C H N O : C, 54.1; H, 7.1; N, 11.8%); δ (DMSO) 1.48 (18 H,
Boc), 2.45 (3 H, s, CH Tos), 3.76 (3 H, s, OMe), 4.59 (1 H, dd,
1
6
25
3
6
H
3
s, Boc), 4.67 (1 H, dd, J 8.7 and 14.5, βCH ), 5.06 (1 H, dd, J 4.8
J 9.6 and 14.4, βCH Ala), 4.94 (1 H, dd, J 4.5 and 14.4, βCH2
2
2
and 14.5, βCH ), 5.47 (1 H, dd, J 4.8 and 8.7, αCH), 6.28 (1 H,
Ala), 5.10 (2 H, d, J 6.9, CH Gly), 5.50 (1 H, dd, J 4.5 and 9.6,
2
2
t, J 2.4, 4-H pyr.), 7.39 (1 H, d, J 2.4, 3- or 5-H pyr.), 7.58 (1 H,
αCH Ala), 6.23 (1 H, t, J 2.1, 4-H pyr.), 7.30 (2 H, d, J 8.1, ArH
Tos), 7.45 (1 H, d, J 2.1, 3- or 5-H pyr.), 7.53 (1 H, d, J 1.5, 5- or
d, J 1.8, 5- or 3-H pyr.); δ (DMSO) 27.48, 50.74, 58.21, 82.40,
C
1
05.22, 130.52, 139.01, 150.94, 169.86.
3-H pyr.), 7.87 (2 H, d, J 8.1, ArH Tos); δ 21.62, 27.71, 27.76,
C
5
0.27, 51.54, 52.49, 57.70, 84.63, 85.43, 105.86, 128.69, 128.98,
Saponification of 1b. The above general method of saponifi-
130.45, 136.82, 140.14, 144.22, 150.54, 151.14, 168.30, 170.63.
cation was used to give 8b (86%), mp 129–129.5 ЊC (from ethyl
acetate–n-hexane) (Found: C, 50.7; H, 7.0; N, 15.2. Calc. for
C H N O : C, 50.55; H, 6.8; N, 15.7%); δ (DMSO) 1.47 (18
Synthesis of Tos-Gly(N-Boc)-Ala[N-Boc-ꢀ-(1,2,4-triazol-1-
yl)]-OMe. The above general method with 1,2,4-triazole gave
Tos-Gly(N-Boc)-Ala[N-Boc-β-(1,2,4-triazol-1-yl)]-OMe 10b in
99% yield, mp 130.5–132 ЊC (from diethyl ether–n-hexane)
(Found: C, 51.8; H, 6.1; N, 11.85; S, 5.6. Calc. for C H N O S:
1
5
24
4
6
H
H, s, Boc), 4.70 (1 H, dd, βCH ), 4.96 (1 H, dd, βCH ), 5.44 (1
2
2
H, dd, αCH), 7.97 (1 H, s, 3- or 5-H triaz.), 8.23 (1 H, s, 5- or
3
1
-H triaz.); δC (DMSO) 27.43, 48.23, 57.73, 82.65, 144.78,
50.90, 151.47, 169.51.
25
35
5
9
C, 51.6; H, 6.1; N, 12.0; S, 5.5%); δH 1.33 (9 H, s, Boc), 1.45
9 H, s, Boc), 2.46 (3 H, s, CH Tos), 3.78 (3 H, s, OMe), 4.62
(
3
Saponification of 1h. The above general method of saponifi-
(1 H, dd, J 9.0 and 14.4, βCH Ala), 4.94 (1 H, dd, J 4.5 and
2
cation was used to give 8h (89%), mp 155–156 ЊC (from ethyl
acetate–n-hexane) (Found: C, 61.05; H, 6.6; N, 6.5. Calc. for
C H N O : C, 61.1; H, 6.5; N, 6.5%); δ (DMSO) 1.32 (18 H,
14.4, βCH Ala), 5.08 (2 H, s, CH Gly), 5.46 (1 H, dd, J 4.5 and
2
2
9.0, αCH Ala), 7.32 (2 H, d, J 8.1, ArH Tos), 7.87 (2 H, d, J 8.1,
ArH Tos), 7.95 (1 H, s, 3- or 5-H triaz.), 8.23 (1 H, s, 5- or 3-H
2
2
28
2
7
H
s, Boc), 4.81 ( 1H, dd, J 9.3 and 14.7, βCH ), 4.93 (1 H, dd, J 4.8
triaz.); δ 21.61, 27.70, 27.75, 47.84, 51.53, 52.72, 57.01, 84.89,
2
C
and 14.7, βCH ), 5.44 (1 H, dd, J 4.8 and 9.3, αCH), 7.27–7.44
85.95, 128.55, 129.05, 136.73, 144.34, 144.43, 150.56, 150.94,
152.36, 167.89, 170.85.
