2392 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 12
Bedos et al.
acid or Boc-(4-aminomethyl)benzoic acid or 5-(N,N′-bis-Boc-
guanidino)pentanoic acid). Reaction times for complete cou-
plings were 15 min for Boc-Ser(Bzl)-OH, Boc-Thr(Bzl)-OH, Boc-
Ala-OH, Boc-Arg(Tos)-OH, Boc-Lys(Z)-OH, Boc-Ala-OH, Boc-
isonipecotic acid, 4-(Boc-aminomethyl)benzoic acid and 5-(N,N′-
bis-Boc-guanidino)pentanoic acid and 1 h for acids 18a -c.
Completion of the reaction was checked by the Kaiser test.
N-R-Boc deblocking was achieved with a mixture of TFA/DCM/
ethanedithiol (40/60/2). Washings of the substituted resin were
performed with isopropyl alcohol and DCM. After coupling of
the last amino acid, the Boc protecting group was removed by
TFA/DCM/ethanedithiol (40/60/2). The total deprotection and
the cleavage from the resin were performed with HF. The
peptidyl resin was placed in a Teflon reactor containing anisole
(1 mL/g of resin). After distillation of HF (10 mL/g of resin)
into the reactor, the mixture was stirred 1 h at 0 °C. HF was
removed by distillation. The expected pseudopeptide was
precipitated by addition of ether, washed with ether and finally
purified by reverse-phase HPLC.
1-Boc-4-[Z-a m in o]p ip er id in e-4-ca r boxa m id e, 13. To a
cold (-15 °C) solution of NR-Z-Nγ-Boc-protected 4-aminopiper-
idine-4-carboxylic acid (Z-Pip(Boc)-OH, 12) (19 g, 50 mmol) in
DME (100 mL) were successively added NMM (5.6 mL, 50
mmol) and IBCF (6.6 mL, 50 mmol). After 5 min stirring,
concentrated NH4OH (10 mL) was added and the mixture was
stirred for 1 h at room temperature. Ethyl acetate (200 mL)
was then added and the solution washed with water, brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was crystallized from ether to afford 13
(16 g, 85%) as a white powder: mp 178-182 °C; 1H NMR
(CDCl3, 250 MHz) δ 1.48 (9 H, s), 2.09 (4 H, m), 3.12 (2 H, m),
3.86 (2 H, m), 5.03 (1 H, s), 5.13 (2 H, s), 5.37 (1 H, s), 6.63 (1
1 h the solvent was removed under reduced pressure and the
residue treated with sodium bicarbonate solution (50 mL). It
was extracted with ethyl acetate (3 × 30 mL). The combined
extracts were washed with water (1 × 30 mL), dried over
sodium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography, with ethyl
acetate as eluent, to yield a pure compound that gave a white
powder by trituration with ether: 2.5 g (65%); mp 50-55 °C;
1H NMR (CDCl3, 400 MHz) δ 1.50 (9 H, s), 1.63 (2 H, m), 1.72
(2 H, m), 1.88 (1H, m), 2.05 (2 H, m), 2.56-2.66 (4 H, m), 3.09
(2 H, m), 3.21 (2 H, m), 3.81 (2 H, m), 5.76 (1 H, br s), 7.06 (1
H, br s), 7.15-7.24 (4 H, m); 13C NMR (CDCl3, 400 MHz) δ
28.8, 32.6, 32.6, 37.3, 39.5, 40.4, 44.5, 59.6, 80.0, 126.9, 129.0,
129.2, 139.9, 155.1, 179.1; MS (ESI) m/z 388 (M + H); HPLC
tR ) 18.62.
1-(2-P h en yleth yl)-8-Boc-1,3,8-tr ia za sp ir o[4.5]d ec-2-en -
4-on e, 16a . A mixture of 15a (3.37 g, 10 mmol), triethyl
orthoformate (7 mL, excess), and acetic acid (1.7 mL) in toluene
was refuxed for 15 h. The mixture was cooled at room
temperature and concentrated in vacuo to a volume of 10 mL.
