Tamura et al.
1
solution of 6b (337 mg, 1.8 mmol) in CH2Cl2 (2 mL) at room
temperature, and the mixture was further stirred at the same
temperature for 3.5 days. Water was added to the mixture,
and the whole was extracted with CHCl3. The organic phase
was washed with brine, dried (MgSO4), and concentrated
under reduced pressure. The crude product was chromato-
graphed (hexane-AcOEt, 5:1) to give 7b (438 mg, 98%) as a
3480, 1750 cm-1; H NMR (500 MHz, CDCl3) δ 0.02 (3H, s),
0.05 (3H, s), 0.93 (9H, s), 2.57 (1H, br dd, J ) 12.7, 8.8 Hz),
2.71 (1H, dd, J ) 12.7, 8.0 Hz), 3.04 (2H, s), 3.50 (2H, s), 4.07
(1H, dd, J ) 9.8, 3.4 Hz), 4.19 (1H, br t, J ) 10.8 Hz), 4.29
(1H, dd, J ) 11.7, 3.4 Hz), 4.36 (1H, br t, J ) 8.1 Hz), 7.03
(1H, t, J ) 7.3 Hz), 7.23-7.44 (9 H, m), 8.11 (1H, br s); 13C
NMR (125 MHz, CDCl3) δ 18.0, 25.9, 30.7, 38.6, 61.8, 62.9,
66.1, 69.5, 86.0, 171.5, 110.8, 119.3, 119.5, 121.9, 124.0, 127.7,
128.2, 128.3, 128.7, 135.9, 171.5. This material was used for
the next step without further purification.
syrup: [R]25 +49.1 (c 0.480, CHCl3); IR (CHCl3) 3605, 3480,
D
1750 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.42 (1H, br s), 2.61
(1H, dd, J ) 12.7, 8.8 Hz), 2.80 (1H, dd, J ) 12.7, 6.3 Hz),
3.08 (2H, s), 3.59 (2H, br s), 4.17-4.32 (4H, m), 6.87 (1H, d, J
) 1.8 Hz), 7.01-7.45 (8H, m), 7.53 (1H, d, J ) 7.3 Hz), 8.12
(1H, s); 13C NMR (125 MHz, CDCl3) δ 30.8, 38.5, 61.8, 63.3,
67.3, 68.9, 85.9, 110.0, 111.1, 119.0, 119.6, 122.0, 123.8, 127.5,
128.0, 128.5, 128.9, 135.6, 135.9, 169.8. Anal. Calcd for
C22H22N2O4‚1/2H2O: C, 68.42; H, 6.00; N, 7.25. Found: C,
68.60; H, 6.10; N, 7.02.
To a stirred solution of the O-TBDMS derivative of 7b (110
mg, 0.22 mmol) in MeCN (4 mL) were added Boc2O (210 mg,
0.88 mmol) and DMAP (3.0 mg, 0.022 mmol) at room temper-
ature, and the mixture was further stirred at the same
temperature for 1 h. Water was added to the mixture, and the
whole was extracted with AcOEt. The organic phase was
washed successively with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The crude product was
chromatographed (hexane-AcOEt, 6:1) to give (2S,5S,8aS)-
2-[(tert-butyldimethylsilyloxy)methyl]-2-[(1-tert-butyloxycarbo-
nylindol-3-yl)methyl]-5-phenyl-1,5,6,8a-tetrahydro-3,7-dioxain-
dolizin-8-one (O-TBDMS-N-Boc derivative of 7b) (126 mg, 97%)
as a syrup: IR (CHCl3) 1730 cm-1; 1H NMR (270 MHz, CDCl3)
δ 0.02 (3H, s), 0.05 (3H, s), 0.92 (9H, s), 1.66 (9H, s), 2.56 (1H,
dd, J ) 12.9, 8.9 Hz), 2.72 (1H, dd, J ) 12.9, 7.9 Hz), 3.04
(2H, s), 3.50 (2H, s), 4.06 (1H, dd, J ) 9.2, 3.6 Hz), 4.19 (1H,
dd, J ) 11.5, 9.2 Hz), 4.30 (1H, dd, J ) 11.5, 3.6 Hz), 4.38
(1H, br t, J ) 8.2 Hz), 7.03 (1H, br t, J ) 7.6 Hz), 7.20-7.45
(8H, m), 8.11 (1H, d, J ) 8.3 Hz); 13C NMR (67.5 MHz, CDCl3)
δ 18.3, 19.7, 25.9, 28.2, 30.6, 38.7, 61.6, 63.4, 65.5, 69.5, 83.5,
85.5, 115.0, 115.3, 119.7, 122.5, 124.2, 125.2, 125.8, 127.6,
128.4, 128.8, 131.1, 135.8, 149.6, 169.7. This material was
immediately used for the next step. To a stirred solution of
O-TBDMS-N-Boc derivative of 7b (120 mg, 0.20 mmol) in THF
(2.4 mL) was added 70% HF‚pyrdine (1 mL) at 0 °C, and the
mixture was further stirred at the same temperature for 1 h.
