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苯环素B的聚合、不对称全合成方法。Daphnicyclidin B是近年来分离的结构相关的Daphnicyclidin生物碱大家族的一员。许多这些天然产物，包括水环素B，已经显示出对小鼠淋巴瘤L1210和人表皮样癌KB细胞系的体外细胞毒性。合成上具有挑战性的融合六环体系包含4个立体中心，一个羟基fulvene部分和一个铝离子，代表了一个令人兴奋的方法发展机会来解决这些问题。提出了一种收敛的合成方法，即分别合成两个中等复杂性的片段，并在合成的中间阶段耦合在一起。一个关键的分子内de Mayo环加成/反醛醇序列将用于生成两个融合的环庚烷环，形成分子的核心并安装四元立体中心。合成的另一个关键步骤是钯催化的“3+2”环化序列，该序列将用于安装羟基氟烯部分。公共卫生相关性：迄今为止，不存在对水环素任何成员的合成入口，仅从自然来源中分离出极少量。因此，水杨环素B的全合成将是生物碱合成领域的一项重要成就，也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。所提出的合成也代表了许多其他水环素的一般方法。

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.