Development of new process for the highly stereoselective synthesis of α-fluoro-β-hydroxy esters

开发高度立体选择性合成α-氟-β-羟基酯新工艺

• 批准号: 11650893
• 负责人: ISHIHARA Takashi
• 金额: $ 1.86万
• 依托单位: Kyoto Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11650893/
• 关键词: α-fluoro-β-hydroxy ester; stereoselective synthesis; radical reaction; allylation reaction; chelation control; aluminum Lewis acid; α-フルオロ置換エステル; 立体選択的還元; 立体選択的アリル化; トレオ選択性; 水素化トリプチルスズ; アリルスタナン

In this research project directed toward the development of new method (process) for the highly stereoselective synthesis of α-fluoro-β-hydroxy esters, we have explored the radicalic allylation reaction of α-bromo-α-fluoro-β-hydroxy carboxylic acid esters 1 with allylic stannanes.The starting β-hydroxy esters 1 were readily prepared by the Reformatsky reaction between ethyl dibromofluoroacetate and various aldehydes in the presence of zinc dust and diethylaluminum chloride in THF at -20 ℃ for 1 h. When α-bromo-α-fluoro-β-(t-butyldimethylsilyl) oxy esters, prepared by the siylation of 1 with t-butyldimethylsilyl (TBS) chloride or triflate, were allowed to react with allylic stannanes in the presence of a catalytic amount of triethylborane in toluene or dichloromethane at -78 ℃ for 10 h, the corresponding α-allylated α-fluoro-β-TBS-oxy esters were obtained in good yields with fairly good erythro-selectivities. On the other hand, on treatment of the β-hydroxy esters 1 with trimethylaluminum in dichloromethane at -15 ℃ for 0.5 h, followed by the reaction with allylic stannanes and triethylborane catalyst at -15 ℃ for 6-8 h, the corresponding α-allylated α-fluoro-β-hydroxy esters were given in good yields in a highly threo-selective manner. These results provide us with the first stereoselective synthetic method for an α-fluoro-β-hydroxy carbonyl framework, and are expected to serve as a very significant example in organic synthetic chemistry as well as organofluorine chemistry.

在这个旨在开发高度立体选择性合成α-氟-β-羟基酯的新方法（工艺）的研究项目中，我们探索了α-溴-α-氟-β-羟基羧酸酯1与烯丙基锡烷的自由基烯丙基化反应。起始β-羟基酯1很容易通过以下方法制备 二溴氟乙酸乙酯与各种醛在锌粉和氯化二乙基铝存在下在THF中于-20℃反应1h进行Reformatsky反应。当1与叔丁基二甲基甲硅烷基(TBS)氯化物或三氟甲磺酸酯甲硅烷基化制备的α-溴-α-氟-β-(叔丁基二甲基甲硅烷基)氧基酯在催化量的三乙基硼烷存在下在甲苯或二氯甲烷中于-78℃反应10小时时， 相应的α-烯丙基化的α-氟-β-TBS-氧基酯以良好的产率获得，并且具有相当好的红选择性。另一方面，用三甲基铝在二氯甲烷中于-15 ℃处理0.5 h，然后与烯丙基锡和三乙基硼烷催化剂在-15 ℃反应6-8 h，相应的α-烯丙基化的α-氟-β-羟基酯以较高的收率得到。 三选择性方式。这些结果为我们提供了第一个α-氟-β-羟基羰基骨架的立体选择性合成方法，并有望成为有机合成化学以及有机氟化学领域的一个非常重要的例子。