K. Schlu¨ter et al. / European Journal of Medicinal Chemistry 41 (2006) 1385e1397
1391
EtOAc (100 mL) and washed with 10% K2CO3 solution
(2 ꢂ 50 mL) and 1 M HCl (2 ꢂ 50 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 give [3-(acetyl-benzyloxy-amino)-1-aryl-
methyl-propyl]-phosphonic acid diethyl esters 5 as colourless
oils.
JC,P ¼ 140.7 Hz, PCH), 43.8 (NCH2), 62.3 (2d, JC,P ¼ 7.2 Hz,
JC,P ¼ 7.1 Hz, POCH2CH3), 76.7 (PhCH2O), 129.0, 129.1,
129.4, 129.6, 130.7, 131.5 (tert., aromat.), 130.9, 132.7,
134.7 (quart., aromat.), 139.9 (d, JC,P ¼ 14.5 Hz, CH2C
quart., aromat.), 172.1 (C]O). IR: 1655 cmꢀ1 (C]O),
1227 cmꢀ1 (P]O). Anal. Calcd for C23H30Cl2NO5P: calcu-
lated C 54.99%, H 6.02%, N 2.79%; found C 55.01%, H
6.24%, N 3.14%.
6.1.4.1. [3-(Acetyl-benzyloxy-amino)-1-benzyl-propyl]-phos-
phonic acid diethyl ester (5a). Yield: 92%. 1H NMR
(DMSO-d6), d (ppm): 1.19 (t, J ¼ 7.1 Hz, 6H, POCH2CH3),
1.56e1.70 (m, 4H, CH2 overlapping acetyl. CH3), 1.72e1.86
(m, 1H, CH2), 2.12e2.24 (m, 1H, PCH ), 2.55e2.68 (m, 1H,
CH2), 2.93e3.01 (m, 1H, CH2), 3.51e3.58 (m, 1H, CH2),
3.71e3.81 (m, 1H, CH2), 3.94e4.02 (m, 4H, POCH2CH3),
4.74 (s, 2H, PhCH2O), 7.18e7.40 (m, 10H, aromat.), 13C
NMR (CDCl3), d (ppm): 16.4, 16.5 (2d, JC,P ¼ 6.1 Hz,
POCH2CH3), 20.5 (acetyl. CH3), 25.4 (d, JC,P ¼ 3.1
6.1.4.4.
propyl]-phosphonic acid diethyl ester (5d). Yield: 87%. H
NMR (CDCl3),
[3-(Acetyl-benzyloxy-amino)-1-(4-methoxy-benzyl)-
1
d
(ppm): 1.20 (t, J ¼ 6.98 Hz, 6H,
POCH2CH3), 1.55e1.84 (m, 2H, CH2), 1.95 (s, 3H, acetyl.
CH3), 2.05e2.22 (m, 1H, PCH ), 2.85e2.97 (m, 1H, CH2),
3.48e3.64 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 3.73e3.84
(m, 1H, CH2), 3.93e4.05 (m, 4H, POCH2CH3), 4.73 (s, 2H,
PhCH2O), 6.80e6.85 (m, 2H, aromat.), 7.13e7.18 (m, 2H, ar-
omat.), 7.29e7.40 (m, 5H, aromat.). 13C NMR (CDCl3),
d (ppm): 16.9 (2d, JC,P ¼ 6.1 Hz, JC,P ¼ 5.8 Hz, POCH2CH3),
Hz, CH2), 34.8 (d, JC,P ¼ 2.5 Hz, CH2), 35.8 (d, JC,P
¼
139.9 Hz, PCH), 43.7 (NCH2), 61.8 (2d, JC,P ¼ 6.6 Hz,
JC,P ¼ 7.1 Hz, POCH2CH3), 76.1 (PhCH2O), 126.5, 128.5,
128.6, 128.9, 129.1, 129.2 (tert., aromat.), 134.4 (quart., aro-
mat.), 139.2 (d, JC,P ¼ 14.3 Hz, CH2C quart., aromat.), 172.0
(C]O). IR: 1662 cmꢀ1 (C]O), 1234 cmꢀ1 (P]O).
HRFAB-MS C23H32NO5P [M þ H]þ: calculated 434.2096;
found 434.2122.
20.9 (acetyl. CH3), 25.6 (JC,P ¼ 3.0 Hz, CH2), 34.2 (d, JC,P ¼
2.6 Hz, CH2), 36.3 (d, JC,P ¼ 139.6 Hz, PCH), 44.2 (NCH2),
55.6 (OCH3), 62.3 (m, POCH2CH3), 76.5 (PhCH2O), 114.3
(OCCH tert., aromat.), 129.1, 129.3, 129.5, 130.5 (tert., aro-
mat.), 131.5 (d, JC,P ¼ 15.0 Hz, CH2C quart., aromat.), 134.8
(quart., aromat.), 158.7 (CH3OC quart., aromat.), 172.4
(C]O). IR: 1664 cmꢀ1 (C]O), 1250 cmꢀ1 (P]O). Anal.
Calcd for C24H34NO6P: calculated C 62.19%, H 7.39%, N
3.02%; found C 62.64%, H 7.45%, N 2.77%.
