Cascade Catalysis: A Valuable Strategy for Complex Molecule Synthesis

描述(申请人提供)：这项研究提案寻求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、基于天然产品的分子的全合成。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，需要一种“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执行。由于在合成路线的每一步都需要分离和提纯中间体，这种经典的多步合成方法在效率和产品选择性方面受到了一些严重的限制。作为另一种方法，我们最近引入了一个新的合成概念，称为有机级联催化，它试图将天然产品生物合成提供的一些优势转化到实验室合成领域。有机级联催化通过将多个顺序转化合并成单个级联序列来模拟生物合成的概念蓝图，每个转化都由有机催化激活的正交模式控制。为此，我们在各种环境中展示了有机级联催化的非凡能力，使简单的非手性底物能够快速转化为复杂的、立体化学丰富的单一对映体加合物。这项研究提案试图通过对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是有价值的全合成基准化合物，通过它们来评估有机合成领域的现状。值得注意的是，每条通向本文提出的目标的合成路线，如果能够实现，在效率和选择性方面都将比以前报道的全合成有显著的改进。具体地说，项目I概述了对映体选择性三有机催化级联序列的开发。从这一转变中产生的共同中间体将迅速发展到阿司匹林、Kopsia和Strychnos天然产物家族的关键成员--即士的宁、阿库阿米星、柯辛宁、柯普三酮、螺杆菌亚胺和长春甲双胺。项目二和项目四设想发展第二代四级联路线，分别通向科普萨诺尼和士的宁。在项目III中，我们将采取一种快速的有机级联方法，将一种常见的中间体送往无精子目和马钱子科的一些成员。关键的有机级联加合物将被推进到橙色胺B。项目V将需要研究一种新的基于级联的策略来获得细胞毒性杀线菌素天然产物，如吲哚内酰胺V及其类似物。最后，项目VI的重点将是开发一种基于SOMO催化的有机级联平台，以及随后将这一新方法应用于天然产物叶绿豆素和鸦胆子醇的全合成。 与公共健康相关：这项研究的目标是建立一种新的化学合成战略，使天然产品、生物活性化合物和医药制剂能够以廉价、廉价和容易获得的起始材料以极快的方式产生。

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.