Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8 2659
Dibenzyl 2-[N-(Benzyloxy)aminomethyl]cyclopropylphosphon-
ate (13a). TFA (2.58 mL, 33.6 mmol) was added dropwise to a
solution of 12a (350 mg, 0.651 mmol) in dry CH2Cl2 (6 mL) at 0
°C, and the mixture was stirred for 45 min at 0 °C. The mixture
was transferred into a separation funnel, and saturated aqueous
NaHCO3 (40 mL) was added. The aqueous layer was extracted
twice with CH2Cl2 (40 mL) and twice with CHCl3 (40 mL). The
combined organic layers were dried on MgSO4 and filtered, and
the solvents were removed under reduced pressure yielding 256
mg of pale yellow solid in a quantitative yield. mp 40-41 °C; 1H
NMR (300.13 MHz, CDCl3) δ 0.61-0.74 (2H, m), 1.04-1.15 (1H,
m), 1.60 (1H, dddddd, J ) 16.1, 8.4, 6.7, 6.7, 5.4 and 5.4 Hz);
2.66 (1H, dd, J ) 13.2 and 6.8 Hz), 2.75 (1H, ddd, J ) 13.2, 6.7
and 1.7 Hz), 4.62 (2H, s), 4.94 (2H, dd, J ) 11.8 and 8.1 Hz),
5.00 (1H, dd, J ) 11.9 and 8.3 Hz), 5.02 (1H, dd, J ) 11.9 and
8.3 Hz), 7.21-7.31 (15H, m); 13C NMR (75.47 MHz, CDCl3) δ
Hz), 173.6 (N-CdO); 31P NMR (121.50 MHz, D2O) δ 22.7; ESMS
m/z 210 ([M] + H+).
Acknowledgment. This study was supported by grants from
the European Commission (QLK2-CT-2002-00887) and INTAS
(03-51-4077). Technical assistance was provided by Dajana
Henschker.
Supporting Information Available: Experimental details (1H,
13C, 31P NMR, MS, HPLC) for intermediates (9b, 5b, 10b-13b,
14b-d, 6, 16-19, and 21) and final products (3b-d, 4); deter-
mination of the relative configuration of the cyclopropane ring. This
References
2
1
9.3 (CH2, JPC ) 5.5 Hz), 10.0 (P-CH, JPC ) 196.0 Hz), 15.9
(1) Kuzuyama, T.; Shimizu, T.; Takahashi, S.; Seto, H. Fosmidomycin,
a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reducto-
isomerase in the nonmevalonate pathway for terpenoid biosynthesis.
Tetrahedron Lett. 1998, 39, 7913-7916.
(2) Zeidler, J.; Schwender, J.; Muller, C.; Wiesner, J.; Weidemeyer, C.;
Beck, E.; Jomaa, H.; Lichtenthaler, H. K. Inhibition of the nonme-
valonate 1-deoxy-D-xylulose-5-phosphate pathway of plant isoprenoid
biosynthesis by fosmidomycin. Z. Naturforsch., C: Biosci. 1998, 53,
980-986.
2
3
(CH, JPC ) 3.8 Hz), 55.3 (NCH2, JPC ) 3.8 Hz), 67.3 (OCH2,
2JPC ) 6.0 Hz), 67.4 (OCH2, JPC ) 6.1 Hz), 76.3 (OCH2), 127.8
2
(dCH), 128.3 (dCH), 128.4 (dCH), 128.5 (dCH), 136.6 (dC,
3JPC ) 6.1 Hz), 136.6 (dC, 3JPC ) 6.1 Hz), 137.8 (dC); 31P NMR
(121.50 MHz, CDCl3) δ 31.1; ESMS m/z 438 ([M] + H+), 460
([M] + Na+), 875 ([2M] + H+).
