Jiang et al.
J ) 6.8 Hz), 1.94-1.80 (4H, m), 1.46-1.47 (18H, m) ppm. 13C
NMR (100 MHz, CDCl3): δ 156.2, 143.7, 141.3, 127.7, 127.1,
125.1, 119.9, 81.9, 67.3, 64.8, 53.1, 47.1, 27.9, 24.2 ppm. IR
(neat): 3371, 2977, 2359, 1707, 1688, 1524, 1365, 1217, 1142,
759 cm-1. FAB-MS (negative ion)-m/z (rel intensity): 538 (M -
H, 100), 342 (M - H - C13H9CH2OH, 63), 316 [M - H - (C13H10
+ CO2), 58]. HRMS (FAB): calcd for C30H36NO8 [M - H]
and the product was extracted with EtOAc (3 × 60 mL). The
combined organic phases were washed consecutively with 1 M
KHSO4, H2O, 5% aqueous NaHCO3, and H2O and dried (Na2SO4),
and the solvent was evaporated. The residue was purified by column
1
chromatography to give 10 as a white solid (4.718 g, 88%). H
NMR (400 MHz, CDCl3): δ 7.28-7.24 (10H, m), 5.68 (1H, d, J
) 8.4 Hz), 5.08-5.15 (4H, m), 4.42 (1H, m), 3.56 (2H, t, J ) 6.0
Hz), 2.31 (1H, br s, OH), 1.89 (1H, m), 1.74 (1H, m), 1.53 (2H,
m) ppm. 13C NMR (100 MHz, CDCl3): δ 172.4, 156.1, 136.2,
135.2, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 67.1, 67.0, 61.8,
53.7, 29.1, 28.1 ppm. IR (neat): 3316, 3033, 2922, 2870, 1730,
1686, 1530, 1254, 1203, 1058 cm-1. FAB-MS m/z (rel intensity):
358 (MH+, 15), 314 (MH+ - CO2, 15), 91 (C7H7+, 100). HRMS
(FAB): calcd for C20H24NO5 [MH+] 358.1654, found 358.1647.
538.244, found 538.244. [R]25 +14.28 (c 0.16, CHCl3).
D
(S)-2-Allyloxycarbonylamino-5,5-bis-tert-butoxycarbonylhep-
tanedioic-1-allylester-7-tert-butyl Ester (9). A solution of NaH-
MDS (1.98 mL, 1.0 M in THF, 1.98 mmol) was added to a solution
of 8 (0.694 g 1.883 mmol) in THF (13 mL) at -30 °C, and the
mixture was stirred for 40 min at room temperature. A solution of
tert-butyl bromoacetate (0.367 g, 3.77 mmol) in THF (4 mL) was
added slowly at 0 °C, and the mixture was stirred for 2 h at room
temperature. The reaction was quenched with saturated aqueous
ammonium chloride, and the product was extracted twice with ethyl
acetate (3 × 30 mL). The combined organic layers were washed
three times with saturated aqueous ammonium chloride (3 × 10
mL) and were dried over sodium sulfate. After evaporation under
reduced pressure the product was purified by silica gel flash
[R]25 -2.96 (c 1.00, CHCl3).
D
(S)-2-Benzyloxycarbonylamino-5-iodopentanoic Acid Benzyl
Ester (11). To a 100 mL flask was added 10 (3.561 g, 9.96 mmol),
imidazole (1.085 g, 15.94 mmol), Ph3P (3.93 g, 14.95 mmol), and
anhydrous THF (109 mL) under a nitrogen atmosphere. Then iodine
(3.79 g, 14.95 mmol) was added in portions at 0 °C. The reaction
mixture was stirred at room temperature for 2 h. Excess iodine
was removed by the addition of aqueous sodium thiosulfate. The
mixture was transferred to a separating funnel. The organic layer
was diluted with ether, washed with water, and dried (MgSO4).
The solid was filtered and the organic solution was concentrated.