Then, water (40 mL) and CHCl3 (40 mL) were added followed
by a 2 N aqueous solution of sodium hydroxyde. The aqueous
layer was extracted with CHCl3 (3 × 30 mL). The combined
organic layers were washed with water and brine, dried over
MgSO4, filtered and concentrated under reduced pressure to
afford 3 g (85%) of the title compound as a white powder: mp
1
55-60 °C; H NMR (CDCl3, 400 MHz) δ 1.51 (9 H, s), 1.55 (2
H, m), 1.83 (2 H, m), 2.99 (2H, t, J ) 7.08 Hz), 3.58 (2H, t, J
) 7.08 Hz), 3.65 (2 H, m), 3.71 (2 H, m), 7.18 (2H, d, J ) 8.2
Hz), 7.3-7.4 (3 H, m), 7.86 (1H, s); MS (ESI) m/z 358 (M +
H); HPLC tR ) 19.61.
1-(2-In d a n yleth yl)-8-Boc-1,3,8-tr ia za sp ir o[4.5]d ec-2-en -
H, s), 7.38 (5 H, m); MS (ESI) m/z 378 (M + H); HPLC tR
20.06.
)
4-on e, 16b. Obtained as described for compound 16a from 1.45
1
g of 15b: yield 1.2 g (80%); mp 70-72 °C; H NMR (CDCl3,
400 MHz) δ 1.53 (9 H, s), 1.79 (2 H, m), 1.96-2.09 (4 H, m),
2.53 (1 H, m), 2.69 (2 H, dd, J 1 ) 7.74 Hz, J 2 ) 15.34 Hz), 3.16
(2 H, dd, J 1 ) 7.76 Hz, J 2 ) 15.14 Hz), 3.51-3.62 (4 H, m),
4.16 (2 H, m), 7.18-7.25 (4 H, m), 7.30 (1 H, s); MS (ESI) m/z
398 (M + H); HPLC tR ) 23.07.
1-(2-P h en yleth yl)-8-Boc-1,3,8-tr ia za sp ir o[4.5]d eca n -4-
on e, 17a . To a solution of compound 16a (2 g, 5 mmol) in
ethanol (100 mL) was added sodium borohydride (250 mg, 2
equiv). The mixture was heated at 80 °C for 4 h. The solvent
was then removed in vacuo and the residue was dissolved in
100 mL of ethyl acetate. This solution was washed with water
and brine, dried over MgSO4, filtered and concentrated in
vacuo to afford the tittle compound as a white solid: yield 1.9
g (96%); mp 140-144 °C; 1H NMR (CDCl3, 400 MHz) δ 1.48 (9
H, s), 1.66 (4 H, m), 2.79 (4 H, m), 3.50 (2 H, m), 3.96 (2 H, m),
4.22 (2 H, s), 6.25 (1 H, br s), 7.21-7.35 (5 H, m); MS (ESI)
m/z 360 (M + H); HPLC tR ) 18.59.
1-(2-In d a n yleth yl)-8-Boc-1,3,8-tr ia za sp ir o[4.5]d eca n -4-
on e, 17b. Obtained as described for compound 17a from 1.1 g
of 16b: yield 1 g (90%); mp 138-142 °C; 1H NMR (CDCl3, 400
MHz) δ 1.48 (9 H, s), 1.78-1.95 (7 H, m), 2.64-2.84 (4 H, m),
3.21 (2 H, dd, J 1 ) 7.53 Hz, J 2 ) 15.10 Hz), 3.62-3.69 (2 H,
m), 4.14-4.20 (2 H, m), 4.40 (2 H, m), 6.20 (1 H, br s), 7.26-
7.34 (4 H, m); MS (ESI) m/z 400 (M + H); HPLC tR ) 21.7.
