3592 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Sibille et al.
(m, 1H), 1.47 (s, 9H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 167.4,
153.5, 131.6 (d, J ) 11.3 Hz), 119.6, 83.6, 79.6, 63.9 (d, J ) 147.7
Hz), 54.3 (d, J ) 7.0 Hz), 53.8 (d, J ) 7.0 Hz), 35.2, 28.2, 27.7;
31P NMR (CDCl3) δ 22.2.
3.76 (d, J ) 6.5 Hz, 3H), 3.72 (d, J ) 6.5 Hz, 3H), 2.30 (ddd, J )
4.4, 15.6, 19.2 Hz, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.51 (m, 1H),
1.31 (s, 9H), 1.01 (m, 1H); 13C NMR (CDCl3) δ 168.9, 158.6 (q,
J ) 36.3 Hz), 115.6 (q, J ) 288.3 Hz), 81.9, 52.7 (d, J ) 6.5 Hz),
52.4 (d, J ) 6.5 Hz), 37.0 (d, J ) 8.9 Hz), 27.3, 24.2 (d, J ) 142.0
Hz), 20.0 (d, J ) 12.1 Hz), 19.3 (d, J ) 4.2 Hz); 31P NMR (CDCl3)
δ 33.0; [R]20D -51.6 (c 1, CH3OH).
tert-Butyl 1-[N-(Trifluoroacetyl)amino]-1-(dimethoxyphos-
phoryl)-3-butenecarboxylate 13. This compound was isolated as
the major secondary product of the previous Arbuzov reaction
(13.1% yield). TLC (silica gel, EtOAc, TDM visualization) Rf 0.39;
1H NMR (CDCl3) δ 7.31 (br s, 1H), 5.44 (m, 1H), 5.15 (d, J ) 5.6
Hz, 1H), 5.09 (s, 1H), 3.81 (d, J ) 11.0 Hz, 3H), 3.74 (d, J ) 11.0
Hz, 3H), 3.49 (m, 1H), 2.97 (m, 1H), 1.47 (s, 9H); 13C NMR
(CDCl3) δ 166.3, 155.4 (q, J ) 37.0 Hz), 129.7 (d, J ) 13.1 Hz),
121.9, 115.4 (q, J ) 288.7 Hz), 85.3, 64.6 (d, J ) 147.8 Hz), 54.8
(d, J ) 7.0 Hz), 53.8 (d, J ) 7.0 Hz), 34.0, 27.6; 31P NMR (CDCl3)
δ 19.4.
tert-Butyl
(1S,2R)-1-[N-(tert-Butoxycarbonyl)amino]-2-
[(dimethoxyphosphoryl)methyl]cyclopropanecarboxylate 8. 8 (4
mg, 0.01 mmol, 5.8%) was obtained as a colorless oil from the
previous reaction: TLC (silica gel, EtOAc, TDM visualization) Rf
1
0.28; H NMR (CDCl3) δ 5.86 (br s, 1H), 3.78 (d, J ) 6.4 Hz,
3H), 3.74 (d, J ) 6.4 Hz, 3H), 2.24 (m, 1H), 1.85 (m, 1H), 1.73
(m, 1H), 1.43 (s, 9H), 1.41 (s, 9H), 1.29 (m, 1H), 0.88 (m, 1H);
13C NMR (CDCl3) δ 171.9, 156.6, 81.2, 79.4, 51.9 (d, J ) 6.5
Hz), 51.5 (d, J ) 6.5 Hz), 38.2, 29.7, 28.3, 27.9, 24.4 (d, J )
151.2 Hz), 21.1; 31P NMR (CDCl3) δ 28.4.
tert-Butyl (1S,6R)-3-Oxo-4-oxa-2-azabicyclo[4.1.0]heptane-1-
carboxylate 9. 9 (9 mg, 0.04 mmol, 23.5%) was obtained from
the previous reaction as colorless crystals: TLC (silica gel, CH2-
1
Cl2/EtOAc 80:20, TDM visualization) Rf 0.32; H NMR (CDCl3)
δ 5.87 (s, 1H), 4.53 (m, 1H), 4.14 (m, 1H), 2.11 (m, 1H), 1.59 (m,
1H), 1.46 (s, 9H), 1.34 (m, 1H); 13C NMR (CDCl3) δ 168.6, 152.9,
83.3, 66.5, 38.7, 28.0, 21.7, 18.9.