The residue was treated with diethyl ether and precipitated triphen-
ylphosphine oxide was removed by filtration. The filtrate was
concentrated and purified by column chromatography to afford 11
1
chromatography and gave 9 as an oil (0.837 g, 80%). H NMR
(400 MHz, CDCl3): δ 5.89 (2H, m), 5.35-5.19 (5H, m), 4.63 (2H,
dd, J ) 1.2, 4.8 Hz), 4.55 (2H, d, J ) 5.6 Hz), 4.36 (1H, m), 2.77
(2H, d, J ) 1.2 Hz), 2.03-1.67 (4H, m), 1.45-1.42 (27H, m) ppm.
13C NMR (100 MHz, CDCl3): δ 170.3, 168.3, 167.8, 154.4, 131.3,
130.2, 117.5, 116.3, 115.8, 80.5, 79.9, 65.1, 64.7, 64.4, 59.1, 54.6,
52.5, 50.5, 37.1,, 26.7, 26.6, 26.5, 25.9, 19.7, 12.9 ppm. IR (neat):
3369, 2978, 2935, 1725, 1368, 1247, 1146, 846 cm-1. FAB-MS
m/z (rel intensity): 556 (MH+, 0.9), 500 (MH+ - C4H8, 2.6), 388
(MH+ - 3C4H18, 51). HRMS (FAB): calcd for C28H45NKO10 [M
1
as a white solid (4.19 g, 90%). H NMR (400 MHz, CDCl3): δ
7.36-7.31 (10H, m), 5.37 (1H, d, J ) 7.6 Hz), 5.19-5.10 (4H,
m), 4.45 (1H, m), 3.13 (2H, m), 1.98-1.75 (4H, m) ppm. 13C
NMR (100 MHz, CDCl3): δ 171.8, 155.8, 136.1, 135.1, 128.7,
128.6, 128.5, 128.3, 128.2, 128.1, 67.3, 67.1, 53.0, 33.6, 29.0
ppm. IR (neat): 3312, 3032, 2968, 2358, 1723, 1688, 1530, 1273,
1251, 729 cm-1. FAB-MS m/z (rel intensity): 468 (MH+, 14), 424
(MH+ - CO2, 6.5), 91 (C7H7+, 100). HRMS (FAB): calcd for
+ K+] 594.268, found 594.267. [R]25 +18.58 (c 0.485, CHCl3).
D
(S)-5,5-Bis-tert-butoxycarbonyl-2-(9H-fluoren-9-ylmethoxy-
carbonylamino)heptanedioic Acid 7-tert-Butyl Ester (3). A
solution of 9 (0.54 g, 0.97 mmol), Et2NH (3.0 mL, 29.0 mmol),
and Pd(PPh3)4 (0.112 g, 0.097 mmol) in 10 mL of methylene
chloride was stirred for 1 h at 25 °C. The solvent was evaporated,
and the residue was redissolved in CH3CN (10 mL). A solution of
NaHCO3 (81.5 mg, 0.97 mmol) in H2O (4.0 mL) was added and
the mixture was stirred for 30 min. The solvents were evaporated,
and the resulting mixture was dried 5 h under vacuum at 50 °C.
The resulting solids were dissolved in DMF (28 mL) and H2O (28
mL), treated with NaHCO3 (163 mg, 1.94 mmol) and Fmoc-OSu
(343 mg, 1.0 mmol), and stirred for 24 h. The solvents were
removed, and the residue was dissolved in EtOAc (150 mL) and
washed with 0.1 M KHSO4 (4 × 40 mL), H2O (4 × 40 mL), and
brine (70 mL). After drying and removal of the solvent, the residue
was purified by chromatography to yield 3 as a white foam (482
C20H23INO4 [MH+] 468.0672, found 468.0700. [R]25 +2.56 (c
D
0.86, CHCl3).
(S)-2-Benzyloxycarbonylamino-6-tert-butoxycarbonylhep-
tanedioic Acid 1-Benzyl Ester 7-tert-Butyl Ester (13). The tert-
butyl malonate (1.47 g, 6.78 mmol) was added to a solution of
NaHMDS (6.78 mL, 1.0 M in THF, 6.78 mmol) in THF (15 mL)
at -78 °C, and the mixture was stirred 30 min at the same
temperature. A solution of iodide 11 (3.17 g, 6.78 mmol) in THF
(15 mL) was added slowly, and the mixture was stirred for 20 min
at -78 °C. Then the reaction mixture was stirred at room
temperature for 2 h. The reaction was quenched with saturated
aqueous ammonium chloride, and the product was extracted twice
with ethyl acetate (2 × 35 mL). The combined organic layers were
washed three times with saturated aqueous ammonium chloride (3
× 10 mL) and were dried over sodium sulfate. After evaporation
under reduced pressure the product was purified by silica gel flash
chromatography to give 12 as a white solid (1.15 g, 50%) and 13
as a oil (1.886 g, 50%).
