略，通过这种策略，天然产物、生物活性化合物和药物可以以高度加速的方式从廉价、便宜且易于获得的起始材料中产生。