(+)-Ethyl (1R,2R)-1-[N-(Trifluoroacetyl)amino]-2-[(dimethox-
yphosphoryl))methyl]cyclopropane-1-carboxylate 14. The (1R,2R)
phosphonate 14 was synthesized from 11 in an identical manner to
the (1S,2R) phosphonate 12 described above. The recovery was
lower with a 17.5% yield: TLC (silica gel, EtOAc, TDM visualiza-
(+)-tert-Butyl (1S,2R)-1-[N-(Trifluoroacetyl)amino]-2-(bro-
momethyl)cyclopropane-1-carboxylate 10. To 5 (1.5 g, 4.3 mmol,
1 equiv) was added a solution of 2 M HCl/AcOEt (130 mL). After
the mixture was stirred at 25 °C for 2h, the HCl/AcOEt was
evaporated and the residue was dried under vacuum. The crude
amine hydrochloride was used without further purification: TLC
(silica gel, CH2Cl2/CH3OH/NH4OH, 85:17:2.5, ninhydrin visualiza-
1
tion) Rf 0.16; H NMR (CDCl3) δ 8.19 (br s, 1H), 4.17 (m, 2H),
3.72 (d, J ) 4.8 Hz, 3H), 3.68 (d, J ) 4.8 Hz, 3H), 2.05 (ddd, J )
0.8, 7.2, 18.4 Hz, 2H), 1.82 (m, 1H), 1.66 (dd, J ) 5.8, 8.0 Hz,
1H), 1.47 (dd, J ) 5.8, 9.2 Hz, 1H), 1.22 (t, J ) 7.2 Hz, 3H); 13
C
NMR (CDCl3) δ 169.2, 158.1 (q, J ) 37.4 Hz), 115.7 (q, J )
287.8 Hz), 61.8, 52.4 (d, J ) 6.3 Hz), 52.3 (d, J ) 6.3 Hz), 37.2
(d, J ) 10.5 Hz), 23.2 (d, J ) 3.2 Hz), 22.5, 21.8 (d, J ) 104.9
Hz), 13.9; 31P NMR (CDCl3) δ 32.6; [R]20D 8.9 (c 1, CHCl3).
Ethyl 1-[N-(Trifluoroacetyl)amino]-1-(dimethoxyphosphoryl)-
3-butenecarboxylate 15. This compound is the major secondary
product of the previous Arbuzov reaction (27.1% yield). TLC (silica
gel, EtOAc, TDM visualization) Rf 0.17; 1H NMR (CDCl3) δ 7.30
(br s, 1H), 5.49 (m, 1H), 5.19 (d, J ) 4.4 Hz, 1H), 5.13 (s, 1H),
4.35 (q, J ) 7.2 Hz, 2H), 3.86 (d, J ) 10.8 Hz, 3H), 3.79 (d, J )
11.2 Hz, 3H), 3.55 (c, J ) 7.2 Hz, 1H), 3.04 (c, J ) 7.2 Hz, 1H),
1.33 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 167.5, 155.5 (q, J
) 35.8 Hz), 129.7 (d, J ) 12.6 Hz), 121.0, 115.3 (q, J ) 288.3
Hz), 64.3 (d, J ) 14.7 Hz), 63.2, 55.0 (d, J ) 6.8 Hz), 54.0 (d, J
) 7.4 Hz), 34.1, 13.9; 31P NMR (CDCl3) δ 19.0.
1
tion) Rf 0.65; H NMR (CD3OD) δ 4.87 (br s, 1H), 3.78 (dd, J )
7.8, 11.1 Hz, 1H), 3.61 (m, 1H), 2.32 (m, 1H), 1.81 (dd, J ) 6.5,
9.6 Hz, 1H), 1.52 (s, 9H), 1.39 (dd, J ) 6.9, 14.1 Hz, 1H); 13C
NMR (CD3OD) δ 170.3, 87.5, 43.8, 31.0, 30.9, 29.8, 22.8.
The amine hydrochloride was suspended in CH2Cl2 (130 mL)
under argon. Trifluoroacetic anhydride TFAA (2.3 mL, 16.3 mmol,
4 equiv) was added dropwise. The mixture was stirred for 1 h.
After evaporation, 10 was obtained as a pale yellow oil (1.41 g,
4.1 mmol, 95.3%): TLC (silica gel, CH2Cl2/EtOAc, 8:2, ninhydrin
1
visualization) Rf 0.75; H NMR (CDCl3) δ 6.98 (br s, 1H), 3.58
(dd, J ) 6.8, 10.8 Hz, 1H), 3.58 (t, J ) 9.6 Hz, 1H), 2.29 (m, 1H),
1.93 (dd, J ) 5.9, 9.2 Hz, 1H), 1.42 (s, 9H), 1.23 (t, J ) 6.6 Hz,
1H); 13C NMR (CDCl3) δ 168.3, 158.8 (q, J ) 37.4 Hz), 115.5 (q,
J ) 288.5 Hz), 83.3, 39.9, 31.3, 28.7, 27.8, 23.9.
(+)-Ethyl (1R,2R)-1-[N-(Trifluoroacetyl)amino]-2-(bromom-
ethyl)cyclopropane-1-carboxylate 11. The (1R,2R) bromide 11
was synthesized from 6 in an identical manner to the (1S,2R)
bromide 10 described above.
