Paper
Organic & Biomolecular Chemistry
(+)-(1R,5S,6R,10S)-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-
bicyclo[4.4.1]undecane-4,9-dione 13
d, J = 15.3 Hz), 4.21 (2H, s), 4.04 (2H, d, J = 15.3 Hz), 3.07 (2H,
d, J = 10.3 Hz), 2.70 (6H, s), 2.30–2.17 (2H, m), 0.95 (6H, d, J =
6.3 Hz), 0.89 (6H, d, J = 6.8 Hz); 13C NMR (101 MHz, CD3CN)
δ 174.8, 83.2, 69.0, 66.0, 37.2, 27.1, 22.4, 20.2; m/z (ES): 319.1
(M + Na+); HRMS (ES; ion trap) calculated for C15H29O2N4
297.2285 (M + H+), found 297.2281.
Rf = 0.16 (petroleum ether–ethyl acetate 1 : 4); mp: 215–218 °C;
[α]D20 = +78.7 (c = 0.75, MeOH); νmax (ATR)/cm−1 2953, 2922,
2804, 1680, 1618; 1H NMR (500 MHz, CDCl3) δ 7.38–7.16 (10H,
m), 4.92 (2H, d, J = 14.9 Hz), 4.24 (2H, s), 4.06 (2H, d, J =
14.9 Hz), 3.93 (2H, dd, J = 10.3, 6.2 Hz), 3.16–3.09 (4H, m), 2.93
(6H, s); 13C NMR (126 MHz, CDCl3) δ 176.5, 137.6, 128.8,
128.7, 126.9, 72.4, 70.8, 62.6, 36.9, 34.6; m/z (ES): 415.2
(M + Na+); HRMS (ES; ion trap) calculated for C23H29O2N4
393.2285 (M + H+), found 393.2282.
(+)-(1R,5S,6R,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-
tetraaza-bicyclo[4.4.1]undecane-4,9-dione 18
Rf = 0.1 (petroleum ether–ethyl acetate 1 : 1); mp: 144–155 °C;
[α]D20 = +21.9 (c = 0.75, MeOH); νmax (ATR)/cm−1 2965, 2924,
2868, 1626; 1H NMR (400 MHz, CD3CN) δ 4.90 (2H, d, J =
14.8 Hz), 4.07 (2H, s), 4.03 (2H, d, J = 14.9 Hz), 2.96 (2H, d,
J = 11.4 Hz), 2.75 (6H, s), 2.34–2.23 (2H, m), 0.95 (6H, d, J =
6.4 Hz), 0.91 (6H, d, J = 6.6 Hz); 13C NMR (101 MHz, CD3CN)
δ 176.6, 77.0, 72.3, 63.5, 36.7, 26.2, 20.8, 20.2; m/z (ES) 319.1
(M + Na+); HRMS (ES; ion trap) calculated for C15H29O2N4
297.2285 (M + H+), found 297.2290.
(−)-(1S,5S,6S,10S)-3,5,8,10-Tetramethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 15
L-Alanine-N-methyl amide (510 mg, 5 mmol) was dissolved in
chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol, 3
equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
the residue crystallised with dichloromethane and 40–60 °C
petroleum ether to give the product as white crystals (280 mg,
47%). Mp: 206–208 °C; [α]2D0 = −(82.8 (c = 1.0, MeOH); νmax
(ATR)/cm–1 2995, 2980, 2931, 2955, 1632; 1H NMR (400 MHz,
CDCl3) δ 4.59 (2H, d, J = 15.2 Hz), 4.27 (2H, d, J = 15.2 Hz),
4.23 (2H, s), 3.67 (2H, q, J = 7.0 Hz), 2.79 (6H, s), 1.32 (6H, d,
J = 7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 174.7, 81.2, 64.2,
57.4, 36.2, 14.9; m/z (ES/APCI): 241.1 (M + H+); HRMS (ES; ion
trap) calculated for C11H21O2N4 241.1659 (M + H+), found
241.1659.
