SYNTHESIS OF TUBULIN BINDING ANTITUMOR AGENTS

描述：拟议的研究结合了方法论和总体 综合。选择进行全合成的目标是何首乌和 根霉毒素。这两种天然产品都相对稀缺，并证明了 通过与微管蛋白上的VincA结构域结合，具有强大的抗有丝分裂活性。在……里面 体内对长春花碱和长春新碱耐药细胞株的活性 导致选择根霉毒素进行II期临床评估，以及 灯盏花素B目前正处于临床前开发阶段。作为一项关键战略 在这两个合成中，都采用了双向链合成。三 还介绍了合成多取代氢化吡喃的新方法。 建议。克莱森重排的计划变化包括串联 乙醇酸酯烯醇化Claisen/闭环复分解序列，a C2对称底物通过二氧杂环己酮重排的去对称化， 阳离子不对称催化二氧杂环己酮-克莱森重排反应 金属络合物。基于第二种方法，简短地合成了KDO，a 提出了革兰氏阴性杆菌的膜成分。

DESCRIPTION: The proposed research combines methodology and total synthesis. The targets chosen for total synthesis are halichondrin and rhizoxin. Both natural products are relatively scarce and demonstrate potent antimitotic activity by binding to the vinca domain on tubulin. In vivo activity against vinblastine and vincristine resistant cell lines has led to the selection of rhizoxin for Phase II clinical evaluation, and halichondrin B is currently in preclinical development. As a key strategy in both syntheses, two-directional chain synthesis is being applied. Three new methods for the synthesis of polysubstituted hydropyrans are also proposed. Planned variations of the Claisen rearrangement include a tandem glycolate ester enolate Claisen/ring-closing metathesis sequence, a desymmetrization of C2-symmetric substrates via a dioxanone rearrangement, and asymmetric catalysis of the dioxanone Claisen rearrangement by cationic metal complexes. Based on the second method, a short synthesis of KDO, a membrane component of Gram-negative bacteria, is proposed.