1-Boc-4-am in opiper idin e-4-car boxam ide, 14. Compound
13 (15 g, 39.8 mmol) was hydrogenated overnight at room
temperature in 95% EtOH containing concentrated hydrochlo-
ric acid (3.6 mL, 39.8 mmol) in the presence of a 10% Pd/C
catalyst. The catalyst was then removed by filtration and the
filtrate concentrated in vacuo to leave a residue that solidified
upon trituration in ether. It was collected, washed with ether
and dried in vacuo over KOH pellets: yield 11.1 g (100%); mp
188-192 °C; 1H NMR (DMSO, 250 MHz) δ 1.42 (9 H, s), 1.74
(2 H, m), 2.09 (2 H, m), 3.22 (2 H, m), 3.76 (2 H, m), 7.76 (1 H,
s), 7.94 (1 H, s), 8.43 (2 H, s); MS (ESI) m/z 244 (M + H); HPLC
tR ) 8.4.
1-Boc-4-[(2-p h en ylet h yl)a m in o]p ip er id in e-4-ca r b ox-
a m id e, 15a . The partially deprotected amino amide 14 (5 g,
17.9 mmol) and phenylacetaldehyde (2.5 mL, 17.9 mmol) were
dissolved in methanol (50 mL) with 1% acetic acid. The
mixture was stirred for 30 min at room temperature. Then, a
solution of sodium cyanoborohydride (2.2 g, 35.8 mmol) in
MeOH was added dropwise over 30 min. After an additional
1 h the solvent was removed under reduced pressure and the
residue treated with sodium bicarbonate solution (100 mL).
It was extracted with ethyl acetate (3 × 50 mL). The combined
extracts were washed with water (1 × 50 mL), dried over
sodium sulfate, and concentrated in vacuo. The residue was
purified by silica gel column chromatography, with ethyl
acetate as eluent, to yield a pure compound that gave a white
powder by trituration with ether: 3.85 g (62%); mp 55-57 °C;
1H NMR (CDCl3, 400 MHz) δ 1.47 (9 H, s), 1.56 (2 H, m), 2.02
(2 H, m), 2.79 (4 H, s), 3.03 (2 H, m), 3.77 (2 H, m), 5.18 (1 H,
br s), 6.75 (1 H, br s), 7.23-7.36 (5H, m); MS (ESI) m/z 348
(M + H); HPLC tR ) 15.13.
1-(2-P h en yleth yl)-8-Boc-1,3,8-tr ia za sp ir o[4.5]d eca n -4-
on e-3-a cetic Acid , 18a . Compound 17a (1.5 g, 4.2 mmol) was
dissolved in 20 mL of anhydrous DMF and cooled at 0 °C.
Sodium hydride (116 mg, 5 mmol) was added all at once, and
the reaction mixture was stirred for 15 min. Then ethyl
bromoacetate was added (468 mL, 4.2 mmol) and the solution
left at room temperature for 5 h. The solution was concentrated
to a small volume and ethyl acetate (50 mL) was added
followed by water (10 mL). After 1 h at room temperature, 40
mL of water was added. The aqueous phase was acidified to
pH 4 with 1 N HCl and extracted with ethyl acetate (3 × 30
mL). The combined organics extracts were washed with water
and brine, dried over MgSO4, filtered and concentrated under
reduced pressure to afford 1.6 g (91%) of a white solid: mp
1-Boc-4-[(2-in d a n ylet h yl)a m in o]p ip er id in e-4-ca r box-
a m id e, 15b. Indanylacetaldehyde (1.6 g, 10 mmol) obtained
from the N,O-dimethylhydroxamate derivative of 2-indanyl-
acetic acid35 was dissolved in a mixture of methanol/acetic acid,
99:1 (30 mL), containing Nγ-Boc-protected 4-aminopiperidine-
4-carboxamide (H-Pip(Boc)-NH2) (2.79 g, 10 mmol). The mix-
ture was stirred for 30 min at room temperature. Then, a
solution of sodium cyanoborohydride (1.24 g, 20 mmol) in
MeOH was added dropwise over 30 min. After an additional
1
78-82 °C; H NMR (CDCl3, 400 MHz) δ 1.48 (9 H, s), 1.63-
1.76 (4 H, m), 2.80 (4 H, m), 3.43-3.52 (2 H, m), 3.89-4.02 (2