2 + 3 ANNULATION PROTOCOL--NATURAL PRODUCT SYNTHESIS

2 3 模拟方案——天然产物合成

• 批准号: 3298413
• 负责人: TOMAS HUDLICKY
• 金额: $ 16.41万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3298413
• 关键词: aldehydes; antiviral agents; azides; carbonyl group; cyclic compound; cyclopropanes; drug design /synthesis /production; enolate; ethylene oxide; furans; heterocyclic compounds; molecular rearrangement; nuclear magnetic resonance spectroscopy; polyvinyls; silicon; stereochemistry

This proposal addresses the continuation of our efforts aimed at the development of mild, stereocontrolled, and enantioselective methodology for the construction of five-membered-ring compounds. The technique has as its ultimate goal annulations leading to cyclopentenes, dihydrofurans, and pyrrolines, as these constitute subunits of many natural products of biological significance. It is based on either the [2+3] intermolecular addition of ester dienolate anions to carbonyl derivatives (for cyclopentenes and dihydrofurans) or the [4+1] intramolecular addition of azides to dienes (for pyrrolines). The most important development addressed in this project will be the detailed investigation of annulations of enones and aldehydes with the dienolate derived from 4- silyloxybromocrotonate. The silicon-mediated rearrangements of vinylcyclopropanes and vinyloxiranes to cyclopentenes and dihydrofurans hold the potential of providing on of the mildest annulation procedures to date. The project will be guided along the following major aims: a. Development of nucleophilic or radical alternatives to the ring opening of vinylcyclopropanes and vinyloxiranes. b. Detailed investigation of the stereochemical course of the additions of dienolate anions derived from 2- bromocrotonates to aldehydes and enones in order to understand the diastereoselectivity of this process. c. Investigation of fluoride- catalyzed rearrangements of silyl-enol-ether-terminated vinyl-cyclopropanes and vinyl-oxiranes and insight into mechanistic details of this process. d. Investigations of enantioselective synthesis of vinyloxiranes and vinylcyclopropanes either by a chiral-auxillary approach (reagent control or by additions of the above dienolates to chiral precursors (substrate control). e. Investigation of possible chirality transfer from rigid chiral silicon auxiliaries. f. Applications of these methodologies to the preparation of specionin (an antifeedant substance), pyrrolizidine and indolizidine alkaloids of known antibiotic or antiviral activities, and the furanoid subunits that are integral parts of many antibiotics; and to the second generation synthesis of retigeranic acid. The direction of research during the next funding period is aimed at the conclusion of investigations that are necessary in order to render the [2+3] asymmetric annulation methodology a permanent tool in the field of carbocylic and heterocylic synthesis. Reliable provision of cyclopentanoid, furanoid, and pyrroline units extends the applications of this methodology to the design of heterocyclic natural products of biological significance.

这项建议涉及我们继续努力， 开发温和的、立体控制的和对映选择性的方法， 五元环化合物的构建。 该技术作为其 最终目标环化，得到环戊烯、二氢呋喃，和 吡咯啉，因为它们构成许多天然产物的亚基， 生物学意义 它是基于[2+3]分子间 将酯二烯醇盐阴离子加成到羰基衍生物上（对于 环戊烯和二氢呋喃）或[4+1]分子内加成 叠氮化物到二烯（对于吡咯啉）。 最重要的发展 在这个项目中将解决的是详细的调查环 烯酮和醛与衍生自4- 甲硅烷氧基溴巴豆酸酯。 硅介导的 乙烯基环丙烷和乙烯基环氧乙烷到环戊烯和二氢呋喃 保持提供最温和的环化手术的潜力， 约会 该项目将沿着以下主要目标进行：a. 发展 亲核或自由基的替代物的开环 乙烯基环丙烷和乙烯基环氧乙烷。 B. 详细调查 衍生自2-羟基-2-甲基-3-甲基-4-（2-甲基-4-苯基）-2-（2-甲基-2 溴巴豆酸酯的醛和烯酮，以了解 该方法的非对映选择性。 C. 氟化物的研究- 甲硅烷基烯醇醚封端的乙烯基环丙烷的催化重排 和乙烯基环氧乙烷和洞察这一过程的机械细节。 D. 乙烯基环氧乙烷对映选择性合成的研究 乙烯基环丙烷或通过手性辅助方法（试剂对照 或通过将上述二烯醇化物添加到手性前体（底物 对照）。 e. 刚性分子可能的手性转移研究 手性硅助剂。 F. 将这些方法应用于 制备specionin（一种拒食物质）、吡咯里西啶和 具有已知抗生素或抗病毒活性的吲哚里西啶生物碱，以及 呋喃类亚基是许多抗生素的组成部分; 第二代瑞替格尔烷酸的合成。 研究方向 在下一个供资期间， 为了使[2+3]不对称环化， 方法学是碳环和杂环领域的永久工具 合成. 可靠地提供环戊烷、呋喃和吡咯啉 单位扩展了这种方法的应用，以设计 具有生物学意义的杂环天然产物。