256
Y. Kacem, B. B. Hassine / Tetrahedron: Asymmetry 25 (2014) 252–257
(d, 1H, J = 4.2 Hz, CH), 5.18 (d, 1H, CH, J = 4.3 Hz), 6.04 (s, 1H, NH),
6.87–7.27 (m, 5H, ArH). 13C NMR (75 MHz, CDCl3): d 22.15, 22.91,
24.87, 26.28, 27.29, 36.16, 56.93, 72.49, 73.68, 79.72, 114.05,
114.18, 121.96, 129.30, 145.17, 170.07, 172.42. HRMS (ES) found
MH+ m/z = 360.2984, C19H26N3O4 requires 360.2978.
diastereopure 6,7-dihydroxy-1-phenylamino-dihydro-1H-pyrrol-
o[1,2-a]imidazole-2,5(3H,6H)-dione.
4.6.1. (3S,6R,7R,7aS)-6,7-Dihydroxy-3-methyl-1-phenylamino-
dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione 9a
Yield (87%), mp = 197–199 °C, ½a D25
¼ þ14:7 (c 1.12, MeOH), IR
ꢀ
4.5.4. (3S,6R,7R,7aS)-3-Benzyl-6,7-isopropylidenedioxy-1-phen-
ylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione
(cmꢁ1): 3321 (OH), 3267 (NH), 2916 (CH), 1726, 1705 (C@O),
1608 (C@C). 1H NMR (300 MHz, CD3OD):
d 1.68 (d, 3H,
8d
J = 7.1 Hz, CH3), 4.45 (q, 1H, J = 7.1 Hz, CH), 4.62 (t, 1H, J = 4.4 Hz,
CH); 4.69 (d, H, J = 3.5 Hz, CH), 5.54 (d, H, J = 3.4 Hz, CH),
6.90–7.35 (m, 5H, ArH). 13C NMR (75 MHz, CD3OD): d 16.08,
60.94, 73.41, 76,13, 81.51, 113.23, 122.84, 129.25, 148.70,
172.93, 173,38. HRMS (ES) found MH+ m/z = 266.1378,
C13H16N3O4 requires 266.1374.
Yield (78%), mp = 128–130 °C, ½a D25
¼ ꢁ31:4 (c 1.25, MeOH), IR
ꢀ
(cmꢁ1): 3275 (NH), 3019 (CH), 1721, 1742 (C@O), 1609 (C@C). 1H
NMR (300 MHz, CDCl3): d 1.31 (s, 3H, CH3), 1.45 (s, 3H, CH3),
3.15 (dd, 1H, J = 13,8 Hz and 5,1 Hz, CH2), 3.31 (dd, 1H,
J = 13,8 Hz and 5,1 Hz, CH2), 3.98 (t, 1H, J = 5.1 Hz, CH), 4.63–4.72
(m, 3H, CH), 5.79 (s, 1H, NH), 6.54–7.21 (m, 5H, ArH), 7.25–7.35
(m, 5H, ArH). 13C NMR (75 MHz, CDCl3): d 25.58, 26.66, 36.31,
59.08, 77.47, 78.21, 81.54, 113.73, 115.04, 122.29, 127.84, 128.85,
129.45, 129.45, 135.20, 145.54, 172.96, 174.11. HRMS (ES) found
MH+ m/z = 394.3024, C22H24N3O4 requires 394.3021.
4.6.2. (3S,6R,7R,7aS)-6,7-Dihydroxy-3-isopropyl-1-phenylamino-
-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione 9b
Yield (75%), mp = 200–202 °C, ½a D25
¼ ꢁ20:5 (c 0.61, MeOH), IR
ꢀ
(cmꢁ1): 3309 (OH), 3231 (NH), 2957 (CH), 1721, 1740 (C@O),
1621 (C@C). 1H NMR (300 MHz, CD3OD): d 0.95 (d, 3H, J = 6.8 Hz,
CH3), 1,11 (d, 3H, J = 7.1 Hz, CH3), 3.09 (qd, 1H, J = 7.2 and 2.7 Hz,
CH), 4.15 (d, 1H, J = 3.5 Hz, CH), 4.62 (m, 2H, 2 CH), 5.37 (d, 1H,
J = 3.4 Hz, CH), 6.83–7.34 (m, 5H, ArH). 13C NMR (75 MHz, CD3OD):
d 18.32, 18.56, 28.69, 64.25, 73.60, 76.38, 82.69, 113.41, 123.78,
130.16, 146.52, 170.24, 173.49. HRMS (ES) found MH+
m/z = 306.1510, C15H20N3O4 requires 306.1506.
