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

描述（由申请人提供）：提出的研究培训计划描述了一种独特的合成方法，五环螺旋-氧吲哚天然产物柠檬酸苷B，将扩展到相关化合物柠檬酸苷a的合成。自2004年和2005年分离和结构阐明以来，柠檬酸苷的复杂结构和报道的生物活性作为小鼠白血病细胞和人表皮样癌的细胞毒性药物，使其成为流行的合成靶点。提出的柑橘苷的合成路线将利用甲氧基吡啶作为合成复杂生物碱的哌啶的替代品。该合成计划取决于一种新型级联环化工艺的发展，该工艺包括Lewis酸介导的aza-Payne重排和开氮化吡啶酮烷基化，以快速组装密集功能化的柠檬苷C、D和E环。底物导向的柑桔苷E环精化将使从后期中间体获得柑桔苷同系物。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-氧化吲哚基序和柑桔苷的C7取代。该途径将通过非手性四取代烯丙醇的Sharpless不对称环氧化反应获得柑橘苷的对映体或中心核心。该研究策略的实施将为柑桔苷的进一步生物学评价提供充分的材料。

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.