Perumal and Pratt
2H), 7.74 (dd, J ) 3 Hz, 5.4 Hz, 2H), 6.44 (ABX, J ) 18.0, 9.6,
2.0 Hz, 2H), 6.02 (ABX, J ) 9.6 Hz, 2.0 Hz, 1H), 4.8 (s, 2H).
Dimethyl 4-Phthalimido-3-oxo-butylphosphonate (28). The
title compound was synthesized by following a procedure reported
by Green.31 Thus, to a solution of dimethyl phosphite (66.5 mg,
0.46 mmol) in methylene chloride (1 mL) at 0 °C was added a 2
M toluene solution of trimethylaluminum (0.23 mL, 0.465 mmol).
After the above solution had been stirred for 20 min, the vinyl
ketone 27 (100 mg, 0.46 mmol) was added. The resulting solution
was allowed to warm to room temperature for over an hour and
stirred overnight. The solution was then poured into a 5% aqueous
solution of HCl and extracted with methylene chloride. The
combined organic extracts were dried over MgSO4 and then
concentrated to yield the title compound. The product was purified
by preparative thin-layer chromatography in 63% yield. Mp 100-
was prepared by modification of the procedure reported by Bose
et al.34 Thus, a mixture of N-(benzyloxycarbonyl)glycine (2.56 g,
12.2 mmol) and PCl5 (2.56 g, 12.2 mmol) was dissolved in dry
DME (25 mL) and stirred at 0 °C under N2 atmosphere for 30 min.
Triethylamine (1.69 mL, 12.2 mmol) was then added slowly to the
above solution and the precipitated triethylamine hydrochloride was
removed by filtration under N2; a solution of N-(benzyloxycarbo-
nyl)glycyl chloride was thus obtained. To this solution was added
[(diethoxyphosphinyl)difluoromethyl]zinc bromide (24.4 mmol),
obtained by employing the procedure reported by Burton et al.,35
followed by the addition of copper(I) bromide (0.35 g, 1.2 mmol).
The above suspension was stirred at room temperature under dry
N2 atm for 4 h. The solvent was then evaporated under reduced
pressure. The residue obtained was then taken into CH2Cl2, and
the solution was successively washed twice with water, with
NaHCO3 solution, and finally with brine, and dried over MgSO4.
The solvent was removed to obtain an oil that was purified by silica
gel chromatography, with ethyl acetate:hexane (35:65) as eluant,
1
106 °C; H NMR (CDCl3) δ 7.88 (dd, J ) 3.3 Hz, 5.4 Hz, 2H),
7.75 (dd, J ) 3 Hz, 6 Hz, 2H), 4.52 (s, 2H), 3.75 (d, J ) 10.5 Hz,
6H), 2.84 (dt, J ) 12.0 Hz, 7.5 Hz, 2H), 2.09 (dt, J ) 18.0 Hz, 7.4
Hz, 2H); 31P NMR (CDCl3) δ 30.23.
1
to obtain the title compound 31 in 6% yield. Ketone: H NMR
(CDCl3) δ 7.3-7.4 (m, 5H), 5.28 (br t, 1H), 5.15 (s, 2H), 4.51 (d,
Dimethyl 4-amino-3-oxobutylphosphonate (29). This com-
pound was obtained by hydrazinolysis32 of 28. Thus, to a stirred
suspension of 28 (0.2 g, 0.6 mmol) in methanol (2 mL) was added
98% anhydrous hydrazine (20 µL, 0.6 mmol). When the addition
was completed, a homogeneous solution was obtained. The reaction
mixture was then stirred for 24 h at room temperature and the
resulting solid was removed by filtration and washed with methanol.
The filtrate was concentrated at 0°C to yield the title compound
which was used immediately as described below.
Dimethyl 4-(N-Benzyloxycarbonyl)amino-3-oxobutylphospho-
nate (30). To a stirred solution of 29 (59 mg, 0.5 mmol) in CHCl3
(2 mL) at 0 °C was added benzyl chloroformate (0.13 g, 0.73
mmol), followed by the addition of triethylamine (74 mg, 0.73
mmol). The above mixture was stirred at room temperature for 12
h before it was diluted with CHCl3 (5 mL) and washed with 20
mL portions of 2 N H2SO4. The combined organic layers were dried
over MgSO4 and concentrated to yield (67%) the title compound.
1H NMR (CDCl3) δ 7.27-7.30 (m, 5H), 5.38 (br t, 1H), 5.05 (s,
2H), 4.04 (d, J ) 5.1 Hz, 2H), 3.66 (d, J ) 11 Hz, 6H), 2.67 (dt,
J ) 7.5 Hz, 12.9 Hz, 2H), 2.01 (dt, J ) 7.8 Hz, 18 Hz, 2H); 31P
NMR (CDCl3) δ 29.84.
Disodium 4-(N-Benzyloxycarbonyl)amino-3-oxobutylphos-
phonate (11). The title compound was obtained by the demeth-
ylation of the dimethyl phosphonate 30 with TMSBr.33 Thus, to a
solution of 30 (96 mg, 0.29 mmol) in dry methylene chloride (3
mL) was added TMSBr (76 µL, 0.59 mmol) dropwise. The mixture
was then stirred for 3 h, after which the volatiles were evaporated
under reduced pressure to give bis(trimethylsilyl)-4-(N-benzyloxy-
carbonyl)amino-3-oxobutylphosphonate. This silylated product was
then stirred with acetone (3 mL) and water (0.2 mL) for an hour.
