664
T. Kurz et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 661–666
(ppm): 164.77, 134.55, 129.27, 129.02, 128.70, 80.82, 61.69 (d, 2JC-P
= 6.1 Hz), 53.62, 26.83 (d, 2JC-P = 3.1 Hz), 22.95 (d, 1JC-P = 145.98 Hz),
18.38, 16.44 (d, 3JC-P = 6.1 Hz); HRFAB-MS C16H26NO5P MW 343.36,
[M+H]+: calculated 344,1627; found 344, 1653.
08C for one hour and was allowed to warm up to room temper-
ature. After 23 h reaction time, the solvent was evaporated and
the residue was dissolved in THF (10 mL). The solution was
treated with water (0.1 mL) and stirred for further 5 min before
the solvent was removed under reduced pressure to yield the
free phosphonic acids.
The resulting crude phosphonic acids were dissolved in anhy-
drous DMF (20 L), treated with TEA (30 mmol) and chloromethyl
pivalate (9 mmol). The mixture was stirred at 708C for 2 h
excluding atmospheric moisture. Another 3 mmol of TEA were
added and the solution was stirred over night. The reaction mix-
ture was treated with Et2O (100 mL) and washed with water
(50 mL), with a saturated aqueous NaHCO3-solution (50 mL) and
once again with water (50 mL). The organic layer was dried over
Na2SO4, the solvent evaporated and the residue purified by col-
umn chromatography on silica gel with Et2O as an eluent to
yield compounds 9a, b and 10a, b as colourless oils.
[3-(Benzyloxy-formyl-amino)-3-phenyl-propy]-
phosphonic acid diethyl ester 7b
Yield 91%, IR mmax (KBr) cm– 1: 1679 (C=O) and 1238 (P=O); 1H-NMR
(400 MHz, DMSO-d6), d (ppm): 8.40 (s, 1H), 7.44–7.29 (m, 10H),
5.24–4.97 (m, 1H), 4.93 (d, 1H, J = 9.2 Hz), 4.61–4.46 (m, 1H),
4.03–3.93 (m, 4H), 2.41–2.30 (m, 1H), 2.19–2.06 (m, 1H), 1.79–
1.67 (m, 2H), 1.21 (t, 6H, J = 7.1 Hz); 13C-NMR (100 MHz, CDCl3), d
(ppm): 164.15, 137.53, 134.39, 129.37, 128.97, 128.86, 128.58,
128.27, 80.14, 61.72 (d, 2JC-P = 6.1 Hz), 59.58, 23.62, 22.78 (d, 1JC-P
=
142.4 Hz), 16.43 (d, 3JC-P = 6.1 Hz); Found: C 61.86, H 7.00, N 3.56%.
C21H28NO5P requires C 62.21, H 6.96, N 3.45%.
General procedure for the synthesis of compounds 8a, b
Acetic acid anhydride (20 mmol) was added to a solution of the
respective hydroxylamine 6a, b (10 mmol) in dry THF (10 mL)
and stirred at room temperature for 2 h. After addition of EtOAc
(100 mL), the organic layer was washed with aqueous KOH
(0.1 M, 2650 mL), water (50 mL) and with aqueous HCl (1 M,
3620 mL). The organic layer was dried over MgSO4, evaporated,
and the residue was purified by column chromatography on
silica gel with EtOAc as an eluent to yield compound 8a as a pale
yellow and compound 8b as colourless oil.
2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-amino)-
butyl]-(2,2-dimethyl-propionyloxymethoxy)-
phosphinoyloxymethyl ester 9a
Yield 34%, IR mmax (KBr) cm– 1: 1753 (C=O, ester), 1680 (C=O,
1
hydroxamic acid) and 1252 (P=O); H-NMR (400 MHz, CDCl3), d
(ppm): 8.32–8.04 (m, 1H), 7.47–7.33 (m, 5H), 5.69–5.63 (m, 4H),
4.97–4.86 (m, 2H), 4.40–3.72 (m, 1H), 2.05–1.73 (m, 4H), 1.32
(m, 3H), 1.22 (s, 18H); 13C-NMR (100 MHz, CDCl3), d (ppm): 176.86,
2
164.80, 134.46, 129.35, 129.09, 128.73, 81.44 (d, JC-P = 5.1 Hz) ,
81.38 (d, 2JC-P = 6.1 Hz), 80.90, 53.25, 38.73, 26.85, 26.33, 23.84 (d,
1JC-P = 141.4 Hz), 18.28; ESI-MS C24H38NO9P, MW 515.55, [M+Na]+:
calculated 538; found 538.
