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C H-2), 4.06 (dq, 1H, J=2.2, 7.2 Hz, C H-4), 3.87 (dd, 1H, J=8.3,
C H-1), 4.26 (dddd, 1H, J=8.3, 4.1, 5.9, 10.4 Hz, C H-3), 4.16 (qd,
a
a
4
b
1
4.5 Hz, CaH(pro-S)-1), 3.75 (d, 1H, J=3.0 Hz, C H-3), 3.74 (d, 1H, J=
1H, J=3.8, 7.0 Hz, C H-2), 4.16 (dddd, 1H, J=9.0, 3.4, 6.5, 7.0 Hz,
3
a
3
.1 Hz, C H-1), 3.70 (s, 3H, COOMe), 3.39 (s, 3H, OMe), 3.38 (s, 3H,
C H-1), 4.16 (qd, 1H, J=4.0, 6.7 Hz, C H-6), 4.10 (qd, 1H, J=2.6,
3
b
a
OMe), 2.68 (dd, 1H, J=3.8, 13.4 Hz, CaH(pro-S)-3), 2.40 (dd, 1H, J=
7.0 Hz, C H-4), 4.10 (dd, 1H, J=3.3, 10.4 Hz, C H-3), 3.90 (d, 1H, J=
a 4
3
2
.7, 14.5 Hz, CaH(pro-R)-1), 2.30 (dd, 1H, J=8.3, 14.5 Hz, CaH(pro-S)-1),
.03 (dd, 1H, J=3.8, 13.4 Hz, CaH(pro-R)-3), 1.53 (d, 1H, J=7.2 Hz,
3.3 Hz, C H-3), 3.85 (d, 1H, J=3.2 Hz, C H-7), 3.73 (d, 1H, J=3.2 Hz,
3 3
C3H-1), 3.70 (s, 3H, COOMe), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe),
C3H-6), 1.41 (br, 9H, Boc and 6H, 2ꢂMe), 1.35 (d, 1H, J=7.2 Hz,
C H-2), 1.35 (d, 1H, J=7.2 Hz, C H-5), 1.33 (d, 1H, J=7.2 Hz, C H-4),
3.38 (s, 3H, OMe), 2.63 (dd, 1H, J=4.1, 13.5 Hz, C H-2), 2.57 (dd,
a
1H, J=5.1, 14.0 Hz, C H-7), 2.40 (dd, 1H, J=3.4, 14.0 Hz, C H-1),
3
3
3
a
a
13
1
.28 (s, 3H, Me), 1.26 ppm (s, 3H, Me); C NMR (CD OD, 150 MHz):
2.34 (dd, J=6.6, 14.0 Hz, C H-1), 2.33 (dd, J=4.8, 14.0 Hz, C H-7),
a a
3
d=175.77, 175.10, 174.72, 174.67, 172.77, 172.62, 157.65, 112.81,
12.55, 106.12, 105.96, 84.90, 84.67, 82.45, 82.38, 82.18, 80.64,
2.13 (dd, J=5.9, 13.5 Hz, C H-4), 1.48 (d, 1H, J=6.7 Hz, Me), 1.43 (s,
a
1
9H, 3ꢂMe), 1.41 (s, 9H, Boc), 1.39 (d, 1H, J=7.4 Hz, Me-8), 1.34 (d,
1H, J=7.0 Hz, Me-5), 1.34 (d, 1H, J=7.0 Hz, Me-4), 1.34 (d, 1H, J=
7.0 Hz, Me-2), 1.28 (s, 3H, Me), 1.28 (s, 3H, Me), 1.27 ppm (s, 3H,
8
2
0.03, 57.55, 52.66, 51.79, 51.48, 49.98, 49.86, 47.89, 38.59, 38.50,
8.69, 26.91, 26.37, 26.28, 17.72, 17.33, 17.29, 17.16 ppm; HRMS
+
1
(
ESI+): m/z calcd for C H N O [M +Na]: 925.4356; found:
Me); H NMR (CD Cl , 600 MHz): d=7.91 (d, 1H, J=7.6 Hz, NH-8),
40
66
6
17
2
2
9
25.4376.
7.85 (d, 1H, J=9.9 Hz, NH-3), 7.79 (m, 1H, NH-6), 7.51 (d, 1H, J=
9
.7 Hz, NH-7), 7.48 (m, 1H, NH-4), 7.38 (d, 1H, J=9.5 Hz, NH-5),
6
.66 (m, 1H, NH-2), 5.79 (d, 1H, J=3.8 Hz, C H-1), 5.76 (d, 1H, J=
1
Boc-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-d-Ala-l-Ala-(S)-b-Caa-l-
Ala-OMe (2)
3.6 Hz, C
H-7), 5.74 (d, 1H, J=3.6 Hz, C H-3), 5.58 (d, 1H, J=8.6 Hz,
1 1
NH-3), 4.53 (d, 1H, J=3.6 Hz, C H-1), 4.52 (m, 2H, C H-3,7), 4.42 (q,
2
2
1
4
H, J=7.6 Hz, C H-8), 4.33 (m, 4H, C H-2, C H-7, C H-3, C H-5),
a a b b a
.18 (m, 1H, C H-4), 4.12 (m, 1H, C H-1), 4.09 (m, 1H, C H-1), 4.02
A solution of ester 6 (0.26 g, 0.30 mmol) treated as described
above gave 6a (0.23 g, 90%) as a white solid, which was used for
the next reaction without further purification.
