Synthesis Strategies for Bioactive Natural Products

描述(由申请人提供)：这是一项关于开发与化学和生物合成相关的新反应和策略的建议。每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)，从而将高度的分子(结构)复杂性引入到产品中。在大多数情况下，这些反应是在对天然产物可能通过的生物合成途径进行关键的、机械的分析后确定的。反过来，这又导致了副主题--AIMS II-V的共同之处--我们将试图利用潜在的“自发”生物合成事件。大局假说是，生物体有时通过无处不在的一类酶(例如，那些通常产生聚酮和萜烯的酶)的集体作用产生代谢物，这些代谢产物恰好具有足够的反应活性，随后它们会经历一系列自发的反应(S)，从而进一步并往往戏剧性地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物质，它们提供的结构可能对有机体具有进化优势。在一定程度上，我们基于机理的特定假设被证明是正确的，然后将发现一些引人注目的新化学反应，有可能引入大量的结构复杂性。目的I.开发高效、第二代天然产物卵青素A(又名haterumalide na，la)的全合成方法。开发一种新的烯丙基硅烷跨环环合成马来酰亚胺的方法，以有效地产生生物碱亮康安定(Ib)中独特的骨架结构。目的II：是自发的单线态氧反应和过氧化内化作用导致了新的过氧性抗疟疾药II的产生吗？目的III.在合成辛基四酸天然产物的背景下，开发自发的分子内Diels-Alder(IMDA)反应性。测试我们的假设，即在自发的双分子Diels-Alder反应中，Prylium离子是活跃的亲双烯化合物，该反应形成了肌酸甲酯(Illf)。目的IV.自发性异Diels-Alder反应、电环反应、氧化反应和Claisen反应是否将Penostatin家族(IV-A-I)的几乎所有成员连接在一起？目的V.自发性电子转移、自由基大环化、氧化、氢原子转移、消除和Diels-Alder事件是否导致多毛内酯A-F(V-A-F)(以及GKK和吡咯烷)？

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)?