3996 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Nilsson et al.
5.21 (s, 2H), 7.29-7.47 (m, 12H), 7.72-7.78 (m, 2H); 13C NMR
(methanol-d4, 75.5 MHz) δ 37.9, 42.5, 52.7, 59.1, 63.5, 67.4,
75.3, 127.4, 128.0, 128.1, 128.1, 128.3, 128.4, 128.4, 129.1,
131.2, 131.8, 136.6, 144.2, 162.0, 168.8, 169.5, 170.9.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-3-oxo-
4-p h en ylm eth a n esu lfon yla m in o-m or p h olin -2-yl]-a ceta -
m id e Acid Ben zyl Ester ((S)-12h ). See general procedure.
1H NMR (methanol-d4, 300 MHz) δ 2.85-2.92 (m, 2H), 3.52-
3.60 (m, 1H), 3.86-4.09 (m, 3H), 4.38 (d, J ) 13.6 Hz, 1H),
4.47 (s, 2H), 4.52-4.57 (m, 1H), 4.60 (d, J ) 13.6 Hz, 1H),
5.29 (s, 2H), 7.29-7.51 (m, 12H), 7.71-7.78 (m, 2H).
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(R)-3-oxo-
4-(3-ph en yl-u r eido)-m or ph olin -2-yl]-acetam ide Acid Ben -
zyl E st er ((R)-12i). See general procedure. Crystallization
from methanol and diethyl ether yielded pure (R)-12i as a
white powder (0.051 g, 91%, two steps from (R)-10i). 1H NMR
(methanol-d4, 300 MHz) δ 2.79-2.90 (m, 2H), 3.39-3.47 (m,
1H), 3.88-4.13 (m, 3H), 4.46 (s, 2H), 4.48-4.56 (m, 1H), 5.18
(s, 2H), 6.94-7.03 (m, 1H), 7.14-7.24 (m, 2H), 7.25-7.50 (m,
9H), 7.76-7.85 (m, 2H).
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(R)-4-iso-
p r op oxyca r b on yla m in o-3-oxo-m or p h olin -2-yl]-a ce t a -
m id e Acid Ben zyl Ester ((R)-12j). See general procedure.
1H NMR (methanol-d4, 300 MHz) δ 1.25 (d, J ) 6.2 Hz, 6H),
2.73 (dd, J ) 15.0; 8.0 Hz, 1H), 2.87 (dd, J ) 15.0; 4.0 Hz,
1H), 3.39-3.47 (m, 1H), 3.75-3.86 (m, 1H), 3.88-4.00 (m, 1H),
4.08 (ddd, J ) 12.0; 4.4; 2.2 Hz, 1H), 4.37-4.51 (m, 2H), 4.59
(dd, J ) 8.0; 4.0 Hz, 1H), 4.90 (sept. J ) 6.2 Hz, 1H), 5.23 (s,
2H), 7.26-7.39 (m, 5H), 7.39-7.46 (m, 2H), 7.76-7.82 (m, 2H);
13C NMR (methanol-d4, 75.5 MHz) δ 21.1, 38.2, 42.6, 51.2, 63.1,
67.5, 69.9, 75.4, 127.5, 128.08, 128.10, 128.13, 128.4, 131.6,
136.5, 144.2, 156.2, 161.5, 168.8, 169.5, 171.2.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2- [(R)-3-oxo-
4-p h en eth yla m in o-m or p h olin -2-yl]-a ceta m id e Acid Ben -
zyl Ester ((R)-12k). See general procedure. 1H NMR (methanol-
d4, 300 MHz) δ 2.66-2.87 (m, 4H), 3.08-3.17 (m, 2H), 3.32-
3.40 (m, 1H), 3.60-3.82 (m, 2H), 4.00 (ddd, J ) 11.6; 4.0; 2.2
Hz, 1H), 4.43 (s, 2H), 4.40-4.49 (m, 1H), 5.19 (s, 2H), 7.11-
7.46 (m, 12H), 7.77-7.83 (m, 2H).
