1,3,5-Triazepan-2,6-dione Dipeptide Mimetics
FULL PAPER
298 K): d=28.0, 28.0 (CH3, 6C), 35.2 (NCH3), 40.4, 51.2, 52.0, 65.2
(CH2), 69.7 (CH), 81.8, 82.2 (Cq), 127.0, 128.6, 129.7 (CH-Ar), 137.2 (Cq-
Ar), 162.0, 168.6, 168.8, 169.2 ppm (CO); IR (solid): n˜ =3032 (Csp2),
2976, 2921, 2850 (Csp3), 1739, 1682, 1637 cmꢀ1 (CO); HRMS (ESI): m/z:
calcd for C24H36N3O6: 462.2599; found: 462.2593.
ꢀ53.0 (c=0.84 in MeOH); 1H NMR (300 MHz, CDCl3, 298 K): d=1.45
(s, 9H; CACTHRE(UGN CH3)3), 2.81 (dd, J=9.2, 14.3 Hz, 1H; CH2Ph), 3.13 (s, 3H;
NCH3), 3.36 (dd, J=4.5, 14.3 Hz, 1H; CH2Ph), 3.86 (d, J=17.7 Hz, 1H;
NCH2CO), 4.17 (d, J=15.7 Hz, 1H; NCH2N), 4.28 (d, J=17.7 Hz, 1H;
NCH2CO), 4.58–4.63 (m, 2H; NCHCO, NH), 5.44 (d, J=15.7 Hz, 1H;
NCH2N), 7.23–7.36 ppm (m, 5H; H-Ar); 13C NMR (75 MHz, CDCl3,
298 K): d=28.1 (CH3, 3C), 34.7 (NCH3), 38.2, 51.5 (CH2), 56.0 (CH),
62.8 (CH2), 82.4 (Cq), 127.3, 129.0, 129.4 (CH-Ar), 136.1 (Cq-Ar), 157.3,
168.9, 169.8 ppm (CO); IR (solid): n˜ =3291, 3221 (NH), 3063 (Csp2),
2975, 2925, 2850 (Csp3), 1741, 1653 cmꢀ1 (CO); HRMS (ESI): m/z: calcd
for C18H26N3O4: 348.1918; found: 348.1917.
(5-Benzyl-8-tert-butoxycarbonylmethyl-4,7-dioxo-octahydro-3a,6,8-triaza-
azulen-6-yl)acetic acid tert-butylester (9i) : Pale yellow solid; C18-RP-
HPLC (A: 0.1% TFA in H2O, B: 0.08% TFA in MeCN, 0–100% B,
1.2 mLminꢀ1, 20 min): tR =17.00 min; [a]2D0 =ꢀ26.8 (c=1.18 in MeOH);
1H NMR (300 MHz, CDCl3, 298 K): d=1.37 (s, 9H; C
ACHTRE(UGN CH3)3), 1.46 (s,
9H; CACHTREUNG(CH3)3), 1.80–1.99 (m, 3H; CH2), 2.25–2.32 (m, 1H; CH2), 2.78 (d,
J=17.7 Hz, 1H; NCH2CO), 3.18 (dd, J=9.6, 13.9 Hz, 1H; CH2Ph), 3.28
(dd, J=3.5, 13.9 Hz, 1H; CH2Ph), 3.50–3.60 (m, 1H; CH2), 3.76 (d, J=
17.9 Hz, 1H; NCH2CO; m, 1H; CH2), 3.97 (d, J=17.9 Hz, 1H;
NCH2CO; m, 1H; NCHCO), 4.07 (d, J=17.7 Hz; NCH2CO), 5.70 (dd,
J=6.0, 8.7 Hz, 1H; NCHN), 7.20–7.32 ppm (m, 5H; H-Ar); 13C NMR
(75 MHz, CDCl3, 298 K): d=21.4 (CH2), 28.0 (CH3, 6C), 30.7, 40.5, 46.4,
46.9, 52.7 (CH2), 69.7, 71.6 (CH), 81.7, 81.9 (Cq), 126.9, 128.5, 129.8 (CH-
Ar), 137.7 (Cq-Ar), 163.9, 167.7, 168.6, 169.2 ppm (CO); IR (solid): n˜ =
2977, 2956, 2922, 2853 (Csp3), 1739, 1679, 1638 (CO), 1221, 1146 cmꢀ1
(6-Isopropyl-1-methyl-4,7-dioxo
