Abstract
An efficient and high yield procedure for the synthesis of the
difluoromethylene analog of β-aspartyl phosphate, β-aspartyl difluoromethylenephosphonate
(βAFP), is described. Preincubation of βAFP with l -aspartate-β-semialdehyde dehydrogenases
from several infectious microorganisms leads to potent time-dependent enzyme
inactivation.
Key words
l -aspartate-β-semialdehyde
dehydrogenase - difluoromethylenephosphonate
References
1 Normark BH.
Normark S.
J. Intern. Med.
2002,
252:
91
2 Cohen GN. In Amino Acids: Biosynthesis and Genetic Regulation
Herrmann KM.
Somerville RL.
Addison-Wesley;
Reading
MA:
1983.
p.147-171
3 Cox RJ.
Sutherland A.
Vederas JC.
Bioorg.
Med. Chem.
2000,
8:
843
4 Harb OS.
Kwaik YA.
Infect. Immun.
1998,
66:
1898
5 Galan JE.
Nakayama K.
Curtiss R.
Gene
1990,
94:
29
6 Cox RJ.
Hadfield AT.
Mayo-Martin MB.
Chem. Commun.
2001,
18:
1710
7 Viola RE.
Acc.
Chem. Res.
2001,
34:
339
8 Moore RA.
Bocik WE.
Viola RE.
Protein
Expr. Purif.
2002,
25:
189
9 Cox RJ.
Gibson JS.
Mayo-Martin MB.
ChemBioChem
2002,
3:
874
10 Berkowitz DB.
Eggen M.
Shen Q.
Shoemaker RK.
J. Org. Chem.
1996,
61:
4666
11 Inoue M.
Hiratake J.
Sakata K.
Biosci.
Biotechnol. Biochem.
1999,
63:
2248
12 Burton DJ.
Ishihara T.
Maruta M.
Chem.
Lett.
1982,
755
13 Burton DJ.
Sprague LG.
Pietrzyk DJ.
Edelmuth SH.
J.
Org. Chem.
1984,
49:
3437
14 Burton DJ.
Sprague LG.
J. Org. Chem.
1988,
53:
1523
15 Grey RA.
J.
Org. Chem.
1984,
49:
2288
16 Fraser JL.
Jackson RF.
Porter B.
Synlett
1995,
819
17 Wiemann A.
Frank R.
Tegge W.
Tetrahedron
2000,
56:
1331
18
Analytical Data
of Compound 3: Rf 0.49 (hexanes-EtOAc, 2:1). 1 H
NMR (400 MHz, CDCl3 ): δ = 7.29 (m,
10 H), 5.92 (d, 1 H, J = 8.4
Hz), 5.06 (s, 2 H), 5.10 (s, 2 H), 4.73 (m, 1 H), 4.21 (q, 4 H, J = 6.8 Hz),
3.4 (dd, 2 H, J = 8.0
Hz), 1.3 (t, 6 H, J = 6.8
Hz). 19 F NMR (188.2 MHz, CDCl3 ): δ = J
F-P = 95.4
Hz).
19
Analytical Data
of βAFP: TOF-ES MS [C5 H8 F2 NPO6 ]H+ : Calcd:
248.0674. Found: 248.0156. 1 H NMR (400 MHz, D2 O): δ = 3.9
(m, 1 H), 3.4 (t, 2 H, J = 3.4
Hz). 13 C NMR (100.6 MHz, D2 O): δ = 205.2,
175.9, 120.6 (dt, J
C-F = 270.5 Hz, J
C-P = 156.4
Hz), 51.9, 33.0. 19 F NMR (188.2 MHz, D2 O): δ = -119.1
(d, 2
J
F-P = 74.9
Hz), -124.5 (d, 2
J
F-P = 78.7 Hz). 31 P
NMR (81.0 MHz, D2 O): δ = 2.35 (t, 2
J
F-P = 75.6 Hz).
Elemental analysis [C5 H6 F2 NPO6 (NH4 )3 Cl]:
Calcd: C, 17.98%; H, 5.41%; N, 16.74%.
Found: C, 18.14%; H, 5.19%; N, 16.34%.
