ASYMMETRIC SYNTHESIS OF ANTITUMOR AGENTS

抗肿瘤剂的不对称合成

• 批准号: 2097238
• 负责人: JAMES S. PANEK
• 金额: $ 12.78万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-13 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2097238
• 关键词: antineoplastic antibiotics; beta lactam antibiotic; bridged cyclic compound; drug design /synthesis /production; enzyme inhibitors; macrolide antibiotics; protein tyrosine kinase; stereochemistry

This research proposal reflects our general interest in the development of new reagents and their use in the asymmetric synthesis of complex organic molecules that may have relevance in the treatment of human cancers. The long term objectives are the eventual achievement of the asymmetric synthesis of representative members of an emerging class of ansabridge macrocyclic lactams possessing a wide range of antitumor and antibiotic activity. Certain members, macbecin-I and herbimycin A have been shown to function as selective inhibitors of tyrosine protein kinase. In this regard we intend to: Demonstrate the utility of diasteromerically and enatimerically pure functionalized (E)-crotylsilane reagents 1, in chiral allylsilane-base bond construction methodology for the asymmetric synthesis of complex organic molecule. Specifically, diasteroface selective addition reactions with achiral aryl an aliphatic acetal will be investigated for the construction of functionalized homoallylic ethers. These homoallylic ethers will be used as key intermediates for the construction of advanced synthons in asymmetric synthesis of ansamycin natural products. The total synthesis of the ansamycin antitumor antibiotic (+)- macbecin I (2a), the total synthesis of structurally related herbimycin A (2b). These natural products and structurally related molecules (synthetic intermediates) will be evaluated as selective inhibitors of tyrosine protein kinases. The approach is based on the diasteroface selective addition of (2R,3R)-1d to aryl acetal. The asymmetric synthesis of trienomycin-A 3a and (+)-mycotirenin I (3b). The approach is based on the development of new methodology for the asymmetric synthesis syn-and anti-1,3-diols and is based on two sequential stereoselective reactions: enantioselective addition of the anti(E)-crotylsilane (2S,3R)-1a to an acetal followed by a suprafacial allelic ester transposition. This protocol will be used for the assembly of the C11, C12 & C13 sterocenters of trienomycin A and (+)-mycotirenin-I. We will begin studies directed at chemical synthesis of the cytotoxic macrolides, ulapualide A & B, other wise known as the halichondramides 4a,b. Utilizing our developing chiral crotylsilane based bond construction methodology for key asymmetric C-C bond forming reactions to be employed in the synthesis of anti- homoallylic alcohol and anti-1,3-diol synthons which are characteristic subunits of the ulapualides.

这项研究计划反映了我们对以下领域的普遍兴趣 新试剂的开发及其在不对称反应中的应用 可能与以下方面相关的复杂有机分子的合成 人类癌症的治疗。 长期目标是 最终实现代表性的不对称合成 ansabridge 大环内酰胺新兴类别的成员 具有广泛的抗肿瘤和抗生素活性。 某些成员，macbecin-I 和除草霉素 A 已被证明可以 作为酪氨酸蛋白激酶的选择性抑制剂。 在 对此，我们打算： 展示非对映体和对映体的实用性 纯官能化 (E)-巴豆基硅烷试剂 1，手性 烯丙基硅烷基不对称键构建方法 复杂有机分子的合成。 具体来说，diasteroface 与非手性芳基和脂肪族缩醛的选择性加成反应 将研究功能化建设 高烯丙基醚。 这些同烯丙基醚将用作关键 用于构建高级合成子的中间体 安沙霉素天然产物的不对称合成。 安沙霉素抗肿瘤抗生素(+)-的全合成 macbecin I (2a)，结构相关的全合成 除草霉素 A (2b)。 这些天然产物与结构相关 分子（合成中间体）将被评估为选择性 酪氨酸蛋白激酶抑制剂。该方法基于 (2R,3R)-1d 选择性加成到芳基缩醛上。 三烯霉素-A 3a 和 (+)-霉菌素 I 的不对称合成 (3b)。 该方法基于新方法的开发 用于不对称合成顺式和反式 1,3-二醇，并且基于 两个连续的立体选择性反应：对映选择性加成 将反(E)-巴豆基硅烷(2S,3R)-1a转化为缩醛，然后 表面等位基因酯转座。 该协议将是 用于组装 C11、C12 和 C13 立体中心 三烯霉素 A 和 (+)-霉菌素-I。 我们将开始针对化学合成的研究 细胞毒性大环内酯类药物，ulapualide A 和 B，也称为 卤虫酰胺 4a、b。 利用我们正在开发的手性 基于巴豆基硅烷的关键不对称键构建方法 用于合成抗-C-C键形成反应 高烯丙醇和抗1,3-二醇合成子是 ulapualides 的特征亚基。