4.5.5. (3S,6R,7R,7aS)-3-Hydroxymethyl-6,7-isopropylidenedioxy
-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,
6H)-dione 8e
Yield (78%), mp = 128–130 °C, ½a D25
¼ ꢁ16:2 (c 0.79, MeOH), IR
ꢀ
(cmꢁ1): 3354 (OH), 3195 (NH), 2918 (CH), 1711, 1743 (C@O),
1647 (C@C). 1H NMR (300 MHz, CDCl3): d 1.27 (s, 3H, CH3), 1.43
(s, 3H, CH3), 3.87–3.92 (dd, 1H, J = 12.0 Hz and 4.2 Hz, CH2),
4.09–4.12 (sbr, 1H, OH), 4.39–4.46 (dd, 1H, J = 12.0 Hz and
4.2 Hz, CH2), 4.70–4.75 (t, 1H, J = 3.6 Hz), 4.79–4.84 (m, 2H, CH),
5.27–5.28 (d, 1H, J = 4.7 Hz, CH), 6.73–7.14 (m, 5H, ArH). 13C
NMR (75 MHz, CDCl3): d 26.59, 27.47, 58.76, 62.49, 74.00, 75.80,
81.42, 114.90, 115.46, 121.81, 113.02, 147.35, 171.85, 174.14.
HRMS (ES) found MH+ m/z = 334.1566, C16H20N3O5 requires
334.1562.
4.6.3. (3S,6R,7R,7aS)-6,7-Dihydroxy-3-isobutyl-1-phenylamino-
dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione 9c
Yield (83%), mp = 211–213 °C, ½a D25
¼ þ32:0 (c 0.46, MeOH), IR
ꢀ
(cmꢁ1): 3310 (OH), 3228 (NH), 2959 (CH), 1726, 1736 (C@O),
1616 (C@C). 1H NMR (300 MHz, CD3OD): d 0.95 (d, 6H, J = 6.8 Hz,
(CH3)2-CH), 1.84 (m, 1H, CH), 2.23 (m, 2H, CH2), 4.36 (t, 1H,
J = 6.3 Hz, CH), 4.54 (t, 1H, J = 4,3 Hz, CH), 4.79 (d, 1H, J = 4.3 Hz,
CH), 5.27 (d, 1H, CH, J = 4.2 Hz), 6.91–7.32 (m, 5H, ArH). 13C NMR
(75 MHz, CD3OD): d 22.96, 23.09, 25.61, 37.76, 64.33, 68.99,
74.68, 82.36, 114.10, 122.86, 129.90, 146.19, 171.26, 172.22. HRMS
(ES) found MH+ m/z = 320.2055, C16H22N3O4 requires 320.2052.
4.5.6. (3S,6R,7R,7aS)-6,7-Isopropylidenedioxy-3-(2-methylthio-
ethyl)-1-phenylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-
2,5 (3H,6H)-dione 8f
Yield (81%), mp = 183–185 °C, ½a D25
¼ þ26:5 (c 0.58, MeOH), IR
ꢀ
(cmꢁ1): 3244 (NH), 2914 (CH), 1721, 1749 (C@O), 1603 (C@C). 1H
NMR (300 MHz, CDCl3): d 1.30 (s, 3H, CH3), 1.46 (s, 3H, CH3),
1.90 (m, 1H, CH2), 2.11 (s, 3H, S-CH3), 2.14 (m, 1H, CH2), 2.69 (t,
2H, J = 7.2 Hz, S-CH2), 3.69 (dd, 1H, J = 4.8 and 7.6 Hz, CH), 4.72
(t, 1H, J = 4.2 Hz, CH); 4.78 (d, 1H, J = 4.1 Hz, CH), 5.33 (d, 1H,
J = 4.3 Hz, CH), 6.22 (s, 1H, NH), 6.79–7.22 (m, 5H, ArH). 13C NMR
(75 MHz, CDCl3): d 14.86, 26.33, 27.69, 29.60, 32.63, 54.94, 72.14,
74.58, 80.25, 113.58, 113.89, 121.15, 129.37, 145.60, 171.52,
173.71. HRMS (ES) found MH+ m/z = 378.2623, C18H24N3O4S
requires 378.2620.
