Alkene Dipeptide Isosteres
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 385
rated aqueous NaHCO3, and brine and dried over MgSO4.
Concentration under reduced pressure followed by flash
column chromatography over silica gel with EtOAc/n-hexane
(2:1) gave a threo-allyl alcohol 6 and an erythro-allyl alcohol
(2R isomer of 6) (12:1), in order of elution (6, 1.5 g, 30% yield
from 5).
Concentration under reduced pressure gave an oily residue of
a crude aldehyde, which was used immediately in the next
step without further purification. To a stirred suspension of
LiCl (230 mg, 5.4 mmol) in MeCN (5 mL) under argon, were
added (EtO)2P(O)CH2CO2Bn (1.5 mL, 5.4 mmol) and (iPr)2NEt
(DIPEA) (0.94 mL, 5.4 mmol) at 0 °C. After 20 min, the above
aldehyde in MeCN (15 mL) was added to the mixture at 0 °C,
and the mixture was stirred at this temperature for 8 h. The
mixture was concentrated under reduced pressure, and the
residue was extracted with EtOAc. The extract was washed
successively with saturated aqueous citric acid and H2O and
dried over MgSO4. Concentration under reduced pressure
followed by chromatography over silica gel with CHCl3/MeOH
(40:1) gave the title compound 9 (1.0 g, 1.5 mmol, 67% yield
from 8) as a colorless oil.
Compound 6: colorless oil. [R]22 -15.74 (c 0.63, CHCl3).
D
1H NMR (270 MHz, CDCl3) δ: 1.40 (9H, s, tert-Bu), 1.57 (2H,
br m, 2-CH2), 1.70 (2H, br m, 1-CH2), 2.26 (3H, s, Ar-p-Me),
2.66 (6H, s, Ar-o-Me), 3.24 (2H, br m, 3-CH2), 3.55 (1H, br,
1-H), 4.08 (1H, br, 2-H), 4.97 (1H, d, J ) 9.7 Hz, NH), 5.18
(1H, d, J ) 10.5 Hz, CHHd), 5.28 (1H, d, J ) 17.3 Hz, CHHd
), 5.77-5.89 (1H, m, CHd), 6.20 (3H, br, guanidino), 6.89 (2H,
s, ArH). m/z (ISMS): 469.5 (MH+). Found (FAB-HRMS):
469.2490. Calcd for C22H37O5N4S (MH+): 469.2485.
1
[R]23 -10.1 (c 1.49, CHCl3). H NMR (270 MHz, CDCl3) δ:
Compound 2R isomer of 6: colorless oil. [R]21D -4.57 (c 2.84,
D
1
1.63 (4H, br m, 1, 2-CH2), 2.17 (3H, s, Ar-p-Me), 2.64 (6H, s,
Ar-o-Me), 3.20 (2H, br m, 3-CH2), 3.22 (1H, br, 2-H), 3.61 (1H,
br, 3-H), 5.15 (2H, s, CH2), 6.18 (1H, dd, J ) 15.7, 0.8 Hz, CHd
), 6.22 (3H, br, guanidino), 6.66 (1H, dd, J ) 15.5, 6.9 Hz, CHd
), 6.88 (2H, s, ArH), 7.34 (5H, s, ArH), 7.56-7.60 (1H, m, ArH),
7.71-7.79 (2H, m, ArH), 8.13-8.17 (1H, m, ArH). m/z (ISMS):
670.5 (MH+). Found (FAB-HRMS): 670.2019. Calcd for
C31H36O8N5S2 (MH+): 670.2005.
CHCl3). H NMR (270 MHz, CDCl3) δ: 1.41 (9H, s, tert-Bu),
1.48 (2H, br m, 2-CH2), 1.64 (2H, br m, 1-CH2), 2.30 (3H, s,
Ar-p-Me), 2.63 (6H, s, Ar-o-Me), 3.15 (2H, br m, 3-CH2), 3.63
(1H, br, 1-H), 4.18 (1H, br, 2-H), 5.12 (1H, br, NH), 5.24 (1H,
d, J ) 10.5 Hz, CHHd), 5.32 (1H, d, J ) 17.0 Hz, CHHd),
5.74-5.85 (1H, m, CHd), 6.32 (3H, br, guanidino), 6.95 (2H,
s, ArH). m/z (ISMS): 469.5 (MH+).
