APPROACH TO THE SPIROKETAL RINGS OF THE ALTOHYRTINS

该altohyrtins包括一类新发现的有效的细胞毒性 海洋来源的大环内酯类。独立隔离的，结构上 相同的海绵他汀类药物显示出对 各种肿瘤类型。这些天然的聚合合成组合 产品是我们的长期目标。 结构独特，这些化合物具有两个独立的螺缩酮 单元，基于1，7-二氧杂螺[5.5]十一烷环系统，其形成 其分子框架的主干。这两种螺酮 具有连接到C（2）-碳的亚甲基羰基。的 这些单独的螺缩酮环系统的合成设计将是 我们的短期目标。 这项研究的第一个目标将是开发一条路线， 具有C（2）乙酸附属物的基本螺缩酮结构， 其中分子内2-氧杂环丁烷酮开环策略形成 基础 一种氧碳正离子，由羰基辅助的环分裂产生 2-氧杂环丁烷酮环的第二个羰基被捕获在内部， 基团以形成螺氧碳正离子。 反应将终止， 硅烷基试剂与该离子的亲核加成。 先前 研究人员的工作表明，螺缩酮的二酮前体 可以通过环戊烯环的氧化裂解来形成， 并原位反应。 第二个目标将是获得一个透彻的了解关键 在这个反应中的立体控制方面。 取代基的影响 关键的螺氧碳正离子的反应构象 根据反应产物的立体化学判断， 被确定。

The altohyrtins comprise a newly-discovered class of potent cytotoxic macrolides of marine origin. The independently-isolated, and structurally identical, spongistatins have shown exceptional activity towards a variety of tumor types. Convergent synthetic assemblage of these natural products is our long term goal. Structurally unique, these compounds possess two separate spiroketal units, based on the 1,7-dioxaspiro[5.5]undecane ring system, which form the backbone of their molecular framework. Both of these spiroketals possess a methylenecarbonyl group attached to the C(2)-carbon. The synthetic design of these individual spiroketal ring systems will be the focus of our short term goals. The first objective of this research will be to develop a route to the basic spiroketal structure possessing a C(2) acetic acid appendage, for which an intramolecular 2-oxetanone ring opening strategy forms the basis. An oxocarbenium ion, generated by carbonyl-assisted ring cleavage of a 2-oxetanone ring, is to be trapped internally by a second carbonyl group to form a spiro-oxocarbenium ion. Reaction would terminate with nucleophilic addition of a silane-based reagent to this ion. Previous work by the investigator suggests that the dione precursor for spiroketal formation could be obtained by oxidative cleavage of a cyclopentene ring, and reacted in situ. The second objective will be to gain a thorough understanding of key aspects of stereocontrol in this reaction. The influence of substituents on the reactive conformation of the key spiro-oxocarbenium ion intermediate, as judged by the stereochemistry of reaction products, will be determined.