4.6.4. (3S,6R,7R,7aS)-3-Benzyl-6,7-dihydroxy-1-phenylamino-
dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dione 9d
Yield (85%), mp = 232–234 °C, ½a D25
¼ þ19:2 (c 1.15, MeOH), IR
ꢀ
(cmꢁ1): 3306 (OH), 3260 (NH), 3011 (CH), 1710, 1744 (C@O),
1618 (C@C). 1H NMR (300 MHz, CD3OD):
d 3.19 (dd, 1H,
J = 13,7 Hz and J = 5,3 Hz, CH2), 3.44 (dd, 1H, J = 13,7 Hz and
J = 5,3 Hz, CH2), 4.52 (t, 1H, J = 5.1 Hz, CH), 4.52–4.74 (m, 2H, CH),
5.31 (d, 1H, CH, J = 3.9 Hz), 6.89–7.37 (m, 10H, ArH). 13C NMR
(75 MHz, CD3OD): d 35.51, 64.00, 75.49, 77.36, 82.51, 114.03,
121.64, 126.88, 128.78, 129.39, 129.80, 136.25, 145.04, 172.36,
174.98. HRMS (ES) found MH+ m/z = 354.2684, C19H20N3O4 re-
quires 354.2679.
4.6. General procedure for the synthesis of 6,7-dihydroxy-1-ph-
enylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-dio-
nes 9a–f
4.6.5. (3S,6R,7R,7aS)-6,7-Dihydroxy-3-hydroxymethyl-1-phen-
ylamino-dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-
dione 9e
Dihydro1-phenylamino-1H-6,7-isopropylidenedioxypyrrol-
o[1,2-a]imidazole-2,5(3H,6H)-dione (1 mmol) was treated with
methanolic hydrochloride acid (MeOH/HCl, 15 mL) at 0 °C for 1 h.
The reaction mixture was concentrated in vacuo to remove all of
the solvent. The residue was quenched by adding 10% aqueous
NaHCO3 solution (10 mL) and stirred for 30 min. The aqueous
phase was extracted with ethyl acetate (3 ꢃ 20 mL). The organic
phase was washed with brine (3 ꢃ 5 mL), dried over MgSO4, and
concentrated in vacuo. The crude residue was purified by column
chromatography on silica gel (15% MeOH–85% CH2Cl2) to afford a
Yield (70%), mp = 242–244 °C, ½a D25
¼ ꢁ33:8 (c 0.94, MeOH), IR
ꢀ
(cmꢁ1): 3347 (OH), 3184 (NH), 2910 (CH), 1718, 1742 (C@O),
1634 (C@C). 1H NMR (300 MHz, CD3OD):
d 3.90 (dd, 1H,
J = 12.6 Hz and J = 4.2 Hz, CH2), 4.26 (dd, 1H, J = 12.6 Hz and
J = 4.2 Hz, CH2), 4.62 (t, 1H, J = 4.1 Hz), 4.34–4.56 (m, 2H, CH),
5.49 (d, 1H, J = 3.9 Hz, CH), 6.71–7.12 (m, 5H, ArH). 13C NMR
(75 MHz, CD3OD): d 59.52, 67.43, 73.09, 77.85, 82.63, 114.47,
123.66, 129.14, 150.08, 171.93, 173.74. HRMS (ES) found MH+
m/z = 282.1513, C13H16N3O5 requires 282.1511.