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

Pd催化3-2环化的开发及瑞环素B的合成

• 批准号: 8131037
• 负责人: James Robert Manning
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131037
• 关键词: 3-hydroxybutanal; Achievement; Address; Aldehydes; Alkaloids; Alkenes; Amines; Anions; Biological Factors; Boxing; Cell Line; Complex; Coupled; Coupling; Cycloheptanes; Cyclopentadienes; Development; Evaluation; Family; Health; Human; Hydrogenation; In Vitro; Ions; KB Cells; Label; Lymphoma; Mediating; Methodology; Mind; Minor; Modification; Mus; Nature; Palladium; Reaction; Rhodium; Route; Scheme; Source; Squamous cell carcinoma; Staging; Structure; System; Titania; Titanium; anti-cancer therapeutic; anticancer activity; cycloaddition; cytotoxicity; daphnipaxinin; fulvene; member; oxidation; stem; stereochemistry

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.

描述(由申请人提供)：提出了一种收敛的、不对称的生物活性生物碱瑞香环素B的全合成方法。瑞香素B是近年来分离得到的结构上与瑞香素相关的生物碱大家族中的一员。其中许多天然产物，包括瑞香草素B，在体外对小鼠淋巴瘤L1210和人表皮样癌KB细胞株都显示出细胞毒作用。这一具有挑战性的稠合六环体系包含4个立体中心、一个羟基富烯部分和一个亚胺离子，这为解决这些问题的方法学发展提供了一个令人兴奋的机会。提出了一种收敛的合成方法，即在合成的中间阶段，将两个中等复杂性的片段分开合成并耦合在一起。一个关键的分子内de Mayo环加成/还原-Aldol序列将被用来生成形成分子核心的两个稠合的环庚烷环，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，该序列将被开发来安装羟基富烯部分。与公共卫生有关：到目前为止，还不存在任何一种瑞香环鸟苷成员的合成条目，从自然来源中分离出的数量也很少。因此，瑞香环素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。建议的合成也代表了对许多其他瑞香环鸟苷类化合物的一般方法。