J. Caroen et al. / Tetrahedron 72 (2016) 148e160
157
1.05e2.00 (m, 20H, containing at 1.49 (s, 9H)) ppm.13C NMR (CDCl3,
75 MHz):
¼174.1 (C), 173.4 (C), 79.0 (C), 53.4 (CH), 52.3 (CH), 48.2
d
¼6.21 (br s, 1H), 4.48 (d, J¼16.8 Hz, 1H), 3.59e3.69 (m, 1H), 3.64
d
(dd, J¼16.7 Hz/1.0 Hz, 1H), 3.23 (app q, J¼4.1 Hz, 1H), 3.06 (s, 3H),
(CH), 39.8 (CH2), 34.4 (CH2), 29.6 (CH2), 27.9 (CH2), 27.7 (CH2), 22.8
(CH2), 22.3 (CH2). IR (HATR): nmax 3270 (m), 3093 (w), 2954 (m),
2869 (w), 1684 (vs), 1654 (s), 1636 (s), 1522 (w), 1443 (w), 1405 (m),
1364 (m),1347 (w),1310 (w),1287 (w),1256 (m),1172 (m),1146 (w),
1108 (m), 1083 (w), 1066 (w), 1022 (w), 990 (w), 952 (w), 902 (w),
794 (m), 741 (m), 629 (w). [a]2D5 ꢃ66.3ꢀ (c 1.515, CHCl3). MS (ES,
pos): m/z¼340.2 (MþHþ, 5), 284.1 (M-isobuteneþHþ, 47), 240.1
(M-isobutene-CO2þHþ, 100). HRMS (ESI, MþHþ): calcd for
1.95e2.20 (m, 2H), 1.25e1.75 (m, 6H). 13C NMR (CDCl3, 75 MHz):
d
¼172.0 (C), 169.2 (C), 54.3 (CH2), 53.3 (CH), 41.5 (CH), 36.6 (CH3),
31.5 (CH2), 26.5 (CH2), 23.5 (CH2), 21.9 (CH2). IR (HATR): nmax
3412 (m), 3295 (w), 3185 (m), 3048 (m), 2954 (w), 2918 (m),
2858 (w), 1644 (s), 1500 (w), 1480 (w), 1461 (m), 1445 (m), 1403
(m), 1366 (w), 1258 (w), 1225 (m), 1130 (w), 1103 (w), 1082 (w),
1036 (w), 1002 (w), 982 (w), 912 (w), 855 (m), 801 (w), 794 (w),
760 (w), 736 (w), 632 (w). MS (ES, pos): m/z¼197.1 (MþHþ, 100).
HRMS (ESI, MþHþ): calcd for C10H17N2O2: 197.1290, found:
197.1282.
C
17H30N3O4: 340.2236, found: 340.2220.
4.6.5. rac-(1S,2R,8S,9R)-3,6-Diazatricyclo[7.2.1.0 2,8]dodecane-4,7-
dione (8e). FC: CH2Cl2/MeOH 95/5; white solid; yield: 27.7 mg,
39%. Rf¼0.12 (CH2Cl2/MeOH 95/5). 1H NMR (DMSO-d6, 300 MHz):
4.6.9. rac-(1R,7S)-5-Isobutyl-2,5-diazabicyclo[5.4.0]undecane-3,6-
dione (8i). FC: gradient elution: n-hexane/EtOAc 3/7/2/8; white
solid; yield: 26.7 mg, 31%. Rf¼0.10 (n-hexane/EtOAc 3/7). 1H NMR
d
¼7.78 (t, J¼6.9 Hz, 1H), 7.36 (s, 1H), 4.05 (dd, J¼14.6 Hz/7.2 Hz,
w0.75H), 4.05 (d, J¼14.7 Hz, w0.25H), 3.70 (d, J¼8.3 Hz, 1H),
2.88e3.00 (m, 1H), 2.77 (br s, 1H), 2.64 (dd, J¼8.3 Hz/1.1 Hz, 1H),
2.30 (br s, 1H), 1.36e1.58 (m, 2H), 1.31 (d, J¼10.0 Hz, 1H), 1.08e1.24
(m, 2H), 1.07 (d, J¼10.0 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz):
(CDCl3, 300 MHz):
d
¼6.10e6.50 (br m, 1H), 4.45 (d, J¼17.0 Hz, 1H),
3.62 (dd, J¼16.9 Hz/0.9 Hz, 1H), 3.53e3.65 (m, 1H), 3.51 (dd,
J¼13.5 Hz/8.4 Hz, 1H), 3.26e3.35 (m, 1H), 3.03 (dd, J¼13.4 Hz/
6.6 Hz, 1H), 1.20e2.20 (m, 9H), 0.88 (d, J¼6.8 Hz, 3H), 0.87 (d,
d
¼173.9 (C), 172.5 (C), 58.0 (CH, major)þ57.9 (CH, minor), 53.5 (CH,
J¼6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
¼171.6 (C), 169.4 (C), 55.9
d
major)þ53.4 (CH, minor), 44.7 (CH2, major)þ44.6 (CH2, minor), 41.7
(CH, major)þ41.7 (CH, minor), 38.0 (CH), 35.3 (CH2), 27.0 (CH2), 26.4
(CH2). MS (ES, pos): m/z¼389.2 (2MþHþ, 7), 195.1 (MþHþ, 100).
