Synthesis Strategies for Bioactive Natural Products

生物活性天然产物的合成策略

• 批准号: 7625177
• 负责人: THOMAS R. HOYE
• 金额: $ 25.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625177
• 关键词: Acids; Alder plant; Alkaloids; Antimalarials; Architecture; Biological Factors; Chemical Structure; Chemicals; Chemistry; Cyclization; DNA Sequence Rearrangement; Development; Diels Alder reaction; Electron Transport; Enzymes; Event; Family; Generations; Grant; Hydrogen; Ions; Lead; Maleimides; Molecular; Organism; Pathway interactions; Polishes; Production; Reaction; Research Personnel; Silanes; Singlet Oxygen; Structure; Terpenes; Testing; base; chemical reaction; cycloaddition; design; equisetin; ilium; integramycin; leuconolam; member; novel; oocydin A; oxidation; penostatin A; penostatin B; programs; silane; skeletal

DESCRIPTION (provided by applicant): This is a proposal for the development of new reactions and strategies that are relevant to both chemical- and bio-synthesis. Each idea is inspired by the structure of a biologically active natural product. In nearly every case the design includes the use of one or more reactions (or reaction cascades) that introduces a large degree of molecular (structural) complexity into the product. In most cases these reactions have been identified following a critical, mechanistic analysis of the biosynthetic pathway by which the natural product has likely been made. In turn, this has led to the subtheme-common to Aims II-V-whereby we will attempt to exploit potentially 'spontaneous' biosynthetic events. The 'big picture' hypothesis is that organisms sometimes produce metabolites, by the collective action of ubiquitous classes of enzymes (e.g., those commonly producing polyketides and terpenes), that just happen to be endowed with sufficient reactivity that they subsequently undergo a spontaneous (set of) reaction(s) that further, and often dramatically, alter their chemical structures. These final 'polishing' steps can reveal much new chemistry and they provide structures that are, presumably, of evolutionary advantage to the organism. To the extent our mechanism-based, specific hypotheses are proven to be correct, then some remarkable new chemical reactions, having the potential to introduce substantial levels of structural complexity, will be discovered. Aim I. Develop a highly efficient, second generation total synthesis of the natural product, oocydin A (aka haterumalide NA, la). Develop a novel transannular cyclization of an allylic silane to a maleimide to efficiently produce the unique skeletal architecture in the alkaloid leuconolam (Ib). Aim II. Are spontaneous singlet oxygen reactions and an endoperoxide metathesis responsible for the production of the new peroxidic, antimalarial agent II, whose structure we have recently deduced? Aim III. Exploit spontaneous intramolecular Diels-Alder (IMDA) reactivity in the context of synthesis of octalinoyltetramic acid natural products Illa-llle. Test our hypothesis that a pyrylium ion is the active dienophile in a spontaneous bimolecular Diels-Alder reaction that forms methyl sarcophytoate (Illf). Aim IV. Do spontaneous hetero-Diels-Alder, electrocyclic, oxidation, and Claisen reactions interlink nearly all members of the penostatin family (IV-A-I)? Aim V. Do spontaneous electron transfer, radical macrocyclization, oxygenation, hydrogen atom transfer, elimination, and Diels-Alder events lead to hirsutellones A-F (V-A-F) (and GKKs and pyrrocidines)?

描述（由申请人提供）：这是一项关于开发与化学合成和生物合成相关的新反应和策略的提案。每一个想法的灵感都来自于一种具有生物活性的天然产品的结构。几乎在每一种情况下，设计都包括使用一个或多个反应（或反应级联），这些反应将很大程度的分子（结构）复杂性引入产物中。在大多数情况下，这些反应是在对可能产生天然产物的生物合成途径进行批判性的机械分析后确定的。反过来，这导致了子主题共同的目标II-V，我们将试图利用潜在的“自发”的生物合成事件。“大局”假设是，生物体有时会产生代谢物，通过普遍存在的酶类的集体作用（例如，那些通常产生聚酮化合物和萜烯的化合物），其恰好被赋予足够的反应性，使得它们随后经历进一步且通常显著地改变其化学结构的自发（一组）反应。这些最后的“抛光”步骤可以揭示许多新的化学物质，它们提供的结构可能对生物体具有进化优势。在某种程度上，我们基于机制的特定假设被证明是正确的，然后一些显着的新的化学反应，有可能引入大量的结构复杂性，将被发现。艾姆岛开发高效、第二代全合成天然产物卵环素A（aka haterumalide NA，la）。开发一种新的烯丙基硅烷到马来酰亚胺的跨环环化，以有效地产生生物碱明可醇胺（Ib）中的独特骨架结构。Aim II.自发单线态氧反应和内过氧化物复分解负责生产新的过氧化物，抗疟剂II，其结构，我们最近推断？Aim III.在合成辛氨酰特特拉姆酸天然产物IIIa-IIIe的背景下利用自发的分子内狄尔斯-阿尔德（IMDA）反应性。验证我们的假设，即吡喃离子是自发双分子Diels-Alder反应中的活性亲双烯体，该反应形成了肉藻酸甲酯（Illf）。目标四。自发的异Diels-桤木反应、电环化反应、氧化反应和Claisen反应是否将几乎所有的penostatin家族（IV-A-I）成员相互联系起来？目的V.自发电子转移、自由基大环化、氧化、氢原子转移、消除和Diels-Alder事件是否导致了多毛碲酮A-F（V-A-F）（以及GKK和吡咯烷）？