A Flexible and Concise Approach to the Citrinadins: Total Synthesis of Citrinadin

一种灵活而简洁的柑橘素方法：柑橘素的全合成

基本信息

批准号：
8311518
负责人：
Devon Allen Mundal
金额：
$ 4.06万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2013-03-01
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The proposed research training plan describes a unique synthetic approach the pentacyclic spiro-oxindole natural product citrinadin B that will be extended to the synthesis of the related compound citrinadin A. Their complex architectures and reported biological activites as cytotoxic agents against murine leukemia cells and human epidermoid carcinoma have made the citrinadins popular synthetic targets since their isolation and structural elucidation in 2004 and 2005. The proposed synthetic route to the citrinadins will capitalize on the use of methoxypyridines as surrogates for piperidines in the synthesis of complex alkaloids. The synthetic plan hinges on the development of a novel cascade annulation process involving a Lewis acid-mediated aza-Payne rearrangement and aziridinium-opening pyridone alkylation to rapidly assemble the densely functionalized C, D and E rings of the citrinadins. Substrate-directed elaboration of the E ring of the citrinadins will enable access to either citrinadin congener from a late stage intermediate. Diastereoselective oxidative rearrangement and transition metal-mediated cross-coupling will establish the spiro-oxindole motif and C7 substitution of the citrinadins. This route will provide access to either enantiomer o the central core of the citrinadins through Sharpless asymmetric epoxidation of an achiral tetrasubstituted allylic alcohol. The execution of this research strategy will provide sufficient material for further biological evaluation of the citrinadins.

描述（由申请人提供）：拟议的研究培训计划描述了五环螺吲哚天然产物柑橘丁 B 的独特合成方法，该方法将扩展到相关化合物柑橘丁 A 的合成。其复杂的结构和报道的作为细胞毒剂的生物活性自 2004 年分离和结构阐明以来，柑橘素因其抗小鼠白血病细胞和人表皮样癌的作用而成为受欢迎的合成靶标。 2005. 拟议的柑橘素合成路线将利用甲氧基吡啶作为复杂生物碱合成中哌啶的替代物。该合成计划取决于新型级联环化过程的开发，该过程涉及路易斯酸介导的氮杂佩恩重排和氮丙啶鎓开环吡啶酮烷基化，以快速组装柑橘素的密集功能化C、D和E环。柑橘素 E 环的底物定向加工将能够从后期中间体获得任一柑橘素同系物。非对映选择性氧化重排和过渡金属介导的交叉偶联将建立螺-羟吲哚基序和柑橘素的 C7 取代。该路线将通过非手性四取代烯丙醇的 Sharpless 不对称环氧化作用提供获得柑橘素中心核的任一对映体的途径。该研究策略的实施将为柑橘素的进一步生物学评价提供足够的材料。