TOTAL SYNTHESIS OF XESTOCYCLAMINE A

Xestocyclamin A 的全合成

• 批准号: 2861474
• 负责人: MARK D CHAPPELL
• 金额: $ 3.03万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2861474
• 关键词: Diels Alder reaction; alkaloids; alkenes; antineoplastic antibiotics; biological products; drug design /synthesis /production; enzyme inhibitors; protein kinase C; stereochemistry

DESCRIPTION The objective of the proposed research is the enantioselective total synthesis of (-)-xestocyclamine A. This natural product belongs to the manzamine family of marine alkaloids and is a potent inhibitor of protein kinase C (PKC). Recent findings show that PKC plays an important role in cellular regulatory functions and is a possible target for cancer treatment. The initial goal of this research is the novel synthesis of a chiral 3-piperidinol containing a tetra-substituted olefin. This intermediate will play a vital role in the establishment of the core ring system stereochemistry and the incorporation of macrocycle precursors. An intramolecular alkyne-azadiene Diels-Alder reactions will simultaneously form three rings, which include a macrocycle and a complex [2,2,2] bridged bicyclic systems. The face- and regioselectivity of the Diels-Alder reaction can be controlled by the tether length of the dienophile and the conformation of the azadiene. The regio-chemistry may also be influenced by electron donating alkynyl auxiliaries, which are easily incorporated into the synthesis. The final macrocycle of xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The xestocyclamine A will be formed by a ring-closing olefin metathesis reaction. The development of this convergent synthesis of xestocyclamine A will ultimately lead to the synthesis of analogs to probe the biological activities of this alkaloid.

描述 拟议研究的目的是对映选择性 （ - ） - XestocyclamineA的合成A.这种天然产物属于 海洋生物碱家族家族，是有效的抑制剂 蛋白激酶C（PKC）。最近的发现表明，PKC发挥了重要的作用 在细胞调节功能中的作用，是 癌症治疗。这项研究的最初目标是小说 手性3-二甲醇的合成，该二醇含有四重取代 烯烃。这个中级将在建立中起着至关重要的作用 核心环系统立体化学和大环的掺入 前体。分子内炔烃 - 扎二烯DIELS-ALDER反应将 同时形成三个环，其中包括大环和一个 复杂[2,2,2]桥接的双环系统。面部和区域选择性 Diels-Alder反应的系列长度可以控制 硫二烯的二磷和构象。区域化学 也可能受到电子捐赠Alkynyl辅助机构的影响，该辅助机构 很容易地纳入合成中。最终的大环 Xestocyclamine A将由插入环的烯烃分解形成 反应。 Xestocyclamine A将由插环的烯烃形成 分解反应。这种收敛合成的发展 Xestocyclamine A最终将导致类似物的合成 探测这种生物碱的生物学活性。