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X. Cattoe¨n, M.A. Pericas / Tetrahedron 65 (2009) 8199–8205
8203
4.3. (4R,40R,5S,50S)-2,20-(Propane-2,2-diyl)bis(4-(4-
bromophenyl)-5-(methoxymethyl)-4,5-dihydrooxazole) (3a)
7.19 (br, 4H), 7.35 (d, 8.2 Hz, 4H), 7.55 (d, 8.2 Hz, 4H). 13C NMR
(100 MHz):
¼21.4 (CH3), 24.4 (CH3), 39.1 (C), 59.5 (CH3), 71.7 (CH),
73.7 (CH2), 86.3 (CH), 125.0 (CH), 127.0 (CH), 127.5 (CH), 128.9 (CH),
d
To a stirred solution of amino alcohol 1 (8.0 mmol) and tri-
ethylamine (1.4 mL, 9.7 mmol) in CH2Cl2 (15 mL) at 0 ꢀC was added
dimethylmalonyl dichloride (0.52 mL, 3.9 mmol). The solution was
allowed to slowly warm up to room temperature, and stirred for 15
additional hours. After dilution with CH2Cl2, the mixture was
washed with 10% aqueous HCl (10 mL), saturated NaHCO3 (10 mL),
water (10 mL) then brine. The bis(hydroxyamide) 2 was obtained
after drying over magnesium sulfate and concentration of the so-
lution, and used in the next step without purification. Crude 2
(4 mmol) was diluted in anhydrous CH2Cl2 (40 mL) and the solution
was cooled to ꢃ78 ꢀC. Diethylaminosulfur trifluoride (DAST)
(1.24 mL, 10.1 mmol) was added. The mixture was allowed to warm
up to room temperature, and then a saturated aqueous solution of
NaHCO3 was slowly added (10 mL). After addition of water (20 mL)
and CH2Cl2 (40 mL), the phases were separated. The organic phase
was washed with water (40 mL) and brine, dried over magnesium
sulfate then concentrated. Purification by flash chromatography on
silicagel (hexane/EtOAc 1/1) yielded the pure BOX 3a in 87% yield:
138.3 (C), 140.8 (C), 140.9 (C), 141.0 (C), 169.8 (C). [a]
20 189.7 (c 0.68,
D
CHCl3). HRMS (ESþ): calcd for C41H47N2O4 (MþH): 631.3536; found:
631.3530.
Compound 3f: yield 69%. 1H NMR (400 MHz):
d
¼1.74 (s, 6H),
3.46 (s, 6H), 3.65 (m, 4H), 3.87 (s, 6H), 4.61 (m, 2H), 5.00 (d, 6.5 Hz,
2H), 6.97 (d, 8.7 Hz, 4H), 7.35 (d, 8.2 Hz, 4H), 7.50 (m, 8H). 13C NMR
(100 MHz):
d
¼24.4 (CH3), 39.1 (C), 55.3 (CH3), 59.5 (CH3), 71.7 (CH),
73.7 (CH2), 86.2 (CH), 114.2 (CH), 127.0 (CH), 127.1 (CH), 128.1 (CH),
133.4 (C), 140.1 (C), 140.5 (C), 159.1 (C), 169.8 (C). [a]
20 197.4 (c 0.65,
CHCl3). HRMS (ESþ): calcd for C39H42N2O6Na (MþDNa): 657.2941;
found: 657.2919.
Compound 3g: yield 61%. 1H NMR (400 MHz):
d
¼1.76 (s, 6H),
2.27 (s, 6H), 3.48 (s, 6H), 3.66 (m, 4H), 4.63 (m, 2H), 5.01 (d, 6.6 Hz,
2H), 7.2–7.4 (m,16H). 13C NMR (100 MHz):
d¼20.5 (CH3), 24.4 (CH3),
39.1 (C), 59.5 (CH3), 71.7 (CH), 73.6 (CH2), 86.3 (CH), 125.6 (CH),
126.4 (CH), 127.3 (CH), 129.5 (CH), 129.8 (CH), 130.3 (CH), 135.4 (C),
20
140.5 (C), 141.3 (C), 141.6 (C), 169.8 (C). [
a
]
147 (c 0.70, CHCl3).
D
HRMS (ESþ): calcd for C41H42N2O4Na (MþNa): 625.3042; found:
1H NMR (400 MHz):
d
¼1.69 (s, 6H), 3.44 (s, 6H), 3.57 (dd, 4.9 and
625.3055.