A saturated aqueous solution of NaHCO3 was added to the
mixture, and the whole was extracted with AcOEt. The organic
phase was washed successively with water and brine, dried
(MgSO4), and concentrated under reduced pressure. The crude
product was chromatographed (hexane-AcOEt, 2:1) to give 12
Reaction of 5 and 6a in the Absence of MgBr2‚OEt2:
7a and Its (2R,5S,8aS)-Isomer (11a). A solution of 5 (50 mg,
0.26 mmol) and 6a (28 mg, 0.39 mmol) in CH2Cl2 (4 mL) was
stirred for 9 days, and the mixture was concentrated under
reduced pressure. The crude product was chromatographed
(hexane-AcOEt, 5:1) to give an inseparable 13:87 mixture of
7a and 11a (63 mg, 92%) as a syrup: 1H NMR (500 MHz,
CDCl3) δ 1.26 (3H × 87/100, s), 1.31 (3H × 13/100, s), 1.83
(13/100H, br s), 2.05 (87/100H, br s), 2.38 (87/100H, dd, J )
12.7, 7.3 Hz), 2.62 (13/100H, dd, J ) 13.2, 6.8 Hz), 2.75 (13/
100H, dd, J ) 13.2, 8.8 Hz), 2.85 (87/100H, dd, J ) 12.7, 10.3
Hz), 3.45-3.52 (2H, m), 4.19-4.41 (2H + 13/100H, m), 4.49
(87/100H, dd, J ) 10.3, 7.3 Hz), 7.32-7.45 (5H, m); 13C NMR
(125 MHz, CDCl3) δ 22.6 (minor), 23.4 (major), 39.3 (major),
39.9 (minor), 62.2 (minor), 62.5 (major), 62.9 (major), 63.9
(minor), 68.8 (minor), 70.1 (major), 82.9 (minor), 84.0 (major),
127.5, 128.5, 128.7, 128.9, 129.0, 135.6, 169.2 (major), 169.8
(minor); HRMS calcd for for C14H17NO4 263.1159, found
263.1156.
Reaction of 5 and 6b in the Absence of MgBr2‚OEt2:
7b and Its (2R,5S,8aS)-Isomer (11b). A solution of 5 (19 mg,
0.10 mmol) and 6b (28 mg, 0.15 mmol) in CH2Cl2 (2 mL) was
stirred for 15 days, and the mixture was concentrated under
reduced pressure. The crude product was chromatographed
(CHCl3-AcOEt, 10:1) to give an inseparable 14:86 mixture of
7b and 11b (37 mg, 97%) as a syrup: 1H NMR (500 MHz,
CDCl3) δ 1.82 (86/100H, br s), 2.45 (14/100H, br s), 2.61 (14/
100H, dd, J ) 12.7, 8.8 Hz), 2.64 (86/100H, dd J ) 12.7, 7.8
Hz), 2.70 (86/100H, dd J ) 12.7, 9.3 Hz), 2.81 (14/100H, dd, J
) 12.7, 6.3 Hz), 2.98 (86/100H, d, J ) 14.7 Hz), 3.05 (86/100H,
d, J ) 14.7 Hz), 3.06 (2H × 14/100, s), 3.47-3.60 (2H, m),
4.15-4.30 (4H, m), 6.83 (14/100H, s), 6.99 (86/100H, s), 7.08
(1H, br t, J ) 7.3 Hz), 7.17 (1H, br t, J ) 7.3 Hz), 7.31 (1H, br
t, J ) 7.3 Hz), 7.34-7.41 (5H, m), 7.46 (1H, br d, J ) 6.8 Hz),
7.62 (1H, br d, J ) 7.8 Hz); 13C NMR (125 MHz, CDCl3) δ 30.9
(minor), 31.8 (major), 37.8 (major), 38.5 (minor), 61.8 (minor),
62.6 (major), 63.3 (major), 65.4 (major), 67.3 (minor), 68.9
(minor), 70.0 (major), 85.9 (minor), 86.7 (major), 110.3, 111.1,
119.2, 119.6, 121.9, 123.7, 127.4, 127.5, 127.7, 128.6, 128.9,
129.0, 135.7, 135.9, 169.5. HRMS calcd for for C22H22N2O4
378.1580, found 378.1583.
