A. Dahlgren et al. / Bioorg. Med. Chem. 10 (2002) 1829–1839
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N-{4-[Amino(imino)methyl]benzyl}-2-((R)-4-isobutyl-3-
oxo-morpholin-2-yl)-acetamide (9). Compound 9 (a color-
less solid) was prepared in 40% yield from 6 according
67.91; H, 6.78; N, 3.77. Found: C, 67.76; H, 6.79; N,
3.91.
22
to Procedure D. 9: ½ꢀꢂd +55.6 (c 0.8, MeOH); 1H NMR
(S)-2-{2-[(1,1-Diphenyl-methyl)-amino]-ethoxy}-succinic
acid dimethyl ester [(S)-12]. Compound (S)-12 was pre-
pared in 77% yield from (S)-3 and a-diphenyl amino-
(methanol-d4, 250 MHz) d 0.92 (d, J=6.6 Hz, 6H), 2.02
(m, 1H), 2.71 (dd, J=8.0 Hz, J=15.0 Hz, 1H), 2.87
(dd, J=4.0 Hz, J=15.0 Hz, 1H), 3.19–3.31 (m, 3H),
3.52–3.67 (m, 1H), 3.75–3.90 (m, 1H), 4.03 (ddd, J=2.6
Hz, J=4.0 Hz, J=12.1 Hz, 1H), 4.41–4.57 (m, 1H),
4.48 (s, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz,
2H); 13C NMR (methanol-d4, 62.9 MHz) d 20.2,
20.4, 27.4, 39.7, 43.6, 49.9, 55.3, 63.9, 75.7, 128.8,
129.0, 129.6, 146.3, 168.1, 170.6, 172.7. HRMS m/z
calcd for C18H27N4O3 (MH+): 347.2083. Found
347.2082.
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methane according to Procedure B. (S)-12: ½ꢀꢂd ꢀ20.2
(c 1.5, CHCl3). Anal. calcd for C21H25NO5: C, 67.91; H,
6.78; N, 3.77. Found: C, 67.69; H, 6.86; N, 3.74.
(R)-2-{2-[((S)-1-tert-Butoxycarbonyl-1-phenyl-methyl)-
amino]-ethoxy}-succinic acid dimethyl ester (13). Com-
pound 13 (a colorless oil) was prepared in 82% yield
from (R)-3 and (S)-2-amino-2-phenyl-acetic acid tert-
butyl ester (the tert-butyl ester of (S)-phenylglycine)
22
according to Procedure C. 13: ½ꢀꢂd +73.5 (c 0.8,
1
(R)-2-(2-Cyclohexylamino-ethoxy)-succinic acid dimethyl
ester (10). Compound 10 (a colorless glue) was pre-
pared in 58% yield from (R)-3 and cyclohexylamine
CHCl3); H NMR (CDCl3, 250 MHz) d 1.38 (s, 9H),
2.45 (bs, 1H), 2.60–2.71 (m, 1H), 2.73–2.88 (m, 3H),
3.53–3.63 (m, 1H), 3.69 (s, 3H), 3.74 (s, 3H), 3.78–3.89
(m, 1H), 4.28 (s, 1H), 4.33 (dd, J=5.1 Hz, J=8.0 Hz,
1H), 7.25–7.42 (m, 5H); 13C NMR (CDCl3, 62.9 MHz)
d 27.9, 37.7, 46.9, 52.0, 52.2, 66.0, 71.0, 75.5, 81.3, 127.4,
127.7, 128.5, 138.8, 170.5, 171.9, 171.9. Anal. calcd for
C20H29NO7: C, 60.74; H, 7.39; N, 3.54. Found: C,
60.72; H, 7.38; N, 3.62.
22
according to Procedure B. 10: ½ꢀꢂd +41.3 (c 0.2,
CHCl3); 1H NMR (CDCl3, 250 MHz) 0.90–1.30 (m,
4H), 1.50–1.95 (m, 6H), 2.28–2.48 (m, 1H), 2.61–2.81
(m, 4H), 3.48–3.59 (m, 1H), 3.62–3.70 (m, 1H), 3.65 (s,
3H), 3.71 (s, 3H), 3.67–3.80 (m, 1H), 4.28 (dd, J=4.8
Hz, J=8.0 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) d
24.9, 26.0, 33.3, 37.6, 46.1, 51.8, 52.1, 56.4, 70.9, 75.2,
.
170.4, 171.7. Anal. calcd for C14H25NO5 0.03CHCl3: C,
57.92; H, 8.67; N, 4.82. Found: C, 58.00; H, 8.32; N,
4.80.
N-{4-[Amino(imino)methyl]benzyl}-2-((R)-4-cyclohexyl-
3-oxo-morpholin-2-yl)-acetamide (14). Compound 14 (a
colorless solid) was prepared in 70% yield from 10
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according to Procedure E. 14: ½ꢀꢂd +40.0 (c 0.2,
(R)-2-{2-[(1,1-Dicyclohexyl-methyl)-amino]-ethoxy}-suc-
cinic acid dimethyl ester [(R)-11]. Compound (R)-11 (a
colorless glue) was prepared in 43% yield from (R)-3
and (dicyclohexylmethyl)-amine17 according to Proce-
MeOH); 1H NMR (D2O, 250 MHz) d 0.95–1.80 (m,
10H), 2.82 (dd, J=4.4 Hz, J=15.0 Hz, 1H), 2.90 (dd,
J=5.9 Hz, J=15.0 Hz, 1H), 3.24–3.44 (m, 2H), 3.72–
3.86 (m, 1H), 3.98–4.18 (m, 2H), 4.43 (s, 2H), 4.45 (dd,
overlapped, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.72 (d,
J=8.4 Hz, 2H); 13C NMR (D2O, 62.9 MHz) d 27.5,
27.7, 27.8, 31.1, 31.3, 40.7, 43.4, 45.3, 56.3, 65.4, 76.4,
129.5, 130.3, 130.5, 146.9, 169.3, 171.6, 175.0. Anal.
