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

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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.