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-3-oxo-
4-p h en eth yla m in o-m or p h olin -2-yl]-a ceta m id e Acid Ben -
zyl Ester ((S)-12k). See general procedure. 1H NMR (methanol-
d4, 300 MHz) δ 2.68-2.88 (m, 4H), 3.07-3.18 (m, 2H), 3.33-
3.41 (m, 1H), 3.61-3.82 (m, 2H), 4.01 (ddd, J ) 11.6; 4.0; 2.2
Hz, 1H), 4.44 (s, 2H), 4.44-4.49 (m, 1H), 5.22 (s, 2H), 7.13-
7.46 (m, 12H), 7.76-7.83 (m, 2H).
(m, 2H), 3.20-3.30 (m, 1H), 3.45-3.56 (m, 1H), 3.70-3.81 (m,
1H), 4.01 (ddd, J ) 11.9; 4.1; 2.2 Hz, 1H), 4.37 (d, J ) 15.6
Hz, 1H), 4.44 (d, J ) 15.6 Hz, 1H), 4.46 (dd, J ) 7.7; 3.9 Hz,
1H), 5.18 (s, 2H), 7.06-7.45 (m, 17H), 7.77-7.85 (m, 2H); 13
C
NMR (methanol-d4, 75.5 MHz) δ 29.0, 33.1, 38.4, 42.5, 44.7,
52.9, 63.2, 66.8, 75.3, 125.7, 127.3, 127.8, 127.9, 128.2, 128.28,
128.31, 133.3, 142.2, 143.5, 169.6, 171.2.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(R)-4-ben -
zyla m in o-3-oxo-m or p h olin -2-yl]-a ceta m id e Acid Ben zyl
1
Ester ((R)-12n ). See general procedure. H NMR (methanol-
d4, 300 MHz) δ 2.70 (dd, J ) 15.0; 7.6 Hz, 1H), 2.83 (dd, J )
14.9; 4.0 Hz, 1H), 3.19-3.28 (m, 1H), 3.49-3.60 (m, 1H), 3.69-
3.80 (m, 1H), 3.94 (ddd, J ) 12.0; 4.3; 2.3 Hz, 1H), 3.99 (s,
2H), 4.45 (s, 2H), 4.48 (dd, J ) 7.6; 4.0 Hz, 1H), 5.25 (s, 2H),
7.22-7.48 (m, 12H), 7.75-7.81 (m, 2H).
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-4-ben -
zyla m in o-3-oxo-m or p h olin -2-yl]-a ceta m id e Acid Ben zyl
1
Ester ((S)-12n ). See general procedure. H NMR (methanol-
d4, 300 MHz) δ 2.70 (dd, J ) 15.0; 7.5 Hz, 1H), 2.81 (dd, J )
15.0; 3.9 Hz, 1H), 3.19-3.28 (m, 1H), 3.49-3.60 (m, 1H), 3.69-
3.79 (m, 1H), 3.89-3.97 (m, 1H), 3.99 (s, 2H), 4.45 (s, 2H), 4.48
(dd, J ) 7.5; 3.9 Hz, 1H), 5.26 (s, 2H), 7.24-7.48 (m, 12H),
7.74-7.80 (m, 2H); 13C NMR (methanol-d4, 75.5 MHz) δ 38.2,
42.5, 49.1, 49.2, 52.8, 62.9, 67.9, 74.8, 127.5, 127.6, 128.21,
128.25, 128.3, 128.4, 129.2, 130.4, 136.1, 137.4, 144.8, 159.8,
168.4, 171.3.
