SYNTHESIS OF THE ANTITUMOR AGENT (+)-SUPERSTOLID

所提出的研究是一个收敛的，对映体特异性合成的 高细胞毒性大环内酯类抗肿瘤剂（+）-Superstatin A（1）。 从一种海绵中分离得到的化合物1具有很高的体外细胞毒性 针对不同的癌细胞系。合成路线是必要的，以获得 足够量的1和类似物用于进一步测试。的基本 探索1和类似物在临床上的潜力的第一步 有用的癌症治疗剂是本发明的以下具体目的 建议研究： * 1的收敛性、对映体特异性合成，适用于1的合成 类似物，将被开发。 * 1的结构和绝对构型将通过 合成和X射线晶体学。 提出的合成策略包括：a）分子内Diels-Alder 反应，以确定四个立体中心的构型， 官能化十氢萘体系和B）迭代双不对称 巴豆基硼化以形成C19-C26丙酸酯衍生的片段。一个 这项研究的另一个好处是， 关于合成复杂的大环内酯类天然产物的见解。

The proposed research is a convergent, enantiospecific synthesis of the highly cytotoxic macrolide antitumor agent (+)-superstolide A (1). Isolated from a marine sponge, 1 has very high in vitro cytotoxicity toward various cancer cell lines. A synthetic route is necessary to obtain sufficient quantities of 1 and analogs for further testing. The essential first steps in exploring the potential of 1 and analogs as clinically useful cancer therapeutics are the following specific aims of this proposed research: * A convergent, enantiospecific synthesis of 1, adaptable to synthesis of analogs, will be developed. * The structure and absolute configuration of 1 will be verified by synthesis and X- ray crystallography. The synthetic strategy proposed includes a) an intramolecular Diels-Alder reaction to define the configuration of four stereocenters of the functionalized decalin system and b) iterative double asymmetric crotylboronation to form the C19-C26 propionate-derived segment. An additional benefit of this research is the likelihood of significant new insights regarding the synthesis of complex macrolide natural products.