Synthesis Strategies for Bioactive Natural Products

生物活性天然产物的合成策略

• 批准号: 7319715
• 负责人: THOMAS R. HOYE
• 金额: $ 25.47万
• 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/7319715
• 关键词: Acids; Alder plant; Alkaloids; Antimalarials; Architecture; Biological Factors; Chemical Structure; Chemicals; Chemistry; Class; 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; Skeletal system; Structure; Terpenes; Testing; UCS 1025A; base; chemical reaction; cycloaddition; design; equisetin; ilium; integramycin; leuconolam; member; novel; oocydin A; oxidation; penostatin A; penostatin B; programs; silane; tetramic acid

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）：这是一项开发与化学和生物合成相关的新反应和策略的提案。每个想法都受到生物活性天然产品结构的启发。几乎在每种情况下，设计都包括使用一个或多个反应（或反应级联），从而在产品中引入很大程度的分子（结构）复杂性。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关键的机械分析后确定的。反过来，这又引出了目标 II-V 中常见的副主题，我们将尝试利用潜在的“自发”生物合成事件。 “大局”假设是，生物体有时会通过普遍存在的酶类（例如那些通常产生聚酮化合物和萜烯的酶）的集体作用来产生代谢物，这些酶恰好被赋予足够的反应性，随后会发生自发的（设置）的）反应进一步（通常是戏剧性地）改变其化学结构。这些最后的“抛光”步骤可以揭示许多新的化学成分，并且它们提供的结构可能对生物体具有进化优势。如果我们基于机制的具体假设被证明是正确的，那么就会发现一些显着的新化学反应，有可能引入大量的结构复杂性。目标 I. 开发天然产物卵胞素 A（又名 hatrumalide NA，la）的高效第二代全合成。开发一种新型的烯丙基硅烷跨环环化成马来酰亚胺的方法，以有效地产生生物碱亮色酰胺 (Ib) 中独特的骨架结构。目标二。自发的单线态氧反应和内过氧化物复分解是否负责产生新的过氧化抗疟剂 II（我们最近推导出了其结构）？目标三。在合成辛酰四酸天然产物 IIIa-IIIle 的背景下利用自发分子内 Diels-Alder (IMDA) 反应性。检验我们的假设，即吡喃鎓离子是自发双分子狄尔斯-阿尔德反应中形成肉植酸甲酯 (Illf) 的活性亲双烯体。目标四。自发的杂狄尔斯-阿尔德反应、电环反应、氧化反应和克莱森反应是否将几乎所有的喷诺他丁家族成员 (IV-A-I) 相互关联？目标 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 事件是否会导致 hirsutellones A-F (V-A-F)（以及 GKK 和吡咯啶）？