Chiral Approaches to Natural Product Synthesis

描述(由申请人提供)：该计划的长期目标包括在实验室合成具有理想生物活性的复杂天然产品，以及开发将简化这一任务的新合成方法。此外，我们将尝试识别、合成和测试这些天然存在的先导化合物的结构简化的类似物，这些类似物可以以比天然化合物本身更实际的方式获得。我们的合成努力将把重点放在允许尽可能简短和高产出的合成的战术上。我们希望完成非常有希望的抗癌和抗阿尔茨海默氏症药物Bryostatin 1的全合成，并尽可能优化这一路线，以便在实验室合成这种极其稀缺的物质。我们将通过合成确定与该制剂的生物功能有关的那些结构特征，并将这些信息用于制备简化的类似物。我们将扩大和继续我们在Bryostatin类似物领域的努力，因为我们预计我们可以制备功能甚至比Brio 1本身或我们目前的类似物更好的试剂。我们还计划启动研究，以更好地定义Bryostatin的细胞靶标，并检查我们准备的类似物的选择性分布。将获得这些类似物的完整生物学特性。此外，我们计划启动两个新结构的工作，我们预计可以使用在我们的Bryostatin和Epothilone工作过程中开发的策略来准备，即针叶素和Peloruside。我们还将研究一种短期的抗癌药物haterumalide的方法，作为进入含有四氢呋喃的材料的初始途径。通过所有这些工作，我们希望实施新的有机反应和策略，这将促进目标化合物的构建，并在更广泛的背景下被证明是有用的。许多具有良好抗癌活性的有机化合物已经从海绵等海洋来源中分离出来；显着的药剂Bryostatin 1就是一个例子。在80多项临床试验中，Bryostatin 1显示出非常有希望的活性，特别是与紫杉醇等其他药物联合使用时。如果要实现这种试剂的潜力，我们必须找到在实验室制造Bryostatin或类似化合物的方法，否则我们永远无法获得足够的供应。这项工作将针对这些任务。

DESCRIPTION (provided by applicant): The long term goals of this program include the laboratory synthesis of complex natural products possessing desirable biological activity as well as the development of new synthetic methodology that will simplify this task. In addition, we will attempt to identify, and to synthesize and test, structurally simplified analogues of these naturally occurring lead compounds which can be accessed in a more practical manner than the natural compounds themselves. Our synthetic efforts will place an emphasis on tactics which allow for as brief and high yielding a synthesis as possible. We expect to complete a total synthesis of the highly promising anti-cancer and anti-Alzheimer's agent bryostatin 1 and to optimize this route as much as possible to allow for the laboratory synthesis of this exceedingly scarce substance. We will determine, through synthesis, those structural features responsible for the biological functions of this agent, and use this information in the preparation of simplified analogues. We will expand and continue our efforts in the bryostatin analogue area as we expect that we can prepare agents that function even better than brio 1 itself or our present analogues. We also plan to initiate studies to better define the cellular targets of bryostatin and to examine selectivity profiles for the analogues we prepare. Full biological characterizations of these analogues will be obtained. In addition, we plan to initiate work on two new structures which we expect can be prepared using the tactics developed in the course of our bryostatin and epothilone work, namely acutiphycin and peloruside. We will also examine a short approach to the anti cancer agent haterumalide, as an initial entry into tetrahydrofuran containing materials. Throughout all of this work, we hope to implement new organic reactions and strategies which will both facilitate the construction of the targeted compounds, as well as prove useful in a broader context. Many organic compounds with promising anti-cancer activity have been isolated from marine sources such as sponges; the remarkable agent bryostatin 1 is an example. In over 80 clinical trials, bryostatin 1 has shown very promising activity, especially when used in combination with other agents such as taxol. If the potential of this agent is to be realized, it is imperative that we find ways to make either bryostatin or similar compounds in the laboratory, as we will never be able to obtain an adequate supply otherwise. This work will be directed towards these tasks.