Efficient Assemblage of Complex Biologically-Active Targets Using Donor-Acceptor

描述（申请人提供）：本研究将探索一种立体选择性合成复杂分子框架的新方法。结果将有效地获得许多具有生物学重要性的多环分子，在某些情况下，首次允许复杂支架的对映选择性合成。该策略将涉及金属催化富电子烯烃的环丙烷化。代替吗?-重氮酯生成供体-受体环丙烷（DAC）环，该环最终被电子稳定基团和潜在亲核试剂取代。用路易斯酸活化可以诱导开环形成两性离子，稳定的碳正离子会被分子内亲核加成所捕获，导致烯烃部分形成净环。这些DAC中间体将作为模板，用于合成一些天然产物，这些天然产物有望成为治疗剂。我们将首先制备由酯和二氧膦基取代的环丙烷，并研究它们重排到-膦- -内酯。将该方法应用于手性2H-chromene底物，首次完成异chamaejasmine的对映选择性合成。这种双黄酮已被证明可以改变几种细胞信号通路，并被发现对几种肿瘤细胞系包括人髓性白血病细胞有活性。然后，我们将把这一策略扩展到碳环的形成，通过制备含有酯的环丙烷，该酯以富电子烯烃的形式被碳基潜在亲核试剂取代。在两性离子形成后，富电子的烯烃将充当内部亲核试剂。在研究的亲核试剂中，烷氧基取代的苯，导致已知的细胞毒性苯并吡喃的对映选择性合成，以及吲哚，可能提供通往dragmacidin E的四环核心的有效途径。dragmacidin E是丝氨酸-苏氨酸蛋白磷酸酶的抑制剂，这类化合物也显示出抗肿瘤活性。这项研究的最终目标是通过识别潜在的先导化合物来推动合成领域的发展，并影响癌症药物治疗领域。上述靶点的合成路线将有助于其全面的临床分析。

DESCRIPTION (provided by applicant): This research will investigate a new approach to the stereoselective synthesis of complex molecular frameworks. The result will be efficient access to a number of polycyclic molecules of biological importance, allowing, in some cases, enantioselective syntheses of complex scaffolds for the first time. The strategy will involve metal-catalyzed cyclopropanations of electron-rich alkenes with ?-substituted ?-diazo esters to generate donor-acceptor cyclopropane (DAC) rings that are geminally substituted with both an electron-stabilizing group and a latent nucleophile. Activation with a Lewis acid is expected to induce ring opening to form a zwitterion, and the stabilized carbocation will be trapped by intramolecular nucleophilic addition, resulting in a net annulation of the alkene moiety. These DAC intermediates will serve as templates for the synthesis of a number of natural products that show promise as therapeutic agents. We will begin by preparing cyclopropanes that are geminally substituted with ester and diethoxyphosphoryl groups and study their rearrangement to ?-phosphono-?-lactones. Applied to a chiral 2H-chromene substrate, this method will be used to complete the first enantioselective synthesis of isochamaejasmine. This biflavonoid has been shown to alter several cell-signaling pathways, and has been found to be active against several tumor cell lines including human myeloid leukemia cells. We will then expand this strategy to the formation of carbocycles by preparing cyclopropanes that contain an ester geminally substituted with a carbon-based latent nucleophile in the form of an electron-rich alkene. Following zwitterion formation, the electron-rich alkene will act as the internal nucleophile. Among the nucleophiles studied will be alkoxy-substituted benzenes, leading to the enantioselective synthesis of a known cytotoxic benzopyran, and indoles, potentially providing an efficient route to the tetracyclic core of dragmacidin E. Dragmacidin E is an inhibitor of serine-threonine protein phosphatase, and compounds in this class have also shown antitumor activity. The ultimate goals of this research are to advance the field of synthesis and impact the field of cancer drug therapy by identifying potential lead compounds. Synthetic routes to the aforementioned targets will facilitate their comprehensive clinical analysis. PUBLIC HEALTH RELEVANCE: This project proposes to develop new synthetic strategies for preparing several medicinally-active natural products that show promise as therapeutic agents. The list includes compounds active against myeloid leukemia, diabetic neuropathy, and tuberculosis. Bio-identical laboratory syntheses of these natural products will facilitate their comprehensive clinical analysis.