(−)-(1S,5S,6S,10S)-5-Benzyl-3,8,10-trimethyl-1,3,6,8-
tetraazabicyclo[4.4.1]undecane-4,9-dione 19
L-Phenylalanine-N-methyl amide (445 mg, 2.5 mmol) and
L-alanine N-methyl amide (255 mg, 2.5 mmol) were dissolved
in chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol,
3 equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
product isolated by flash chromatography (gradient elution
from 50% ethyl acetate in petroleum ether to 100% ethyl
acetate) to give a white crystalline solid (260 mg, 34%). Rf =
0.14 (petroleum ether–ethyl acetate 1 : 4); mp: 216–218 °C;
[α]D20 = −106.8 (c = 1.0, MeOH); νmax (ATR)/cm−1 2982, 2953,
(5S,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo-
[4.4.1]undecane-4,9-dione 17 and 18
1
2922, 2862, 1626; H NMR (400 MHz, CDCl3) δ 7.33–7.16 (5H,
L-Valine-N-methyl amide (650 mg, 5 mmol) was dissolved in
chloroform (20 mL). Paraformaldehyde (450 mg, 15 mmol,
3 equiv.) and ytterbium(III) trifluoromethanesulfonate hydrate
(31 mg, 0.05 mmol, 1 mol%) were added. The mixture was
stirred at 60 °C for 18 h. Once cooled to ambient temperature
the mixture was diluted with dichloromethane (30 mL),
washed with saturated sodium hydrogen carbonate (3 ×
20 mL), brine (30 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and
the two diastereomers separated by flash chromatography
(gradient elution from 50% ethyl acetate in petroleum ether to
100% ethyl acetate) to give first 17 (198 mg, 27%) and second
18 (390 mg, 53%) as white crystalline solids.
m), 4.67 (1H, d, J = 15.2 Hz), 4.66 (1H, d, J = 15.2 Hz), 4.39 (1H,
d, J = 15.3 Hz), 4.32 (1H, d, J = 15.3 Hz), 4.23 (1H, d, J = 14.2
Hz), 4.14 (1H, d, J = 14.2 Hz), 3.83 (1H, dd, J = 9.3, 5.2 Hz), 3.70
(1H, q, J = 7.0 Hz), 3.37 (1H, dd, J = 14.8, 5.2 Hz), 2.94 (1H, dd,
J = 14.8, 9.3 Hz), 2.94 (3H, s), 2.87 (3H, s), 1.39 (3H, d, J =
7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 175.3, 174.7, 139.7,
129.2, 128.3, 126.3, 82.2, 65.1, 64.8, 64.3, 58.2, 37.0, 36.9, 34.6,
15.5; m/z (ES/APCI): 317.3 (M + H+); HRMS (ES; ion trap) calcu-
lated for C17H24O2N4 317.1972 (M + H+), found 317.1978.
Also recovered 197 mg, 20% (−)-(1S,5S,6S,10S)-5,10-
dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]undecane-
4,9-dione 12.
( )-5,10-Dibenzyl-3,8-dimethyl-1,3,6,8-tetraaza-bicyclo[4.4.1]-
undecane-4,9-dione 12, 13 and 20
(−)-(1S,5S,6S,10S)-5,10-Diisopropyl-3,8-dimethyl-1,3,6,8-
tetraaza-bicyclo[4.4.1]undecane-4,9-dione 17
DL-Phenylalanine N-methyl amide (890 mg, 5 mmol) was dis-
Rf = 0.35 (petroleum ether–ethyl acetate 1 : 1); mp: 125–127 °C; solved in chloroform (20 mL). Paraformaldehyde (450 mg,
[α]2D0 = −12.9 (c = 0.82, MeOH); νmax (ATR)/cm−1 2967, 2955, 15 mmol, 3 equiv.) and ytterbium(III) trifluoromethanesulfo-
2926, 2876, 2862, 1640; 1H NMR (400 MHz, CD3CN) δ 4.73 (2H, nate hydrate (31 mg, 0.05 mmol, 1 mol%) were added. The
Org. Biomol. Chem.
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