A. K. Das et al. / Tetrahedron 63 (2007) 7432–7442
7439
4.2.4. Boc–Ala(1)–Val(2)–Ala(3)–OEt 1. Rf¼0.75 (CHCl3/
MeOH¼9:1); Yield¼2.48 g (6.4 mmol, 80%); mp 106–
was cooled in an ice-water bath and isopropanol (0.54 g,
9 mmol) was added. It was then added to the reaction mix-
ture, followed immediately by DCC (0.93 g, 4.5 mmol)
and HOBt (0.61 g, 4.5 mmol). The reaction mixture was
stirred for three days. The residue was taken up in ethyl ace-
tate (40 mL) and the DCU was filtered off. The organic layer
was washed with 2 M HCl (3ꢂ40 mL), brine (2ꢂ50 mL),
1 M sodium carbonate (3ꢂ40 mL), brine (2ꢂ40 mL), dried
over anhydrous sodium sulfate, and evaporated in vacuo to
yield 4 as a white solid. Purification was done by silica gel
column (100–200 mesh) using chloroform–methanol as an
eluent.
1
110 ꢀC; IR (KBr) 3318, 1743, 1696, 1638, 1520 cmꢁ1; H
NMR (300 MHz, CDCl3) d 6.75 (d, 1H, J¼8.1 Hz); 6.53
(d, 1H, J¼5.1 Hz); 4.97 (d, 1H, J¼5.8 Hz); 4.54 (m, 1H);
4.27 (m, 1H); 4.23 (m, 1H); 4.11 (m, 2H); 2.20 (m, 1H);
1.45 (s, 9H); 1.41 (d, 3H, J¼5 Hz); 1.36 (d, 3H,
J¼6.9 Hz); 1.30 (t, 3H); 0.95 (m, 6H); 13C NMR
(300 MHz, CDCl3) d 172.78, 172.49, 170.56, 155.36,
61.19, 58.06, 52.14, 49.98, 47.79, 30.99, 28.11, 18.86,
18.06, 17.79, 13.90; Anal. Calcd for C18H33N3O6 (387): C,
55.81; N, 10.85; H, 8.53%. Found: C, 55.84; N, 10.83; H,
8.5%; [a]2D0 ꢁ78.9 (c 1.05, CH3OH); MS (ESI) m/z 388.4
(M+H)+, m/z 797.5 (2M+Na)+.
Rf¼0.75 (CHCl3/MeOH¼9:1); Yield¼1.08 g (2.7 mmol,
60%); mp 110–116 ꢀC; IR (KBr) 3323, 1737, 1694, 1644,
1
4.2.5. Boc–Ala(1)–Val(2)–Ala(3)–O–n-Pr 2. Rf¼0.65
(CHCl3/MeOH¼9:1); Yield¼2.45 g (6.1 mmol, 76%); mp
108–113 ꢀC; IR (KBr) 3316, 1739, 1692, 1646,
1523 cmꢁ1; H NMR (300 MHz, CDCl3) d 6.71 (d, 1H,
J¼7.1 Hz); 6.43 (d, 1H, J¼7.6 Hz); 4.93 (d, 1H,
J¼5.5 Hz); 4.48 (m, 1H); 4.26 (m, 1H); 4.17 (m, 1H); 3.49
(m, 1H); 2.17 (m, 1H); 1.45 (s, 9H); 1.39 (d, 3H,
J¼7.2 Hz); 1.35 (d, 3H, J¼6.9 Hz); 1.24 (d, 6H); 0.95 (m,
6H); 13C NMR (300 MHz, CDCl3) d 172.77, 172.14,
170.45, 69.16, 58.32, 49.44, 48.27, 33.96, 33.24, 30.98,
28.31, 25.63, 24.96, 24.83, 21.71, 19.17, 18.17, 18.12,
17.78; Anal. Calcd for C19H35N3O6 (401): C, 56.86; N,
10.47; H, 8.73%. Found: C, 56.86; N, 10.48; H, 8.7%;
[a]2D0 ꢁ47.1 (c 1.02, CH3OH); ESI-MS m/z 424.2
(M+Na)+, m/z 825.5 (2M+Na)+.
1
1530 cmꢁ1; H NMR (300 MHz, CDCl3) d 6.84 (d, 1H,
J¼8.4 Hz); 6.73 (d, 1H, J¼6.9 Hz); 5.09 (d, 1H,
J¼6.9 Hz); 4.56 (m, 1H); 4.29 (m, 1H); 4.19 (m, 1H); 4.11
(m, 2H); 2.18 (m, 1H); 1.66 (m, 2H); 1.44 (s, 9H); 1.41 (d,
3H, J¼7.2 Hz); 1.36 (d, 3H, J¼7.4 Hz); 0.96 (m, 6H);
0.92 (m, 3H); 13C NMR (300 MHz, CDCl3) d 172.85,
172.69, 170.72, 170.62, 66.92, 58.20, 52.30, 50.16, 48.03,
33.86, 31.06, 28.24, 21.82, 19.05, 18.06, 17.89, 10.20;
Anal. Calcd for C19H35N3O6 (401): C, 56.86; N, 10.47; H,
8.73%. Found: C, 56.88; N, 10.5; H, 8.69%; [a]2D0 ꢁ75.0
(c 1.05, CH3OH); ESI-MS m/z 402.2 (M+H)+, m/z 825.5
(2M+Na)+.
4.2.10. Ac–Ala(1)–Val(2)–Ala(3)–OMe 5. Boc–Ala(1)–
Val(2)–Ala–OMe 11 (2.24 g, 6 mmol) was taken and tri-
fluoroacetic (5 mL) acid was added, and the removal of
Boc group monitored by TLC. After 2 h, trifluoroacetic
acid was removed under vacuum. The residue was taken in
water (20 mL) and washed with diethyl ether (2ꢂ30 mL).
