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: 7675014
• 负责人: James Robert Manning
• 金额: $ 4.72万
• 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 2012-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675014
• 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; 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; Therapeutic; Titanium; anticancer activity; cycloaddition; cytotoxicity; daphnipaxinin; fulvene; member; oxidation; public health relevance; 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）：提出了生物活性生物碱瑞环素B的收敛、不对称全合成。 Daphnicyclidin B 是近年来分离出来的结构相关的 Daphnicyclidin 生物碱大家族的成员。许多这些天然产物，包括瑞环素 B，已显示出针对小鼠淋巴瘤 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，为解决这些问题的方法开发提供了令人兴奋的机会。提出了一种聚合方法，即分别合成两个中等复杂度的片段，并在合成的中间阶段将其偶联在一起。关键的分子内 de Mayo 环加成/逆羟醛序列将用于生成两个稠合的环庚烷环，形成分子的核心并安装四元立构中心。合成中的另一个关键步骤是钯催化的“3+2”环化序列，该序列将被开发用于安装羟基富烯部分。公共健康相关性：迄今为止，还没有合成任何瑞环素成员，并且仅从天然来源中分离出极少量的化合物。因此，daphnicyclidin B的全合成将是生物碱合成领域的一项重要成就，也将为更全面地评估其抗癌活性和治疗潜力提供额外的材料。所提出的合成方法也代表了许多其他瑞环素的通用方法。