Dibenzyl 2-[N-Acetyl,N-(benzyloxy)aminomethyl]cyclopro-
pylphosphonate (14a). Amine 13a (256 mg, 0.586 mmol) was
dissolved in dry pyridine (6 mL). Ac2O (615 µL, 6.51 mmol) was
added dropwise, and the mixture was stirred overnight at room
temperature. The mixture was transferred to a separation funnel,
and a 1 M HCl solution (70 mL) was added. The aqueous layer
was extracted twice with CH2Cl2 (70 mL) and twice with CHCl3
(70 mL). The combined organic fractions were dried on anhydrous
MgSO4 and filtered, and the solvents were removed on rotary
evaporation. The residual oil was dissolved in CH2Cl2 (40 mL),
saturated aqueous NaHCO3 (40 mL) was added, the layers were
separated, and the aqueous phase was extracted twice with CH2Cl2
(40 mL) and once with CHCl3 (40 mL). The combined organic
layers were dried on anhydrous MgSO4 and filtered, and the solvents
were removed under reduced pressure. The residual oil was purified
via column chromatography (hexane/CH2Cl2/MeOH: 50/48/2)
giving 253 mg of a pale yellow oil in an overall yield of 90%. 1H
NMR (300.13 MHz, CDCl3) δ 0.81 (1H, dddd, J ) 12.0, 9.4, 5.3,
4.3 Hz), 0.89-0.97 (1H, m), 1.11 (1H, dddd, J ) 18.2, 8.4, 5.7
and 4.4 Hz), 1.73 (1H, dddddd, J ) 15.7, 8.4, 7.0, 6.8, 5.4 and 5.4
Hz), 2.00 (3H, s), 3.47 (1H, dd, J ) 14.9 and 7.4 Hz), 3.53 (1H,
ddd, J ) 14.9, 6.6 and 1.8 Hz), 4.79 (2H, s), 4.95 (1H, dd, J )
12.1 and 7.7 Hz); 4.97 (1H, dd, J ) 11.8 and 8.4 Hz), 5.02 (1H,
dd, J ) 11.8 and 8.4 Hz), 5.03 (1H, dd, J ) 12.3 and 8.4 Hz),
7.19-7.30 (15H, m); 13C NMR (75.47 MHz, CDCl3) δ 9.4 (CH2,
(3) Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer,
C.; Hintz, M.; Turbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler,
H. K.; Soldati, D.; Beck, E. Inhibitors of the nonmevalonate pathway
of isoprenoid biosynthesis as antimalarial drugs. Science 1999, 285,
1573-1576.
(4) Lell, B.; Ruangweerayut, R.; Wiesner, J.; Missinou, M. A.; Schindler,
A.; Baranek, T.; Hintz, M.; Hutchinson, D.; Jomaa, H.; Kremsner,
P. G. Fosmidomycin, a novel chemotherapeutic agent for malaria.
Antimicrob. Agents Chemother. 2003, 47, 735-738.
(5) Missinou, M.; Borrmann, S.; Schindler, A.; Issifou, S.; Adegnika,
A. A.; Matsiegui, P. B.; Binder, R.; Lell, B.; Wiesner, J.; Baranek,
T.; Jomaa, H.; Kremsner, P. G. Fosmidomycin for malaria. Lancet
2002, 360, 1941-1942.
(6) Borrmann, S.; Issifou, S.; Esser, G.; Adegnika, A. A.; Ramharter,
M.; Matsiegui, P. B.; Oyakhirome, S.; Mawili-Mboumba, D. P.;
Missinou, M. A.; Kun, J. F. J.; Jomaa, H.; Kremsner, P. G.
Fosmidomycin-clindamycin for the treatment of Plasmodium falci-
parum malaria. J. Infect. Dis. 2004, 190, 1534-1540.
(7) Borrmann, S.; Adegnika, A. A.; Matsiegui, P. B.; Issifou, S.;
Schindler, A.; Mawili-Mboumba, D. P.; Baranek, T.; Wiesner, J.;
Jomaa, H.; Kremsner, P. G. Fosmidomycin-clindamycin for Plas-
modium falciparum infections in African children. J. Infect. Dis. 2004,
189, 901-908.
(8) Borrmann, S.; Adegnika, A. A.; Moussavou, F.; Oyakhirome, S.;
Esser, G.; Matsiegui, P. B.; Ramharter, M.; Lundgren, I.; Kombila,
M.; Issifou, S.; Hutchinson, D.; Wiesner, J.; Jomaa, H.; Kremsner,
P. G. Short-course regimens of artesunate-fosmidomycin in treatment
of uncomplicated Plasmodium falciparum malaria. Antimicrob Agents
Chemother. 2005, 49, 3749-3754
(9) Steinbacher, S.; Kaiser, J.; Eisenreich, W.; Huber, R.; Bacher, A.;
Rohdich, F. Structural basis of fosmidomycin action revealed by the
complex with 2-C-methyl-D-erythritol 4-phosphate synthase (IspC)
- Implications for the catalytic mechanism and anti-malaria drug
development. J. Biol. Chem. 2003, 278, 18401-18407.
