SYNTHESIS OF 3-FLUORODIAMINOPIMELIC ACID ISOMERS AS INHIBITORS OF DIAMINOPIMELATE EPIMERASE - STEREOCONTROLLED ENZYMATIC ELIMINATION OF HYDROGEN-FLUORIDE

Two hydroxylated and four fluorinated analogues of diaminopimelic acid (DAP) were synthesized in stereochemically pure form and examined for inhibition of diaminopimelate epimerase from Escherichia coli. The hydroxylated derivative of L, L-DAP, (2S,3R,6S)-2,6-diamino-3-hydroxydiaminopimelic acid (3a), and the corresponding analogue of meso-DAP, (2R,3S,6S)-2,6-diamino-3-hydroxydiaminopimelic acid (4a), were prepared by Seebach condensation of (2S)-1-benzoyl-2-(1,1-dimethylethyl)-3-methyl-4-imidazolidinone (5) and its enantiomer 8, respectively, with (S)-3-(benzyloxycarbonyl)-4-(3-oxopropyl)-5-oxazolidinone (6). Compounds 3a and 4a proved to be very weak inhibitors of DAP epimerase (50% inhibition at 2.5 and 4.0 mM, respectively). Compound 3a was epimerized at the nonhydroxylated end, but 4a was not transformed. The 3-fluoro analogues of 1, 1-DAP, the 2R,35,6S isomer 1a and the 2R,3R,6S isomer 1b, were synthesized by Schoellkopf aldol condensation of (3R)-3,6-dihydro-2,5-dimethoxy-3-(1-methylethyl)pyrazine (11) with aldehyde 6, followed by fluorination with (diethylamino)sulfur trifluoride and subsequent hydrolytic deprotection. Corresponding 3-fluoro derivatives of meso-DAP, the 25,3R,6S isomer 2a and the 2S,3S,6S isomer 2b, were generated analogously from 12 (the enantiomer of 11) and 6. All four fluoro DAP analogues were potent competitive inhibitors of DAP epimerase (IC50 4-25 μ). Compounds 1b and 2a, having a 3R configuration at the carbon bearing fluorine, undergo rapid epimerase-catalyzed elimination of hydrogen fluoride without detectable epimerization at C-2 to eventually form tetrahydrodipicolinic acid (19). In contrast, the enzyme epimerizes 1a and 2b extensively at C-2 before slow elimination of hydrogen fluoride occurs. The results are discussed in terms of stereoelectronic requirements for elimination and possible conformational orientations of the enzyme-bound fluoro DAP analogues.© 1993, IEEE. All rights reserved. © 1990, American Chemical Society. All rights reserved.