ACHTRE[UNG 1,3,5]triazepan-3-yl)acetic acid tert-butyl
ester (11c): White solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B: 0.08%
TFA in MeCN, 0–100% B, 1.2 mLminꢀ1, 20 min): tR =12.18 min; [a]2D0
=
ꢀ49.1 (c=0.43 in MeOH); 1H NMR (300 MHz, CDCl3, 298 K): d=1.02
(d, J=7.0 Hz, 3H; CH3), 1.04 (d, J=7.0 Hz, 3H; CH3), 1.43 (s, 9H;
CH3), 2.15–2.22 (m, 1H; CHCATHER(UGN CH3)2), 3.07 (s, 3H; NCH3), 3.91–3.97 (m,
2H; NCH2CO, NCHCO), 4.19 (d, J=17.7 Hz, 1H; NCH2CO), 4.47 (d,
J=15.6 Hz, 1H; NCH2N), 4.84 (d, J=3.8 Hz, 1H; NH), 5.09 ppm (d, J=
15.6 Hz, 1H; NCH2N); 13C NMR (75 MHz, CDCl3, 298 K): d=18.0, 19.7,
28.0 (CH3), 30.6 (NCH3), 34.7 (CH), 51.3 (CH2), 61.4 (CH), 62.8 (CH2),
83.1 (Cq), 157.9, 168.9, 170.0 ppm (CO); IR (solid): n˜ =3392, 3296, 3226
(NH), 2921, 2850 (Csp3), 1734, 1651 cmꢀ1 (CO); HRMS (ESI): m/z: calcd
for C14H26N3O4: 300.1918; found: 300.1907.
ꢀ
(C O); HRMS (ESI): m/z: calcd for C26H38N3O6: 488.2755; found:
488.2755.
3,7-Dibenzyl-5-methylACHTREUNG[1,3,5]triazepane-2,6-dione (10a): BnBr (80 mL,
0.67 mmol) and KF/Al2O3 40% wt (930 mg, 6.4 mmol) were added to a
solution of 4a (150 mg, 0.64 mmol) in CH2Cl2 (6 mL) under Ar. The mix-
ture was stirred for 24 h at RT under Ar. After this time, the reaction
mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4,
and concentrated. The crude residue was purified by silica-gel chroma-
tography (ethyl acetate/cyclohexane/AcOH 50:50:1 v/v/v) to yield 10a
(141 mg, 68%) as a white powder. C18-RP-HPLC (A: 0.1% TFA in H2O,
(5-Benzyl-4,7-dioxo-octahydro-3a,6,8-triaza-azulen-8-yl)acetic acid tert-
butylester (11i) : Colorless oil; C18-RP-HPLC (A: 0.1% TFA in H2O, B :
0.08% TFA in MeCN, 0–100% B, 1.2 mLminꢀ1, 20 min): tR =14.33 min;
1H NMR (300 MHz, CDCl3, 298 K): d=1.45 (s, 9H; C
ACHTRE(UNG CH3)3), 1.91–2.21
(m, 4H; CH2), 2.81 (dd, J=9.7, 14.3 Hz, 1H; CH2Ph), 3.44 (dd, J=4.2,
14.3 Hz, 1H; CH2Ph), 3.56–3.69 (m, 2H; CH2), 3.74 (d, J=18.1 Hz, 1H;
NCH2CO), 4.43 (d, J=18.1 Hz, 1H; NCH2CO; m, 1H; NCHCO), 4.57
(brs; NH), 5.76 (dd, J=3.9, 6.3 Hz, 1H; NCHN), 7.22–7.37 ppm (m, 5H;
H-Ar); IR (solid): n˜ =3272 (NH), 3058 (Csp2), 2927, 2874 (Csp3), 1735,
1705, 1674 (CO), 1612 cmꢀ1 (C=C); HRMS (ESI): m/z: calcd for
C20H27N3O4: 374.2074; found: 374.2086.