1
mg, 76%). H NMR (400 MHz, CDCl3): δ 7.75 (2H, d, J ) 7.6
Hz), 7.62 (2H, d, J ) 7.6 Hz), 7.39 (2H, dd, J ) 7.2 Hz), 7.30
(2H, dt, J ) 1.2, 7.2 Hz), 5.67 (1H, d, J ) 7.6 Hz), 4.40 (2H, m),
4.32 (1H, m), 4.22 (1H, t, J ) 7.4 Hz), 2.80 (2H, s), 2.10-1.78
(4H, m), 1.45-1.41 (27H, m) ppm. 13C NMR (100 MHz, CDCl3):
δ 169.8, 169.1, 156.2, 143.8, 143.7, 141.2, 127.7, 127.6, 127.1,
125.2, 119.9, 82.0, 81.4, 67.3, 55.9, 53.6, 47.0, 38.4, 27.9, 27.7,
26.5 ppm. IR (neat): 3135, 2978, 1725, 1682, 1367, 1146, 841
cm-1. FAB-MS (negative ion)-m/z (rel intensity): 652 (M - H,
28), 456 (M - H - C13H9CH2OH, 100), 430 [M - H - (C13H10
+ CO2), 60). HRMS (FAB): calcd for C36H46NO10 [M - H]
Compound 12: 1H NMR (400 MHz, CDCl3) δ 7.37-7.21 (10H,
m), 5.22-4.98 (4H, m), 4.44 and 4.37 (each dd, J ) 3.6, 8.8 Hz,
0.5H), 3.63 (1H, m), 3.49 (1H, m), 3.33 (1H, m), 2.02-1.83 (3H,
m) ppm.
Compound 13: 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (10H,
m), 5.30 (1H, d, J ) 8.4 Hz), 5.15 (2H, s), 5.09 (2H, s), 4.41 (1H,
m), 3.06 (1H, t, J ) 7.4 Hz), 1.91-1.65 (4H, m), 1.49-1.44
(18H, m), 1.35 (2H, m) ppm. 13C NMR (100 MHz, CDCl3): δ
172.1, 168.6, 155.8, 136.2, 135.2, 128.6, 128.5, 128.4, 128.2, 128.1,
128.0, 81.4, 67.1, 66.9, 53.8, 53.6, 32.3, 28.1, 27.9, 22.9 ppm. IR
652.312, found 652.316 [R]25 +10.46 (c 0.375, CHCl3).
D
(S)-Benzyloxycarbonylamino-5-hydroxypentanoic Acid Ben-
zyl Ester (10). To a stirred solution of N-protected amino acid
Z-Glu-OBzl (5.571 g, 15.0 mmol) in THF (75 mL) at -10 °C was
added N-methylmorpholine (1.65 mL, 15 mmol) followed by ethyl
chloroformate (1.434 mL, 15 mmol). After 10 min, NaBH4 (1.70
g, 45 mmol) was added in one portion. MeOH (150 mL) was then
added dropwise to the mixture over a period of 20 min at 0 °C.
The solution was stirred for an additional 30 min and then
neutralized with 1 M KHSO4. The organic solvents were removed,
(neat): 3359, 2977, 2934, 1721, 1368, 1248, 1163, 1136, 696 cm-1
.
FAB-MS with KCl-m/z (rel intensity): 594 (M + K+, 3.2), 500
(MH+ - C4H8, 5), 91 (C7H7+, 100). HRMS (FAB): calcd for
C31H41NO8K [M + K+] 594.247, found 594.248. [R]25 -1.42 (c
D
1.465, CHCl3).
7312 J. Org. Chem., Vol. 71, No. 19, 2006