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

Abstract

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 trifluoro-norleucines ((S)-6 and (R)-6) with high enantiomeric purities (95-100% 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, 87-89% ee) is also obtained via the asymmetric hydrogenation of (Z)-iV-benzoyldehydrotrifluoroleucine ethyl ester (lOa-Z) with a chiral rhodium catalyst, [Rh(diPAMP)-(NBD)]C104, followed by hydrolysis. Unexpectedly high diastereoselectivities (80-87% ee) are observed in the hydrogenation of (Z)-N-benzoyldehydrotrifluoroleucine ethyl ester (lib) and (Z)-N-benzoyl-4-(pentafluoro-phenyl)dehydronorvaline (14-Z) over palladium/carbon. 4,5,6,7-Tetrafluorotryptophan (25) and 4,5,6,7-tetra-hydrotryptamine (30) are synthesized from 3-formyl-4,5,6,7-tetrafluoroindole (22a) in 51% (four steps) and 83% (two steps) overall yields, respectively. 4,5,6,7-Tetrafluoroindoleacetic acid (28) is obtained from l-acetyl-3-(acetoxymethyl)-4,5,6,7-tetrafluoroindole (23a) in four steps in 65% 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-(penta-fluorophenyl)propanal (2-PFPPA), in good yields. © 1989, American Chemical Society. All rights reserved.