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Y. Gök et al. / Tetrahedron: Asymmetry 21 (2010) 2275–2280
refluxed for 24 h after which, methanol was removed in vacuo. The
residue was cooled to 0 °C and acidified with aqueous HCl (6 M).
The acidified mixture was extracted with ether (3 ꢀ 20 mL). The
organic phase was dried over anhydrous Na2SO4, filtered off and
concentrated to give 8, 0.890 g (98%), as a colourless oil. The crude
(2R,3R)-diacid was used in the next step without further purifica-
tion. 1H NMR (300 MHz, CDCl3): d 3.95 (s, 2H), 7.20–7.40 (m,
10H), 9.50 (br s, 2H) ppm. 13C NMR (75.4 MHz, CDCl3): d 38.3
(CH), 43.1 (C), 127.9 (CH), 128.5 (CH), 128.9 (CH), 133.6 (C),
171.5 (C) ppm. IR (HATR): 3029, 2549, 1978, 1685, 1497, 1417,
4.3.3. (2R,3R)-1,1-Bis-[N-(10R)-(10-tert-butyl-20-hydroxyethyl)
aminocarbonyl]-2,3-diphenylcyclopropane 11
The reaction was performed on (2R,3R)-diacid
8 (0.3 g,
1.06 mmol) according to the typical procedure, using (R)-tert-leu-
cinol (0.230 g, 1.95 mmol). Purification by flash chromatography
over silica gel (hexane/EtOAc, 30/70) resulted in pure bishydroxya-
mide 11 as a white solid, 0.340 g (67%). 1H NMR (300 MHz, CDCl3):
d 0.70 (s, 18H), 2.82–2.90 (m, 2H), 3.26–3.35 (m, 2H), 3.45–3.55 (m,
2H), 3.72 (s, 2H), 6.30 (d, J = 9.1 Hz, 2H), 7.20–7.30 (m, 2H), 7.35–
7.52 (m, 8H) ppm. 13C NMR (75.4 MHz, CDCl3): d 26.7 (CH3), 32.2
(CH), 33.2 (C), 47.9 (C), 60.4 (CH), 62.8 (CH2), 127.9 (CH), 128.5
(CH), 129.0 (CH), 135.3 (C), 167.7 (C) ppm. IR (HATR): 3405,
3312, 2956, 2878, 1665, 1638, 1498, 1475, 1366, 1346, 1232,
1296, 1150, 778, 732, 693 cmꢁ1
.
ES-MS: 281 [MꢁH]ꢁ.
½
a 2D0
ꢂ
¼ þ56:5 (c 1.02, CHCl3). HRMS (EI) calcd for C17H14O4:
282.0892; found 282.0898.
1050, 979, 739, 698 cmꢁ1. ES-MS: 481 [M+H]+. ½a 2D0
¼ þ28:7 (c
ꢂ
4.3. A typical procedure for the preparation of the
bishydroxyamides 9–13
1.0, CHCl3). Mp 147–149 °C. HRMS (EI) calcd for C29H40N2O4:
480.2988; found 480.2991.
Oxalyl chloride (0.652 g, 5.13 mmol) was added dropwise to a
4.3.4. (2R,3R)-1,1-Bis-[N-(10S)-(10-phenyl-20-hydroxy ethyl)ami-
solution of (2R,3R)-diacid 8 (0.5 g, 1.77 mmol) and DMF (30
l
L)
nocarbonyl]-2,3-diphenylcyclopropane 12
in CH2Cl2 (5 mL) over 20 min at 0 °C under an argon atmosphere.
The mixture was allowed to warm to room temperature and was
stirred for another 5 h. The volatiles were removed under reduced
pressure to afford the crude acid chloride. The acid chloride was
dissolved in CH2Cl2 and then added dropwise to a mixture of the
corresponding amino ethanol (3.45 mmol) and Et3N (0.875 g,
8.65 mmol) in CH2Cl2 (5 mL) over 40 min. After 1 h, the resulting
suspension was diluted with CH2Cl2 and washed with HCl (1 M,
20 mL); saturated with NaHCO3 (20 mL) and brine (20 mL). The
combined organic phases were dried over Na2SO4, filtered off and
concentrated in vacuo. The crude product was purified by flash
chromatography (CH2Cl2/MeOH, 90/10) to give the corresponding
bishydroxyamide 9–13.
The reaction was performed on (2R,3R)-diacid 8 (0.3 g,
1.06 mmol) according to the typical procedure, using (S)-phenyl-
glycinol (0.265 g, 1.90 mmol). Purification by flash chromatogra-
phy over silica gel (hexane/EtOAc, 30/70) resulted in pure
bishydroxyamide 12 as a white solid, 0.475 g (86%). 1H NMR
(300 MHz, CDCl3): d 3.50 (m, 2H), 3.70 (s, 2H), 3.77 (m, 4H), 4.95
(m, 2H), 6.65 (d, J = 7.3 Hz, 4H), 6.77 (d, J = 8.5 Hz, 2H), 6.97–7.12
(m, 10H), 7.20 (m, 4H) ppm. 13C NMR (75.4 MHz, CDCl3): d 33.2
(CH), 49.5 (C), 55.6 (CH), 65.6 (CH2), 126.4 (CH), 126.7 (CH),
127.2 (CH), 127.4 (CH), 128.2 (CH), 128.4 (CH), 135.1 (C), 137.6
(C), 167.0 (C) ppm. IR (HATR): 3408, 3307, 2958, 2873, 1665,
1635, 1524, 1498, 1475, 1366, 1051, 1031, 743, 700 cmꢁ1. ES-MS:
521 [M+H]+. ½a 2D0
¼ þ134:4 (c 1.0, CHCl3). Mp 121–123 °C. HRMS
ꢂ
(EI) calcd for C33H32N2O4: 520.2362; found 520.2377.