B: 0.08% TFA in MeCN, 0–100% B, 1.2 mLminꢀ1
, 20 min): tR =
14.07 min; [a]2D0 =ꢀ74.1 (c=0.63 in MeOH); H NMR (500 MHz, CDCl3,
298 K): d=2.65 (s, 3H; NCH3), 2.83 (dd, J=9.1, 14.3 Hz, 1H;
CHCH2Ph), 3.36 (dd, J=4.5, 14.3 Hz, 1H; CHCH2Ph), 4.13 (d, J=
15.6 Hz, 1H; NCH2N), 4.39 (d, J=15.1 Hz, 1H; NCH2Ph), 4.55–4.59 (m,
2H; NCHCO, NH), 4.79 (d, J=15.1 Hz, 1H; NCH2Ph), 5.15 (d, J=
15.6 Hz, 1H; NCH2N), 7.26–7.36 ppm (m, 10H; H-Ar); IR (solid): n˜ =
3296, 3199 (NH), 3063 (Csp2), 2956, 2923, 2853 (Csp3), 1653 cmꢀ1 (CO);
HRMS (ESI): m/z: calcd for C19H22N3O2: 324.1707; found: 324.1702.
1
(7-Benzyl-1-carboxymethyl-5-methyl-2,6-dioxoACHTREU[NG 1,3,5]triazepan-3-yl)acetic
acid (12): Pale yellow solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B :
0.08% TFA in MeCN, 0–100% B, 1.2 mLminꢀ1, 20 min): tR =11.74 min;
1H NMR (300 MHz, CDCl3, 298 K): d=2.91 (s, 3H; CH3), 3.10 (dd, J=
7.5, 13.6 Hz, 1H; CH2Ph), 3.22 (dd, J=6.9, 13.6 Hz, 1H; CH2Ph), 3.52 (d,
J=17.5 Hz, 1H; NCH2), 3.79 (d, J=17.5 Hz, 1H; NCH2), 3.92 (d, J=
17.6 Hz, 1H; NCH2), 4.05 (d, J=17.6 Hz, 1H; NCH2), 4.15 (t, J=7.2 Hz,
1H; NCHCO), 4.82 (q, J=17.9 Hz, 1H; NCH2N), 7.18–7.30 ppm (m,
5H; CH-Ar) ; 13C NMR (75 MHz, CDCl3, 298 K): d=34.58 (CH3), 39.6,
50.6, 50.8, 62.8 (CH2), 68.8 (CH), 127.0, 128.6, 130.0 (CH-Ar), 137.5 (Cq-
Ar), 160.3, 169.0, 171.5, 171.7 ppm (CO); IR (solid): n˜ =3448 (OH), 2927
(Csp3), 2622, 2531 (OH), 1713, 1918 cmꢀ1 (CO); HRMS (ESI): m/z: calcd
for C16H20N3O6: 350.1347; found: 350.1343.
3-Benzyl-7-isopropyl-5-methylACHTRE[UGN 1,3,5]triazepane-2,6-dione (10c): White
solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B: 0.08% TFA in MeCN, 0–
100% B, 1.2 mLminꢀ1, 20 min): tR =12.45 min; [a]2D0 =ꢀ54.4 (c=0.82 in
MeOH); 1H NMR (300 MHz, CDCl3, 298 K): d=1.03 (d, J=6.7 Hz, 3H;
CH3), 1.06 (d, J=6.7 Hz, 3H; CH3), 2.14–2.25 (m, 1H; CHACHTRE(UNG CH3)2), 2.62
(s, 3H; NCH3), 3.93 (dd, J=4.2, 6.8 Hz, 1H; NCHCO), 4.43 (d, J=
15.3 Hz, 1H; NCH2Ph), 4.50 (d, J=15.0 Hz, 1H; NCH2N), 4.71 (d, J=
15.0 Hz, 1H; NCH2N), 4.83–4.88 (m, 2H; NCH2Ph, NH), 7.26–7.37 ppm
(m, 5H; H-Ar); 13C NMR (75 MHz, CDCl3, 298 K): d=18.1, 19.8 (CH3),
31.0 (CH), 34.2 (NCH3), 51.5, 60.7 (CH2), 127.9, 128.3, 128.9 (CH-Ar),
137.6 (Cq-Ar) 158.6, 170.0 ppm (CO); IR (solid): n˜ =3393, 3199 (NH),
3063 (Csp2), 2959, 2920, 2850 (Csp3), 1647 cmꢀ1 (CO); HRMS (ESI): m/z:
calcd for C15H22N3O2: 276.1680; found: 276.1691.
