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）：本研究提案旨在建立我们新引入的有机级联催化范例的能力，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，通常由该领域的学术和制药从业者采用，需要一种“停-走”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。由于在合成路线的沿着每个阶段都需要分离和纯化中间体，这种多步合成的经典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。有机级联催化模拟生物合成的概念蓝图，通过合并多个连续的转换，每个由有机催化活化的正交模式，到一个单一的级联序列。为此，我们已经证明，在各种设置中，有机级联催化的显着能力，使简单的非手性底物的复杂的，立体化学丰富的，单一的对映体加合物的快速转换。这项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充当有价值的全合成基准化合物，通过其来评估有机合成领域的当前状态。值得注意的是，本文提出的靶的每种合成路线，如果可实现的话，将代表在效率和选择性方面相对于先前报道的全合成的显著改进。具体而言，项目I概述了对映选择性三重有机催化级联序列的发展。从这种转化产生的共同中间体将迅速发展为Aspidosperma，Kopsia和Strychnos家族的天然产物的关键成员-即士的宁，akuammicine，kopsinine，kopsanone，aspidospermidine和vincadifformine。项目二和项目四设想分别开发第二代、四重级联途径，以生产kopsanone和士的宁。在项目III中，我们将采用快速的有机级联方法来获得一种常见的中间体，该中间体可用于Aspidosperma和Strychnos家族的许多成员。关键的有机级联加合物将被推进为铬胺B。项目V将需要对细胞毒性teleocidin天然产物，如吲哚内酰胺V，及其类似物的新的级联为基础的战略的调查。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Phyllantidine和Bruceol的全合成。 公共卫生关系：本研究的目的是建立一种新的化学合成策略，使天然产物，生物活性化合物和药物制剂可以在一个高度加速的方式从廉价，廉价和容易获得的起始材料。