APPROACH TO THE SPIROKETAL RINGS OF THE ALTOHYRTINS

尿囊素由一类新发现的强效细胞毒素组成。 海洋来源的大环内酯类化合物。独立隔离的，在结构上 相同的，海绵他汀类药物表现出非凡的活性 肿瘤类型多种多样。这些天然的汇聚的合成集合 产品是我们的长期目标。 结构独特，这些化合物含有两种不同的螺酮 基于1，7-二氧杂螺[5.5]十一烷环系的单元，它们形成 它们分子框架的主干。这两种螺环酮 具有连接在C(2)-碳上的亚甲基羰基。这个 这些单独的螺酮环系统的综合设计将是 关注我们的短期目标。 这项研究的第一个目标将是开发一条通往 具有C(2)乙酸基的螺酮类基本结构，用于 其中分子内2-氧杂环酮开环策略形成 基础。一种氧碳正离子，由羰基辅助的环裂解生成 2-氧杂环己酮的第二个羰基在内部被捕获 基团形成螺氧卡宾正离子。反应将终止于 以硅烷为基础的试剂对该离子的亲核加成。上一首 研究人员的工作表明，螺环酮的二酮前体 可以通过环戊烯环的氧化裂解来获得形成， 并进行了原位反应。 第二个目标将是彻底了解关键 这种反应中的刻板控制的几个方面。取代基的影响 关键螺环氧碳正离子的反应构象研究 中间体，根据反应产物的立体化学判断，将 要下定决心。

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.