S. K. Maji et al. / Tetrahedron 60 (2004) 3251–3259
3257
(288): C, 54.16; N, 9.72; H, 8.33. Found: C, 54.4; N, 9.8; H,
8.5.
was filtered off. The organic layer was washed with 2 M
HCl (3£40 mL), brine, 1 M sodium carbonate (3£40 mL),
brine (2£40 mL), dried over anhydrous sodium sulfate and
evaporated in vacuum to yield 1.6 g (4 mmol) of white
solid. Purification was done by silica gel column (100–200
mesh) using ethyl acetate as eluent.
4.1.3. Boc-Ala(1)-Aib(2)-OH (6). To a sample of 5 (4.6 g,
16 mmol), MeOH (40 mL) and 2 M NaOH (24 mL) were
added and the progress of saponification was monitored by
thin layer chromatography (TLC). The reaction mixture was
stirred. After 10 h, methanol was removed under vacuum,
the residue was taken up in 30 mL of water, washed with
diethyl ether (2£20 mL). Then the pH of the aqueous layer
was adjusted to 2 using 1 M HCl and it was extracted with
ethyl acetate (3£20 mL). The extracts were pooled, dried
over anhydrous sodium sulfate, and evaporated in vacuum
to yield 2.72 g of 6 as white solid.
Yield¼1.6 g, 80%. Mp 178 8C. 1H NMR (CDCl3, 300 MHz,
d ppm): 7.08 [Ile(3) NH, 1H, d, J¼8.16 Hz]; 6.68 [Aib(2)
NH 1H, s]; 4.96 [Ala(1) NH,1H, d, J¼7.5 Hz]; 4.51–4.55
[CaH of Ala(1), 1H, m]; 4.09–4.11 [CaH of Ile(3), 1H, m];
3.72 [–OCH3, 3H, s]; 1.89–1.94 [CbHs of Ile(3), 1H, m];
1.61 [CbH3 s of Aib(2), 6H, s]; 1.45 [Boc-CH3 s, 9H, s];
1.34–1.39 [CbHs of Ala(1), 3H, d, J¼8.82 Hz]; 1.25 [Cgs of
Ile(3), 3H, d]; 0.89–0.96 [Cgs & CdHs of Ile(3), 5H, m].
Anal. Calcd for C19H35N3O6 (401): C, 56.85; N, 10.47; H,
8.72. Found: C, 56.71; N, 10.35; H, 8.8. Mass spectral data
MþNaþ þHþ¼425, Mcalcd¼401.
Yield¼2.72 g (13.6 mmol, 85%). Mp 176 8C. 1H NMR
((CD3)2SO, 300 MHz, d in ppm): 11.8 [–COOH, 1H, br.];
7.8 [Aib(2) NH, 1H, s]; 6.73 [Ala(1) NH, 1H, d]; 3.94 [CaHs
of Ala(1), 1H, m]; 1.41 [CbH3 s of Aib(2), 6H, s]; 1.36 [Boc-
CH3 s, 9H, s]; 1.14 [CbH3 s of Ala(1), 3H, m]. Anal. Calcd
for C12H22N2O5 (274): C, 52.55; N, 10.21; H, 8.029. Found:
C, 52.6; N, 10.16; H, 8.2.
4.1.6. Boc-Ala(1)-Gly(2)-OBz (7). A sample of Boc-Ala-
OH (3.78 g, 20 mmol) was dissolved in a mixture
of dichloromethane-N,N-dimethylformamide (DCM/DMF)
(30 mL) in an ice-water bath. H-Gly-OCH2Ph was isolated
from of the corresponding benzyl ester p-toluene sulphonate
(13.48 g, 40 mmol) by neutralization, subsequent extraction
with ethyl acetate and concentration (10 mL) and this was
added to the reaction mixture, followed immediately by
di-cyclohexaylcarbodiimide (DCC) (4.12 g, 20 mmol) and
1-hydroxybenzotriazole (HOBt) (2.7 g, 20 mmol). The
reaction mixture was allowed to come to room temperature
and stirred for 24 h. DCM was evaporated, the residue was
taken in ethyl acetate (40 mL), and dicyclohexylurea (DCU)
was filtered off. The organic layer was washed with 2 M
HCl (3£40 mL), brine, 1 M sodium carbonate (3£40 mL)
and brine (2£40 mL) and dried over anhydrous sodium
sulfate, and evaporated in vacuum to yield of the dipeptide 7
as white solid.
