ASYMMETRIC SYNTHESIS OF ANTITUMOR AGENTS

这项研究建议反映了我们对 新试剂的发展及其在不对称反应中的应用 复杂有机分子的合成，这些分子可能与 人类癌症的治疗。长期目标是 代表化合物不对称合成的最终实现 一类新兴的大环内酰胺类抗生素 具有广泛的抗肿瘤和抗菌活性。 某些成员，Macbecin-I和Herbimycin A已被证明 作为酪氨酸蛋白激酶的选择性抑制剂。在……里面 在这方面，我们打算： 以非对映异构体和终结体的方式演示 纯官能化(E)-巴豆基硅烷试剂1，手性 烯丙基硅烷基键的不对称构筑方法 复杂有机分子的合成。具体地说，非星面 与无手性芳基脂肪族缩醛的选择性加成反应 将被调查用于功能化建设 高烯丙基醚。这些高烯丙基醚将被用作密钥 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)。这些天然产物在结构上与 分子(合成中间体)将被评估为选择性 酪氨酸蛋白激酶的抑制剂。该方法的基础是 芳香缩醛与(2R，3R)-1D的非对映界面选择性加成反应。 三环素-A3a和(+)-霉菌肾素I的不对称合成 (3B)。这种方法是基于新方法论的发展。 对于不对称合成1，3-二醇和反1，3-二醇，其基础是 两个连续的立体选择反应：对映选择性加成 将(E)-巴豆基硅烷(2S，3R)-1a转化为缩醛 面部表面等位基因酯转位。该协议将是 用于组装C11、C12和C13空间中心 三环素A和(+)-霉菌肾素-I。 我们将开始针对化学合成的研究 细胞毒性大环内酯类，乌拉帕利内酯A和B，也称为 利用我们正在开发的手性化合物4a，b 基于丁基硅烷的键不对称构筑方法 C-C成键反应在抗氧剂合成中的应用 高烯丙醇和反1，3-二醇合成子 乌拉帕里德的特征亚基。

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.