Grison et al.
lidine Carboxylic Acid 1,1-Dimethylethylester (5c):14 45.0
mg (84% isolated); white solid; mp 114 °C; R 0.42 (ethyl
acetate); IR (5.52 mM/DCM, CaF ) νmax 3424, 3325, 1682,
637, 1524, 1500 cm ; (5.64 mM/DMSO, CaF ) νmax 1682,
45%: 13.4, 18.6, 18.9, 22.6, 24.9, 28.4, 30.9, 41.6, 46.8, 47.8,
f
49.0, 55.2, 79.5, 133.2, 136.3, 155.2, 169.0, 172.1, 172.4; [R]
D
-
2
-90° (c 0.5, HCCl
3
); MS (CI ) calcd for C22
38 4 5
H N O : 438.6 [M
-
1
-
-
1
1
2
- 1] , found 438.3, (49%), 364.4 [M - tBuO] , 100%. Anal.
-
1
1
13 1
628, 1565 cm ; H NMR (250 MHz, CDCl
3
), H NMR(250
38 4 5
Calcd for C22 H N O : C, 60.25; H, 8.73; N, 12.77. Found: C,
3
MHz, DMSO-d
6
), δppm 1.03 (m, 6 H), 1.12 (d, JH-H ) 7.0 Hz,
60.42; H, 8.48; N, 12.63.
3
3
H), 1.31 (s, 9 H), 1.80 (s, 3 H), 1.55-2.77 (m, 4 H), 3.17-
General Procedure for the Preparation of the Divi-
nylogous Dipeptides 9c-g and 10c-e. The divinylogous
dipeptides 9c-g and 10c-e were obtained by coupling Boc-
.45 (m, 2 H), 3.79 (m, 1 H), 4.28 (m, 1 H), 4.43 (m, 1 H), 6.15
3
(
d, JH-H ) 8.0 Hz, 1 H), 7.62 (m, 2 H).
tr
cis
General Procedure for the Preparation of the Monovi-
or Piv-“Xaa ”-OH or Boc- or Piv-“Xaa ”-OH with the corre-
tr
cis
nylogous Tripeptides 7c-8d. Removal of Boc of monoviny-
sponding HCl, H-“Ala ”-NH-i-Pr or HCl, H-“Ala ”-NH-i-Pr.
The coupling procedure was the same as that described for
the preparation of aminoamides 1a-j.
tr
cis
logous dipeptides Boc-“Pro ”-Ala-NH-i-Pr 5c, Boc-“Pro ”-Ala-
tr
cis
NH-i-Pr 5d, Boc-“Pro ”-Ala-NH-Me 6c, or Boc-“Pro ”-Ala-NH-
Me 6d was effected with the procedure previously described
(S)-(S)-2-{2-Methyl-3-[[2(Z)-1,3-dimethyl-4-[(1-methyl-
ethyl)amino]-4-oxo-2-butenyl]amino]-(1E)-3-oxo-1-prope-
nyl}-1-pyrrolidine Carboxylic Acid 1,1-Dimethylethyl
tr
using anhydrous gaseous HCl in Et
2
O to afford HCl, H-“Pro ”-
cis
tr
Ala-NH-i-Pr; HCl, H-“Pro ”-Ala-NH-i-Pr; HCl, H-“Pro ”-Ala-
tr
NH-Me; or HCl, H-“Pro ”-Ala-NH-Me; respectively. Then,
Ester (9e): 52.0 mg (73% isolated); powder; mp 130 °C; R
(ethyl acetate); IR (4.29 mM/DCM, CaF ) νmax 3445, 3244,
1685, 1668, 1547, 1508 cm ; (4.29 mM/DMSO, CaF
f
0.32
these last compounds were coupled with Boc-Ala-OH using
BOP as coupling reagent according to the procedure described
above for the preparation of aminoamides 1a-j.