4.1.4. Boc-Ala(1)-Aib(1)-Val(3)-OMe 1. A sample of Boc-
Ala-Aib-OH (0.82 g, 3 mmol) in DMF (8 mL) was cooled in
an ice-water bath and H-Val-OMe was isolated from the
corresponding methyl ester hydrochloride (1.0 g, 6 mmol)
by neutralization, subsequent extraction with ethyl acetate
and concentration (5 mL) and it was added to the reaction
mixture, followed immediately by DCC (0.62 g, 3 mmol)
and HOBt (0.4 g, 3 mmol). The reaction mixture was stirred
for 3 days. The residue was taken in ethyl acetate (20 mL)
and the DCU was filtered off. The organic layer was washed
with 2 M HCl (3£20 mL), brine, 1 M sodium carbonate
(3£20 mL), brine (2£20 mL), dried over anhydrous sodium
sulfate and evaporated in vacuum to yield 0.77 g (2 mmol,
66.66 %) of white solid. Purification was done by silica gel
column (100–200 mesh) using ethyl acetate as eluent.
Colourless single crystals were grown from dimethylsulph-
oxide by slow evaporation.
Yield¼5.712 g (17 mmol, 85%). Mp 73 8C. 1H NMR
(CDCl3, 300 MHz, d ppm): 7.35 [Ph, 5H, m]; 6.73 [Gly(2)
NH, 1H, t]; 5.18 [-benzyl CH2, 2H, s]; 5.01–5.03 [Ala(1)
NH, 1H, d]; 4.22 [CaH of Ala(1), 1H, t]; 4.04–4.09
[CaHs of Gly(2), 2H, t]; 1.44 [Boc-CH3, 9H, s]; 1.35–1.37
[CbHs of Ala(1), 3H, d]. Anal. Calcd for C17H24N2O5
(336): C, 60.71; H, 7.14; N, 8.33. Found: C, 60.67; H, 6.98;
N, 8.36.
1
Yield¼0.77 g (2 mmol, 66.66 %). Mp 184 8C. H NMR
(CDCl3, 300 MHz, d ppm): 7.06 [Val (3) NH, 1H, d, J¼
4.58 Hz]; 6.71 [Aib(2) NH, 1H, s]; 4.96 [Ala(1) NH, 1H, d,
J¼4.98 Hz]; 4.50 [CaH of Ala(1), 1H, m]; 4.09 [CaH of
Val(3), 1H, m]; 3.74 [–OCH3, 3H, s]; 2.16–2.20 [CbH of
Val(3), 1H, m]; 1.54 [CbHs of Aib, 6H, s]; 1.45 [Boc-CH3,
9H, s]; 1.35, 1.36 [CbHs of Ala(1), 3H, d, J¼4.23 Hz];
0.89–0.94 [CgHs of Val (3), 6H, m]. Anal. Calcd for
C18H33N3O6 (387): C, 55.81; H, 8.53; N, 10.85. Found: C,
55.75; H, 8.37; N, 11.92. Mass spectral data MþNaþ¼410,
Mcalcd¼387.
4.1.7. Boc-Ala(1)-Gly(2)-OH (8). To Boc-Ala(1)-Gly(2)-
OBz 7 (4.37 g, (13 mmol), MeOH (40 mL) and 2 M NaOH
(15 mL) were added and the progress of saponification
was monitored by thin layer chromatography (TLC). The
reaction mixture was stirred. After 10 h methanol was
removed under vacuum, the residue was taken in 20 mL of
water, washed with diethyl ether (2£20 mL). Then the pH
of the aqueous layer was adjusted to 2 using 1 M HCl and
it was extracted with ethyl acetate (3£20 mL). The
extracts were pooled, dried over anhydrous sodium
sulfate, and evaporated in vacuum to yield 2.70 g of 8 as
white solid.
4.1.5. Boc-Ala(1)-Aib(2)-Ile(3)-OMe (2). Boc-Ala-Aib-
OH (1.37 g, 5 mmol) in DMF (15 mL) was cooled in an
ice-water bath and H-Ile-OMe was isolated from
the corresponding methyl ester hydrochloride (1.82 g,
10 mmol) by neutralization and subsequent extraction with
ethyl acetate and the ethyl acetate extract was concentrated
to 8 mL. It was then added to the reaction mixture, followed
immediately by DCC (1.03 g, 5 mmol) and HOBt (0.68 g,
5 mmol). The reaction mixture was stirred for 3 days. The
residue was taken up in ethyl acetate 20 mL and the DCU
Yield¼2.70 g (11 mmol, 84.61%). Mp 88 8C. 1H NMR
(70% (CD3)2SOþ30% CDCl3, 300 MHz, d in ppm): 12.4
[–COOH, 1H, br]; 7.93 [Gly(2) NH, 1H, t]; 6.67 [Ala(1)