N-(4-Ben zyloxycar bon ylam idin o-ben zyl)-2-[(S)-4-diben -
zyla m in o-3-oxo-m or p h olin -2-yl]-a ceta m id e Acid Ben zyl
1
Ester ((S)-12o). See general procedure. H NMR (methanol-
d4, 300 MHz) δ 2.50 (dd, J ) 14.9; 8.8 Hz, 1H), 2.59-2.68 (m,
1H), 2.84 (dd, J ) 14.9; 3.5 Hz, 1H), 2.87-2.98 (m, 1H), 2.98-
3.09 (m, 1H), 3.39-3.47 (m, 1H), 4.03 (d, J ) 12.1 Hz, 1H),
4.11 (d, J ) 12.3 Hz, 1H), 4.28 (dd, J ) 8.8; 3.5 Hz, 1H), 4.33-
4.49 (m, 4H), 5.17 (s, 2H), 7.23-7.44 (m, 17H), 7.75-7.81 (m,
2H); 13C NMR (methanol-d4, 75.5 MHz) δ 38.4, 42.5, 51.9, 57.3,
57.7, 62.6, 66.8, 75.2, 127.3, 127.59, 127.65, 127.8, 127.9, 128.1,
128.2, 128.3, 129.5, 129.6, 133.3, 137.1, 137.6, 137.8, 143.4,
169.8, 171.4.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-4-(2,5-
d im et h oxy-b en zen esu lfon yla m in o)-3-oxo-m or p h olin -2-
yl]-a ceta m id e Acid Ben zyl Ester ((S)-12p ). See general
1
procedure. H NMR (methanol-d4, 300 MHz) δ 2.54 (dd, J )
15.1; 7.4 Hz, 1H), 2.62 (dd, J ) 15.1; 4.1 Hz, 1H), 3.65-3.72
(m, 1H), 3.76 (s, 3H), 3.79-3.91 (m, 2H), 3.94 (s, 1H), 3.99-
4.05 (m, 1H), 4.34 (dd, J ) 7.4; 4.1 Hz, 1H), 4.40 (s, 2H), 5.24
(s, 2H), 7.09 (d, J ) 9.0 Hz, 1H), 7.16 (dd, J ) 9.0; 3.1 Hz,
1H), 7.30-7.47 (m, 8H), 7.74-7.80 (m, 2H); 13C NMR (methanol-
d4, 75.5 MHz) δ 38.0, 42.5, 52.4, 55.4, 56.2, 63.2, 67.7, 75.1,
114.1, 114.9, 120.6, 127.4, 127.5, 128.1, 128.15, 128.18, 128.4,
131.1, 136.3, 144.4, 152.2, 152.9, 168.5, 168.6, 171.0.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(R)-3-oxo-
4-(3-ph en yl-pr opylam in o)-m or ph olin -2-yl]-acetam ide Acid
Ben zyl Ester ((R)-12l). See general procedure. 1H NMR
(methanol-d4, 300 MHz) δ 1.71-1.83 (m, 2H), 2.63-2.70 (m,
2H), 2.70-2.91 (m, 4H), 3.32-3.41 (m, 1H), 3.60-3.72 (m, 1H),
3.78-3.89 (m, 1H), 4.03 (ddd, J ) 12.1; 4.3; 2.2 Hz, 1H), 4.43
(s, 2H), 4.49 (dd, J ) 7.4; 4.0 Hz, 1H), 5.22 (s, 2H), 7.09-7.39
(m, 8H), 7.39-7.46 (m, 4H), 7.75-7.82 (m, 2H); 13C NMR
(methanol-d4, 75.5 MHz) δ 29.5, 33.0, 38.1, 42.5, 47.9, 48.4,
63.0, 67.4, 74.8, 125.7, 127.4, 128.06, 128.08, 128.11, 128.2,
128.3, 128.4, 131.6, 136.5, 142.0, 144.3, 161.6, 168.1, 168.8,
171.3.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-4-(2,4-
d iflu or o-ben zen esu lfon yla m in o)-3-oxo-m or p h olin -2-yl]-
a ceta m id e Acid Ben zyl Ester ((S)-12q). See general pro-
cedure. 1H NMR (methanol-d4, 300 MHz) δ 2.54 (dd, J ) 15.2;
7.2 Hz, 1H), 2.62 (dd, J ) 15.2; 4.2 Hz, 1H), 3.69-3.75 (m,
1H), 3.86-3.94 (m, 2H), 4.02-4.08 (m, 1H), 4.35 (dd, J ) 7.2;
4.4 Hz, 1H), 4.41 (s, 2H), 5.25 (s, 2H), 7.03-7.18 (m, 2H), 7.28-
7.46 (m, 7H), 7.75-7.81 (m, 2H), 7.87-7.96 (m, 1H); 13C NMR
(methanol-d4, 75.5 MHz) δ 37.8, 42.5, 52.4, 63.2, 67.7, 75.2,
105.5 (t, J ) 26.2 Hz), 111.4 (dd, J ) 22.3; 3.4 Hz), 127.5,
128.13, 128.16, 128.17, 131.0, 132.7 (dd, J ) 10.8; 1.1 Hz),
136.3, 144.5, 168.6, 168.7, 170.9. Some signals lost in the noise
(approximately 124 (dd), 161 (dd), 167 (dd)).
