Synthesis Strategies for Bioactive Natural Products

描述（由申请人提供）：这是一份发展与化学和生物合成相关的新反应和策略的提案。每个想法的灵感都来自于一种具有生物活性的天然产物的结构。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），这些反应将很大程度上的分子（结构）复杂性引入产品中。在大多数情况下，这些反应是在对天然产物可能产生的生物合成途径进行关键的机械分析后确定的。反过来，这又导致了目标ii - v的共同主题，即我们将尝试利用潜在的“自发”生物合成事件。“大图景”假说认为，生物体有时通过无所不在的酶类（例如，通常产生聚酮和萜烯的酶类）的集体作用产生代谢物，这些代谢物恰好具有足够的反应活性，随后发生自发的（一系列）反应，这些反应通常会显著地进一步改变它们的化学结构。这些最后的“抛光”步骤可以揭示许多新的化学成分，并提供可能对生物体具有进化优势的结构。在某种程度上，我们基于机制的特定假设被证明是正确的，那么一些引人注目的新化学反应将被发现，它们有可能引入相当程度的结构复杂性。目的1 .开发一种高效的第二代天然产物卵黄素a（又名haterumalide NA， la）的全合成方法。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白松素（Ib）中独特的骨架结构。目的二世。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物抗疟药II，其结构我们最近已推断出来？第三目标。利用分子内自发Diels-Alder （IMDA）反应合成辛烷酰四乙酸天然产物Illa-llle。验证我们的假设，即在自发的双分子Diels-Alder反应中，一个吡啶离子是活性的亲二烯试剂，该反应形成了甲基石酸酯（Illf）。自发的杂diels - alder、电环、氧化和Claisen反应是否将几乎所有的抑素家族成员（IV- a - i）连在一起？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事件是否会导致毛酮A-F (V-A-F)（以及GKKs和吡啶）？

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)?