(CH2), 54.0 (CH), 53.2 (CH2), 40.6 (CH), 31.6 (CH2), 27.5 (CH), 26.8
(CH2), 24.0 (CH2), 21.4 (CH2), 20.0 (CH3). IR (HATR): nmax 3197 (w),
3059 (w), 2954 (m), 2912 (m), 2860 (w),1665 (s), 1640 (s), 1501 (m),
1465 (m), 1440 (m), 1422 (w), 1382 (w), 1364 (m), 1339 (w), 1306
(w),1282 (w),1259 (w),1239 (w),1226 (m),1207 (m),1129 (w),1115
(w), 1086 (w), 1065 (w), 1041 (w), 1021 (w), 969 (w), 913 (w), 896
(w), 854 (m), 823 (m), 792 (m), 758 (m), 733 (w), 636 (w). MS (ES,
pos): m/z¼239.1 (MþHþ, 100). HRMS (ESI, MþHþ): calcd for
4.6.6. (1R,2S,8R,9S)-5S-Isobutyl-3,6-diazatricyclo[7.2.1.0 2,8]dodec-
ane-4,7-dione (8f). FC: CH2Cl2/MeOH 98/2; white solid; yield:
33.5 mg, 73%. Rf¼0.27 (CH2Cl2/MeOH 95/5). 1H NMR (CDCl3,
500 MHz):
d
¼6.05e6.26 (m,1H), 5.96 (s,1H), 4.01 (app dt, J¼5.6 Hz/
8.4 Hz, 1H), 3.70 (app d, J¼8.2 Hz, 1H), 3.03 (br s, 1H), 2.62 (app d,
J¼8.1 Hz, 1H), 2.22 (br s, 1H), 1.56e1.80 (m, 5H), 1.51 (ddd,
J¼14.1 Hz/8.4 Hz/5.8 Hz, 1H), 1.19e1.34 (m, 3H), 0.94 (d, J¼6.6 Hz,
C13H23N2O2: 239.1760, found: 239.1747.
4.6.10. rac-(1R,7S)-5-(4-tert-Butyloxycarbonylamino)butyl-2,5-
diazabicyclo[5.4.0]undecane-3,6-dione (8j). FC: gradient elution: n-
hexane/EtOAc 1/9/0/10; white foam; yield: 64.0 mg, 49%.
3H), 0.91 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3, 125 MHz):
¼174.1 (C),
d
173.3 (C), 58.5 (CH), 54.6 (CH), 50.2 (CH), 43.7 (CH), 38.5 (CH), 36.8
(CH2), 35.4 (CH2), 27.3 (CH2), 27.0 (CH2), 24.3 (CH), 22.9 (CH3), 22.0
(CH3). IR (HATR): nmax 3390 (w), 3271 (w), 3207 (m), 3090 (w), 2950
(m), 2873 (w),1667 (s), 1650 (vs),1540 (w),1455 (w), 1410 (m),1385
(m), 1309 (m), 1287 (w), 1260 (m), 1192 (w), 1106 (w), 1047 (w), 959
(w), 926 (w), 897 (w), 884 (w), 871 (w), 856 (w), 786 (w), 765 (m),
729 (m), 650 (m), 624 (m). [a]2D5 ꢃ65.9ꢀ (c 1.675, CHCl3). MS (ES,
pos): m/z¼501.3 (2MþHþ, 30), 251.2 (MþHþ, 100). HRMS (ESI,
MþHþ): calcd for C14H23N2O2: 251.1760, found: 251.1762.
Rf¼0.11 (n-hexane/EtOAc 1/9). 1H NMR (CDCl3, 300 MHz):
¼6.41
d
(br s, 1H), 4.62 (br s, 1H), 4.39 (d, J¼16.8 Hz, 1H), 3.57 (d, J¼16.8 Hz,
1H), 3.45e3.70 (m, 2H), 3.15e3.35 (m, 2H), 2.95e3.12 (m, 2H),
1.95e2.15 (m, 2H), 1.25e1.75 (m, 10H), 1.37 (s, 3H). 13C NMR
(CDCl3, 75 MHz):
d
¼171.5 (C), 169.5 (C), 155.9 (C), 79.0 (C), 53.7
(CH), 52.6 (CH2), 48.3 (CH2), 40.8 (CH), 40.0 (CH2), 31.5 (CH2), 28.3
(CH3), 27.2 (CH2), 26.7 (CH2), 25.3 (CH2), 23.8 (CH2), 21.5 (CH2). IR
(HATR): nmax 3234 (w), 3183 (w), 3075 (w), 2956 (w), 2929 (m),
2884 (w), 2863 (w), 1687 (vs), 1644 (vs), 1509 (w), 1478 (m), 1445
(m), 1421 (w), 1399 (s), 1363 (m), 1338 (m), 1287 (w), 1256 (w),
1241 (w),1220 (m),1172 (s),1145 (w), 1124 (m), 1106 (w), 1091 (m),
1055 (w), 1037 (w), 1022 (m), 979 (w), 915 (w), 897 (w), 839 (m),
827 (m), 791 (m), 762 (m), 737 (w), 701 (w), 654 (w), 631 (w). MS
(ES, pos): m/z¼254.1 (M-isobutene-CO2þHþ, 100). HRMS (ESI, M-
isobutene-CO2þHþ): calcd for C13H24N3O2: 254.1869, found:
254.1859.