The solvent was then evaporated and the product obtained was
treated with an aqueous solution of NaHCO3 (49 mg, 0.58 mmol)
and thereby the pH brought to 8. This solution was extracted with
ethyl acetate. The aqueous layer was lyophilized and the product
purified by Sephadex G-10 chromatography. The appropriate
fractions (characterized by UV absorption) after lyophilization
afforded 11 in 18% yield. 1H NMR (D2O) δ 7.27 (m, 5H), 4.97 (s,
2H), 3.97 (s, 2H), 2.56 (dt, J ) 8.4 Hz, 12 Hz, 2H), 1.58 (dt, J )
8.4 Hz, 17.1 Hz, 2H); 31P NMR (D2O) δ 23.72; exact mass (ES+)
MH+ calculated for C12H15NO6PNa2 346.0432, found 346.0441.
Sodium Ethyl 3-(Benzyloxycarbonyl)amino-2-oxo-1,1-difluo-
ropropylphosphonate (12). See Scheme 6.
J ) 4.8 Hz, 2H), 4.31 (quint, J ) 6.9 Hz, 4H), 1.38 (t, J ) 7.2 Hz,
2
6H); 19F NMR (CDCl3) δ -119.69 (d, JPF ) 95 Hz); 31P NMR
2
1
(CDCl3) δ 3.28 (t, JPF ) 96 Hz). Hydrate: H NMR (CDCl3) δ
7.3-7.4 (m, 5H), 5.28 (br t, 1H), 5.15 (s, 2H), 4.10 (quint, J ) 6.9
Hz, 4H), 3.57 (d, J ) 4.8 Hz, 2H), 1.36 (t, J ) 7.2 Hz, 6H); 19F
NMR (CDCl3) δ -122.26 (d, 2JPF ) 97 Hz); 31P NMR (CDCl3) δ
2
7.79 (t, JPF ) 96 Hz).
Sodium Ethyl 3-(Benzyloxycarbonyl)amino-2-oxo-1,1-difluo-
ropropylphosphonate (12). The synthesis of this compound was
achieved by a procedure employed by Marecek and Griffith.36 To
a solution of 31 (44 mg, 0.117 mmol) in acetone was added sodium
iodide (17.6 mg, 0.117 mmol). The mixture was heated gently at
50 °C for 4 h. The solvent was then removed under reduced
pressure. The residue obtained was redissolved in ether and the
solution extracted with water. The aqueous extract was then
lyophilized to obtain the crude product, which was purified by
Sephadex G-10 chromatography. The appropriate fractions (char-
acterized by UV absorption) after lyophilization yielded 12 in 52%
yield. Ketone: 1H NMR (D2O) δ 7.24-7.32 (m, 5H), 5.02 (s, 2H),
4.33 (s, 2H), 3.93 (quint, J ) 7.50 Hz, 2H), 1.13 (t, J ) 7.2 Hz,
2
3H); 19F NMR (D2O) δ - 119.69 (d, JPF ) 87 Hz); 31P NMR
(D2O) δ 4.65 (t, 2JPF ) 88 Hz). Hydrate: 1H NMR (D2O) δ 7.24-
7.32 (m, 5H), 5.01 (s, 2H), 4.33 (quint, J ) 6.9 Hz, 2H), 3.43 (s,
2H), 1.13 (t, J ) 7.2 Hz, 3H); 19F NMR (D2O) δ -122.25 (d, 2JPF
) 88 Hz); 31P NMR (D2O) δ 4.47 (t, 2JPF ) 88.7 Hz); exact mass
(ES+) MH+ calculated for C13H16NO6PF2Na 374.0581, found
374.0570.
Disodium N-[N′-(Benzyloxycarbonyl)aminoacetyl]amino-
methylphosphonate (13). To a solution of aminomethylphosphonic
acid (1.0 g, 9 mmol) in water (15 mL) was added sodium
bicarbonate (2.5 g) and the mixture was stirred at room temperature
until all the components were dissolved. To the above solution was
added Z-glycine N-hydroxysuccinimide ester (2.76 g, 9 mmol) and
the reaction mixture was stirred at room temperature for 26 h.37
The mixture was then diluted with water (15 mL) and the pH
adjusted to 8. This solution was extracted with ethyl acetate and
the aqueous layer was lyophilized. The excess salts were removed
by desalting chromatography, using Dowex Ion-Retardation 11A8
resin, and further purified by ion-exchange chromatography, using
Sephadex QAE ion-exchange resin with an ammonium bicarbonate
(34) Bose, A. K.; Manhas, M. S.; Chawla, H. P. S.; Dayal, B. J. Chem.
Soc., Perkin Trans. 1 1975, 1880-1884.
Diethyl 3-(N-Benzyloxycarbonyl)amino-1,1-difluoro-2-oxo-
propylphosphonate (31). N-(Benzyloxycarbonyl)glycyl chloride
(35) Burton, D. J.; Sprague, L. G. J. Org. Chem. 1989, 54, 613-617.
(36) Marecek, J. F.; Griffith, D. L. J. Am. Chem. Soc. 1970, 92, 917-
921.
(31) Green, K. Tetrahedron. Lett. 1989, 30, 4807-4810.
(32) Jacobsen, N. E.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 654-
657.
(33) Campbell, M. M.; Carruthers, N. I.; Mickel, S. J. Tetrahedron 1982,
38, 2513-2524.
(37) Kumar, S.; Adediran, S. A.; Nukaga, M.; Pratt, R. F. Biochemistry
2004, 43, 2664-2672. Nukaga, M.; Kumar, S.; Nukaga, K.; Pratt, R. F.;
Knox, J. R. J. Biol. Chem. 2004, 279, 9344-9352. Pratt, R. F. Science
1989, 246, 917-918.
4784 J. Org. Chem., Vol. 71, No. 13, 2006