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

在设计新的氟化剂时，考虑到五元内酰胺结构的高立体选择性和氟化能力，我们将重点放在五元内酰胺结构上。化合物1和2分别由苯甘氨酸乙酯和半胱氨酸乙酯制得。化合物3由巯基乙酸、苯甲醛和碳酸铵缩合制得。化合物7和8分别由丙氨酸乙酯和苯甘氨酸乙酯制得，再经F_2重结晶得到N-氟代化合物9和10，但产率不高。我们接着从（S）-（-）-α-苯乙胺制备化合物11。用FCIO_3氟化11得到12，产率为52%。虽然12与各种活泼亚甲基化合物反应得到了相应的氟代衍生物，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体分离，得到了13的光学活性形式。用F_2氟化13得到14。尝试了（+）-14和（-）-14与各种烯醇化物的反应，当（-）-14与α-甲基四氢萘酮反应时得到最佳结果，得到相应的氟代衍生物，产率为42%，ee为74%。

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.