Papageorgiou et al.
orated and the residue was diluted with EtOAc (100 mL) and
washed with 1 M KHSO , saturated aq NaHCO , and brine,
dried, and evaporated. Flash chromatography [1:4 EtOAc-
hexanes] followed by trituration with Et O-hexanes gave 6
as fluffy white crystals (2.33 g, 86%), mp 80-81 °C (from
Hz, 1H), 7.12 (t, J ) 8.1 Hz, 1H), 6.42 (d, J ) 8.1 Hz, 1H),
4.86 (dd, J ) 5.2, 9.3 Hz, 1H), 4.66 (s, 2H), 4.04-4.10 (m, 2H),
3.79 (s, 3H), 3.18 (t, J ) 8.6 Hz, 2H), 2.50-2.60 (m, 2H), 2.42-
2.48 (m, 1H), 2.18-2.25 (m, 1H), 1.48 (s, 18H), 1.46 (s, 9H).
4
3
2
+
+
Low resolution MS (ES ): m/z 593.4 (M + H) , calcd for
1
+
Et
2
O-hexanes): H NMR (500 MHz) δ 7.86 (d, J ) 8.1 Hz,
(C30
H
44
N
2
O
10 + H) 593.3.
1
H), 7.15 (t, J ) 8.1 Hz, 1H), 6.56 (d, J ) 8.1 Hz, 1H), 4.86
{1-[4S-(4-ter t-Bu toxyca r bon yl)-4-(d i-ter t-bu toxyca r bo-
(
dd, J ) 9.0, 5.7 Hz, 1H), 4.02-4.09 (m, 2H), 3.83 (s, 3H), 3.09
n ylam in o)bu tan oyl]in dolin -4-yloxy}acetic Acid (14). Aque-
ous NaOH (1 M, 11 mL, 11 mmol) was added to a solution of
(t, J ) 8.5 Hz, 2H), 2.50-2.60 (m, 2H), 2.41-2.47 (m, 1H),
2
.16-2.25 (m, 1H), 1.48 (s, 18H), 1.45 (s, 9H). Anal. Calcd for
1
1 (4.35 g, 7.3 mmol) in MeOH (200 mL). After 2.5 h, when
consumption of the starting material was confirmed by TLC
90:10:1 EtOAc-hexanes-AcOH), the solution was neutralized
C
7
28
H
42
N
2
O
8
: C, 62.90; H, 7.92; N, 5.24. Found: C, 63.02; H,
.98; N, 5.23.
-[4S-(4-ter t-Bu toxyca r bon yl)-4-(ter t-bu toxyca r bon yl-
a m in o)]bu ta n oyl-4-m eth oxy-7-n itr oin d olin e (7). A solu-
tion of 6 (2.14 g, 4 mmol) in CCl (16 mL) and acetic anhydride
8 mL) was stirred at room temperature for 22 h with a
suspension of claycop (2.56 g, prepared as described in ref 14).
The solid was filtered off and washed with CCl , and the
combined filtrates were evaporated. The residue was dissolved
in EtOAc and washed with saturated NaHCO and brine,
dried, and evaporated to a brown viscous oil that was dissolved
in CH Cl (80 mL), treated with TFA (1 M solution in CH Cl
mL), and stirred at room temperature for 20 h. The solvent
was evaporated and the residue was dissolved in EtOAc (100
mL), washed with saturated NaHCO and brine, dried, and
evaporated. Flash chromatography (1:1 EtOAc-hexanes) fol-
lowed by crystallization (CHCl -hexanes) gave 7 (1.56 g, 81%)
as yellow crystals, mp 145-147 °C, identical with the material
(
1
with 1 M aq citric acid (11 mL) and concentrated. The residue
was diluted with water, acidified to pH 2 with 1 M aq citric
acid, and washed with EtOAc. The combined organic phases
were washed with brine, dried, and evaporated to a pale foam
which, after trituration with EtOH, gave 14 as white crystals
4
(
1
4
(3.07 g, 72%), mp 65-67 °C (Et O-hexanes):
2
H NMR (500
MHz) δ 7.91 (d, J ) 8.2 Hz, 1H), 7.13 (t, J ) 8.2 Hz, 1H), 6.46
(d, J ) 8.2 Hz, 1H), 4.86 (dd, J ) 4.9, 9.1 Hz, 1H), 4.68 (s,
2H), 4.02-4.11 (m, 2H), 3.16 (t, J ) 8.6 Hz, 2H), 2.51-2.60
3
2
2
2
2
;
(
1
7
m, 2H), 2.43-2.49 (m, 1H), 2.16-2.24 (m, 1H), 1.48 (s, 18H),
6
.46 (s, 9H). Anal. Calcd for C29
.40; N, 4.69. Found: C, 58.72; H, 7.40; N, 4.69.