N-[(1,1-Dimethylethoxy)carbonyl]-L-alanyl-[(2E)-3-(pyr-
rolidin-2-yl)-2-methyl-2-propenoyl]-L-alanine Isopropy-
lamide (7c): 40.0 mg (74% isolated); powder; mp 194-195 °C;
2
-
1
2
) νmax
3
) δppm
-
1 1
1680, 1666, 1630, 1530 cm ; H NMR (250 MHz, CDCl
3
3
1.22 (d, JH-H ) 6.5 Hz, 6 H), 1.26 (d, JH-H ) 7.0 Hz, 3 H),
1.45 (s, 9 H), 1.90 (s, 3 H), 1.94 (s, 3 H), 1.52-2.13 (m, 4 H),
3
3.34 (m, JH-H ) 7.0 Hz, 2 H), 4.09 (m, 1 H), 4.51 (m, 1 H),
3
3
R
f
0.42 (acetone/ethyl acetate/hexane 1/1/1); IR (6.36 mM/DCM,
2
4.76 (m, 1 H), 5.25 (d, JH-H ) 10 Hz, 1 H), 5.56 (d, JH-H )
3 4
-
1
CaF
) νmax 3426, 3340, 1700, 1672, 1644, 1521, 1505 cm
) νmax 1704, 1664, 1655, 1636, 1533
cm ; H NMR (250 MHz, CDCl ) δppm major trans conformer
;
7.5 Hz, 1 H), 6.24 (dd, JH-H ) 9.0 Hz, JH-H ) 1.0 Hz, 1 H),
3 1
(
5.47 mM/DMSO, CaF
2
6
9.38 (d, JH-H ) 6.5 Hz, 1 H); H NMR (250 MHz, DMSO-d )
3 3
-
1
1
3
δppm 1.13 (d, JH-H ) 6.5 Hz, 6 H), 1.20 (d, JH-H ) 6.5 Hz, 3
1
3
(
Ala -Pro bond) 55% 1.11 (d, JH-H ) 6.7 Hz, 3 H), 1.15 (d,
H), 1.43 (s, 9 H), 1.82 (s, 3H), 1.82 (s, 3H), 1.50-2.18 (m 4 H),
3.21-3.49 (m, 2 H), 3.91 (m, 1 H), 4.47 (m, 1 H), 4.64 (m, 1
3
3
3
J
J
H-H ) 6.7 Hz, 3 H), 1.28 (d, JH-H ) 7.7 Hz, 3 H), 1.43 (d,
3
3
H-H ) 7.0 Hz, 3 H), 1.43 (s, 9 H), 1.81-1.93 (m, 2 H), 1.95
H), 5.41 (d, JH-H ) 10.75 Hz, 1 H), 6.12 (d, JH-H ) 9.0 Hz, 1
3 3
(
s, 3 H), 2.24-2.37 (m, 2 H), 3.48-3.76 (m, 2 H), 4.00 (m, 1
H), 7.51 (d, JH-H ) 7.0 Hz, 1 H), 8.92 (d, JH-H ) 6.5 Hz, 1
13
3
H), 4.37-4.53 (m, 3 H), 5.20 (d, JH-H ) 9.6 Hz, 1 H), 6.11 (d,
H); C NMR (62.896 MHz, CDCl
3
) δppm 13.0, 19.9, 21.0, 22.6,
3
3
3
J
J
H-H ) 8.2 Hz, 1 H), 6.30 (d, JH-H ) 6.4 Hz, 1 H), 7.58 (d,
23.7, 28.4, 32.6, 41.5, 43.8, 46.9, 55.3, 80.1, 130.3, 131.1, 133.5,
1
+
H-H ) 7.6 Hz, 1 H); minor cis conformer (Ala -Pro bond)
136.5, 155.2, 168.3, 168.8; [R]
D
57° (c 0.9, HCCl
[M + 1] : 407.27, found 407.0 (2%), 169.0
)-CO-NH-CH(CH )-CHdC(CH )-CO-
NH-iPr] , 22%, 154.0 [M - tBu-CO-NH-CH(CH )-CHd
)-CO-NH-iPr] , 56%, 138.0 [M - tBuO-CO-NH-
3
); MS (EI )
3
3
+
4
5%: 1.14 (d, JH-H ) 6.7 Hz, 3 H); 1.15 (d, JH-H ) 6.7 Hz, 3
calcd for C22
[M - CHdC(CH
37 3 4
H N O
3
3
H), 1.30 (d, JH-H ) 7.4 Hz, 3 H), 1.38 (d, JH-H ) 6.9 Hz, 3
3
3
3
+
H), 1.43 (s, 9 H), 1.68-1.75 (m, 2 H), 1.95-2.18 (m, 2 H), 2.02
(
3
4
+
d, JH-H ) 0.9 Hz, 3 H), 3.55-3.66 (m, 2 H), 4.02 (m, 1 H),
.37-4.53 (m, 2 H), 4.80 (m, 1 H), 5.38 (d, JH-H ) 7.8 Hz, 1
C(CH
CH(CH
tBuOCO-CO-NH-CH(CH
3
3
+
4
3
)-CHdC(CH
3
)-CO-NH-iPr] , 59%, 110 [M
)-CHdC(CH )-CO-NH-iPr] ,
37 3 4
100%. Anal. Calcd for C22 H N O : C, 64.84; H, 9.15; N, 10.31.
