An Efficient Cascade Approach to the Total Synthesis of (-)-Nakadomarin A

(-)-Nakadomarin A 全合成的高效级联方法

• 批准号: 8208286
• 负责人: SusAnn Marie Winbush
• 金额: $ 4.92万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-13 至 2012-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208286
• 关键词: Alkaloids; Architecture; Biological; Biological Factors; CDK4 gene; Carbon; Complex; Cyclization; Diamines; Evaluation; Event; Exhibits; Furans; Island; Laboratories; Marines; Nature; Porifera; Property; Reporting; Route; Staging; Technology; Testing; cell growth; chemical synthesis; cytotoxic; interest; nakadomarin A; novel; public health relevance

DESCRIPTION (provided by applicant): The novel structural architecture and cytotoxic nature of the marine alkaloid (-)-Nakadomarin A, render this natural product as an important synthetic target. Isolated from the marine sponge Amphimedon sp. (SS-264) native to the Kerama Islands off the Okinawa coast, (-)-Nakadomarin A is a structurally complex Manzamine-related alkaloid. This natural product is recognized for its novel furan containing 8/5/5/5/15/6 hexacyclic diamine core, a feature previously unobserved in other related alkaloids. (-)-Nakadomarin A exhibits a range of interesting biological activities, most notably its inhibitory activity against the cell growth cycle regulator (CDK4); however, the limited quantities have prohibited further evaluation. This alkaloid may possess other biological properties that have gone undetected, properties which may be of vital importance. Only two laboratories have reported completed syntheses, neither of which is able to access the natural product in quantities relevant to pharmacological studies. An efficient cascade approach to the total synthesis of (-)-Nakadomarin A is proposed. The application of a late-stage transannular Mannich-Pictet-Spengler cyclization should proceed through a cascade event to establish the hexacyclic network of Nakadomarin A. This tandem act is predicted to fuse the hexacyclic framework making up the molecule, while enantioselectively establishing two of the molecule's four stereogenic centers, one of which is a quaternary carbon. The exploration of this annulation strategy and the technologies used within, will presumably define a general means by which to access this structurally related class of alkaloidal natural products. The convergency of this proposed synthesis is expected to provide sufficient quantities of the alkaloid to support critical biological evaluation, an objective which has not yet been successfully achieved to date. PUBLIC HEALTH RELEVANCE: (-)-Nakadomarin A exhibits a range of interesting biological activities; however, the limited quantities have prohibited further evaluation. Chemical synthesis may be the only practical means of providing material for further critical pharmacological testing.

描述（由申请人提供）：海洋生物碱（ - ） - nakadomarin A的新型结构结构和细胞毒性性质，将这种天然产物作为重要的合成目标。从海洋海绵两栖sp中分离出来。 （SS-264）原产于冲绳海岸附近的Kerama群岛，（ - ） - 中纳马林A是一种结构上与Manzamine相关的生物碱。这种天然产物因其新颖的Furan含有8/5/5/5/15/6六边形二胺核心而被认可，这是其他相关生物碱以前未观察到的特征。 （ - ） - 纳卡多素A表现出一系列有趣的生物学活性，最著名的是其对细胞生长周期调节剂的抑制活性（CDK4）；但是，有限的数量禁止进一步评估。这种生物碱可能具有未被发现的其他生物学特性，这些特性可能至关重要。只有两个实验室报告了完成的合成，它们都无法以与药理研究相关的数量访问天然产品。提出了一种有效的级联反应方法（ - 中纳卡多素A）。后期跨阶段的横向曼尼奇 - 小腿 - 旋转器环化的应用应通过级联事件进行，以建立nakadomarin A的六边形网络。预测，这种串联法可以融合组成分子的六边性框架，同时敌意的两个分子的四个centern centern centern centern centern centern centern centern centern centern is e One是一个，这是一个是一个，这是一个是一个，这是一个是一个构成的，这是一个均为一项。对这种环状策略的探索和内部使用的技术可能会定义一种访问这种与结构相关的生物碱天然产物类别的一般手段。预计该提出的合成的融合有望提供足够数量的生物碱以支持关键的生物学评估，这一目标尚未成功实现。 公共卫生相关性：（ - ） - 纳卡多龙A展示了一系列有趣的生物学活动；但是，有限的数量禁止进一步评估。化学合成可能是提供进一步关键药理测试材料的唯一实际手段。