New and Effective Routes to Fluoro Analogues of Aliphatic and Aromatic Amino Acids

Article abstract of DOI:10.1021/jo00280a014

New and efficient syntheses of 4,4,4-trifluorovaline (1), 5,5,5-trifluoronorvaline (2), 5,5,5-trifluoroleucine (5), 6,6,6-trifluoronorleucine (6), 4,5,6,7-tetrafluorotryptophan (25), and α-(trifluoromethyl)-β-alanine are studied.Trifluorovaline (1) and trifluoronorvaline (2) are synthesized through amidocarbonylation of 2-(trifluoromethyl)propanal (2-TFMPA) and 3-(trifluoromethyl)propanal (3-TFMPA), respectively, followed by hydrolysis.Trifluoroleucine (5) and trifluoronorleucine (6) are synthesized by using modified Erlenmeyer's azlactone method from 2-TFMPA and 3-TFMPA, respectively. (S)- and (R)-trifluoronorvalines <(S)-2 and (R)-2> and trifluoronorleucines <(S)-6 and (R)-6> with high enantiomeric purities (95-100percent ee) are obtained through enzymatic optical resolution of N-acetyltrifluoronorvaline (4) and N-acetyltrifluoronorleucine (17) with the use of a porcine kidney acylase I.Optically active trifluoronorleucine <(S)-6, 87-89percent ee> is also obtained via the asymmetric hydrogenation of (Z)-N-benzoyldehydrotrifluoroleucine ethyl ester (10a-Z) with a chiral rhodium catalyst, ClO4, followed by hydrolysis.Unexpectedly high diastereoselectivities (80-87percent ee) are observed in the hydrogenation of (Z)-N-benzoyldehydrotrifluoroleucine ethyl ester (11b) and (Z)-N-benzoyl-4-(pentafluorophenyl)dehydronorvaline (14-Z) over palladium/carbon. 4,5,6,7-Tetrafluorotryptophan (25) and 4,5,6,7-tetrahydrotryptamine (30) are synthesized from 3-formyl-4,5,6,7-tetrafluoroindole (22a) in 51percent (four steps) and 83percent (two steps) overall yields, respectively. 4,5,6,7-Tetrafluoroindoleacetic acid (28) is obtained from 1-acetyl-3-(acetoxymethyl)-4,5,6,7-tetrafluoroindole (23a) in four steps in 65percent overall yield.The 3-formyl- and 1-acetyl-3-(acetoxymethyl)tetrafluoroindoles (22a, 23a) are prepared through selenium dioxide oxidation of 1-acyl-3-methyl-4,5,6,7-tetrafluoroindole (21), which is obtained via the cyclization of a Schiff base of 2-(pentafluorophenyl)propanal (2-PFPPA), in good yields.