2
(
3 H, complex signal, 5-, 6- and 7-H ind.), 7.75 (1 H, s, 2-H
ind.), 8.30 (1 H, d, J 5.4, 4-H ind.), 9.99 (1 H, s, CHO); δC
DMSO) 27.17, 46.03, 57.84, 82.65, 110.70, 117.76, 120.99,
(
Synthesis of Tos-Gly(N-Boc)-Ala[N-Boc-ꢀ-(imidazol-1-yl)]-
OMe. The above general method with imidazole gave Tos-
Gly(N-Boc)-Ala[N-Boc-β-(imidazol-1-yl)]-OMe 10c in 75%
yield, mp 108–109.5 ЊC (from diethyl ether–n-hexane) (Found:
C, 53.7; H, 6.2; N, 9.4; S, 5.4. Calc. for C H N O S: C, 53.8; H,
1
22.45, 123.55, 124.64, 137.44, 141.27, 151.07, 169.61, 184.64.
Saponification of 1j. The above general method of saponifi-
cation was used to give 8j (94%), mp 156–156.5 ЊC (from ethyl
acetate–n-hexane) (Found: C, 59.3; H, 6.8; N, 10.0. Calc. for
C H N O : C, 59.25; H, 6.7; N, 10.4%); δ (DMSO) 1.30 (18
26
36
4
9
6.25; N, 9.65; S, 5.5%); δH 1.33 (9 H, s, Boc), 1.43 (9 H, s, Boc),
2.45 (3 H, s, CH Tos), 3.77 (3 H, s, OMe), 4.38 (1 H, dd, J 8.4
2
0
27
3
6
H
3
H, s, Boc), 4.67 (1 H, dd, J 10.2 and 14.7, αCH), 5.45 (2H, m,
and 14.9, βCH Ala), 4.70 (1 H, dd, J 4.8 and 14.9, βCH Ala),
2
2
βCH ), 6.51 (1H, d, J 3.3, 3-H ind.), 7.13 (1 H, d, J 3.3, 2-H
5.11 (2 H, d, J 10.2, CH Gly), 5.25 (1 H, dd, J 4.8 and 8.4, αCH
2
2
ind.), 7.21 (1 H, dd, J 4.8 and 7.8, 5-H ind.), 8.04 (1 H, d, J 7.8,
Ala), 6.96 (1 H, t, J 1.2, 4- or 5-H imid.), 7.04 (1 H, s, 5- or
4-H imid.), 7.33 (2 H, d, J 8.4, ArH Tos), 7.54 (1 H, s, 2-H
imid.), 7.87 (2 H, d, J 8.4, ArH Tos); δC 21.65, 27.69, 27.78,
45.58, 51.61, 52.71, 58.06, 84.92, 86.18, 119.62, 128.58,
4-H ind.), 8.42 (1 H, d, J 4.8, 6-H ind.); δC (DMSO) 27.74,
44.12, 58.33, 82.65, 99.91, 116.17, 120.64, 128.85, 129.79,
142.79, 147.76, 151.19, 170.51.
1
29.09, 129.74, 136.75, 137.82, 144.39, 150.56, 150.96, 168.10,
Coupling reactions of ꢀ-substituted alanine derivatives
170.76.
Synthesis of Boc-DL-Ala[N-Boc-ꢀ-(pyrazol-1-yl)]-L-Phe-OEt
a. Compound 8a was treated on a 1-mmolar scale with H-Phe-
OEtؒHCl in ethyl acetate by using the standard DCC–1-
hydroxybenzotriazole(HOBt) procedure to give Boc-Ala-
Synthesis of Tos-Gly(N-Boc)-Ala[N-Boc-ꢀ-(3-formylindol-1-
9
yl)]-OMe. The above general method with 3-formylindole gave
Tos-Gly(N-Boc)-Ala[N-Boc-β-(3-formylindol-1-yl)]-OMe 10h
in 74% yield, mp 117.0–119.0 ЊC (from diethyl ether–n-hexane)
[
N-Boc-β-(pyrazol-1-yl)]--Phe-OEt as a pure oil that solidified
(
Found: C, 58.6; H, 5.9; N, 6.65; S, 4.32. Calc. for C H N O S:
32 39 3 10
on storage (80%) (Found: C, 61.0; H, 7.3; N, 10.45. Calc. for
C H N O : C, 61.1; H, 7.2; N, 10.6%).
