Chiral Approaches to Natural Product Synthesis

描述（由申请人提供）：该计划的长期目标包括具有理想生物活性的复杂天然产物的实验室合成以及将简化该任务的新合成方法的开发。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类似物，这些类似物可以以比天然化合物本身更实用的方式获得。我们的合成工作将把重点放在那些能使合成尽可能简短和高产的策略上。我们期望完成一种非常有前途的抗癌和抗阿尔茨海默病药物苔藓抑素1的全合成，并尽可能优化这一途径，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这些结构特征，这些结构特征负责该制剂的生物功能，并将这些信息用于制备简化的类似物。我们将扩大并继续在苔藓抑素类似物领域的努力，因为我们期望我们可以制备出比brio 1本身或我们目前的类似物功能更好的药物。我们还计划开展研究，以更好地定义苔藓抑素的细胞靶点，并检查我们制备的类似物的选择性概况。将获得这些类似物的完整生物学特性。此外，我们计划启动两种新结构的工作，我们预计可以利用我们在苔藓抑素和埃泊霉素工作过程中开发的策略，即acutiphycin和peloruside。我们还将研究抗癌剂haterumalide的简短方法，作为初始进入含四氢呋喃的材料。在所有这些工作中，我们希望实现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证明有用。许多具有抗癌活性的有机化合物已经从海绵等海洋资源中分离出来；非凡的苔藓虫素1就是一个例子。在80多个临床试验中，苔藓抑素1显示出非常有希望的活性，特别是当与其他药物如紫杉醇联合使用时。如果要实现这种药物的潜力，我们必须找到在实验室中制造苔藓抑素或类似化合物的方法，否则我们将永远无法获得足够的供应。这项工作将针对这些任务进行。

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.