-[4S-(4-ter t-Bu toxyca r bon yl)-4-(ter t-bu toxyca r bon yl-
H
42
N
2
O
10 + H
2
O: C, 58.38; H,
3
1
a m in o)bu ta n oyl]-7-n itr oin d olin -4-yloxya cetic Acid (4).
Claycop (3.2 g) was added to a solution of 14 (1.15 g, 2 mmol)
in a solution of CCl (50 mL) and acetic anhydride (25 mL)
4
3
1
2c
previously described (mp, H NMR).
and the mixture was stirred at room temperature over-
night, when the consumption of the starting material was
confirmed by TLC [100:2 EtOAc-AcOH]. The solid was filtered
off and washed thoroughly with EtOAc (200 mL) and the
combined filtrate was washed with brine, dried, and evapo-
rated, then re-evaporated from toluene (2 × 50 mL). The
Meth yl {1-[4S-(4-ter t-Bu toxyca r bon yl)-4-(ter t-bu toxy-
ca r bon yla m in o)bu ta n oyl]in d olin -4-yloxy}a ceta te (10). A
solution of methyl (1-acetylindolin-4-yloxy)acetate1 (8) (2.74
g, 11 mmol) in a mixture of MeOH (230 mL), water (36 mL),
and concentrated HCl (18 mL) was refluxed for 4 h. The
solution was diluted with water (100 mL), concentrated to
residue was dissolved in dry CH
M TFA in CH Cl
overnight. The solution was diluted with CH
2 2
Cl (50 mL), treated with 1
∼
3
200 mL, basified with solid NaHCO , and extracted with
EtOAc (3 × 100 mL). The combined organic phases were
2
2
(3 mL), and stirred at room temperature
Cl (100 mL) and
2
2
washed with brine, dried, and evaporated to give methyl
washed with brine, dried, and evaporated to a brown viscous
oil. Flash chromatography (100:2 EtOAc-AcOH) gave 4 as a
pale yellow foam (0.90 g, 86%), contaminated with a small
proportion of the 5-isomer. This material was used in the next
step without further purification.
(
indolin-4-yloxy)acetate (9) (1.77 g, 77%) as pale crystals: 1
H
NMR (90 MHz) δ 6.92 (t, J ) 7.5 Hz, 1H), 6.31 (d, J ) 7.5 Hz,
1
H), 6.12 (d, J ) 7.5 Hz, 1H), 4.62 (s, 2H), 3.76 (s, 3H), 3.56 (t,
J ) 8 Hz, 2H), 3.05 (t, J ) 8 Hz, 2H). The crude indoline (1.77
g, 8.5 mmol) was dissolved in dry MeCN (80 mL) and treated
with N-tert-BOC-L-glutamic acid γ-tert-butyl ester (2.88 g, 9.5
mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide‚
HCl (2.30 g, 12 mmol). The mixture was stirred at room
temperature for 18 h, then evaporated. The residue was
dissolved in EtOAc and washed with 0.5 M aq HCl, saturated
4
-{2-[1-[4S-(4-Am in o-4-ca r boxybu ta n oyl)]-7-(n itr oin d o-
lin -4-yloxy)a ceta m id o]eth oxy}-4′-[2-(d ih yd r oxyp h osp h o-
r yloxy)eth oxy]ben zop h en on e (3). A solution of the azide
1
1
5 (779 mg, 1.5 mmol, prepared as described ) in THF (10.25
mL) containing water (40 µL, 2.25 mmol) was treated with
triphenylphosphine (590 mg, 2.25 mmol) and the mixture was
stirred at room temperature under nitrogen for 20 h. TLC [4:1
EtOAc-hexanes] confirmed that all the azide was reduced to
the amine 16. The solvent was evaporated and the residue was
aq NaHCO
3
, and brine, dried, and evaporated to give a white
foam that, after trituration with ether, gave 10 as white
crystals (3.73 g, 89%), mp 120-122 °C (EtOAc-hexanes): 1
H
NMR (500 MHz) δ 7.88 (d, J ) 8.1 Hz, 1H), 7.13 (t, J ) 8.1
Hz, 1H), 6.44 (d, J ) 8.1 Hz, 1H), 5.22 (d, J ) 7 Hz, 1H), 4.66
3
dissolved in CHCl (30 mL), dried, and evaporated to a viscous
oil (1.41 g) that contained material identical with 16 as
previously described1 (assessed by 1H NMR), together with
triphenylphosphine oxide and unreacted triphenylphosphine.