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-[(S)-3-oxo-
4-(3-ph en yl-pr opylam in o)-m or ph olin -2-yl]-acetam ide Acid
Ben zyl Ester ((S)-12l). See general procedure. 1H NMR
(methanol-d4, 300 MHz) δ 1.71-1.85 (m, 2H), 2.58-2.97 (m,
6H), 3.32-3.41 (m, 1H), 3.63-3.76 (m, 1H), 3.78-3.89 (m, 1H),
3.96-4.07 (m, 1H), 4.43 (s, 2H), 4.49 (dd, J ) 7.5; 4.1 Hz, 1H),
5.18 (s, 2H), 7.09-7.44 (m, 12H), 7.79-7.84 (m, 2H); 13C NMR
(methanol-d4, 75.5 MHz) δ 29.5, 33.0, 38.2, 42.5, 47.9, 48.4,
63.1, 66.9, 74.8, 125.7, 127.4, 128.0, 128.07, 128.12, 128.2,
128.3, 128.4, 133.2, 137.1, 142.0, 144.5, 168.0, 168.2, 171.3.
N-(4-Ben zyloxyca r bon yla m id in o-ben zyl)-2-{(R)-4-[bis-
(3-p h en yl-p r op yl)-a m in o]-3-oxo-m or p h olin -2-yl}-a cet a -
m id e Acid Ben zyl Ester ((R)-12m ). See general procedure.
N-(4-Ben zyloxyca r b on yla m id in o-b en zyl)-2-[(S)-4-(4-
ch lor o-2,5-d im eth yl-ben zen esu lfon yla m in o)-3-oxo-m or -
p h olin -2-yl]-a ceta m id e Acid Ben zyl Ester ((S)-12r ). See
general procedure. 1H NMR (methanol-d4, 300 MHz) δ 2.36
(s, 3H), 2.52 (dd, J ) 15.1; 7.3 Hz, 1H), 2.60 (dd, J ) 15.1; 4.1
Hz, 1H), 2.66 (s, 3H), 3.64-3.70 (m, 1H), 3.80-3.91 (m, 2H),
3.97-4.07 (m, 1H), 4.30 (dd, J ) 7.3; 4.1 Hz, 1H), 4.41 (s, 2H),
5.25 (s, 2H), 7.28-7.47 (m, 9H), 7.74-7.80 (m, 2H); 13C NMR
(methanol-d4, 75.5 MHz) δ 18.3, 19.1, 37.9, 42.5, 52.4, 60.4,
63.3, 67.7, 75.2, 127.5, 128.1, 128.18, 128.19, 128.4, 130.8,
1
Yield: 98%, two steps from (R)-10m . H NMR (methanol-d4,
300 MHz) δ 1.64-1.84 (m, 4H), 2.55-2.84 (m, 6H), 2.70 (dd, J
) 15.0; 7.7 Hz, 1H), 2.84 (dd, J ) 15.0; 3.9 Hz, 1H), 2.87-3.04