Chiral Approaches to Natural Product Synthesis

描述（由申请人提供）：该计划的长期目标包括实验室合成具有理想生物活性的复杂天然产物，以及开发新的合成方法，以简化这项任务。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，可以以比天然化合物本身更实用的方式获得。我们的综合努力将把重点放在策略上，这些策略允许尽可能简短和高产的综合。我们期望完成非常有前途的抗癌和抗阿尔茨海默氏症药物苔藓抑素1的全合成，并尽可能优化这一路线，以允许这种极其稀缺的物质的实验室合成。我们将通过合成来确定负责该试剂的生物学功能的那些结构特征，并使用这些信息来制备简化的类似物。我们将扩大并继续我们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功能甚至比brio 1本身或我们目前的类似物更好的药物。我们还计划开展研究，以更好地确定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表征。此外，我们计划启动两个新结构的工作，我们希望可以使用我们在苔藓抑素和埃博霉素工作过程中开发的策略来制备，即acutiphycin和peloruside。我们还将研究一种抗癌剂haterumalide的简短方法，作为含四氢呋喃材料的初始入口。在所有这些工作中，我们希望实施新的有机反应和策略，这将有助于目标化合物的构建，并在更广泛的背景下证明是有用的。许多具有抗癌活性的有机化合物已从海绵等海洋来源中分离出来;引人注目的药物苔藓抑素1就是一个例子。在超过80项临床试验中，苔藓抑素1显示出非常有前途的活性，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。

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.