S. Dutta et al. / Bioorg. Med. Chem. 17 (2009) 3900–3908
3907
mixture was stirred overnight at room temperature. The organic
layer was extracted with ethyl acetate, dried over sodium sulfate
and concentrated to get brown oil. The compound 5 was isolated
as pure white crystal by column chromatography using 30% ethyl
acetate in hexane as eluent; Yield: 88%, mp 115–120 °C, dY: 7.31–
7.21 (5H, m, Ar-H), 4.98 [1H, m, NHCOOC(CH3)3 ], 4.86 (1H, d,
J = 14.4 Hz, COCHHO), 4.71 (1H, d, J = 14.4 Hz, COCHHO), 4.67
(1H, m, PhCH2CH), 3.55 (2H, m, CH2CH2NCH2), 3.31–3.05 (4H, m,
CH2CH2NCH2, PhCH2CH), 1.66–1.58 (4H, m, NCH2CH2CH2CH2),
1.38 [11H, s, NHCOOC(CH3)3, NCH2CH2CH2CH2]. dC: 171.7, 164.0,
155.1, 136.2, 129.4, 128.4, 128.3, 126.7, 79.7, 61.8, 54.3, 45.5,
43.0, 38.1, 28.2, 26.2, 25.2, 24.3, Mass (ESI+) m/z 391.225 (MH+),
413.22 (MNa+); HRMS calculated for C21H30N2O5 + H+: 391.2234,
found: 391.2237.
acid, brine, dried over sodium sulfate and evaporated to get an oily
residue. From the oily residue the compound was isolated pure by
column chromatography using 25% ethyl acetate in hexane as elu-
ent. Yield: 53%, dH 7.36–7.09 (9H, m, Ar-H), 6.9 (1H, br s, NH), 6.55
(1H, br s, NH), 4.87 [1H, m, OCH (pyran)], 4.8 (1H, br s, NH), 4.57–
4.41 [3H, m, CCCH2O (pyran), NHCHCH2Ph], 3.99 (1H, m, CH3
CHNHBoc), 3.79–3.77 (1H, m, OCHHCH2), 3.50–3.42 (2H, m,
NHCHCH2Ph), 3.4 (1H, m, OCHHCH2), 3.02–2.99 (2H, m, CH2CH2
NHCO), 2.56–2.49 (2H, m, CH2CH2NHCO), 1.56–1.43 [6H, m,
CHCH2CH2CH2CH2O (pyran)], 1.32 [9H, s, NHCOOC(CH3)3], 1.20–
1.14 (3H, m, CH3CHNHBoc); Mass (ESI+) m/z 602.32 (MH+), 624.32
(MNa+); HRMS calcd for C35H43N3O6 + H+ 602.3232, found:
602.3233.
Compound 10: To the compound 9 (0.169 mmol) dissolved in
dry ethanol (10 ml) PPTS was added and the reaction was stirred
for 24 h at 40 °C. The resulting mixture was concentrated in vac-
uum and the product was obtained pure as white semi solid by col-
umn chromatography using 50% ethyl acetate in hexane as eluent.
Yield: 90%, dH 7.34–7.09 (9H, m, Ar-H), 6.9 (1H, br s, NH), 6.6 (1H, br
s, NH), 4.85 (1H, br s, NH), 4.7 (1H, m, NHCHCH2Ph), 4.57–4.5 (2H,
m, CCCH2OH), 4.109 (1H, m, CH3CHNHBoc), 3.6–3.35 (2H, m,
NHCHCH2Ph), 3.1–3.07 (2H, m, CH2CH2NHCO), 2.57–2.55 (2H, m,
CH2CH2NHCO), 1.4 [9H, s, NHCOOC(CH3)3], 1.3–1.14 (3H, m,
CH3CHNHBoc); Mass (ESI+) m/z 518.33 (MH+); HRMS calcd for
C30H35N3O5 + H+: 518.2657, found: 518.2661.
