(described later) (22) in CH2Cl2 (200 mL) was gradually
added to the cold solution (ca. 5 °C) at argon atmosphere.
The mixture was warmed to room temperature and stirred
for 1 h. After addition of 5% aqueous HCl (100 mL) under
ice-cooling, the whole was stirred at the same temperature
for ca. 15 min and warmed to room temperature. The organic
layer was separated, washed successively with water and
brine, and dried over anhydrous MgSO4. The solvent was
evaporated to leave a mixture (ca. 40.1 g) of 26, 4, and N-(9-
fluorenylmethoxycarbonyl)-D-alanine as a purple amorphous
solid, which was used in the next step without further
purification. The analysis of the mixture was carried out by
HPLC [column, Shiseido capcell pak C18 (Shiseido Co., Ltd.,
Japan); 4.6 mm i.d. × 150 mm; eluent, water containing
0.05% CF3CO2H/MeCN ) 3/7; flow rate, 1.0 mL/min;
column temperature, 25 °C; detection, 254 nm]. The retention
times of 26, 4, and N-(9-fluorenylmethoxycarbonyl)-D-
alanine were 6.0, 3.7, and 1.9 min, respectively. A small
amount of the mixture was chromatographed on silica gel
with CHCl3/MeOH ) 100/1 to give a pure 26 as an
of (R)-7 and its enantiomer were 23.1 and 17.2 min,
respectively.
Preparation of N-(9-fluorenylmethoxycarbonyl)-D-alanyl
chloride18 (22): Oxalyl chloride (7.0 mL, 80 mmol) was
portionwise to a suspension of N-(9-fluorenylmethoxycar-
bonyl)-D-alanine (23.35 g, 75 mmol) in a mixture of CH2-
Cl2 (240 mL) and N,N-dimethylformamide (DMF, 0.4 mL)
at room temperature. The mixture was stirred at the same
temperature for 1 h. After evaporation of the volatiles, the
residual solid containing 22 was obtained. The residue was
used in the next reaction without further purification.
(2R)-7-Benzyloxy-3-[2-(tert-butoxycarbonylamino)pro-
pyl]-1H-indole (30). After the mixture of (R)-7‚(CO2H)2
(50.0 g, 135 mmol), K2CO3 (28.0 g, 0.20 mol), H2O (500
mL), and AcOEt (250 mL) was stirred at room temperature
for 2 h, di-tert-butyl dicarbonate (29.5 g, 135 mmol) was
added portionwise under ice-cooling. The whole was warmed
at room temperature and stirred for 3 h. The organic layer
was separated, washed with brine, and dried over anhydrous
MgSO4. After evaporation of the solvent, hexane (150 mL)
was added to the residue. The resulting precipitate was
collected by filtration and dried to give 47.2 g (92%, 98.5%
1
amorphous solid. H NMR (200 MHz) δ 1.49 (d, 3H, J )
7), 4.20 (t, 1H, J ) 7), 4.37 (d, 2H, J ) 7), 5.27 (s, 2H),
6.00 (d, 1H, J ) 7), 6.82 (d, 1H, J ) 8), 7.14-7.5 (m, 11H),
7.59 (d, 2H, J ) 7), 7.74 (d, 2H, J ) 7), 7.87 (d, 1H, J )
3), 7.94 (d, 1H, J ) 8), 9.40 (br s, 1H). MS m/z: 517 (MH+).
Crude amorphous solid containing 26 thus obtained (ca.
40.1 g) was completely dissolved in a mixture of MeCN (100
mL) and 2-PrOH (15 mL, 0.20 mol) under warming. Sodium
borohydride (5.7 g, 0.15 mol) was portionwise added to the
solution, and then the mixture was heated to reflux for 5 h
and cooled to ca. 5 °C. After careful addition of MeOH (100
mL), the mixture was raised to room temperature and then
concentrated to dryness. The residue was dissolved in AcOEt
(250 mL) and washed with water (100 mL) and dried over
anhydrous MgSO4. The reaction mixture was analyzed by
HPLC (column, Shiseido capcell pak C18; 4.6 mm i.d. ×
150 mm; eluent, water containing 0.05% CF3CO2H/MeCN
) 7/3; flow rate, 1.0 mL/min; column temperature, 25 °C;
detection, 215 nm). The retention times of 28, (R)-7, and 29
were 5.7, 9.4, and 7.3 min, respectively.
ee) of 30 as a white crystalline material, mp 94-95 °C. [R]25
D
-21.0° (c 1.0, MeOH). 1H NMR (300 MHz) δ 1.11 (d, 3H,
J ) 6.6), 1.43 (s, 9H), 2.83 (dd, 1H, J ) 14.5, 6.7), 2.94
(dd, 1H, J ) 14.5, 5.1), 4.00 (m, 1H), 4.44 (m, 1H), 5.18 (s,
2H), 6.71 (d, 1H, J ) 7.5), 6.97 (d, 1H, J ) 2.2), 7.02 (t,
1H, J ) 7.9), 7.20 (s, 1H), 7.24-7.51 (m, 5H), 8.30 (s, 1H).
