ENANTIOSELECTIVE APPROACH TO ANTITUMOR AGENTS

一种立体选择性合成稠合 吡喃环系统对应的细胞毒性的亚基 海洋天然产物冈田酸（1）和软海绵素B（2） 分离自海绵Halichondria okadia Kadora， 介绍了 对映选择性化学合成（+）- sesbanimide A（3），一种从植物中分离的有效细胞毒性剂 田菁种子的提取物，和六个结构相关的 提出了类似物。 3的类似物，对应于 制备B-环和C-环的结构修饰， 评价为潜在的细胞毒性剂。 抗肿瘤概况 活动与结构变化的对比将努力 将细胞毒性与结构特征的差异联系起来。 B环类似物的设计是基于该方法， 3是对映体发散的，并且允许制备 对跖点 设计C环类似物是为了尝试 增加四氢呋喃环的化学稳定性， 含有不稳定的半缩醛。 该方法是基于 C1-含氧烯丙基硅烷表现为双官能的可能性 碳亲核试剂。 田菁亚胺的化学合成 结构的设计是基于纯手性C1- 氧化的烯丙基硅烷将参与与 手性醛作为构型稳定的，sp3杂化的，α- 烷氧基烯丙基阴离子等价物， 活性1，2-二醇单元。 稠合吡喃的合成方法 冈田酸和软海绵素B的亚基是基于 C1-氧化的烯丙基硅烷和E-巴豆基硅烷作为 用于立体选择性引入高烯醇化物的等价物 通过捕获产生的氧鎓离子， 在吡喃或呋喃环上。

A stereoselective approach to the chemical synthesis of fused pyran ring systems corresponding to subunits of the cytotoxic marine natural products okadaic acid (1) and halichondrin B (2) isolated from the sea sponge Halichondria okadia Kadora is described. An enantioselective approach to the chemical synthesis of (+)- sesbanimide A (3), a potent cytotoxic agent isolated from plant extracts of Sesbania drummundii seed, and six structurally related analogues is proposed. Analogues of 3, that correspond to structural modifications of the B- and C-rings will be prepared and evaluated as potential cytotoxic agents. A profile of antitumor activity versus changes in structure will be developed in an effort to correlate cytotoxicity with differences in structural features. The B-ring analogues were designed on the basis that the approach to 3 is enantiodivergent and allows for the preparation of both antipodes. The C-ring analogues are designed in an attempt to increase the chemical stability of the tetrahydrofuran ring which contains a labile hemiacetal. The approach is based on the potential for C1-oxygenated allylsilanes to behave as bifunctional carbon nucleophiles. The chemical synthesis of the sesbanimide structures is designed on the expectation that homochiral C1- oxygenated allylsilanes will participate in addition reactions with chiral aldehydes as configurationally stable, sp3 hybridized, alpha- alkoxy allyl anion equivalents for the construction of optically active 1,2-diol units. The synthetic approach to the fused pyran subunits of okadaic acid and halichondrin B is based on the ability of C1-oxygenated allylsilanes and E-crotylsilanes to function as homoenolate equivalents for the stereoselective introduction of a propionaldehyde equivalent by traping an oxonium ion generated on a pyran or furan ring.