-
3
3
+
H), 5.91 (d, JH-H ) 7.6 Hz, 1 H), 6.11 (d, JH-H ) 8.2 Hz, 1
3
3
3
1
H), 6.22 (d, JH-H ) 9.7 Hz, 1 H); H NMR (400 MHz, DMSO-
1
d
6
) δppm major trans conformer (Ala -Pro bond) 65% 1.04 (d,
Found: C, 64.72; H, 9.40; N, 10.68.
3
3
J
J
H-H ) 7.0 Hz, 3 H), 1.06 (d, JH-H ) 7.0 Hz, 3 H), 1.17 (d,
3
3
H-H ) 6.5 Hz, 3 H), 1.22 (d, JH-H ) 7.2 Hz, 3 H), 1.38 (s, 9
Acknowledgment. We are very grateful to Dr. Van
Dorsselaer (University Louis Pasteur, Strasbourg) for
his mass spectroscopic assistance.
H), 1.61 (m, 1 H), 1.86 (s, 3 H), 1.71-1.95 (m, 2 H), 2.03 (m, 1
H), 3.55-3.63 (m, 2 H), 3.81 (m, 1 H), 4.19-4.34 (m, 2 H), 4.66
3
3
(
m, 1 H), 6.10 (d, JH-H ) 8.7 Hz, 1 H), 6.89 (d, JH-H ) 7.2
3 3
Hz, 1 H), 7.61 (d, JH-H ) 7.3 Hz, 1 H); 7.74 (d, JH-H ) 7.6
Supporting Information Available: General methods
and description of the data for compounds 1c,e-j, 2b-d, 3b,
1
Hz, 1 H); minor cis conformer (Ala -Pro bond) 35%: 1.01 (d,
3
3
3
J
J
H-H ) 7.0 Hz, 3 H), 1.08 (d, JH-H ) 7.0 Hz, 3 H), 1.20 (d,
1
4
a, 5d, 6c,d, 7d, 8c,d, 9c,d,f,g, and 10c,e. H NMR (CDCl
3
)
3
H-H ) 7.0 Hz, 3 H), 1.27 (d, JH-H ) 7.0 Hz, 3 H), 1.36 (s, 9
of compounds 1a,b,e-j, 2b-d, 3a,b, 4a, 5c,d, 6c,d, 7d, 8c,d,
H), 1.61 (m, 1 H), 1.84 (s, 3 H), 1.71-1.95 (m, 2 H), 2.03 (m, 1
H), 3.55-3.63 (m, 2 H), 3.81 (m, 1 H), 4.13 (m, 1 H), 4.34 (m,
1
1
9
8
1
c-g, and 10c-e. H NMR (DMSO-d
6
) of compounds 6c,d and
13
d. C NMR of compounds 5c,d, 6c,d, 7d, 8c,d, 9c-g, and
3
3
H), 4.66 (m, 1H), 6.19 (d, JH-H ) 8.7 Hz, 1 H), 6.99 (d, JH-H
1
1
3
0c-e. H- H NMR (CDCl ) of compound 7d. NOESY and
3
3
)
7.2 Hz, 1 H), 7.52 (d, JH-H ) 7.6 Hz, 1 H; 7.66 (d, JH-H
)
TOCSY of compound 7c. Crystallographic information files
CIF format) for compounds 2b and 8d. This material is
1
3
7
.4 Hz, 1 H); C RMN (62.896 MHz, CDCl
3
) δppm major trans
(
1
conformer (Ala -Pro bond) 55%: 12.8, 16.6, 18.3, 22.6, 22.7,
available free of charge via the Internet at http://pubs.acs.org.
24.9, 28.4, 33.4, 41.3, 46.9, 47.3, 49.4, 55.2, 80.0, 130.6, 135.4,
154.4, 168.0, 171.2, 171.7; minor cis conformer (Ala -Pro bond)-
1
JO051483Y
10764 J. Org. Chem., Vol. 70, No. 26, 2005