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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）：拟定的研究培训计划描述了一种独特的合成方法，即五环螺-羟吲哚天然产物桔霉素B，该方法将扩展到相关化合物桔霉素A的合成。自2004年和2005年分离和结构鉴定以来，其复杂的结构和报道的作为针对小鼠白血病细胞和人表皮样癌的细胞毒性剂的生物活性使得桔霉素成为流行的合成靶标。建议的合成路线，以citrinadins将利用使用甲氧基吡啶作为替代哌啶在合成复杂的生物碱。该合成计划取决于一种新的级联成环过程的发展，该过程涉及刘易斯酸介导的氮杂-Payne重排和氮丙啶鎓开放吡啶酮烷基化，以快速组装桔霉素的密集官能化的C、D和E环。桔霉素E环的底物定向加工将使从后期中间体获得任一桔霉素同系物成为可能。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C7取代的桔霉素。这条路线将提供通过Sharpless不对称环氧化的非手性四取代烯丙醇的任一对映体或桔霉素的中心核心。该研究策略的实施将为桔霉素的进一步生物学评价提供足够的材料。