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）：这是针对与化学和生物合成相关的新反应和策略的发展的建议。每个想法都受到生物活性天然产品的结构的启发。在几乎每种情况下，设计都包括使用一个或多个反应（或反应级联反应），该反应将大量分子（结构）复杂性引入产品中。在大多数情况下，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之后，已经确定了这些反应。反过来，这导致了子主题的目标II-V-我们将尝试利用潜在的“自发”生物合成事件。 “大图”假设是，有时通过无处不在的酶（例如那些通常产生聚酮化合物和萜烯的酶的酶的集体作用）产生代谢产物，而这些酶恰好具有足够的反应性，以使它们随后经历了自发性（设置）（设置）反应的进一步且通常很大程度上改变了其化学结构。这些最终的“抛光”步骤可以揭示出许多新的化学反应，并且它们提供了对生物体进化优势的结构。如果我们基于机制的特定假设被证明是正确的，那么将发现一些显着的新化学反应，具有引入大量结构复杂性的潜力。 AIM I.开发了自然产物卵母素A（又名Haterumalide NA，LA）的高效，第二代的总合成。开发一种新型的烯丙基硅烷到马来酰亚胺的透射环化，以有效地产生生物碱白酚（IB）中的独特骨骼结构。目标II。自发的单重氧反应和内氧化物的分解是否负责产生新的过氧化抗性剂II，我们最近推出了我们的结构？目标三。在合成八烯丙基二烯酸酸天然产物Illa-llle的背景下，剥削自发分子内多尔（IMDA）反应性。检验我们的假设是，吡fyrium离子是形成甲基甲植物（ILLF）的自发双分子二烷 - alder反应中的活性二磷。目标IV。自发的异氧化物 - alder-alder，电循环，氧化和Claisen反应是否相互链接几乎所有Penostatin家族的所有成员（IV-A-I）？ Aim V.自发电子转移，自由基大环化，氧合，氢原子转移，消除和Diels-Alder事件导致Hirsutellones A-F（V-A-F）（V-A-F）（以及GKKS和GKKS和吡咯烷）？