Compound 11: The mesylate dissolved in dry DMF was treated
with K2CO3 (1.45 mmol) and the mixture was stirred for 3 h at
room temperature. It was then partitioned between EtOAc and
water. The organic layer was further washed with water, dried
and evaporated. From this residue, the title compound was isolated
by column chromatography as pure white solid using 25% ethyl
acetate in hexane as eluent. Yield: 95%, mp:230–240 °C dH 8.25
(2H, d, J = 9.2 Hz, Ar-H), 8.11 (2H, d, J = 8.8 Hz, Ar-H), 7.29–7.26
(4H, m, Ar-H), 4.34 (2H, s, NCH2CC), 3.75 (2H, t, J = 5.2 Hz,
CH2CH2NSO2Ar), 2.78 (2H, t, J = 5.2 Hz, CH2CH2NSO2Ar); Mass
(ESI+) m/z 367.07 (MH+); HRMS calcd for C19H14N2O4S +
H+:367.0754, found: 367.0757.
Compound 12: The compound 11 (0.152 mmol) was dissolved in
dry DMF (4 ml) followed by dry potassium carbonate (3 equiv) and
thiophenol (1.2 equiv). The reaction mixture was stirred for 30 min
at room temperature. The organic layer was extracted with ethyl
acetate and concentrated in vacuum. The cyclic enediyne amine
12 was obtained pure by column chromatography as brown oil
using 10% methanol in dichloromethane as eluent. Yield: 70%, dH
7.24–7.20 (2H, m, Ar-H), 7.15–7.12 (2H, m, Ar-H), 3.78 (NH), 3.58
(2H, s, CH2N), 3.18 (2H, t, J = 5.4 Hz, CH2CH2N), 2.48 (2H, t,
J = 5.4 Hz, CH2CH2N); Mass (ESI+) m/z 183 (MH+).
Compound 13: To a solution of compound 12 (0.1365 mmol) in
CH2Cl2 at 0 °C, Et3N (1.1 equiv) was added followed by slow addi-
tion of bromo acetylchloride (1.0 equiv). The reaction was allowed
to stir under N2 atmosphere for 15 min. Then it was partitioned be-
tween CH2Cl2 and water, extracted twice with CH2Cl2, washed with
brine and dried over Na2SO4. The compound was isolated pure by
column chromatography using 25% ethyl acetate in hexane as elu-
ent. Yield: 80%, dY (400 VYz, CDCl3): 7.35–7.31 (2H, m, Ar-H), 7.27–
7.24 (2H, m, Ar-H), 4.39 (2H, s, CH2Br), 3.94 (2H, s, NCH2), 3.77 (2H,
t, J = 5.4 Hz, NCH2CH2), 2.94 (2H, t, J = 5.4 Hz, NCH2CH2); Mass
(ESI+) m/z 378 (MH+).
Compound 14: The cyclic sulfonamide (0.126 mmol) was dis-
solved in dry DMF (4 ml) followed by dry potassium carbonate
(3 equiv) and thiophenol (1.2 equiv). The reaction mixture was
stirred for 30 min at 20 °C. The organic layer was extracted with
ethyl acetate and concentrated in vacuum. The cyclic enediyne
amine 15 was obtained pure by column chromatography as brown
oil 10% methanol in dichloromethane as eluent. Yield: 89%, dH 5.90
(1H, d, J = 8.8 Hz, CHCH), 5.83 (1H, d, J = 8.8 Hz, CCHCHC), 3.78
Compound 6: To a solution of Boc-L-phe in dry CH2Cl2, EDC
(1 equiv) and HOBT (1 equiv) were added and the mixture was stir-
red for 1 h at 0 °C. Then the tetrahydroisoquinoline 18 (0.78 mmol)
dissolved in CH2Cl2 (2 ml) was added dropwise followed by DIPEA
(2 equiv). The reaction mixture was stirred overnight at room tem-
perature. After partitioning between CH2Cl2 and water, the organic
layer was washed with sodium bicarbonate, then with dilute hydro-
chloric acid, brine, dried over sodium sulfate and evaporated to get
anoily residue. The compoundwas isolated pureby column chroma-
tography using 10% ethyl acetate in hexane system. Yield: 88%, dH
7.19–6.83 (9H, m, Ar-H), 5.53 [1H, m, NHCOOC(CH3)3], 4.92 (1H, m,
CHCH2Ph), 4.76–3.94 (2H, m, CH2CH2NCH2), 3.83–3.11 (2H, m,
CH2CH2N), 3.05–2.93 (2H, m, PhCH2CH), 2.79–2.31 (2H, m,
CH2CH2N), 1.39 [9H, s, NHCOOC(CH3)3]; dC 170.7, 170.4, 155.1,
155.0, 136.5, 136.2, 134.5, 134.0, 132.1, 129.5, 129.3, 128.6, 128.5,
128.3, 128.2, 126.9, 126.8, 126.7, 126.6, 126.5, 126.3, 126.1, 79.7,
76.8, 51.8, 51.6, 47.0, 44.5, 43.0, 40.5, 40.4, 40.1, 31.6, 29.1, 28.4,
28.3; Mass (ESI+) m/z 381.21 (MH+), 403.217 (MNa+); HRMS calcu-
lated for C23H28N2O3 + H+: 381.2180, found: 381.2182.