4.6.7. rac-(1R,7S)-5-Benzyl-2,5-diazabicyclo[5.4.0]undecane-3,6-
dione (8g). The crude product is purified via RP-HPLC, gradient
elution: acetonitrile/water 0/100/100/0 in 15 min, tret¼13.1 min;
white solid; yield: 60 mg, 60%. Rf¼0.28 (CH2Cl2/MeOH 95/5). 1H
NMR (CDCl3, 300 MHz):
d
¼7.24e7.35 (m, 5H), 6.02 (br s, 1H), 4.86
(d, J¼14.7 Hz, 1H), 4.48 (d, J¼14.4 Hz, 1H), 4.31 (d, J¼16.8 Hz, 1H),
3.68 (dd, J¼17.0 Hz/1.1 Hz, 1H), 3.63 (m, 1H), 3.31 (app q, J¼4.3 Hz,
1H), 2.05e2.25 (m, 2H), 1.30e1.85 (m, 6H). 13C NMR (CDCl3,
75 MHz):
d
¼171.9 (C), 169.1 (C), 136.7 (C), 128.7 (CH), 128.1 (CH),
4.6.11. rac-(1R,7R)-5-Benzyl-2,5-diazabicyclo[5.4.0]undecane-3,6-
dione (8k). FC: CH2Cl2/MeOH 98/2; white solid; yield: 32 mg, 32%.
Rf¼0.27 (CH2Cl2/MeOH 95/5). 1H NMR (CDCl3, 300 MHz):
127.7 (CH), 53.7 (CH), 52.0 (CH2), 51.7 (CH2), 41.2 (CH), 31.6 (CH2),
26.7 (CH2), 23.7 (CH2), 21.7 (CH2). IR (HATR): nmax 3291 (w), 3188
(w), 3057 (w), 2926 (m), 2856 (w), 1652 (vs), 1494 (m), 1441 (s),
1359 (m), 1349 (m), 1344 (m), 1321 (w), 1266 (w), 1255 (w), 1241
(w), 1210 (s), 1176 (m), 1133 (m), 1109 (w), 1091 (w), 1080 (m), 1044
(w),1029 (w),1003 (w), 949 (w), 954 (m), 914 (w), 905 (w), 882 (m),
858 (m), 838 (w), 812 (m), 793 (m), 750 (s), 726 (m), 702 (s), 659
(w), 647 (m), 614 (w). MS (ES, pos): m/z¼295.1 (MþNaþ, 10), 273.1
(MþHþ, 100). HRMS (ESI, MþHþ): calcd for C16H21N2O2: 273.1603,
found: 273.1589.
d
¼7.20e7.35 (m, 5H), 6.21 (br s, 1H), 4.79 (d, J¼14.7 Hz, 1H), 4.53 (d,
J¼14.9 Hz, 1H), 4.34 (d, J¼17.3 Hz, 1H), 3.70 (d, J¼17.5 Hz, 1H),
3.21e3.35 (m, 1H), 2.82 (app dt, J¼11.5 Hz/3.6 Hz, 1H),1.60e2.15 (m,
5H), 1.15e1.45 (m, 3H). 13C NMR (CDCl3, 75 MHz):
d¼172.5 (C), 168.6
(C), 136.6 (C), 128.7 (CH), 128.1 (CH), 127.7 (CH), 55.5 (CH), 51.6
(CH2), 51.3 (CH2), 44.2 (CH), 36.4 (CH2), 27.1 (CH2), 24.2 (CH2), 24.1
(CH2). IR (HATR): nmax 3292 (w), 3187 (w), 3062 (w), 2926 (m), 2858
(w), 1650 (vs), 1496 (w), 1472 (w), 1450 (m), 1440 (m), 1358 (m),
1344 (w), 1307 (w), 1290 (w), 1250 (w), 1219 (m), 1207 (m), 1178
(w), 1125 (w), 1111 (w), 1080 (w), 1044 (w), 1029 (w), 985 (w), 968
(w), 959 (w), 918 (w), 857 (m), 830 (m), 759 (w), 732 (m), 722 (m),
694 (m), 664 (w), 652 (w). MS (ES, pos): m/z¼273.1 (MþHþ, 100).
4.6.8. rac-(1R,7S)-5-Methyl-2,5-diazabicyclo[5.4.0]undecane-3,6-
dione (8h). FC: n-hexane/EtOAc 1/9; white solid; yield: 17.6 mg,
24%. Rf¼0.08 (n-hexane/EtOAc 1/9). 1H NMR (CDCl3, 300 MHz):