[2(S)-Hydroxy-1(S)-[3-[[imino[[(2,4,6-trimethylphenyl)-
sulfonyl]amino]methyl]amino]propyl]but-3-enyl][(2-nitro-
phenyl)sulfonyl]amine, 7. To a mixture of allyl alcohol 6
(4.2 g, 9.0 mmol) and anisole (0.97 mL, 9.0 mmol) at 0 °C was
added 4 M HCl/dioxane (100 mL), and the mixture was stirred
at room temperature for 2 h. The mixture was concentrated
under reduced pressure. To a stirred solution of the residue
in CHCl3 (20 mL) at 0 °C were added 2-nitrobenzenesulfonyl
chloride (2.38 g, 10.8 mmol), triethylamine (Et3N) (5 mL), and
pyridine (20 mL), and the mixture was allowed to warm to
room temperature, stirred at this temperature for 12 h, and
extracted with CHCl3. The extract was washed with saturated
aqueous citric acid, saturated aqueous NaHCO3, and brine and
dried over MgSO4. Concentration under reduced pressure
followed by chromatography over silica gel with CHCl3/MeOH
Phenylmethyl 8-[[Imino[[(2,4,6-trimethylphenyl)sul-
fonyl]amino]methyl]amino]-5(S)-[[(2-nitrophenyl)sulfo-
nyl]amino]-2(R)-(naphthylmethyl)oct-3-enoate [Ns-L-Arg-
(Mts)-ψ[(E)-CHdCH]-L-Nal-OBn], 10. To a stirred solution
of CuCN (219 mg, 2.45 mmol) and LiCl (207 mg, 4.89 mmol)
in dry THF (3.0 mL) under argon at -78 °C, was added
dropwise 0.5 M (2-naphthylmethyl)zincbromide in THF solu-
tion (4.9 mL, 2.45 mmol), and the mixture was stirred at 0 °C
for 10 min. A solution of enoate 9 (273 mg, 0.408 mmol) in dry
THF (9.0 mL) was added dropwise to the above mixture at
-78 °C with stirring, and the stirring was continued for 30
min followed by quenching with 10 mL of a 1:1 saturated
aqueous NH4Cl/28% NH4OH solution. The mixture was ex-
tracted with Et2O, and the extract was washed with saturated
aqueous NH4Cl and brine and dried over MgSO4. Concentra-
tion under reduced pressure gave an oily residue, which was
purified by chromatography over silica gel with n-hexane/
(18:1) gave 3.2 g (5.8 mmol, 65% from 6) of 7 as a yellow oil.
1
[R]23 -57.79 (c 1.83, CHCl3). H NMR (270 MHz, CDCl3)
D
δ: 1.61 (4H, br m, 1, 2-CH2), 2.27 (3H, s, Ar-p-Me), 2.64 (6H,
s, Ar-o-Me), 3.15 (2H, br m, 3-CH2), 3.50 (1H, br, 1-H), 3.72-
3.78 (1H, m, 2-H), 4.72 (1H, d, J ) 10.5 Hz, CHHd), 5.07 (1H,
d, J ) 17.0 Hz, CHHd), 5.42-5.48 (1H, m, CHd), 5.90 (1H, d,
J ) 8.1 Hz, NH), 6.26 (3H, br, guanidino), 6.90 (2H, s, ArH),
7.65-7.69 (2H, m, ArH), 7.78-7.82 (1H, m, ArH), 8.04-8.08
(1H, m, ArH). m/z (ISMS): 554.5 (MH+). Found (FAB-HRMS):
554.1735. Calcd for C23H32O7N5S2 (MH+): 554.1743.
EtOAc (1:2) to yield 273 mg (0.337 mmol, 83% yield from 9) of
1
compound 10 as a yellow oil. [R]33 -80.9 (c 0.61, CHCl3). H
D
NMR (270 MHz, CDCl3) δ: 1.35 (2H, br m, 2-CH2), 1.55 (2H,
br m, 1-CH2), 2.04 (3H, s, Ar-p-Me), 2.26 (6H, s, Ar-o-Me), 2.97
(2H, br, CH2), 2.98 (2H, br m, 3-CH2), 3.20-3.25 (1H, m, 2-H),
3.90 (1H, br, 5-H), 4.93 (2H, s, CH2), 5.24 (1H, dd, J ) 15.5,
6.9 Hz, CHd), 5.50 (1H, dd, J ) 15.4, 8.4 Hz, CHd), 5.67 (1H,
d, J ) 4.6 Hz, NH), 5.95 (3H, br, guanidino), 6.89 (2H, s, ArH),
7.05-7.28 (7H, m, ArH), 7.42-7.77 (9H, m, ArH), 7.96-8.00
(1H, m, ArH). m/z (ISMS): 814.0 (MH+). Found (FAB-HRMS):