(-)-(1S,2R)-1-Amino-2-phosphonomethylcyclopropane-
carboxylic Acid 1. Compound 12 (440 mg, 1.17 mmol) was
refluxed in 6 N HCl (10 mL) for 22 h. The solvent was evaporated,
and the remaining yellow oil was diluted in 700 mL H2O (pH 3),
applied to an AG50-X4 cation-exchange column. The column was
eluted with H2O. Evaporation of the combined ninhydrin positive
fractions containing the desired material gave a white solid (219
Amine hydrochloride: TLC (silica gel, CH2Cl2/CH3OH/NH4-
1
OH, 85:17:2.5, ninhydrin visualization) Rf 0.75; H NMR (CD3-
OD) δ 4.36 (q, J ) 7.2 Hz, 2H), 3.88 (dd, J ) 6.0, 10.8 Hz, 1H),
3.54 (t, J ) 10.4 Hz, 1H), 2.31 (m, 1H), 1.80 (m, 2H), 1.37 (t, J
) 7.2 Hz, 3H); 13C NMR (CD3OD) δ 170.0, 66.1, 42.8, 32.6, 31.5,
24.2, 16.4.
1
mg, 1.12 mmol, 96.0%): HPLC tR 15.9 min; H NMR (D2O) δ
1.82-2.10 (br m, 3H), 1.55-1.69 (m, 2H); 13C NMR (D2O) δ
174.7, 41.3 (d, J ) 11.0 Hz), 28.0 (d, J ) 133.6 Hz), 24.7 (d, J )
3.7 Hz), 21.3 (d, J ) 8.4 Hz); 31P NMR (D2O) δ 22.0; [R]20D -51.5
(c 1, H2O); Anal. (C5H10NO5P·2/3H2O) C, N. H: calcd; 5.52; found,
5.25.
11: TLC (silica gel, CH2Cl2/EtOAc, 8:2, ninhydrin visualization)
1
Rf 0.73; H NMR (CDCl3) δ 8.01 (br s, 1H), 4.24 (q, J ) 7.2 Hz,
2H), 3.75 (dd, J ) 6.8, 10.4 Hz, 1H), 3.54 (t, J ) 10.0 Hz, 1H),
2.08 (m, 1H), 1.89 (dd, J ) 6.4, 7.6 Hz, 1H), 1.67 (dd, J ) 6.4,
9.2 Hz, 1H), 1.27 (t, J ) 7.2 Hz, 3H); 13C NMR δ 173.9, 158.6
(q, J ) 37.9 Hz), 115.2 (q, J ) 287.3 Hz), 62.8, 39.8, 32.4, 29.3,
24.8, 13.7.
(-)-(1R,2R)-1-Amino-2-phosphonomethylcyclopropane-
carboxylic Acid 2. The (1R,2R) phosphonate 2 was synthesized
from 14 in an identical manner to the (1S,2R) phosphonic acid 1
described above. HPLC tR 18.1 min; 1H NMR (D2O) δ 1.72-2.09
(br m, 4H), 1.34 (t, J ) 7.0 Hz, 1H); 13C NMR (D2O) δ 175.9,
40.6, 28.5 (d, J ) 133.1 Hz), 23.3 (d, J ) 3.6 Hz), 22.3 (d, J ) 7.0
Hz); 31P NMR (D2O) δ 23.5; [R]20546 -9.8 (c 1, H2O); Anal. (C5H10-
NO5P·2/3H2O) C, N. H: calcd, 5.52; found, 5.11.
(-)-tert-Butyl
(1S,2R)-1-[N-(Trifluoroacetyl)amino]-2-
[(dimethoxyphosphoryl))methyl]cyclopropane-1-carboxylate 12.
To 10 (1.41 g, 4.1 mmol, 1 equiv) under argon was added P(OMe)3
(2.0 mL, 16.9 mmol, 4 equiv). The resulting mixture was heated
under reflux for 8 h. The solution was cooled and evaporated. The
crude mixture was extracted with EtOAc (200 mL), and the organic
phase was washed with H2O (100 mL), saturated NaHCO3 solution
(2 × 100 mL), and brine (3 × 100 mL), dried over MgSO4, and
evaporated. The residue was purified by flash-chromatography.
Elution with increasing amounts of EtOAc (10-100%) in CH2Cl2
afforded 12 (782 mg, 2.1 mmol, 50.9%): TLC (silica gel, EtOAc,
The enantiomers were prepared in an identical fashion.
(-)-tert-Butyl (1R,2S)-1-(tert-butoxycarbonylamino)-2-(bro-
momethyl)cyclopropane-1-carboxylate ((-)-5): [R]20
D
-2.8
(c 1, CHCl3). (-)-Ethyl (1S,2S)-1-(tert-butoxycarbonylamino)-
2-(bromomethyl)cyclopropane-1-carboxylate ((-)-6): [R]20D -46.5
(c 1, CHCl3). (+)-tert-Butyl (1R,2S)-1-[N-(trifluoroacetyl)amino]-
2-[(dimethoxyphosphoryl))methyl]cyclopropane-1-carboxylate
((+)-12): [R]20D 54.0° (c 1, CH3OH). (-)-Ethyl (1S,2S)-1-[N-
1
TDM visualization) Rf 0.35; H NMR (CDCl3) δ 8.83 (br s, 1H),