The pH of the aqueous solution was then adjusted to 8
with aq NH3. The aqueous portion was evaporated and acetic
anhydride (0.5 mL) was added followed by triethylamine
(0.7 mL) with continuous stirring. The final compounds
were evaporated in vacuo to yield peptide 5 as a white solid.
4.2.6. Boc–Ala(1)–Val(2)–Ala(3)–OBzl 3. Rf¼0.72
(CHCl3/MeOH¼9:1); Yield¼2.95 g (6.56 mmol, 82%);
mp 116–119 ꢀC; IR (KBr) 3301, 1741, 1674, 1642,
1546 cmꢁ1 1H NMR (300 MHz, CDCl3) d 7.42–7.32
;
(5H); 6.83 (d, 1H, J¼8.4 Hz); 6.73 (d, 1H, J¼7.2 Hz);
6.19 (d, 2H, J¼6.8 Hz); 5.06 (d, 1H, J¼7 Hz); 4.61 (m,
1H); 4.28 (m, 1H); 4.15 (m, 1H); 2.17 (m, 1H); 1.44 (s,
9H); 1.41 (d, 3H, J¼7.2 Hz); 1.36 (d, 3H, J¼6.9 Hz); 0.92
(m, 6H); 13C NMR (300 MHz, CDCl3) d 172.77, 172.3,
170.59, 135.16, 128.4, 128.22, 126.79, 66.92, 64.98,
58.08, 52.19, 47.93, 33.73, 30.92, 28.12, 24.77, 18.92,
17.94, 17.78; Anal. Calcd for C23H35N3O6 (449): C, 61.47;
N, 9.35; H, 7.8%. Found: C, 61.49; N, 9.36; H, 7.82%;
[a]2D0 ꢁ69.0 (c 1.14, CH3OH); ESI-MS m/z 450.4 (M+H)+,
m/z 921.5 (2M+Na)+.
Rf¼0.55 (CHCl3/MeOH¼9:1); Yield¼1.32 g (4.2 mmol,
70%); mp 102–106 ꢀC; IR (KBr) 3285, 1744, 1632,
1
1550 cmꢁ1; H NMR (300 MHz, CDCl3+20% (CD3)2SO)
d 8.43 (d, 1H, J¼9.8 Hz); 7.71 (d, 1H, J¼6.9 Hz); 7.46 (d,
1H, J¼9.8 Hz); 4.48 (m, 1H); 4.42 (m, 1H); 4.29 (m, 1H);
3.73 (s, 3H); 2.18 (m, 1H); 1.99 (s, 3H); 1.41 (d, 3H,
J¼6.6 Hz); 1.35 (d, 3H, J¼7.2 Hz); 0.95 (m, 6H); 13C
NMR (300 MHz, CDCl3+20% (CD3)2SO) d 178.92,
175.35, 174.49, 172.55, 63.31, 53.52, 52.77, 35.64, 34.19,
24.19, 23.26, 22.73, 22.35, 13.52; Anal. Calcd for
C14H25N3O5 (315): C, 53.33; N, 13.33; H, 7.94%. Found:
C, 53.31; N, 13.35; H, 7.96%; [a]2D0 ꢁ77 (c 0.8, CH3OH);
ESI-MS m/z 316.1 (M+H)+, m/z 653.3 (2M+Na)+.
4.2.7. Boc–Ala(1)–Val(2)–Ala(3)–OMe 8. See Ref. 15.
4.2.8. Boc–Ala(1)–Val(2)–Ala(3)–OH 12. Yield¼1.83 g
(5.1 mmol, 85%); mp 112–115 ꢀC; IR (KBr) 3321, 1722,
1
1696, 1642, 1531 cmꢁ1; H NMR (300 MHz, (CD3)2SO))
d 12.43 (br, 1H); 8.26 (d, 1H, J¼6.6 Hz); 7.57 (d, 1H,
J¼8.4 Hz); 7.05 (d, 1H, J¼7.5 Hz); 4.19 (m, 1H); 4.15 (m,
1H); 3.97 (m, 1H); 1.94 (m, 1H); 1.35 (s, 9H); 1.25 (d, 3H,
J¼7.2 Hz); 1.13 (d, 3H, J¼7 Hz); 0.82 (m, 6H); 13C NMR
(300 MHz, CDCl3) d 177.0, 175.4, 174.7, 157.5, 70.6,
62.8, 54.0, 53.6, 28.7, 28.0, 17.1, 16.3, 16.2; Anal. Calcd
for C16H29N3O6 (359): C, 53.48; N, 11.7; H, 8.01%. Found:
C, 53.44; N, 11.73; H, 8.02%.
4.2.11. Piv–Ala(1)–OH 13. A solution of alanine (1.34 g,
15 mmol) in a mixture of methanol (15 mL) and 1 M
NaOH (15 mL) was stirred and cooled in an ice-water
bath. Pivaloyl chloride (1.6 mL, 15 mmol) was added
and stirring was continued at room temperature for 6 h.
Then the solution was concentrated in vacuo to about 40–
60 mL, cooled in an ice-water bath, covered with a layer
of ethyl acetate (about 50 mL), and acidified with a dilute so-
lution of KHSO4 to pH 2–3 (Congo red). The aqueous phase
4.2.9. Boc–Ala(1)–Val(2)–Ala(3)–i-Pr 4. Boc–Ala(1)–
Val(2)–Ala–OH 12 (1.62 g, 4.5 mmol) in DMF (10 mL)