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

本研究旨在开发高立体选择性合成α-氟-β-羟基酯的新方法(工艺)。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。以二溴氟乙酸乙酯和各种醛为原料，在锌粉和二乙基氯化铝的存在下，在-20℃的四氢呋喃中反应1 h，得到α-溴-α-氟-β-(叔丁基二甲基硅氧基)氧基酯。在-78℃的甲苯或二氯甲烷中催化三乙基硼烷与烯丙基锡烷反应10h，得到了相应的α-烯丙化α-氟-β-TBS-氧基酯，产率较高，具有较好的赤道选择性。另一方面，β-羟基酯1在二氯甲烷中与三甲基铝在-15℃下反应0.5h，然后与烯丙基锡烷和三乙基硼催化剂在-15℃下反应6~8h，以较高的三元选择性高产率地得到了相应的α-烯丙化α-氟-β-羟基酯。这些结果为我们提供了第一种α-氟-β-羟基羰基骨架的立体选择性合成方法，有望在有机合成化学和有机氟化学中起到非常重要的作用。

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.