MS m/z: 381 (MH+), 325, 281, 264. IR cm-1; 3410, 3348,
2978, 1678, 1526, 1501, 1259, 11173. Anal. Calcd for
C23H28N2O3; C: 72.61, H: 7.42, N: 7.36. Found; C: 72.50,
H: 7.50, N: 7.42. Chiral HPLC [column, CHIRALCEL AD;
4.6 mm i.d. × 250 mm; eluent, hexane/2-PrOH ) 70/30;
flow rate, 0.8 mL/min; column temperature, 25 °C; detection,
254 nm]; the retention times of 30 and its enantiomer were
8.8 and 9.9 min, respectively.
(2R)-[3-[2-(tert-Butoxycarbonylamino)propyl]-1H-in-
dol-7-yloxy]-N,N-diethylacetamide (32). A solution of 30
(750 g, 2.0 mol) in MeOH (3750 mL) was hydrogenated
over 10% palladium on carbon (22.5 g) at ca. 35 °C at
atmospheric pressure. After the calculated amount of the
hydrogen was absorbed (ca. 1.5 h), the catalyst was removed
by filtration. The filtrate was concentrated to dryness to give
a residue containing (2R)-3-[2-(tert-butoxycarbonylamino)-
propyl]-7-hydroxy-1H-indole (31). A mixture of 31, K2CO3
(329 g, 2.4 mol), ClCH2CONEt2 (3256 g, 2.4 mol), KI (17.5
g, 0.105 mol), and acetone (4500 mL) was heated to reflux
for 5 h and cooled to room temperature. After the insoluble
materials were filtered off, the filtrate was concentrated to
dryness. The residue was dissolved in CHCl3 (5000 mL) and
H2O (2000 mL), and the organic layer was separated and
dried over anhydrous MgSO4. The solvent was evaporated,
and the residual solid was triturated with a mixture of AcOEt
(750 mL) and hexane (2250 mL) to afford 788 g (99%,
A solution of oxalic acid (4.5 g, 50 mmol) in AcOEt (45
mL) was added to the dry solution containing (R)-7 at room
temperature, and the mixture was stirred for 2 h. The
resulting precipitate was collected by filtration, washed with
AcOEt (100 mL), and dried to give 11.2 g (60% from 4,
98% ee) of (R)-7‚(CO2H)2, mp 206-208 °C. [R]25D -46.2°
1
(c 1.0, DMF). H NMR (DMSO-d6, 200 MHz) δ 1.14 (d,
3H, J ) 7), 2.80 (dd, 1H, J ) 14, 8), 3.03 (dd, 1H, J ) 14,
5), 3.42 (m, 1H), 5.26 (s, 2H), 5.94 (br, 4H), 6.75 (d, 1H, J
) 8), 6.92 (t, 1H, J ) 8), 7.11-7.22 (m, 2H), 7.32-7.48
(m, 3H), 7.51-7.62 (m, 2H), 11.11 (s, 1H). MS m/z: 281
(MH+), 264. IR cm-1; 3337, 1624, 1576, 1231. Anal. Calcd
for C18H20N2O‚C2H2O4‚1/4H2O; C: 64.07, H: 6.05, N: 7.47.
Found; C: 64.11, H: 5.92, N: 7.39. Chiral HPLC [column,
CHIRALCEL AD (Daicel Chemical Industries, Ltd., Japan);
4.6 mm i.d. × 250 mm; eluent, hexane/2-PrOH/Et2NH )
90/10/0.2; flow rate, 1.0 mL/min; column temperature, 25
°C; detection, 254 nm]; the retention times of the free base
>99% ee) of 32 as a white crystalline material, mp 124 °C.
1
[R]25 -26.3° (c 1.0, MeOH). H NMR (300 MHz) δ 1.10
D
(d, 3H, J ) 6.6), 1.17 (t, 3H, J ) 7.1), 1.22 (t, 3H, J ) 7.1),
1.43 (s, 9H), 2.83 (dd, 1H, J ) 13.9, 7.0), 2.94 (dd, 1H, J )
244
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Vol. 8, No. 2, 2004 / Organic Process Research & Development