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1
dure B. (R)-11: ½ꢀꢂd +26.7 (c 0.3, MeOH); H NMR
(CDCl3, 250 MHz) d 0.90–1.33d (m, 10H), 1.39–1.82 (m,
12H), 1.91–2.02 (m, 2H), 2.70–2.98 (m, 4H), 3.52–3.64
(m, 1H), 3.70 (s, 3H), 3.77 (s, 3H), 3.70–3.85 (m, 1H),
4.32 (dd, J=5.1 Hz, J=7.7 Hz, 1H); 13C NMR (CDCl3,
62.9 MHz) d 26.5, 26.6, 26.8, 28.5, 30.9, 37.7, 40.2, 51.0,
52.0, 52.3, 68.6, 71.0, 75.4, 170.5, 172.0. Anal. calcd for
C21H37NO5: C, 65.77; H, 9.72; N, 3.65. Found: C,
65.61; H, 10.00; N, 3.65.
.
.
calcd for C20H28N4O3 1.17HOAc 1.50H2O: C, 57.12; H,
7.66; N, 11.93. Found: C, 57.15; H, 7.35; N, 12.10.
N-{4-[Amino(imino)methyl]benzyl}-2-[(R)-4-(1,1-dicyclo-
hexyl-methyl)-3-oxo-morpholin-2-yl]-acetamide [(R)-15].
Compound (R)-15 (a colorless solid) was prepared in
94% yield from (R)-11 according to Procedure E. (R)-
(S)-2-{2-[(1,1-Dicyclohexyl-methyl)-amino]-ethoxy}-suc-
cinic acid dimethyl ester [(S)-11]. Compound (S)-11 was
pepared in 71% yield from (S)-3 and (dicyclohexyl-
methyl)-amine17 according to Procedure B. (S)-11:
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15: ½ꢀꢂd +30.0 (c 0.3, MeOH); 1H NMR (on the acetate
salt) (methanol-d4, 250 MHz) d 0.90–1.41 (m, 10H),
1.60–1.90 (m, 13H), 1.93 (s, 3H), 2.68 (dd, J=8.6 Hz,
J=14.8 Hz, 1H), 2.88 (dd, J=3.9 Hz, J=14.8 Hz, 1H),
3.41–3.56 (m, 1H), 3.69–3.86 (m, 1H), 3.95–4.07 (m,
1H), 4.25–4.36 (m, 1H), 4.50 (d, J=4.4 Hz, 2H), 4.57
(dd, J=3.9 Hz, J=8.6 Hz, 1H), 7.54 (d,J=8.4 Hz, 2H),
7.77 (d, J=8.4 Hz, 2H); 13C NMR (on the acetate salt)
(methanol-d4, 62.9 MHz) d 23.5, 27.7, 27.9, 28.0, 28.1,
30.6, 30.8, 31.9, 32.1, 39.0, 39.2, 40.7, 43.9, 45.4, 50.6,
62.2, 64.4, 76.0, 128.5, 129.4, 129.5, 147.5, 168.6, 171.4,
173.1, 180.0. HRMS m/z calcd for C27H41N4O3 (MH+):
469.3181. Found 469.3197.
22
½ꢀꢂd ꢀ26.2 (c 0.8, MeOH). Anal. calcd for C21H37NO5:
C, 65.77; H, 9.72; N, 3.65. Found: C, 65.59; H, 9.82; N,
3.63.
(R)-2-{2-[(1,1-Diphenyl-methyl)-amino]-ethoxy}-succinic
acid dimethyl ester [(R)-12]. Compound (R)-12 (a color-
less solid) was prepared in 78% yield from (R)-3 and a-
diphenyl aminomethane according to Procedure B. (R)-
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12: ½ꢀꢂd +21.9 (c 1.1, CHCl3); 1H NMR (CDCl3,
250 MHz) d 2.20 (s, 1H), 2.67–2.87 (m, 4H), 3.58 (s,
3H), 3.55–3.68 (m, 1H), 3.72 (s, 3H), 3.81–3.91 (m, 1H),
4.37 (dd, J=4.0 Hz, J=8.2 Hz, 1H), 4.85 (s, 1H), 7.14–
7.49 (m, 10H); 13C NMR (CDCl3, 62.9 MHz) d 37.7,
47.4, 51.9, 52.2, 67.1, 70.8, 75.4, 126.9, 127.2, 128.4,
144.1, 170.6, 171.9. Anal. calcd for C21H25NO5: C,
N-{4-[Amino(imino)methyl]benzyl}-2-[(S)-4-(1,1-dicyclo-
hexyl-methyl)-3-oxo-morpholin-2-yl]-acetamide [(S)-15].
Compound (S)-15 was prepared in 77% yield from (S)-
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11 according to Procedure E. (S)-15: ½ꢀꢂd ꢀ30.3 (c 0.6,