6.1.4.2. [3-(Acetyl-benzyloxy-amino)-1-(2,5-dimethyl-benzyl)-
1
propyl]-phosphonic acid diethyl ester (5b). Yield: 91%. H
NMR (CDCl3), d (ppm): 1.23e1.37 (m, 6H, POCH2CH3),
1.79e1.93 (m, 2H, CH2), 1.97 (s, 3H, acetyl. CH3), 2.06e
2.18 (m, 1H, PCH ), 2.24 (s, 3H, PhCH3), 2.25 (s, 3H,
PhCH3), 2.50e2.64 (m, 1H, CH2), 3.07e3.21 (m, 1H, CH2),
3.50e3.83 (m, 2H, CH2), 4.01e4.21 (m, 4H, POCH2CH3),
4.65 (s, 2H, PhCH2O), 6.88e7.06 (m, 3H, aromat.), 7.21e
7.41 (m, 5H, aromat.). 13C NMR (CDCl3), d (ppm): 16.5 (2d,
JC,P ¼ 6.1 Hz, POCH2CH3), 19.0, 20.9 (PhCH3), 20.5 (acetyl.
CH3), 25.4 (d, JC,P ¼ 3.4 Hz, CH2), 32.3 (d, JC,P ¼ 2.5 Hz,
CH2), 34.4 (d, JC,P ¼ 139.4 Hz, PCH), 43.8 (NCH2), 62.1 (2d,
JC,P ¼ 6.8 Hz, JC,P ¼ 6.6 Hz, POCH2CH3), 76.0 (PhCH2O),
127.2, 128.6, 128.8, 129.1, 130.5, 130.8 (tert., aromat.),
133.1, 135.3, 137.0 (quart., aromat.), 137.6 (d, JC,P ¼ 14.3 Hz,
CH2C quart., aromat.), 175.5 (C]O). IR: 1664 cmꢀ1 (C]O),
1232 cmꢀ1 (P]O). HRFAB-MS C25H36NO5P [M þ H]þ: cal-
culated 462.2409; found 462.2425.
6.1.4.5.
[3-(Acetyl-benzyloxy-amino)-1-(naphthalene-2-yl-
methyl)-propyl]-phosphonic acid diethyl ester (5e). Yield:
95%. MP: 78.5 ꢁC. H NMR (CDCl3), d (ppm): 1.20e1.36
1
(m, 6H, POCH2CH3), 1.78e2.10 (m, 5H, acetyl. CH3 overlap-
ping CH2), 2.17e1.32 (m, 1H, PCH ), 2.74e2.90 (m, 1H,
CH2), 3.26e3.41 (m, 1H, CH2), 3.53e3.91 (m, 2H, CH2),
4.04e4.19 (m, 4H, POCH2CH3), 4.95 (s, 2H, PhCH2O),
7.09e7.50 (m, 8H, aromat.), 7.63e7.84 (m, 4H, aromat.). 13
C
NMR (CDCl3), d (ppm): 16.9 (2d, JC,P ¼ 5.7 Hz, POCH2CH3),
20.9 (acetyl. CH3), 25.8 (CH2), 35.4 (d, JC,P ¼ 2.7 Hz, CH2),
35.8 (PCH), 44.2 (NCH2), 62.3 (m, POCH2CH3), 76.5
(PhCH2O), 125.9, 126.5, 127.7, 128.0, 128.1, 128.6, 129.0,
129.2, 129.4 (tert., aromat.), 132.7, 133.9, 134.7 (quart., aro-
mat.), 137.0 (d, JC,P ¼ 15.0 Hz, CH2C quart., aromat.), 175.5
(C]O). IR: 1651 cmꢀ1 (C]O), 1227 cmꢀ1 (P]O). Anal.
Calcd for C27H34NO5P: calculated C 67.07%, H 7.09%, N
3.20%; found C 67.16%, H 7.14%, N 2.99%.
6.1.4.3. [3-(Acetyl-benzyloxy-amino)-1-(3,4-dichlor-benzyl)-
propyl]-phosphonic acid diethyl ester (5c). Yield: 95%. MP:
66.8 ꢁC. 1H NMR (CDCl3), d (ppm): 1.24e1.33 (m, 6H,
POCH2CH3), 1.68e1.85 (m, 1H, CH2), 1.90e2.19 (m, 5H,
acetyl. CH3 overlapping PCH, CH2), 2.56e2.72 (m, 1H,
CH2), 2.98e3.10 (m, 1H, CH2), 3.59e3.89 (m, 2H, CH2),
3.97e4.16 (m, 4H, POCH2CH3), 4.74 (s, 2H, PhCH2O),
7.00e7.10 (m, 1H, aromat.), 7.23e7.46 (m, 7H, aromat.).
13C NMR (CDCl3), d (ppm): 16.8 (2d, JC,P ¼ 6.1 Hz,
JC,P ¼ 6.0 Hz, POCH2CH3), 20.9 (acetyl. CH3), 25.8 (d,
JC,P ¼ 2.8 Hz, CH2), 34.4 (d, JC,P ¼ 2.8 Hz, CH2), 35.9 (d,
6.1.4.6.
[3-(Acetyl-benzyloxy-amino)-1-(naphthalene-1-yl-
methyl)-propyl]-phosphonic acid diethyl ester (5f). Yield:
94%. 1H NMR (CDCl3), d (ppm): 1.29e1.37 (m, 6H,
POCH2CH3), 1.81 (s, 3H, acetyl. CH3), 1.84e2.03 (m, 2H,
CH2), 2.20e2.40 (m, 1H, PCH ), 2.83e2.98 (m, 1H, CH2),
3.37e3.84 (m, 3H, CH2), 4.04e4.23 (m, 4H, POCH2CH3),
4.50 (s, 2H, PhCH2O), 7.10e7.20 (m, 2H, aromat.), 7.28e
7.39 (m, 5H, aromat.), 7.44e7.55 (m, 2H, aromat.), 7.68e7.76
(m, 1H, aromat.), 7.81e7.88 (m, 1H, aromat.), 8.01e8.07
(m, 1H, aromat.). 13C NMR (CDCl3), d (ppm): 16.9, 17.0