a
4
b
(m, 1H, C H-7), 3.98 (m, 1H, C H-3), 3.94 (m, 1H, C H-6), 3.87 (d,
4
4
a
1
H, J=3.0 Hz, C H-7), 3.67 (d, 1H, J=3.2 Hz, C H-3), 3.64 (d, 1H,
3 3
A solution of 6a (0.10 g, 0.12 mmol), HOBt (0.01 g, 0.14 mmol), and
EDCI (0.22 g, 0.14 mmol) in dry CH Cl (5 mL) was stirred at 08C for
J=2.6 Hz, C
3
H-1), 3.63 (s, 3H, COOMe), 3.32 (s, 3H, OMe), 3.31 (s,
H-1, C H-7, C H-3),
H-1), 2.16 (dd, 1H, J=4.1, 13.2 Hz,
H-3), 1.36 (m, 18H, Boc, 3ꢂMe), 1.32 (d, 3H, Me-
3H, OMe), 3.29 (s, 3H, OMe), 2.48 (m, 3H, C
2.37 (dd, 1H, J=6.5, 14.0 Hz, C
H-7), 2.12 (m, C
2
2
a
a
a
[6a]
1
5 min and treated with the known salt 8 (0.06 g, 0.11 mmol)
and DIPEA (0.03 mL, 0.17 mmol) under a nitrogen atmosphere for
h. Workup as described for 6 and purification of the residue by
a
C
a
a
5
8), 1.29 (s, 3H, Me), 1.26 (d, 3H, J=7.0 Hz, Me-2), 1.24 (d, 3H, J=
column chromatography (60–120 mesh silica gel, 4.2% MeOH in
7.0 Hz, Me-4), 1.22 (s, 6H, 2ꢂMe), 1.19 (s, 3H, Me), 1.18 ppm (d,
3H, J=7.3 Hz, Me-5); C NMR (CD OH, 150 MHz): d=174.52,
3
174.26, 173.81, 173.55, 173.13, 171.48, 171.40, 156.37, 111.49,
111.42, 111.29, 104.86, 104.79, 104.69, 83.63, 83.58, 83.40, 81.23,
81.17, 81.11, 80.93, 79.82, 79.40, 78.76, 56.30, 51.58, 50.71, 50.26,
50.18, 48.65, 48.56, 46.57, 37.34, 37.24, 37.12, 29.33, 27.43, 25.67,
13
CHCl ) afforded 2 (0.06 g, 42%) as a white solid. M.p. 230–2328C;
3
2
0
[
2
1
a] =ꢀ41.08 (c=0.1 in CHCl ); IR (CHCl ): n=3423, 3317, 3020,
D
3
3
996, 2937, 2833, 1727, 1659, 1532, 1455, 1378, 1314, 1297, 1250,
ꢀ1
1
163, 1119, 1081, 1024, 887, 856, 752 cm
;
H NMR (CDCl3,
6
00 MHz): d=8.09 (d, 1H, J=7.8 Hz, NH-8), 7.93 (d, 1H, J=8.5 Hz,
NH-3), 7.86 (d, 1H, J=4.0 Hz, NH-6), 7.82 (d, 1H, J=6 Hz, NH-4),
25.09, 25.01, 16.49, 16.34, 16.16, 15.93, 15.70 ppm; HRMS (ESI+):
+
7
1
3
.66 (d, 1H, J=9.0 Hz, NH-5), 7.54 (d, 1H, J=9.5 Hz, NH-7), 6.75 (d,
m/z calcd for C54
H
88
N
O23 [M +Na]: 1239.5843; found: 1239.5854.
8
H, J=4.5 Hz, NH-2), 5.92 (d, 1H, J=3.6 Hz, C H-1), 5.88 (d, 1H, J=
1
.6 Hz, C H-6), 5.88 (d, 1H, J=3.6 Hz, C H-3), 5.52 (d, 1H, J=8.0 Hz,
1
1
NH-1), 4.8 (d, 1H, J=3.6 Hz, C H-1), 4.60 (d, 1H, J=3.6 Hz, C H-7),
2
2
Boc-l-Ala-d-Ala-l-Ala-(S)-b-Caa-l-Ala-OMe (10)
4
4
.58 (d, 1H, J=3.6 Hz, C H-3), 4.54 (qd, 1H, J=7.6, 7.8 Hz, C H-8),
2 a
.48 (dd, 1H, J=8.5, 5.6 Hz, C H-3), 4.47 (qd, 1H, J=7.6, 9.0 Hz,
A solution of acid 9 (0.15 g, 0.58 mmol), HOBt (0.1 g, 0.7 mmol),
b
C H-5), 4.44 (tdd, 1H, J=9.5, 4.9, 3.5 Hz, C H-7), 4.34 (qd, 1H, J=
and EDCI (0.13 g, 0.70 mmol) in dry CH Cl (10 mL) was stirred at
a
b
2
2
7
7
.5, 4.7 Hz, C H-7), 4.27 (dd, J=7.0, 3.2 Hz, C H-1), 4.23 (qd, 1H, J=
08C for 15 min and treated with salt 8 (0.06 g, 0.11 mmol) and
DIPEA (0.15 mL, 0.88 mmol) under a nitrogen atmosphere for 5 h.