Compound 7: To the solution of the mesylate in dry DMF, NaN3
(5.49 mmol) was added and stirred for overnight at room temper-
ature. The mixture was then partitioned between EtOAc and water.
The organic layer was thoroughly washed with water, dried, fil-
tered and then evaporated. The compound was isolated pure by
column chromatography using 10% ethyl acetate in hexane system
as pale brown oil. Yield: 88%, dH (200 MHz, CDCl3): 7.41–7.32 (2H,
m, Ar-H), 7.25–7.17 (2H, m, Ar-H), 4.95 [1H, t, J = 3.1 Hz, OCH (pyr-
an)], 4.49 (2H, s, CH2OTHP), 3.88–3.78 [2H, m, OCH2 (pyran)], 3.57–
3.44 [4H, m, CH2CH (pyran), CH2N3], 2.72 (2H, t, J = 6.9 Hz,
CH2CH2N3), 1.85–1.51 [4H, m, CH2CH2 (pyran)]; Mass (ESI+) m/z
310 (MH+); HRMS calculated for C18H19N3O2 + H+: 310.1557,
found: 310.1560.
Compound 8: The amine 8 was prepared from the corre-
sponding azide7 via reaction with PPh3/H2O. To the solution of
azide (0.42 mmol) in THF (15 ml), 1.5 equiv of PPh3 and water
were added and stirred at room temperature for 24 h. The
THF was removed by high vacuum pump and the product was
obtained by column chromatography 10% methanol in dichloro-
methane as eluent. Yield: 91%, dH (200 MHz, CDCl3): 7.45–7.37
(2H, m, Ar-H), 7.25–7.20 (2H, m, Ar-H), 4.94 (1H, t, J = 3.1 Hz,
OCH (pyran)), 4.52 (2H, d, J = 2.3 Hz, CH2OTHP), 3.89–3.80 [2H,
m, OCH2 (pyran)], 3.59–3.53 [2H, m, CH2CH (pyran)], 3.00 (2H,
t, J = 6.1 Hz, CH2NH2), 2.67 (2H, t, J = 6.1 Hz, CH2CH2NH2), 1.82–
1.56 [4H, m, CH2CH2 (pyran)]; Mass (ESI+) m/z 284.16 (MH+),
306.16 (MNa+).
Compound 9: To a solution of Boc-
L
-alaꢀ
L-phe in dry CH2Cl2, EDC
(1 equiv) and HOBT (1 equiv) were added and the mixture was stir-
red for 1 h at 0 °C. Then the amine 8 (0.314 mmol) dissolved in
CH2Cl2 (1 ml) was added dropwise followed by DIPEA (2 equiv).
The reaction mixture was stirred overnight at room temperature.
After partitioning between CH2Cl2 and water, the organic layer was
washed with sodium bicarbonate, then with dilute hydrochloric