C, 58.4; H, 5.9; N, 6.4; S, 4.86%); δ 1.06 (9 H, s, Boc), 1.35 (9 H,
H
2
7
38
4
7
s, Boc), 2.47 (3 H, s, CH Tos), 3.80 (3 H, s, OMe), 4.65 (1 H, dd,
3
J 9.0 and 15.0, βCH Ala), 5.00 (1 H, dd, J 4.8 and 15.0, βCH2
2
Synthesis of Boc-DL-Ala[N-Boc-ꢀ-(7-azaindol-1-yl)]-L-Phe-
OEt 9j. Compound 8j was treated on a 1-mmolar scale as above
to give Boc-Ala[N-Boc-β-(7-azaindol-1-yl)]--Phe-OEt as a
pure oil that solidified on storage (86%) (Found: C, 64.05; H,
Ala), 5.11 (2 H, d, J 5.7, CH Gly), 5.33 (1 H, m, αCH Ala),
2
7
(
.29–7.43 (5 H, m, 2-, 5- and 6-H ind. ϩ ArH Tos), 7.87–7.92
3 H, m, 7-H ind. ϩ ArH Tos), 8.32 (1 H, dd, J 2.7 and 6.2, 4-H
ind.), 9.98 (1 H, s, CH); δC 21.66, 27.16, 27.80, 45.52, 51.75,
7
.1; N, 9.7. Calc. for C H N O : C, 64.1; H, 6.9; N, 9.65%).
31 40 4 7
5
1
1
2.78, 56.83, 85.06, 85.97, 109.57, 118.91, 122.65, 123.13,
24.36, 125.36, 128.46, 129.15, 136.86, 137.10, 140.24, 144.44,
50.69, 150.82, 168.11, 171.01, 184.99.
Michael addition to dehydroalanine dipeptides
General method. To a solution of 0.25 mmol of the fully
protected dehydro dipeptide in acetonitrile, viz. Tos-Gly(N-
Boc)-∆Ala(N-Boc)-OMe 10 or Boc-Ala(N-Boc)-∆Ala(N-Boc)-
Synthesis of Tos-Gly(N-Boc)-Ala[N-Boc-ꢀ-(7-azaindol-1-yl)]-
OMe. The above general method with 7-azaindole gave Tos-
Gly(N-Boc)-Ala[N-Boc-β-(7-azaindol-1-yl)]-OMe 10j in 90%
yield, mp 141.5–143 ЊC (from diethyl ether-n-hexane) (Found:
C, 57.0; H, 6.2; N, 8.7; S, 5.2. Calc. for C H N O S: C, 57.1; H,
3
OMe 11 (2.5 cm ) was added K CO (6 equiv.), followed by 1
2
3
equiv. of pyrazole with rapid stirring at room temperature. The
reaction was monitored by TLC and when no starting material
was detected the solution was filtered, and evaporated at
reduced pressure to give the corresponding addition product.
30
38
4
9
6.1; N, 8.9; S, 5.1%); δH 1.05 (9 H, s, Boc), 1.34 (9 H, s, Boc),
2.45 (3 H, s, CH Tos), 3.77 (3 H, s, OMe), 4.73 (1 H, dd, J 9.6
3
and 14.6, βCH Ala), 5.13 (3 H, m, βCH Ala, CH Gly), 5.49
2
2
2
Synthesis of Tos-Gly(N-Boc)-Ala[N-Boc-ꢀ-(pyrazol-1-yl)]-
OMe. The above general method with pyrazole gave Tos-
Gly(N-Boc)-Ala[N-Boc-β-(pyrazol-1-yl)]-OMe 10a in 76%
yield, mp 129.5–131 ЊC (from diethyl ether–n-hexane) (Found:
C, 53.6; H, 6.25; N, 9.3; S, 5.7. Calc. for C H N O S: C, 53.8;
(1 H, dd, J 3.6 and 9.6, αCH Ala), 6.46 (1 H, d, J 5.1, 3-H ind.),
7.07 (1 H, dd, J 5.1 and 7.8, 5-H ind.), 7.27 (3 H, m, 2-H ind.,
ArH Tos), 7.88 (3 H, m, 4-H ind., ArH Tos), 8.35 (1 H, dd, J 1.5
and 5.1, 6-H ind.); δC 21.63, 27.20, 27.75, 51.21, 51.75, 52.37,
57.47, 84.50, 84.80, 105.68, 128.78, 128.91, 130.14, 136.93,
140.09, 142.94, 144.13, 151.15, 170.70, 168.45.
26
36
4
9
H, 6.25; N, 9.65; S, 5.5%); δH 1.33 (9 H, s, Boc), 1.44 (9 H, s,
J. Chem. Soc., Perkin Trans. 1, 2000, 3317–3324
3323