ALLENIC PAUSON KHAND REACTION--SYNTHETIC APPLICATIONS

这项提议的主要目标是开发新的方法， 将允许合成化学家获得更多类别的化合物 比现有的方法更快速和立体地选择。第二个目标 是通过应用来演示这些新方法的适用性 它们被用来合成具有重要药用价值的化合物。 Pauson-Khandd反应是一个多组分的反应，它已经 广泛而成功地用于天然产物的合成。 我们已经成功地证明了联烯可以用来代替 P-K环加成反应中的烯烃生成环戊酮。自.以来 关于异烯P-K环加成反应可行性的初步研究 在只使用单取代联烯的情况下，我们扩大了范围 3，3-和1，3-二取代联烯的这种联烯环加成反应。 有趣的是，这些新的联烯环加成反应的结果 衬底表现出衬底结构对 二烯-P-K反应的进程。从而更完整地扩展了 这种异构化-P-K反应的范围非常诱人，许多 具有有趣的官能化和替代的环系统 并提出了相应的模式。异构化P-K反应也将被用于 用手性异丙烯制备对映体环戊烯酮 环加成工艺。此外，这些令人兴奋的结果提供了 变成了两组重新浮出水面的天然产品的骨架 作为医学上可行的化合物，伊卢丁和J系列 前列腺素。 联烯-P-K反应在合成双环戊二烯中的应用 羟甲基酰富烯，一种伊利定类似物，目前正在进入 作为抗癌剂的第二阶段临床试验是在内部提出的。 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。我们也在应用这种方法 15-脱氧-三角洲-12，14-前列腺素J2的合成 最近被确定为第一个天然的过氧化酶体配体 增殖物激活受体。这两个步骤的关键步骤 合成涉及异丙烯-P-K反应。 合成，最大限度地减少亚甲基环戊酮对 其他化学操作。 我们发现并开发了一种制备联烯的新方法。 涉及烯丙基质子的动力学去质子化的基团 一种烯醇磷酸盐。我们计划将这种方法扩展到One-pot 从简单的烯酮制备烯丙炔，然后将使用它 目的：获得新的烯烃P-K环加成前体。此外， 使用手性碱或手性碱获得手性联烯 手性配体的存在对映体选择性去质子化的影响 是提议的。

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.