Stereocontrolled Synthesis of Bioactive Alkaloids

描述（由申请人提供）：该计划的总体目标是为结构复杂的生物碱的立体选择性合成开发简洁，通用的策略和方法。研究计划的方法部分分为三大领域。第一部分介绍了重要抗癌药物长春碱和长春新碱及其类似物的合成研究。在上一个资助期内，我们开发了一种高效、实用的Aspidosperma生物碱（Aspidosperma生物碱的“较低”部分）合成方法，该方法基于专门为此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一个实用的化学合成的生物碱。在这种情况下，我们将开发新的简洁，不对称合成文多灵，长春质碱的第一个不对称合成，“上”（velbenamine）的一部分，并开发新的方法耦合两个部分产生生物活性的生物碱。还将制备结构上不同的马唐生物碱类似物。第二部分介绍了新开发的化学应用于各种生物活性的天然产物，这些天然产物是从geissoclavine生物遗传学上衍生的，包括阿卡波糖，多果芸香胺和strictamine。第三部分描述石蒜科生物碱和hapalindoles的简明、通用路线。这两个家族都有表现出显著抗癌活性的成员。所提出的合成路线有效地利用了我们实验室在上一次资助期间开发的不对称DA化学。在整个研究计划部分，我们提供了广泛的初步结果，以支持拟议的新化学。总体而言，这些调查预计不仅会导致有效的合成范围广泛的吲哚生物碱，但也在开发有用的新方法，特别是钯催化过程和不对称Diels-Alder反应。通过这项工作开发的方法应该证明对其他合成工作有用。这项工作有望导致许多具有生物活性的天然产物（特别是抗癌药物）及其类似物的合成。这些合成化合物，包括高级中间体，将提交进行生物学试验。

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.