The evolution of a stereoselective synthesis of the C1-C16 fragment of bryostatins.
The evolution of a stereoselective synthesis of the C1-C16 fragment of bryostatins.
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DOI：
10.1039/c6ob01804a
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发表时间：
2016-10
影响因子：
3.2
通讯作者：
Matthew Ball;A. Baron;Ben Bradshaw;Raphael Dumeunier;M. O’Brien;E. Thomas
中科院分区：
文献类型：
--
作者：
Matthew Ball;A. Baron;Ben Bradshaw;Raphael Dumeunier;M. O’Brien;E. Thomas
描述了苔藓抑素 C1-C16 片段的合成方法，其中关键步骤是用于组装顺式 2,6-二取代四氢吡喃和已安装的环外烯烃的立体选择性氧-迈克尔反应。继使用 Stille 反应制备氧-迈克尔反应前体的早期工作之后，设计了一种基于酮膦酸酯-醛缩合的更有效的路线来制备关键的二烯酮。酮膦酸酯缩合所需的醛的合成涉及将源自烯丙基溴化镁和碘化亚铜的二有机铜酸酯高度立体选择性地加成到通过使用锂化丙炔酸甲酯使受保护的缩水甘油开环而制备的5-羟基己-2-炔酸甲酯上。酯还原、选择性醇保护和末端双键的氧化裂解得到所需的醛。使用基于螯合控制羟醛缩合和 3-羟基酮的反选择性还原的合成方法，由 (R)-泛内酯分 13 个步骤制备酮膦酸酯。在酮膦酸酯-醛反应之后，选择性脱保护，然后用碱处理，进行氧-迈克尔反应，通过热力学控制得到顺式-2,6-二取代的四氢吡喃。随后的官能团操作导致从 (R)-泛内酯经过 23 个步骤合成了与苔藓抑素的 C1-C16 片段相对应的羟基酯。使用略有不同的保护基重复合成，以研究苔藓抑素的闭环复分解方法。
The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is described. Following early work using Stille reactions to prepare precursors for oxy-Michael reactions, a more efficient route was devised based on a ketophosphonate-aldehyde condensation to prepare the key dienone. Synthesis of the aldehyde required for the ketophosphonate condensation involved the highly stereoselective addition of a diorganocuprate derived from allylmagnesium bromide and copper(i) iodide to the methyl 5-hydroxyhex-2-ynoate prepared by ring-opening of a protected glycidol using lithiated methyl propiolate. Ester reduction, selective alcohol protection and oxidative cleavage of the terminal double bond gave the required aldehyde. The ketophosphonate was prepared in 13 steps from (R)-pantolactone using a synthesis based on a chelation controlled aldol condensation and an anti-selective reduction of a 3-hydroxyketone. Following the ketophosphonate-aldehyde reaction, selective deprotection followed by treatment with base effected the oxy-Michael reaction that gave the cis-2,6-disubstituted tetrahydropyran via thermodynamic control. Subsequent functional group manipulation led to the synthesis of a hydroxy ester that corresponded to the C1-C16 fragment of the bryostatins in 23 steps from (R)-pantolactone. The synthesis was repeated using slightly different protecting groups for a study of a ring-closing metathesis approach to the bryostatins.