ALLENIC PAUSON KHAND REACTION--SYNTHETIC APPLICATIONS

ALLENIC PAUSON KHAND 反应--合成应用

• 批准号: 6017090
• 负责人: Kay M Brummond
• 金额: $ 15.57万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 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 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6017090
• 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， 将允许合成化学家获得更多的化合物类别 比现有的方法更快速和立体选择性。 第二个目的 是通过应用这些新方法来证明其适用性， 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， 它被广泛应用于天然产物的合成。 我们已经成功地证明，可以用丙二烯来代替 烯烃在P-K环加成反应中生成环戊烯酮。 以来 初步研究表明，这种联烯P-K环加成的可行性 在仅使用单取代的联烯的情况下，我们扩大了范围 与3，3-和1，3-二取代联烯的环加成反应。 有趣的是，这些新的联烯环加成反应的结果 衬底显示出衬底结构依赖于 丙二烯-P-K反应的过程。 因此，更完整的扩展 这种等位基因-P-K反应的范围非常诱人， 具有有趣的官能度和取代的环系统 提出了模式。 丙二烯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提供了路线， 两组天然产物的骨架 作为可药用化合物，伊鲁定和J-系列的 兰丁 丙二烯-P-K反应在合成 羟甲基酰基富烯，一种目前正在进入 作为抗癌剂的第二阶段临床试验，在其中提出。 我们建议使用我们的方法快速组装 羟甲基酰基富烯结构。 我们也在应用这种方法 涉及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 这两个关键步骤 合成过程中涉及一个丙二烯-P-K反应， 合成，使亚甲基环戊烯酮暴露于 其他化学操作。 我们发现并发展了一种制备联烯的新方法， 基团，涉及烯丙基质子的动力学去质子化， 烯醇磷酸盐。 我们计划将这种方法扩展到一锅法 从简单的烯酮制备丙二烯炔，然后将其用于 以获得新的丙二烯P-K环加成前体。 此外该 通过使用手性碱或手性碱中的碱获得手性联烯 存在手性配体以实现对映选择性去质子化 本文提出