812.2803. Calcd for C42H46O8N5S2 (MH+): 812.2788.
3(S)-[3-[[Imino[[(2,4,6-trimethylphenyl)sulfonyl]ami-
no]methyl]amino]propyl]-1-[(2-nitrophenyl)sulfonyl]-
2(R)-vinylaziridine, 8. To a stirred solution of allyl alcohol
7 (3.1 g, 5.6 mmol) in dry THF (30 mL) at 0 °C were added
triphenylphosphine (1.6 g, 6.2 mmol) and diethyl azodicar-
bonate (2.4 mL of a 40% solution in toluene, 6.2 mmol), and
the reaction mixture was stirred at this temperature for 30
min. The mixture was concentrated under reduced pressure
and purified by chromatography over silica gel with EtOAc/
n-hexane (2:1) to give 2.8 g (5.2 mmol, 93% yield from 7) of
Phenylmethyl 5(S)-[(Fluoren-9-ylmethoxy)carbonyl-
amino]-8-[[imino[[(2,4,6-trimethylphenyl)sulfonyl]ami-
no]methyl]amino]-2(R)-(2-naphthylmethyl)oct-3-enoate
[Fmoc-L-Arg(Mts)-ψ[(E)-CHdCH]-L-Nal-OBn], 11. To a
stirred solution of enoate 10 (81 mg, 0.10 mmol) in DMSO/
MeCN (1:49, 5 mL), were added thiophenol (31 µL, 0.3 mmol)
and K2CO3 (55 mg, 0.4 mmol) at room temperature, and the
mixture was stirred at 50 °C for 1 h. The solution was filtered,
and the filtrate was concentrated under reduced pressure. The
residue was extracted with EtOAc, washed with brine, and
dried over MgSO4. Concentration under reduced pressure gave
an oily residue, which was dissolved in THF/H2O (1:1, 50 mL).
Fmoc-OSu (33 mg, 0.1 mmol) and Et3N (27 µL, 0.19 mmol)
were added to the above solution at 0 °C. After being stirred
for 6 h, the mixture was acidified with 0.1 M HCl and then
extracted with EtOAc. The extract was washed with 0.1 M
HCl and brine and dried over MgSO4. Concentration under
reduced pressure followed by chromatography over silica gel
with n-hexane/EtOAc (1:2) gave the title compound 11 (60 mg,
70.9 µmol, 71% yield from 10) as a colorless oil.
aziridine 8 as a yellow oil.
1
[R]23 -10.45 (c 2.20, CHCl3). H NMR (270 MHz, CDCl3)
D
δ: 1.48 (4H, br m, 1, 2-CH2), 2.26 (3H, s, Ar-p-Me), 2.65 (6H,
s, Ar-o-Me), 3.02 (1H, br, 2-H), 3.15 (2H, br m, 3-CH2), 3.46
(1H, br, 3-H), 5.29 (1H, d, J ) 9.7 Hz, CHHd), 5.42 (1H, d, J
) 17.0 Hz, CHHd), 5.45-5.53 (1H, m, CHd), 6.41 (3H, br,
guanidino), 6.88 (2H, s, ArH), 7.45-7.50 (2H, m, ArH), 7.54-
7.75 (2H, m, ArH). m/z (ISMS): 536.5 (MH+). Found (FAB-
HRMS): 536.1630. Calcd for C23H30O6N5S2 (MH+): 536.1638.
Phenylmethyl 3-3(S)-[3-[[Imino[[(2, 4, 6-trimethylphe-
nyl)sulfonyl]amino]methyl]amino]propyl]-2(R)-[(2-nitro-
phenyl)sulfonyl-2-aziridinyl]prop-2-enoate, 9. To a solu-
tion of aziridine 8 (1.2 g, 2.2 mmol) in CH2Cl2 (30 mL) was
bubbled O3 gas at -78 °C until a blue color persisted. To the
above solution was added Me2S (1.7 mL, 22 mmol), and the
mixture was stirred for 30 min and then dried over MgSO4.
1
[R]29 -11.2 (c 0.63, CHCl3). H NMR (270 MHz, CDCl3) δ:
D
1.26 (4H, br m, 1, 2-CH2), 2.18 (3H, s, Ar-p-Me), 2.63 (6H, s,