10.4 Hz, 2H), 3.63 (dd, 5.7 and 10.4 Hz, 2H), 4.47 (m, 2H), 4.92 (d,
Compound 3h: yield 67%. 1H NMR (400 MHz):
d
¼1.77 (s, 6H),
2.02 (s, 12H), 3.47 (s, 6H), 3.68 (m, 4H), 4.60 (m, 2H), 4.99 (d, 6.6 Hz,
2H), 7.1–7.2 (m, 10H), 7.3–7.4 (m, 4H). 13C NMR (100 MHz):
6.5 Hz, 2H), 7.16 (d, 8.5 Hz, 4H), 7.46 (d, 8.5 Hz, 4H). 13C NMR
(100 MHz):
d
¼24.3 (CH3), 39.1 (C), 59.5 (CH3), 71.3 (CH), 73.4 (CH2),
d¼20.9
20
86.0 (CH), 121.5 (C), 128.3 (CH), 131.8 (CH), 141.1 (C), 170.0 (C). [
a
]
(CH3), 24.5 (CH3), 39.1 (C), 59.5 (CH3), 71.8 (CH), 73.7 (CH2), 86.4
(CH), 126.7 (CH), 127.0 (CH), 127.3 (CH), 129.4 (CH), 136.1 (C), 140.3
D
141.1 (c 0.55, CHCl3). HRMS (ESþ): calcd for C25H29Br2N2O4 (MþH):
579.0494; found: 579.0506.
(C), 140.4 (C), 141.5 (C), 169.9 (C). [a]
20 141.1 (c 0.88, CHCl3). HRMS
D
(ESþ): calcd for C41H47N2O4 (MþH): 631.3536; found: 631.3558.
4.4. General procedure for the Suzuki reaction on
bis(oxazoline) 3a
Compound 3i: yield 94%. 1H NMR (400 MHz):
d¼1.73 (s, 6H),
3.46 (s, 6H), 3.61–3.74 (m, 4H), 3.72 (s, 12H), 4.68 (m, 2H), 4.96 (d,
6.5 Hz, 2H), 6.65 (d, 8.2 Hz, 4H), 7.28 (d, 8.2 Hz, 2H), 7.31 (m, 8H). 13C
A solution of the substrate (1 mmol), the arylboronic acid
(2.2 mmol), cesium carbonate (4 mmol), S-Phos (0.08 mmol), and
Pd2(dba)3$C6H6 (1 mmol) in dry, degassed toluene (5 mL) was
heated to 100 ꢀC for 16 h. After cooling, the mixture was filtered
over Celite and concentrated. Purification by flash chromatography
yielded the corresponding BOX 3b–3i.
NMR (100 MHz):
(CH), 73.9 (CH2), 86.1 (CH), 104.2 (CH), 119.4 (C), 126.0 (CH), 128.6
d
¼24.4 (CH3), 39.0 (C), 55.9 (CH3), 59.4 (CH3), 71.8
(CH), 131.2 (CH), 133.4 (C), 140.2 (C), 157.7 (C), 169.6 (C). [a]
20 120.9
D
(c 0.70, CHCl3). HRMS (ESþ): calcd for C41H46N2O6Na (MþNa):
717.3152; found: 717.3159.
Compound 3b: yield 77%. 1H NMR (400 MHz):
3.47 (s, 6H), 3.66 (m, 4H), 4.61 (m, 2H), 5.01 (d, 6.6 Hz, 2H), 7.37 (m,
6H), 7.44 (m, 4H), 7.58 (m, 8H). 13C NMR (100 MHz):
d
¼1.75 (s, 6H),
4.5. 4-Bromostyrene oxide (5)
d
¼24.4 (CH3),
To a solution of 4-bromobenzaldehyde 4 (7.4 g, 40 mmol), Me3SI
(8.1 g, 40 mmol), and tetrabutylammonium bromide (0.19 g,
0.6 mmol) in CH2Cl2 (40 mL), was added a 50% aqueous sodium
hydroxide solution (40 mL). After 60 h heating at reflux, the mix-
ture was cooled, poured onto ice, and extracted with CH2Cl2
(2ꢂ20 mL) The combined organic extracts were sequentially
washed with water (40 mL), saturated aqueous sodium meta-
bisulfite (30 mL), water (40 mL), and brine, then dried over mag-
nesium sulfate, yielding 7.6 g (96%) of 5 as an oil that crystallized
upon standing.
