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E. Vaz et al. / Tetrahedron: Asymmetry 14 (2003) 1935–1942
7.82 (d, J=8.1 Hz, 1H, Phe NH), 7.30–7.21 (m, 3H, Ph),
7.15 (m, 2H, Ph), 4.85 (m, 1H, H2), 3.72 (s, 3H, CH3Oꢀ),
3.66 (s, 3H, CH3Oꢀ), 3.29 (d, J=17.3 Hz, 1H, H2%), 3.21
(d, J=17.3 Hz, 1H, H2%), 3.19 (dd, J=13.9 and 5.8 Hz,
1H, H3), 3.10 (dd, J=13.9 and 7.0 Hz, 1H, H3), 2.84 (m,
1H, H3¦), 2.43 (dd, J=15.5 and 5.0 Hz, 1H, H2¦), 2.31
(dd, J=15.5 and 7.2 Hz, 1H, H2¦), 1.65 (s, 1H, NH), 1.30
(m, 2H, H4¦), 1.25 (m, 15H, H5¦–H11¦), 0.89 (t, J=6.8 Hz,
3H, H12¦); 13C NMR (CDCl3, 100 MHz): l 172.7 (s),
172.0 (s), 171.9 (s), 136.2 (s), 129.2 (d), 128.5 (d), 127.0
(d), 55.1 (d), 52.9 (d), 52.2 (q), 51.6 (q), 49.5 (t), 38.7 (t),
36.8 (t), 34.1 (t), 31.9 (t), 29.6 (t), 29.5 (2t), 29.3 (t), 25.9
(t), 22.7 (t), 14.1 (q); MS (FAB+): m/z (%) 450 (M++2,
29), 449 (M++1, 100), 375 (10), 242 (21); HRMS (FAB+):
calcd for C25H41N2O5 449.3015, found 449.3001; IR
(NaCl, cm−1): 3338, 2926, 2854, 1739, 1677.
in a Schlenk tube. The reaction mixture was evaporated
and the residue purified by HPLC (column: Spherisorb
S5 NH2, 10×250 mm, hexane/i-PrOH 10%, 2.5 mL/min,
tR=15.4 min) to afford 2.4 mg (40%) of a white solid and
6.4 mg of starting material as a yellow oil. [h]2D5=−37.6
1
(c 0.71, CHCl3); H NMR (CDCl3, 400 MHz): l 7.33–
7.19 (m, 5H, Ph), 6.08 (bs, 1H, NH), 4.67 (m, 1H, H3¦),
4.17 (m, 1H, H2), 3.66 (d, J=17.2 Hz, 1H, H2%), 3.65 (s,
3H, CH3Oꢀ), 3.41 (d, J=17.2 Hz, 1H, H2%), 3.22 (dd,
J=13.7 and 3.6 Hz, 1H, H3), 2.95 (dd, J=13.7 and 8.2
Hz, 1H, H3), 2.50 (dd, J=15.1 and 6.2 Hz, 1H, H2¦), 2.37
(dd, J=15.1 and 6.2 Hz, 1H, H2¦), 1.55–1.49 (m, 2H,
H4¦), 1.22 (bs, 14H, H5¦–H11¦), 0.85 (t, J=6.7 Hz, 3H,
H
12¦); 13C NMR (CDCl3, 100 MHz): l 171.1 (s), 165.8
(s), 165.7 (s), 135.4 (s), 129.6 (d), 129.0 (d), 127.6 (d), 57.0
(d), 51.9 (q), 51.4 (d), 45.0 (t), 40.4 (t), 36.7 (t), 31.8 (t),
31.0 (t), 29.5 (t), 29.4 (t), 29.2 (t), 29.1 (t), 26.0 (t), 22.6
(t), 14.1 (q); MS (FAB+): m/z (%) 418 (27), 417 (M++1,
100), 416 (12), 289 (14); HRMS (FAB+): calcd for
C24H37N2O4 417.2753; found 417.2734; IR (NaCl, cm−1):
2924, 1735, 1652.
3.12. Methyl (3S)-3-[(2-{[(1R)-1-benzyl-2-methoxy-2-
oxoethyl]amino}-2-oxoethyl)amino]dodecanoate, (R,S)-5
The spectroscopic data were identical to those for the
corresponding (S,R)-5 enantiomer. [h]2D0=−13.1 (c 0.08,
CHCl3).
3.16. Methyl (3S)-3-[(3R)-3-benzyl-2,5-dioxopiper-
azinyl]dodecanoate, (R,S)-11
3.13. Methyl (3S)-3-[(2-{[(1S)-1-benzyl-2-methoxy-2-
oxoethyl]amino}-2-oxoethyl)amino]dodecanoate, (S,S)-5
The spectroscopic data were identical to those for the
corresponding (S,R)-11 enantiomer. [h]2D6=+37.1 (c 0.76,
CHCl3).
