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: 8012977
• 负责人: David W MacMillan
• 金额: $ 31.89万
• 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/8012977
• 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天然产物分子的全合成。目前流行的复杂分子合成方法，通常被该领域的学术和制药从业者采用，需要一个“走走停停”的策略，其中每个单独的化学转化作为一个单独的过程来执行。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，它寻求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。有机级联催化通过合并多个顺序转化来模拟生物合成的概念蓝图，每个顺序转化都由有机催化激活的正交模式控制，形成单个级联序列。为此，我们已经证明，在各种环境下，有机级联催化的非凡能力，使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。本研究计划旨在通过一系列高知名度天然产物的全合成来证明有机级联催化的前所未有的合成能力。由于它们的复杂性，以及它们的历史和医学意义，本文所针对的天然产物作为有价值的全合成基准化合物，通过它来评估有机合成领域的现状。值得注意的是，本文提出的每一种达到目标的合成途径，如果能够实现，将比以前报道的全合成在效率和选择性方面有重大改进。具体来说，项目I概述了一个对映选择性三重有机催化级联序列的发展。从这种转化中产生的常见中间体将迅速发展为蛇床子属、Kopsia和马钱子属天然产物家族的关键成员，即马钱子碱、阿库米明、kopsinine、kopsanone、蛇床子精胺和长春异福明。项目II和项目IV设想开发第二代四级联路线，分别生产kopsanone和士的宁。在项目III中，我们将寻求一种快速的有机级联方法，以获得一种常见的中间体，同时获得一些Aspidosperma和Strychnos家族的成员。关键的有机级联加合物将被推进到ochrosamine B.项目V将需要研究一种新的基于级联的策略来研究细胞毒性远杀毒素天然产物，如吲哚内酰胺V及其类似物。最后，第六项目的重点将放在基于somo催化的有机级联平台的开发上，以及随后将这种新方法应用于天然产物叶绿苷和布鲁斯酚的全合成。