(10) MacSweeney, A.; Lange, R.; Fernandes, R. P. M.; Schulz, H.; Dale,
G. E.; Douangamath, A.; Proteau, P. J.; Oefner, C. The crystal
structure of E. coli 1-deoxy-D-xylulose-5-phosphate reductoisomerase
in a ternary complex with the antimalarial compound fosmidomycin
and NADPH reveals a tight-binding closed enzyme conformation.
J. Mol. Biol. 2005, 345, 115-127.
(11) Silber, K.; Heidler, P.; Kurz, T.; Klebe, G. AFMoC enhances
predictivity of 3D QSAR: A case study with DOXP-reducto-
isomerase. J. Med. Chem. 2005, 48, 3547-3563.
(12) Ortmann, R.; Wiesner, J.; Reichenberg, A.; Henschker, D.; Beck,
E.; Jomaa, H.; Schlitzer, M. Alkoxycarbonyloxyethyl ester prodrugs
of FR900098 with improved in vivo antimalarial activity. Arch.
Pharm. 2005, 338, 305-314.
(13) Ortmann, R.; Wiesner, J.; Reichenberg, A.; Henschker, D.; Beck,
E.; Jomaa, H.; Schlitzer, M. Acyloxyalkyl ester Prodrugs of
FR900098 with improved in vivo anti-malarial activity. Bioorg. Med.
Chem. Lett. 2003, 13, 2163-2166.
2JPC ) 5.0 Hz), 10.4 (P-CH, 1JPC ) 185.4 Hz), 15.8 (CH, 2JPC
)
2
3.8 Hz), 20.4 (CH3), 50.0 (NCH2), 67.3 (OCH2, JPC ) 6.0 Hz)
2
67.4 (OCH2, JPC ) 6.0 Hz), 76.9 (OCH2), 127.7 (dCH), 127.8
(dCH), 128.3 (dCH), 128.5 (dCH), 128.7 (dCH), 129.0 (dCH),
3
129.1 (dCH), 134.4 (dC), 136.5 (dC, JPC ) 6.1 Hz), 136.6 (d
3
C, JPC ) 6.6 Hz), 167.8 (N-CdO); 31P NMR (121.50 MHz,
CDCl3) δ 30.5; ESMS m/z 480 ([M] + H+).
2-[N-(Acetyl),N-(hydroxy)aminomethyl]-cyclopropylphospho-
nic Acid (3a). To a solution of 14a (253 mg, 0.528 mmol) in MeOH
(5 mL) was added Pd/C (100 mg, 10%). The reaction was placed
under H2 (1 atm) and was stirred overnight at room temperature.
The mixture was filtered over Celite, and the Celite was washed
with portions of MeOH. The filtrate was evaporated under reduced
pressure; the residual oil was dissolved in a minimal amount of
water and lyophilized. The resulting solid was purified via reversed
phase HPLC using a gradient elution of 5 mM NH4OAc solution
to MeCN in 20 min. The appropriate fractions were lyophilized,
giving 80 mg of an amber amorphous solid in a yield of 72%. mp
100-102 °C;1H NMR (300.13 MHz, MeOD) δ 0.45 (1H, m), 0.57
(1H, m), 0.77 (1H, m), 1.27 (1H, m), 1.95 (3H, s), 3.14-3.21 (1H,
m), 3.53 (1H, dd, J ) 14.3 and 5.3 Hz); 13C NMR (75.47 MHz,
(14) Reichenberg, A.; Wiesner, J.; Weidemeyer, C.; Dreiseidler, E.;
Sanderbrand, S.; Altincicek, B.; Beck, E.; Schlitzer, M.; Jomaa, H.
Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial
activity. Bioorg. Med. Chem. Lett. 2001, 11, 833-835.
2
1
MeOD) δ 9.6 (CH2, JPC ) 5.1 Hz), 14.6 (CH, JPC ) 177.8 Hz),
2
3
15.8 (CH, JPC ) 6.1 Hz), 20.2 (CH3), 52.7 (NCH2, JPC ) 3.3