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: 8141278
• 负责人: David W MacMillan
• 金额: $ 31.5万
• 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/8141278
• 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）：该研究提案旨在建立我们新引入的OrganoScade催化范式的能力，以实现前所未有的效率水平，是一系列复杂的基于自然产物的分子的总合成。当前的复杂分子合成方法通常由该领域的学术和药物从业人员采用，这是一种“停止和行动”策略，其中每个化学转化都被作为一个单独的过程执行。由于需要沿着合成途径的每个阶段隔离和纯化中间体的隔离和纯化，因此，这种经典的多步合成方法受到了许多严重的限制，这些局限性在效率和产品的选择性方面受到了许多严重的限制。作为另一种方法，我们最近引入了一种新型的合成概念，称为OrganoScade催化，该概念旨在将自然产品生物合成所提供的一些优势转化为实验室合成领域。 OrganoScade催化通过合并多个顺序转换的合并来模拟生物合成的概念蓝图，每种转化都由有机催化激活的正交模式控制为单个级联序列。为此，我们已经在各种环境中证明了OrganoScade催化能够快速转化简单的ACHIRAL底物转换为复杂，立体化学上富含的单一象征加合物。这项研究建议旨在通过一系列备受瞩目的天然产物的总合成来证明OrganoScade催化的前所未有的合成能力。由于它们的复杂性及其历史和医学意义，针对此处的天然产品是有价值的总合成基准化合物，可以评估有机合成领域的当前状态。值得注意的是，与先前报道的总合成相比，本文提出的每种综合途径（如果可实现）将代表显着改善。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。由于这种转变而产生的常见中间体将迅速发展为天然产物的天aspidosperma，kopsia和Strychnos家族的主要成员 - 即，士宁宁，阿瓜氨酸，山雀，山雀，山雀，aspidospermidine和vincadifformine和vincadifformine。 II和IV项目分别设想了第二代，四级级联路线的发展，分别是山台酮和斯特里宁。在III项目中，我们将采取一种快速的OrganoScade方法，以通往Aspidosperma和Strychnos家族的许多成员的常见中间体。关键的OrganoScade加合物将推进灰油胺B。项目V将需要对基于级联反应的新策略进行调查，以实现细胞毒性远程毒素天然产品，例如Indolactam V及其类似物。最后，项目VI的重点将放在基于Somo-calsy分析的有机体平台的开发上，以及随后这种新型方法应用于天然产品Phyllantidine和Bruceol的总合成。 公共卫生相关性：这项研究的目的是建立一种新的化学综合策略，即天然产品，生物活性化合物和药用剂可以通过廉价，廉价且易于获得的起始材料以高度加速的方式生成。