The mixture was dissolved in dry MeCN (50 mL) and treated
with the crude acid 4 (785 mg, 1.5 mmol) and 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide‚HCl (401 mg, 2.1 mmol).
The mixture was stirred at room temperature under nitrogen
for 18 h, then evaporated. The residue was dissolved in EtOAc
(
3
1
s, 2H), 4.12-4.26 (m, 1H), 4.03-4.09 (m, 2H), 3.78 (s, 3H),
.20 (t, J ) 8.5 Hz, 2H), 2.44-2.58 (m, 2H), 2.22-2.30 (m, 1H),
.99-2.08 (m, 1H), 1.47 (s, 9H), 1.42 (s, 9H). Anal. Calcd for
25 36 2 8
C H N O : C, 60.96; H, 7.37; N, 5.68. Found: C, 60.88; H,
7
.47; N, 5.59.
Met h yl {1-[4S-(4-ter t-Bu t oxyca r b on yl)-4-(d i-ter t-b u -
toxycar bon ylam in o)bu tan oyl]in dolin -4-yloxy}acetate (11).
A solution of 10 (3.94 g, 8 mmol) in a mixture of dry CH Cl
32 mL) and Et N (48 mL) was treated with di-tert-butyl
2
2
and washed with 0.5 M aq HCl, saturated aq. NaHCO
brine, dried, and evaporated. Flash chromatography (95:5
CHCl -MeOH) gave a pale yellow foam (700 mg, 52%), which
3
, and
(
3
dicarbonate (4.36 g, 20 mmol) and DMAP (98 mg, 0.8 mmol)
and the mixture was refluxed under nitrogen for 6 h. The
solvents were evaporated and the residue was dissolved in
3
was used in the next step without further characterization.
This material (645 mg, 0.71 mmol) was dissolved in TFA (30
mL), stirred at room temperature for 1 h, and concentrated in
vacuo. The residue was dissolved in water (180 mL) and
adjusted to pH 7.1 with 1 M aq NaOH. The solution was
washed with ether and analyzed by reverse-phase HPLC
Et
NaHCO
2
O (100 mL) and washed with 1 M aq KHSO
4
, saturated aq
3
and brine, dried, and evaporated to give a viscous
oil. Flash chromatography (2:3 EtOAc-hexanes) gave 11 as a
pale foam (4.61 g, 97%) that was used in the next step without
1
further purification: H NMR (500 MHz) δ 7.90 (d, J ) 8.1
[
t
mobile phase 25 mM Na phosphate, pH 6.0-MeCN (10:3 v/v)],
R
3.9 min, with a small additional peak at 6.3 min. The
(14) Laszlo, P.; Corn e´ lis, A. Aldrichim. Acta 1988, 21, 97.
solution was lyophilized, dissolved in 25 mM Na phosphate,
7
232 J . Org. Chem., Vol. 69, No. 21, 2004