(103 mg, 100%) as a syrup: [R]25 +44.8 (c 0.400, CHCl3); IR
D
(CHCl3) 3570, 1730 cm-1; H NMR (500 MHz, CDCl3) δ 1.67
1
(9H, s), 2.63 (1H, dd, J ) 12.7, 8.8 Hz), 2.80 (1H, dd, J ) 12.7,
7.3 Hz), 3.01 (1H, d, J ) 14.6 Hz), 3.06 (1H, d, J ) 14.6 Hz),
3.59 (1H, d, J ) 11.7 Hz), 3.63 (1H, d, J ) 11.7 Hz), 4.19 (1H,
dd, J ) 9.3, 3.4 Hz), 4.24 (1H, dd, J ) 11.2, 9.3 Hz), 4.34 (1H,
dd, J ) 11.2, 3.4 Hz), 4.36 (1H, br t, J ) 7.8 Hz), 7.28 (1H, br
t, J ) 7.3 Hz), 7.29 (1H, br t, J ) 7.3 Hz), 7.32-7.41 (6H, m),
7.46 (1H, d, J ) 7.8 Hz), 8.11 (1H, br d, J ) 7.3 Hz); 13C NMR
(125 MHz, CDCl3) δ 20.0, 28.2, 30.4, 38.4, 61.8, 63.7, 67.1, 69.0,
85.2, 114.8, 115.1, 119.4, 122.6, 124.4, 124.9, 126.0, 128.5,
129.0, 129.5, 130.9, 135.6, 150.0, 170.0. Anal. Calcd for
C27H30N2O6: C, 67.40; H, 6.47; N, 5.65. Found: C, 67.70; H,
6.32; N, 5.85.
(2S,4S)-4-tert-Butyloxycarbonylamino-2-[(1-tert-butyl-
oxycarbonylindol-3-yl)methyl]-2-(hydroxymethyl)oxolan-
5-one (14). A mixture of 12 (20 mg, 0.042 mmol) and 20%
Pd(OH)2 on charcoal (20 mg) in MeOH (0.5 mL) was stirred
at room temperature under an atmosphere of hydrogen for 5
h. The mixture was passed through a pad of Celite, and the
filtrate was concentrated under reduced pressure. The residue
was dissolved in a mixture of MeCN (0.5 mL) and a saturated
aqueous solution of NaHCO3 (one drop). To the stirred mixture
was added Boc2O (46 mg, 0.21 mmol) at room temperature,
and the mixture was further stirred at the same temperature
for 24 h. Water was added to the mixture, and the whole was
extracted with AcOEt. The organic phase was washed with
brine, dried (MgSO4), and concentrated under reduced pres-
sure. The crude product was chromatographed (hexane-
AcOEt, 2:1) to give 14 (15.6 mg, 81%) as a syrup: [R]25D -3.26
(c 0.854, CHCl3); IR (CHCl3) 3435, 1780, 1720 cm-1; 1H NMR
(2S,5S,8aS)-2-[(1-tert-Butyloxycarbonylindol-3-yl)meth-
yl]-2-(hydroxymethyl)-5-phenyl-1,5,6,8a-tetrahydro-3,7-
dioxaindolizin-8-one (12). To a stirred solution of 7b (900
mg, 2.4 mmol) in DMF (6 mL) were added imidazole (654 mg,
9.6 mmol) and tert-butyldimethylsilyl chloride (434 mg, 2.9
mmol) at 0 °C, and the mixture was further stirred at room
temperature for 3 h. Water was added to the mixture, and the
whole was extracted with Et2O. The organic phase was washed
successively with water and brine, dried (MgSO4), and con-
centrated under reduced pressure. The crude product was
chromatographed (hexane-AcOEt, 4:1) to give (2S,5S,8aS)-
2-[(tert-butyldimethylsilyloxy)methyl]-2-[(indol-3-yl)methyl]-5-
phenyl-1,5,6,8a-tetrahydro-3,7-dioxaindolizin-8-one (O-TB-
DMS derivative of 7b) (1.14 g, 97%) as a syrup: IR (CHCl3)
4574 J. Org. Chem., Vol. 70, No. 12, 2005