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

描述（由申请人提供）：海洋生物碱(-)- nakadomarin A的新颖结构和细胞毒性使其成为重要的合成靶点。（-）- nakadomarin A是从原产于冲绳海岸的Kerama群岛的海绵Amphimedon sp. （SS-264）中分离出来的，是一种结构复杂的与manzamine相关的生物碱。该天然产物因其含有8/5/5/5/15/6六环二胺核心的新型呋喃而被认可，这一特征在其他相关生物碱中未被发现。（-）- nakadomarin A表现出一系列有趣的生物活性，最显著的是其对细胞生长周期调节因子（CDK4）的抑制活性；然而，由于数量有限，无法进行进一步评价。这种生物碱可能具有其他未被发现的生物学特性，这些特性可能是至关重要的。只有两个实验室报告完成了合成，这两个实验室都无法获得与药理学研究相关的数量的天然产物。提出了一种高效的全合成(-)-中毒素A的级联方法。应用后期跨环Mannich-Pictet-Spengler环化应该通过级联事件来建立Nakadomarin a的六环网络，这种串联行为预计将融合构成分子的六环框架，同时对映选择性地建立分子的四个立体中心中的两个，其中一个是一个四元碳。对这种环化策略和其中使用的技术的探索，可能会定义一种获取这种结构相关类生物碱天然产物的一般方法。这一拟议合成的趋同预计将提供足够数量的生物碱，以支持关键的生物学评价，这一目标迄今尚未成功实现。

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.