Synthesis of Anticancer Agents Using Prins Cyclizations

在这个提议中的主要合成目标是一种非常有效的抗癌剂-佛波唑B。针对NCI的panel肿瘤细胞系测试了Phorboxazole B，发现其例如抑制结肠肿瘤细胞HCT-116（GI 50 4.36 × 10（-10）M）的生长。两个关键片段的phorboxazole制备在前一个赠款期间使用我们的片段耦合普林斯环化。通过组装大环内酯A并连接侧链B完成合成。合成phorboxazole将提供给合作者，以评估其作用模式，并评估其作为抗癌剂的潜力。我们正在开发Prins环化反应，用于合成在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，我们将研究链段耦合Prins环化反应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ratjadone合成的关键步骤。我们还将开发两种新的氧碳环化反应：Mukaiyama aldol-Prins（MAP）环化反应和碳捕获Prins环化反应。这两种新反应的简单版本已在进度报告中演示和介绍。MAP反应结合了烷烯醇醚的Mukaiyama羟醛缩合反应和Prins环化反应，产生两个新的碳-碳键，一个新的环和几个立体中心。这是一个建议的高度收敛的合成白木香内酯A的基础。碳捕获Prins环化产生两个新的碳-碳键，一个环和几个立体中心。这是从传统中药植物中分离的抗癌化合物epicalyxin F的拟议合成的基础。这些新方法将为四氢吡喃天然产物的组装提供强有力的工具。选择用于研究的每种合成靶标都具有抗肿瘤活性。Phorboxazole B显然是最重要的，因为它的极端效力，因为缺乏天然可用的材料。然而，其他合成目标，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.