4.3.1. (2R,3R)-1,1-Bis-[(20-hydroxyethyl)aminocarbonyl]-2,3-
diphenylcyclopropane 9
4.3.5. (2R,3R)-1,1-Bis-[N-(10R)-(10-phenyl-20-hydroxyethyl)
The reaction was performed on (2R,3R)-diacid
8
(0.5 g,
aminocarbonyl]-2,3-diphenylcyclopropane 13
1.77 mmol) according to the typical procedure, using amino etha-
nol (0.211 g, 3.45 mmol). Purification by flash chromatography
over silica gel (CH2Cl2/MeOH, 90/10) resulted in pure bishydroxya-
mide 9 as a pale yellow solid, 0.542 g (85%). 1H NMR (300 MHz,
CDCl3): d 3.15 (m, 4H), 3.25 (m, 2H), 3.40 (m, 2H), 3.72 (s, 2H),
6.70 (t, J = 5.8 Hz, 2H), 7.25–7.40 (m, 10H) ppm. 13C NMR
(75.4 MHz, CDCl3): d 33.0 (CH), 42.6 (CH2), 48.9 (C), 61.4 (CH2),
127.3 (CH), 128.3 (CH), 128.4 (CH), 135.4 (C), 167.3 (C) ppm. IR
(HATR): 3277, 3064, 2940, 1630, 1540, 1493, 1304, 1055, 1030,
The reaction was performed on (2R,3R)-diacid 8 (0.3 g,
1.06 mmol) according to the typical procedure, using (R)-phenyl-
glycinol (0.265 g, 1.90 mmol). Purification by flash chromatogra-
phy over silica gel (hexane/EtOAc, 30/70) resulted in pure
bishydroxyamide 13 as a white solid, 0.440 g (80%). 1H NMR
(300 MHz, CDCl3): d 3.30–3.40 (m, 2H), 3.40–3.50 (m, 2H), 3.85
(s, 2H), 4.8 (m, 2H), 6.60 (d, J = 7.5 Hz, 2H), 6.95 (m, 4H), 7.10–
7.20 (m, 6H), 7.40–7.50 (m, 10H) ppm. 13C NMR (75.4 MHz, CDCl3):
d 32.6 (CH), 48.5 (C), 55.9 (CH), 65.8 (CH2), 126.5 (CH), 126.5 (CH),
127.7 (CH), 127.7 (CH), 128.5 (CH), 128.8 (CH), 135.2 (C), 138.2 (C),
166.4 (C) ppm. IR (HATR): 3426, 3387, 3276, 3028, 2361, 1625,
1553, 1496, 1449, 1284, 1060, 1028, 977, 745, 695 cmꢁ1. ES-MS:
744, 695 cmꢁ1. ES-MS: 369 [M+H]+. ½a 2D0
¼ þ84:8 (c 1.0, EtOH).
ꢂ
Mp 115–117 °C. HRMS (EI) calcd for C21H24N2O4: 368.1736; found
368.1744.
521 [M+H]+. ½a 2D0
¼ ꢁ13:7 (c 1.0, CHCl3). Mp 193–195 °C. HRMS
ꢂ
4.3.2. (2R,3R)-1,1-Bis-[N-(10S)-(10-tert-butyl-20-hydroxyethyl)
(EI) calcd for C33H32N2O4: 520.2362; found 520.2352.
aminocarbonyl]-2,3-diphenylcyclopropane 10
The reaction was performed on (2R,3R)-diacid
8
(0.3 g,
4.4. A typical procedure for the preparation of the bisoxazoline
ligands 2–6
1.06 mmol) according to the typical procedure, using (S)-tert-leu-
cinol (0.230 g, 1.95 mmol). Purification by flash chromatography
over silica gel (hexane/EtOAc, 30/70) resulted in pure bishydroxya-
mide 10 as a white solid, 0.380 g (75%). 1H NMR (300 MHz, CDCl3):
d 0.45 (s, 18H), 3.30 (m, 2H), 3.60–3.75 (m, 4H), 3.80 (s, 2H), 6.12
(d, J = 9.6 Hz, 2H), 7.25 (m, 2H), 7.32 (m, 4H), 7.45 (m, 4H) ppm.
13C NMR (75.4 MHz, CDCl3): d 26.4 (CH3), 32.7 (C), 33.0 (CH),
50.4 (C), 60.0 (CH), 62.3 (CH2), 127.2 (CH), 128.5 (CH), 128.6
(CH), 135.3 (C), 167.5 (C) ppm. IR (HATR): 3379, 3322, 2950,
2356, 2335, 1637, 1539, 1498, 1364, 1294, 1046, 1023, 998, 742,
A mixture of bishydroxyamide 9–13 (0.81 mmol) and Et3N
(0.923 g, 9.12 mmol) in CH2Cl2 (10 mL) was stirred at 0 °C. Next,
MsCl (0.186 g, 1.62 mmol) was added dropwise over 10 min. The
mixture was allowed to warm to room temperature and was stir-
red for an additional hour. The mixture was washed with water
and the organic phases were dried over Na2SO4, filtered off and
concentrated in vacuo to give the corresponding crude bismesylate
as a yellow oil. Next, the crude bismesylate was dissolved in
CH3OH (10 mL) and was treated with aq NaOH (1 M, 2 mL) at room
temperature for 2 h. After removal of methanol in vacuo, CH2Cl2
was added and washed with water. The organic phases were dried
694 cmꢁ1. ES-MS: 481 [M+H]+. ½a 2D0
¼ þ43:5 (c 1.0, CHCl3). Mp
ꢂ
112–114 °C. HRMS (EI) calcd for C29H40N2O4: 480.2988; found
480.3007.