Synthesis of Anticancer Agents Using Prins Cyclizations

该提案中的主要合成靶点是佛波唑 B，一种非常有效的抗癌剂。佛波唑 B 针对 NCI 的肿瘤细胞系进行了测试，结果发现，例如，它可以抑制结肠肿瘤细胞 HCT-116 (GI50 4.36 X 10(-10) M) 的生长。佛波唑的两个关键片段是在之前的资助期内使用我们的片段偶联 Prins 环化制备的。合成的完成将通过组装大环内酯 A 并连接侧链 B 来完成。合成佛波唑醇将提供给合作者来评估其作用方式，并评估其作为抗癌药物的潜力。我们正在开发 Prins 环化，用于合成许多天然产物中发现的复杂四氢吡喃环。在这个新的资助期内，我们将研究片段偶联 Prins 环化的立体选择性和区域选择性。该反应的区域选择性版本是天然产物拉贾酮合成中的关键步骤。我们还将开发两种新的氧碳鎓离子环化：Mukaiyama aldol-Prins (MAP) 环化和碳捕获 Prins 环化。这两种新反应的简单版本已在进度报告中进行了演示和介绍。 MAP反应将烷基烯醇醚的Mukaiyama羟醛反应与Prins环化结合起来，产生两个新的碳-碳键、一个新的环和几个立体中心。它是拟定的高度收敛合成 leucascandrolide A 的基础。碳捕获 Prins 环化产生两个新的碳-碳键、一个环和几个立构中心。它是拟议合成 Epicalyxin F（一种从传统中药植物中分离出来的抗癌化合物）的基础。这些新方法将成为组装四氢吡喃天然产物的有力工具。选择用于研究的每个合成靶点都具有抗肿瘤活性。佛波唑 B 显然是最重要的，因为它具有极强的效力，而且天然可用的物质非常缺乏。然而，其他合成靶标，leucascandrolide A、epicalyxin F 和ratjadone 也具有有趣的抗肿瘤活性，这些合成产品将提供给合作者进行评估。

The principle synthetic target in this proposal is phorboxazole B, a remarkably potent anticancer agent. Phorboxazole B was tested against the NCI's panel tumor cell lines and was found, for example, to inhibit the growth of colon tumor cells HCT-116 (GI50 4.36 X 10(-10) M). Two of the key segments of phorboxazole were prepared in the previous grant period using our segment-coupling Prins cyclization. Completion of the synthesis will be accomplished by assembly of the macrolide A and attaching the side chain B . Synthetic phorboxazole will be made available to collaborators to evaluate its mode of action, and to evaluate its potential as an anticancer agent. We are developing Prins cyclizations for the synthesis of complex tetrahydropyran rings found in many natural products. In this new grant period we will investigate the stereoselectivity and regioselectivity of the segment-coupling Prins cyclization. A regioselective version of this reaction is the key step in a proposed synthesis of the natural product ratjadone. We will also develop two new oxacarbenium ion cyclizations: the Mukaiyama aldol-Prins (MAP) cyclization and the carbon-trapping Prins cyclizations. Simple versions of both of these new reactions have been demonstrated and presented in the progress report. The MAP reaction combines a Mukaiyama aldol reaction of alkyl enol ether with a Prins cyclization to produce two new carbon-carbon bonds, one new ring and several stereogenic centers. It is the basis for a proposed highly convergent synthesis of leucascandrolide A. The carbon-trapping Prins cyclization produces two new carbon-carbon bonds, one ring and several stereogenic centers. It is the basis of a proposed synthesis of epicalyxin F, an anticancer compound isolated from a traditional Chinese medicinal plant. These new methods will be powerful tools for the assembly of tetrahydropyran natural products. Each of the synthetic targets selected for investigation has antitumor activity. Phorboxazole B is clearly the most important because of its extreme potency and because of the dearth of naturally available material. However, the other synthetic targets, leucascandrolide A, epicalyxin F and ratjadone also have interesting antitumor activity, and these synthetic products will be made available to collaborators for evaluation.