Following the above procedure for the preparation of the
dipeptide (S,R)-5, the amine (S)-5 (260.7 mg, 1.14
mmol), DIEA (0.4 mL, 2.27 mmol) and (S)-N-bromo-
acetylphenylalanine methyl ester (S)-6 (340.9 mg, 1.14
mmol) in DMF (10.7 mL) were reacted to afford 451.0
mg (88%) of a yellow oil. [h]2D1=+40.6 (c 0.06, CHCl3);
1H NMR (CDCl3, 400 MHz): l 7.74 (d, J=8.3 Hz, 1H,
Phe NH), 7.27–7.19 (m, 3H, Ph), 7.12 (m, 2H, Ph), 4.84
(dd, J=6.7 and 1.6 Hz, 1H, H2), 3.71 (s, 3H, CH3Oꢀ),
3.67 (s, 3H, CH3Oꢀ), 3.21 (d, J=17.2 Hz, 1H, H2%), 3.19
(d, J=17.5 Hz, 1H, H2%), 3.14 (dd, J=13.9 and 5.8 Hz,
1H, H3), 3.07 (dd, J=13.9 and 7.0 Hz, 1H, H3), 2.78 (m,
1H, H3¦), 2.36 (dd, J=15.5 and 4.9 Hz, 1H, H2¦), 2.24
(dd, J=15.4 and 7.4 Hz, 1H, H2¦), 1.69 (s, 1H, NH), 1.29
(m, 1H, H4¦), 1.21 (bs, 15H, H5¦–H11¦), 0.85 (t, J=6.8 Hz,
3H, H12¦); 13C NMR (CDCl3, 100 MHz): l 172.7 (s),
171.9 (s), 171.6 (s), 136.2 (s), 129.2 (d), 128.5 (d), 126.9
(d), 55.0 (d), 52.7 (d), 52.1 (q), 51.6 (q), 49.3 (t), 38.6 (t),
37.9 (t), 34.0 (t), 31.8 (t), 29.5 (2t), 29.4 (t), 29.2 (t), 25.8
(t), 22.6 (t), 14.0 (q); MS (FAB+): m/z (%) 450 (M++2,
28), 449 (100), 375 (9), 272 (16), 242 (24); HRMS (FAB+):
calcd for C25H41N2O5 449.3015, found 449.2997; IR
(NaCl, cm−1): 3338, 2926, 2854, 1739, 1677.
3.17. Methyl (3S)-3-[(3S)-3-benzyl-2,5-dioxopiper-
azinyl]dodecanoate, (S,S)-11
Following the above procedure for the preparation of
dioxopiperazine (S,R)-11, the dipeptide (S,S)-5 (105.6
mg, 0.235 mmol) in toluene (5.0 mL) was reacted to
afford, after purification by chromatography (silica gel,
hexane/EtOAc 50% to EtOAc), 47.1 mg (66%) of a white
solid and 28.9 mg of starting material as a yellow oil.
[h]2D0=−68.8 (c 0.43, CHCl3); 1H NMR (CDCl3, 400
MHz): l 7.35–7.21 (m, 5H, Ph), 6.25 (bs, 1H, NH), 4.67
(m, 1H, H3¦), 4.23 (dd, J=6.5 and 3.6 Hz, 1H, H2), 3.70
(d, J=17.3 Hz, 1H, H2%), 3.66 (s, 3H, CH3Oꢀ), 3.37 (bd,
J=17.2 Hz, 1H, H2%), 3.25 (dd, J=13.8 and 3.2 Hz, 1H,
H3), 3.02 (dd, J=13.8 and 7.8 Hz, 1H, H3), 2.58–2.47 (m,
2H, H2¦), 1.55–1.43 (m, 2H, H4¦), 1.27 (bs, 14H, H5¦–
H
11¦), 0.89 (t, J=6.8 Hz, 3H, H12¦); 13C NMR (CDCl3,
100 MHz): l 171.1 (s), 166.0 (s), 165.7 (s), 135.3 (s), 129.7
(d), 129.0 (d), 127.5 (d), 56.6 (d), 51.9 (q), 51.7 (d), 45.3
(t), 40.0 (t), 36.4 (t), 31.8 (t), 31.3 (t), 29.5 (t), 29.4 (t),
29.3 (t), 29.2 (t), 26.1 (t), 22.7 (t), 14.1 (q); MS (FAB+):
m/z (%) 418 (27), 417 (M++1, 100), 416 (13), 205 (9);
HRMS (FAB+): calcd for C24H37N2O4 417.2753; found
417.2738; IR (NaCl, cm−1): 2924, 1735, 1652.
3.14. Methyl (3R)-3-[(2-{[(1R)-1-benzyl-2-methoxy-2-
oxoethyl]amino}-2-oxoethyl)amino]dodecanoate, (R,R)-5
The spectroscopic data were identical to those for the
corresponding (S,S)-5 enantiomer. [h]2D0=−39.9 (c 0.07,
CHCl3).
3.18. Methyl (3R)-3-[(3R)-3-benzyl-2,5-dioxopiper-
azinyl]dodecanoate, (R,R)-11
3.15. Methyl (3R)-3-[(3S)-3-benzyl-2,5-dioxopiper-
azinyl]dodecanoate, (S,R)-11
The spectroscopic data were identical to those for the
corresponding (S,S)-11 enantiomer. [h]2D6=+67.2 (c 0.54,
CHCl3).
A solution of the dipeptide (S,R)-5 (12.9 mg, 0.029
mmol) in toluene (0.5 mL) was stirred for 5 days at 130°C