[3-(Acetyl-benzyloxy-amino)-butyl]-phosphonic acid
diethyl ester 8a
Yield 85%, IR mmax (KBr) cm– 1: 1665 (C=O) and 1246 (P=O); 1H-NMR
(400 MHz, DMSO-d6), d (ppm): 7.46–7.36 (m, 5H), 4.93 (dd, 2H, JA-B
= 22.1 Hz), 4.39–4.21 (m, 1H), 4.01–3.91 (m, 4H), 2.11 (s, 3H),
1.95–1.83 (m, 1H), 1.79–1.61 (m, 3H), 1.21 + 1.20 (2t, 6H, J =
7.1 Hz); 13C-NMR (100 MHz, CDCl3), d (ppm): 174.24, 134.59,
128.88, 128.75, 128.70, 79.08, 61.60 (d, 2JC-P = 6.1 Hz), 61.57 (d, 2JC-P
= 6.1 Hz), 54.60 (d, 3JC-P = 16.3 Hz), 27.00 (d, 2JC-P = 4.6 Hz), 23.02 (d,
2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-amino)-
3-phenyl-propyl]-(2,2-dimethyl-propionyloxymethoxy)-
phosphinoyloxymethyl ester 9b
Yield 27%, IR mmax (KBr) cm– 1: 1753 (C=O, ester), 1680 (C=O,
1
hydroxamic acid) and 1256 (P=O); H-NMR (400 MHz, CDCl3), d
(ppm): 8.23 (s, 1H), 7.47–7.30 (m, 8H), 7.23–7.13 (m, 2H), 5.67 (d,
3
1JC-P = 142.4 Hz), 21.20, 18.47, 16.43 (d, JC-P = 6.1 Hz); HRFAB-MS
3
4H, JH-P = 13 Hz), 5.50–5.20 (m, 1H), 4.60–4.31 (m, 2H), 2.55–
C17H28NO5P MW 357.39, [M+H]+: calculated 358.1783; found
358,1773.
2.28 (m, 2H), 1.94–1.72 (m, 2H), 1.19 + 1.18 (2s, 18H); 13C-NMR
(100 MHz, CDCl3), d (ppm): 176.87, 176.84, 163.97, 137.11,
134.32, 129.45, 129.00, 128.92, 128.69, 128.62, 128.32, 81.45 (d,
2JC-P = 6.1 Hz), 79.96, 59.34, 38.70, 26.81, 23.82 (d, 1JC-P = 142.4 Hz),
23.23; ESI-MS C29H40NO9P, MW 577.62, [M+H]+: calculated 578;
found 578.
[3-(Acetyl-benzyloxy-amino)-3-phenyl-propyl]-
phosphonic acid diethyl ester 8b
Yield 88%, IR mmax (KBr) cm– 1: 1665 (C=O) and 1242 (P=O); 1H-NMR
(400 MHz, DMSO-d6), d (ppm): 7.43–7.29 (m, 10H), 5.44 (t, 1H, J =
7.7 Hz), 4.81 (d, 1H, J = 9.4 Hz), 4.54 (d, 1H, J = 9.4 Hz), 4.06–3.91
(m, 4H), 2.43–2.31 (m, 1H), 2.26–2.09 (m, 4H), 1.84–1.64 (m, 2H),
1.21 (t, 6H, J = 7.1 Hz);13C-NMR (100 MHz, CDCl3), d (ppm): 173.60,
138.36, 134.34, 128.86, 128.81, 128.69, 128.58, 128.51, 128.21,
78.75, 61.66 (d, 2JC-P = 7.1 Hz), 60.21 (d, 3JC-P = 19.3 Hz), 23.40 (d, 2JC-P
= 3.1 Hz), 22.95 (d, 1JC-P = 142.4 Hz), 21.05, 16.42 (d, 3JC-P = 6.1 Hz);
Found: C 62.75, H 7.17, N 3.27%. C22H30NO5P calc. C 63.00, H 7.21,
N 3.34%.
2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-amino)-
butyl]-(2,2-dimethyl-propionyloxymethoxy)-
phosphinoyloxymethyl ester 10a
Yield 41%, IR mmax (KBr) cm– 1: 1752 (C=O, ester), 1668 (C=O,
hydroxamic acid) and 1261 (P=O);1H-NMR (400 MHz, DMSO-d6), d
(ppm): 7.45–7.37 (m, 5H), 5.63–5.55 (m, 4H), 4.91 (dd, 2H, JAB
=
19.7 Hz), 4.36–4.23 (m, 1H), 2.10 (s, 3H), 1.89–1.78 (m, 3H),
1.73–1.62 (m, 1H), 1.21 (d, 3H, J = 6.9 Hz), 1.14 (s, 18H); 13C-NMR
(100 MHz, CDCl3), d (ppm): 176.86, 174.28, 134.46, 128.93,
2
2
General procedure for the synthesis of
bis(pivaloyloxymethyl)esters 9a-b, 10a-b
To a stirred solution of the respective phosphonic acid diethyl
esters 7 or 8 (3 mmol) in anhydrous CH2Cl2 (20 mL) was added tri-
methylsilyl bromide (1.5 mL) at 08C. The solution was stirred at
128.81, 128.74, 82.42 (d, JC-P = 7.1 Hz), 81.35 (d, JC-P = 6.1 Hz),
3
2
79.21, 54.28 (d, JC-P = 21.4 Hz), 38.71, 26.84, 26.49 (d, JC-P
=
4.1 Hz), 23.94 (d, 1JC-P = 141.4 Hz), 21.19, 18.38; MW 529.57, Anal.
Calc. for C25H40NO9P: C 56.70, H 7.61, N 2.64%. Found: C 56.48, H
7.72, N 2.77%.
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim