Development of a Pd Catalyzed 3+2 Annulation and Synthesis of Daphnicyclidin B

描述（由申请人提供）：提出了生物活性生物碱daphnicyclidin B的收敛、不对称全合成方法。Daphnicyclidin B是近年来分离的结构相关的Daphnicyclidin生物碱的较大家族的成员。许多这些天然产物，包括daphnicyclidin B，已经显示出对鼠淋巴瘤L1210和人表皮样癌KB细胞系的体外细胞毒性。具有合成挑战性的稠合六环系统包含4个立体中心，一个羟基富烯部分和一个亚胺离子，并代表了一个令人兴奋的机会，方法开发，以解决这些问题。一个收敛的方法，提出了合成，其中两个片段的中等复杂性分别合成和耦合在一起的中间阶段的合成。关键的分子内de马约环加成/逆羟醛序列将用于生成形成分子核心并安装季立体中心的两个稠合环庚烷环。合成中的另一个关键步骤是钯催化的“3+2”环化序列，其将被开发以安装羟基富烯部分。公共卫生相关性：到目前为止，没有合成条目的任何成员的daphnicyclidins存在，只有非常小的数量已被分离出的天然来源。因此，daphnicyclidin B的全合成将是生物碱合成领域中的重要成就，并且还将为更全面地评价其抗癌活性和治疗潜力提供额外的材料。建议的合成也代表了一个通用的方法，许多其他daphnicyclidins。

DESCRIPTION (provided by applicant): A convergent, asymmetric total synthesis of the biologically active alkaloid daphnicyclidin B is proposed. Daphnicyclidin B is a member of a larger family of structurally related daphnicyclidin alkaloids to be isolated in recent years. Many of these natural products, including daphnicyclidin B, have shown in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cell lines. The synthetically challenging fused hexacyclic ring system contains 4 stereogenic centers, a hydroxyfulvene moiety and an iminium ion and represents an exciting opportunity for methodology development to address these issues. A convergent approach is proposed for the synthesis, whereby two fragments of moderate complexity are synthesized separately and coupled together at an intermediate stage of the synthesis. A key intramolecular de Mayo cycloaddition/retro-aldol sequence will be used to generate the two fused cycloheptane rings that form the core of the molecule and install the quaternary stereocenter. Another key step in the synthesis is a palladium catalyzed "3+2" annulation sequence that will be developed to install the hydroxyfulvene moiety. PUBLIC HEALTH RELEVANCE: To date, no synthetic entry to any members of the daphnicyclidins exists and only very small quantities have been isolated from natural sources. Thus, a total synthesis of daphnicyclidin B would be an important achievement in the field of alkaloid synthesis and would also provide additional material for a more complete evaluation of its anticancer activity and therapeutic potential. The proposed synthesis also represents a general approach to many of the other daphnicyclidins.