Stereocontrolled Synthesis of Bioactive Alkaloids

描述(由申请人提供)：该项目的总体目标是开发简明、通用的策略和方法，用于立体选择性地合成结构复杂的生物碱。研究计划的方法部分分为三个大的领域。第一部分介绍了针对重要抗癌药物长春花碱和长春新碱及其类似物的合成的研究。在上一次资助期间，我们开发了一种高效、实用的Aspidosperma生物碱(长春花碱的“较低”部分)的合成方法，该方法基于专门为该应用开发的对映选择性Diels-Alder(DA)反应。我们在这个项目中的下一个目标是完成长春花碱的实际化学合成。在此背景下，我们将开发新的简明、不对称合成长春花碱的新方法，这是长春花碱的第一个不对称合成，也是第一个不对称合成的“上部”(绒毛胺)部分，并开发将这两个部分偶联以产生生物活性长春花碱的新方法。还将制备结构多样的长春花碱类似物。第二部分描述了新开发的化学在各种生物活性天然产物中的应用，这些生物活性天然产物是从吉三氮生物衍生而来的，包括阿卡格林、多卡帕胺和斯特拉明。第三部分描述了石蒜科生物碱和哈帕林内酯的简明一般路线。这两个家族都有表现出显著抗癌活性的成员。建议的合成路线有效地利用了我们实验室在上一次赠款期间开发的不对称DA化学。在整个研究计划部分，我们提供了广泛的初步结果来支持拟议的新化学。总体而言，这些研究不仅有望有效地合成广泛的吲哚生物碱，而且还将开发有用的新方法，特别是钯催化的过程和不对称的Diels-Alder反应。通过这项工作开发的方法应该被证明对其他合成努力有用。这项工作有望导致合成许多具有生物活性的天然产物(特别是抗癌剂)及其类似物。这些合成化合物，包括高级中间体，将被提交进行生物测试。

DESCRIPTION (provided by applicant): The overall goal of this program is to develop concise, general strategies and methods for the stereoselective synthesis of structurally complex alkaloids. The methods section of the research plan is divided into three broad areas. The first part describes studies directed toward the synthesis of the important anticancer agents vinblastine and vincristine, and their analogs. During the last funding period we developed an efficient, practical synthesis of Aspidosperma alkaloids ("lower" part of Vinca), based on an enantioselective Diels-Alder (DA) reaction that was specifically developed for this application. Our next objective in this project is to complete a practical chemical synthesis of the Vinca alkaloids. In this context, we will develop new concise, asymmetric syntheses of vindoline, the first asymmetric synthesis of catharanthine, the "upper" (velbenamine) part, and develop new methods for coupling the two parts to produce bioactive Vinca alkaloids. Structurally diverse analogs of the Vinca alkaloids will also be prepared. The second part describes the application of the newly developed chemistry to a diverse range of bioactive natural products that are derived biogenetically from geissoschizine, including akagerine, pleiocarpamine, and strictamine. The third part describes concise, general routes to Amaryllidaceae alkaloids and hapalindoles. Both families have members that exhibit significant anticancer activity. The proposed synthetic routes make efficient use of the asymmetric DA chemistry that was developed in our labs during the last grant period. Throughout the research plan section, we provide extensive preliminary results to support the proposed new chemistry. Overall, these investigations are expected to result not only in efficient syntheses of a wide range of indole alkaloids, but also in the development of useful new methodologies, particularly palladium-catalyzed processes and asymmetric Diels-Alder reactions. The methods developed through this work should prove useful to other synthetic endeavors. The work is expected to lead to the synthesis of many biologically active natural products (especially anticancer agents) and their analogs. These synthetic compounds, including advanced intermediates, will be submitted for biological testing.