Development of the Reagents for Electrophilic Fluorination Directing for New Type of Medicinals

在设计新的氟化剂时，我们把重点放在了五元内酰胺结构上，既考虑了高的立体选择性，又考虑了氟化能力。化合物1和2分别由苯甘氨酸乙酯和半胱氨酸乙酯合成。化合物3是由巯基乙酸与苯甲醛和碳酸铵缩合而成。然而，尝试用F_2或FCIO_3对1-3进行氟化，没有得到所需的化合物4-6。丙氨酸乙酯和苯甘氨酸乙酯分别制备了化合物7和8，它们分别用F_2氟化得到N-氟化合物9和10，但产率较低。接下来，我们以(S)-(-)-α-苯乙胺为原料合成了化合物11。11用FCIO_3氟化得到12，产率为52%。虽然12与不同活性的亚甲基化合物反应生成了相应的氟衍生物，但这些化合物的对映体过量无法测定。通过樟脑磺酰亚胺衍生物的非对映异构体分离得到了光学活性形式13。13与F_2氟化得到14，(+)-14和(-)-14分别与不同的烯醇类化合物反应，其中(-)-14与α-甲基四氢呋喃反应得到相应的氟衍生物，ee为74%，产率为42%。

In designing new fluorinating agents, we focused on five-membered lactam structure, considering both the high stereoselectivity and the fluorinating ability. The compounds 1 and 2 were prepared from ethyl phenylglycinate and ethyl cysteinate, respectively. Compound 3 was prepared by condensation of mercaptoacetic acid with benzaldehyde and ammonium carbonate. However, attempted fluorination of 1-3 with F_2 or FCIO_3 did not produce the desired compounds 4-6.Compounds 7 and 8 were prepred from ethyl alaninate and ethyl phenylglycinate, respectively, which were subjected to fluorination using F_2 to give N-fluoro compounds 9 and 10, although in poor yield. We next prepared compound 11 from (S)-(-)-alpha-phenethylamine. Fluorination of 11 with FCIO_3 afforded 12 in 52% yield. Although reaction of 12 with various active methylene compounds gave the corresponding fluoro derivatives, the enantiomeric excess of those compounds could not be determined.We then focused on the compound 13, which was prepared successfully from saccharin. The optically active form of 13 was obtained through the diastereomer separation of the camphor sulfonimide derivatives. Fluorination of 13 with F_2 gave 14. Reaction of (+) -14 and (-) -14 with various enolates was attempted.Best result was obtained when (-) -14 was reacted with alpha-methyltetralone to afford the corresponding fluoro derivative with 74% ee in 42% yield.