39.1 (C), 59.5 (CH3), 71.6 (CH), 73.7 (CH2), 86.2 (CH), 127.08 (CH),
127.14 (CH), 127.3 (CH), 127.5 (CH), 128.8 (CH), 140.6 (C), 140.9 (C),
141.1 (C), 169.8 (C). [a]
20 206 (c 0.33, CHCl3). HRMS (ESþ): calcd for
D
C37H39N2O4 (MþH): 575.2990; found: 575.2896.
Compound 3c: yield 52%. 1H NMR (400 MHz):
d
¼1.75 (s, 6H),
3.47 (s, 6H), 3.66 (m, 4H), 4.60 (m, 2H), 5.03 (d, 6.4 Hz, 2H), 7.41 (d,
8.0 Hz, 4H), 7.56 (d, 8.0 Hz, 4H), 7.67 (m, 8H). 13C NMR (100 MHz):
d
¼24.3 (CH3), 39.2 (C), 59.5 (CH3), 71.6 (CH), 73.6 (CH2), 86.1 (CH),
124.3 (q, 272 Hz, CF3), 125.7 (q, 3.7 Hz, CH), 127.3 (CH), 127.4 (CH),
127.6 (CH), 129.4 (q, 33 Hz, C), 139.0 (C), 142.2 (C), 144.3 (C), 170.0
(C). 19F NMR (471 MHz):
d¼ꢃ62.6. [
a]
D
20 166.4 (c 0.67, CHCl3). HRMS
(ESþ): calcd for C39H36F6N2O4Na (MþNa): 579.0494; found:
4.6. Hydrolytic kinetic resolution of 4-bromostyrene oxide (5)
579.0506.
Compound 3d: yield 76%. 1H NMR (400 MHz):
d¼1.75 (s, 6H),
To a solution of the (R,R)-Co(salen) catalyst (1.7 g, 2.8 mmol) in
toluene (20 mL), acetic acid (4.6 mL, 80 mmol) was added. The
mixture was stirred for 30 min under a gentle stream of air, then
concentrated in vacuo. A solution of rac-4-bromostyrene oxide 5
(18.7 g, 94 mmol) in THF (10 mL) was then added; the mixture was
cooled to 0 ꢀC, and water (0.93 mL, 52 mmol) was added slowly.
The reaction mixture was stirred for 2 days at room temperature
and then passed through a pad of silica, eluting with an hexanes/
AcOEt mixture (9/1). After concentration, the red residue was dis-
tilled under reduced pressure (90 ꢀC, 1 mbar), to yield optically
pure (R)-4-bromostyrene oxide as a white solid (6.5 g, 35%). The
enantiomeric excess was determined by HPLC: Chiralcel AD-H
3.48 (s, 6H), 3.67 (m, 4H), 4.57 (m, 2H), 5.06 (d, 6.4 Hz, 2H), 7.44 (d,
8.0 Hz, 4H), 7.59 (d, 8.0 Hz, 4H), 7.86 (br, 2H), 7.98 (br, 4H). 13C NMR
(100 MHz):
d
¼24.3 (CH3), 39.2 (C), 59.5 (CH3), 71.5 (CH), 73.5 (CH2),
86.1 (CH),120.9 (sept, 3.7 Hz, CH),123.3 (q, 273 Hz, C),127.1 (m, CH),
127.57 (CH), 127.59 (CH), 132.1 (q, 33 Hz, C), 137.5 (C), 142.9 (C),
20
143.0 (C), 170.1 (C). 19F NMR (471 MHz):
d
¼ꢃ63.0. [
a
]
134.6 (c
D
0.72, CHCl3). HRMS (ESþ): calcd for C41H34F12N2O4Na (MþNa):
869.2225; found: 869.2222.
Compound 3e: yield 71%. 1H NMR (400 MHz):
d
¼1.76 (s, 6H),
2.38 (s, 12H), 3.46 (s, 6H), 3.64 (dd, 4.7 and 10.7 Hz, 2H), 3.68 (dd,
6.0 and 10.7 Hz, 2H), 4.59 (m, 2H), 5.00 (d, 6.5 Hz, 2H), 7.00 (br, 2H),