(6-Benzyl-1-methyl-4,7-dioxo
solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B: 0.08% TFA in MeCN, 0–
100% B, 1.2 mLminꢀ1 20 min): tR =10.35 min; 1H NMR (300 MHz,
ACHTRE[UNG 1,3,5]triazepan-3-yl)acetic acid (13): White
,
[D6]DMSO, 298 K): d=2.78 (dd, J=6.8, 14.1 Hz, 1H; CH2Ph), 2.95, (s,
3H; NCH3), 3.06 (dd, J=6.6, 14.1 Hz, 1H; CH2Ph), 4.03 (q, J=17.6 Hz,
2H; NCH2), 4.35 (d, J=15.6 Hz, 1H; NCH2N), 4.77–4.80 (m, 1H;
NCHCO), 5.56 (d, J=15.6 Hz, 1H; NCH2N), 6.28 (s; NH), 7.16–
7.32 ppm (m, 5H; H-Ar); 13C NMR (75 MHz, [D6]DMSO, 298 K): d=
33.4 (CH3), 36.2, 50.3 (CH2), 54.1 (CH), 61.5 (CH2), 126.2, 129.0, 129.4
(CH-Ar), 138.1 (Cq-Ar), 156.3, 170.5, 171.6 ppm (CO); IR (solid): n˜ =
3277 (NH), 2924 (Csp3), 2455 (OH), 1702, 1672, 1608 cmꢀ1 (CO); HRMS
(ESI): m/z: calcd for C14H18N3O4: 292.1292; found: 292.1294.
5,8-Dibenzyl-hexahydro-3a,6,8-triaza-azulene-4,7-dione
solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B: 0.08% TFA in MeCN, 0–
100% B, 1.2 mLminꢀ1 20 min): tR =14.57 min; 1H NMR (300 MHz,
(10i): White
,
CDCl3, 298 K): d=1.76–1.86 (m, 2H; CH2), 1.96–2.06 (m, 1H; CH2),
2.18–2.28 (m, 1H; CH2), 2.84 (dd, J=9.2, 14.2 Hz, 1H; CHCH2Ph), 3.44–
3.68 (m, 3H; CH2, CHCH2Ph), 4.38–4.44 (m, 1H; NCHCO), 4.54 (d, J=
16.8 Hz, 1H; NCH2Ph), 4.80 (d, J=16.8 Hz, 1H; NCH2Ph), 5.12 (d, J=
2.4 Hz, 1H; NH), 5.69 (dd, J=4.4, 6.8 Hz, 1H; NCHN), 7.19–7.35 ppm
(m, 10H; CH-Ar); 13C NMR (75 MHz, CDCl3, 298 K): d=22.6, 30.6,
38.6, 45.7, 47.5 (CH2), 58.0, 69.2 (CH), 126.3, 127.1, 127.1, 128.8, 128.8,
129.6 (CH-Ar), 136.8, 138.8 (Cq-Ar), 160.4, 163.4 ppm (CO); IR (solid):
n˜ =3211 (NH), 3029 (Csp2), 2925 (Csp3), 1663, 1635 cmꢀ1 (CO); HRMS
(ESI): m/z: calcd for C21H24N3O2: 350.1863; found: 350.1866.
(9-Methyl-6,10-dioxo-5,8,9,10,10a,11-hexahydro-5a,7,9-triazacyclohep-
ta[b]naphthalen-7-yl)acetic acid tert-butylester (14) : White solid; C18-
RP-HPLC (A: 0.1% TFA in H2O, B: 0.08% TFA in MeCN, 0–100% B,
1.2 mLminꢀ1
,
20 min): tR =14.92 min; 1H NMR (300 MHz, CDCl3,
298 K): d=1.46 (s, 9H; CH3), 3.11–3.31 (m, 3H; NCH3, CHCH2Ph), 4.07
(s, 2H; NCH2Ph), 4.29–4.39 (m, 2H; NCH2CO, NCHCO), 4.59 (d, J=
15.1 Hz, 1H; NCH2N), 4.72 (d, J=16.4 Hz, 1H; NCH2CO), 4.98 (d, J=
(6-Benzyl-1-methyl-4,7-dioxo
ester (11a): White solid; C18-RP-HPLC (A: 0.1% TFA in H2O, B: 0.08%
TFA in MeCN, 0–100% B, 1.2 mLminꢀ1, 20 min): tR =13.82 min; [a]2D0
ACHTRE[UNG 1,3,5]triazepan-3-yl)acetic acid tert-butyl
=
15.1 Hz, 1H; NCH2N), 7.12–7.20 ppm (m, 4H; H-Ar)
;
13C NMR
Chem. Eur. J. 2006, 12, 8498 – 8512
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8509