ALLENIC PAUSON KHAND REACTION--SYNTHETIC APPLICATIONS

ALLENIC PAUSON KHAND 反应--合成应用

• 批准号: 6386322
• 负责人: Kay M Brummond
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386322
• 关键词: alkenes; antineoplastics; chemical addition; chemical synthesis; cyclic ketone; diene; drug design /synthesis /production; prostaglandin analogs; protonation; stereochemistry

The primary objective of this proposal is to develop new methods that will allow synthetic chemists access to classes of compounds more quickly and stereoselectively than existing methods. A second objective is to demonstrate the applicability of these new methods by applying them to the synthesis of medicinally important compounds. The Pauson-Khand reaction is a multi-component reaction that has been used extensively and successfully in the synthesis of natural products. We have successfully demonstrated that allenes can be used in place of olefins in the P-K cycloaddition to generate cyclopentenones. Since the initial study to show the feasibility of this allenic P-K cycloaddition where only monosubstituted allenes were used, we have extended the scope of this allenic cycloaddition to 3,3- and 1,3-disubstituted allenes. Interestingly, the results from these new allenic cycloaddition substrates demonstrate a dependence of the substrate structure upon the course of the allenic-P-K reaction. Thus a more complete extension of the scope of this allenic-P-K reaction is very enticing and a number of ring systems possessing interesting functionality and substitution patterns are proposed. The allenic P-K reaction will also be used to prepare enantiopure cyclopentenones by using a chiral allene in the cycloaddition process. In addition, these exciting results offer routes into skeletons of two groups of natural products that have resurfaced as medicinally viable compounds, the illudins and the J-series of prostaglandins. The application of the allenic-P-K reaction to the synthesis of hydroxymethylacylfulvene, an illudin analog that is currently entering phase two clinical trials as an anticancer agent, is proposed within. We are proposing to use our methodology to rapidly assemble hydroxymethylacylfulvene structure. We are also applying this method to the synthesis of 15-deoxy-delta 12,14-prostaglandin J2 which has recently been identified as the first natural ligand for the peroxisome proliferator activated receptor. The key steps of both of these synthesis involve an allenic-P-K reaction during the end-game of the synthesis, minimizing the exposure of the methylene cyclopentenones to other chemical manipulations. A new method to prepare allenes has been discovered and developed in our group which involves the kinetic deprotonation of an allylic proton of an enol phosphate. We plan to extend this methodology to the one-pot preparation of allenynes from simple alkenones, which will then be used to access novel allenic P-K cycloaddition precursors. In addition, the attainment of chiral allenes by using chiral bases or bases in the presence of chiral ligands to effect the enantioselective deprotonation is proposed.

该提案的主要目标是开发新方法 将使合成化学家能够更多地了解化合物类别 比现有方法快速且立体选择性。 第二个目标 是通过应用来证明这些新方法的适用性 它们用于合成重要的药用化合物。 Pauson-Khand 反应是一种多组分反应， 广泛并成功地用于天然产物的合成。 我们已经成功证明丙二烯可以用来代替 烯烃在P-K环加成反应中生成环戊烯酮。 自从 初步研究表明这种联烯 P-K 环加成的可行性 如果仅使用单取代丙二烯，我们扩大了范围 该丙二烯环加成至3,3-和1,3-二取代丙二烯。 有趣的是，这些新的联烯环加成的结果 基板证明了基板结构的依赖性 联烯-P-K反应的过程。 从而更完整地扩展 这种联烯-P-K 反应的范围非常诱人，并且许多 具有有趣功能和取代的环系统 提出了模式。 联烯 P-K 反应也将用于 通过使用手性丙二烯制备对映体纯环戊烯酮 环加成过程。 此外，这些令人兴奋的结果还提供了路线 变成两组重新出现的天然产物的骨架 作为药用上可行的化合物，隐伞素和 J 系列 前列腺素。 联烯-P-K反应在合成中的应用 羟甲基酰基富烯，一种目前正在进入市场的隐伞素类似物 作为抗癌剂的二期临床试验已在其中提出。 我们建议使用我们的方法来快速组装 羟甲基酰基富烯结构。 我们也在应用这个方法 15-脱氧-δ 12,14-前列腺素 J2 的合成 最近被鉴定为过氧化物酶体的第一个天然配体 增殖物激活受体。 这两个步骤的关键步骤 合成涉及在最后阶段的联烯-P-K反应 合成，最大限度地减少亚甲基环戊烯酮的暴露 其他化学操作。 我们发现并开发了一种制备丙二烯的新方法 涉及烯丙基质子的动力学去质子化的基团 烯醇磷酸酯。 我们计划将这种方法扩展到一锅法 从简单的烯酮制备丙炔，然后使用 获得新型联烯 P-K 环加成前体。 此外， 通过使用手性碱基或以下碱基获得手性丙二烯 手性配体的存在可影响对映选择性去质子化 被提议。