Workup as described for 6 and purification of the residue by
column chromatography (60–120 mesh silica gel, 2.8% MeOH in
a
4
.0, 6.0 Hz, C H-4), 4.19 (dd, 1H, J=9.6, 3.2 Hz, C H-7), 4.08 (dd, 1H,
a
4
J=9.6, 3.1 Hz, C H-3), 4.05 (d, 1H, J=3.2 Hz, C H-7), 4.0 (qd, 1H,
J=7.5, 4.0 Hz, C H-6), 3.83 (d, 1H, J=3.1 Hz, C H-3), 3.74 (d, J=
4
3
a
3
3
2
1
2
3
3
.2 Hz, C H-1), 3.71 (s, 3H, COOMe), 3.41 (s, 3H, OMe), 3.38 (s, 6H,
CHCl ) afforded 10 (0.14 g, 48%) as a white solid. M.p. 164–1668C;
[a] = +163.66 (c=0.1 in CHCl ); IR (KBr): n=3303, 3080, 2983,
D
3
3
3
20
ꢂOMe), 2.97 (dd, J=12.8, 4.9 Hz, CaH(pro-R)-1), 2.64 (dd, 1H, J=
3.3, 4.9 Hz, CaH(pro-R)-7), 2.62 (dd, 1H, J=12.8, 4.9 Hz, CaH(pro-R)-3),
.50 (dd, 1H, J=12.8, 6.5 Hz, CaH(pro-S)-1), 2.27 (dd, 1H, J=13.3,
.5 Hz, CaH(pro-S)-7), 2.2 (dd, 1H, J=12.8, 5.6 Hz, CaH(pro-S)-3), 1.50 (d,
H, J=7.5 Hz, Me), 1.48 (s, 6H, Me), 1.43 (s, 9H, Boc), 1.41 (d, 3H,
2937, 17501, 1647, 1547, 1453, 1376, 1333, 1252, 1218, 1166, 1113,
ꢀ1
1
1074, 1025, 894, 855, 761, 647, 518, 434 cm
; H NMR (CDCl3,
600 MHz): d=7.97 (d, 1H, J=7.6 Hz, NH-5), 7.49 (d, 1H, J=9.5 Hz,
NH-4), 7.46 (d, 1H, J=8.4 Hz, NH-2), 7.39 (d, 1H, J=4.4 Hz, NH-3),
J=7.6 Hz, Me), 1.38 (s, 3H, Me), 1.38 (d, 3H, J=7.5 Hz, Me), 1.36 (d,
5.89 (d, 1H, J=3.7 Hz, C H-1), 5.24 (d, 1H, J=6.0 Hz, NH-1), 4.61 (d,
1
3
1
H, J=7.0 Hz, Me), 1.31 (s, 6H, 2ꢂMe), 1.29 (d, 3H, J=7.6 Hz, Me),
1H, J=3.7 Hz, C H-1), 4.56 (m, 1H, C H-2), 4.54 (qt, 1H, J=7.6 Hz,
C H-5), 4.45 (tdd, 1H, J=9.5, 4.7, 3.8 Hz, C H-4), 4.2 (dd, 1H, J=
a b
a
a
1
.28 ppm (s, 3H, Me); H NMR (CD OH, 600 MHz): d=9.15 (d, 1H,
3
J=8.3 Hz, NH-3), 8.82 (d, 1H, J=8.2 Hz, NH-5), 8.54 (d, 1H, J=
.5 Hz, NH-8), 8.38 (d, 1H, J=3.8 Hz, NH-2), 8.33 (d, 1H, J=2.6 Hz,
NH-4), 8.19 (d, 1H, J=8.5 Hz, NH-6), 7.86 (d, 1H, J=4.0 Hz, NH-7),
3.1, 9.1 Hz, C H-4), 4.07 (dq, 1H, J=4.4, 7.2 Hz, C H-3), 4.03 (qd, 1H,
4 a
J=6.0, 7.3 Hz, C H-1), 3.99 (d, 1H, J=3.1 Hz, C H-4), 3.72 (s, 3H,
a 3
6
COOMe), 3.39 (s, 3H, OMe), 2.58 (dd, 1H, J=4.7, 13.5 Hz, C H-4),
a
6
1
.79 (d, 1H, J=9.8 Hz, NH-1), 5.83 (d, 1H, J=3.6 Hz, C H-7), 5.81 (d,
2.28 (dd, 1H, J=3.8, 13.5 Hz, CaH(pro-R)-1), 1.48 (s, 3H, Me), 1.43 (s,
9H, Boc and 6H, 2ꢂMe), 1.35 (d, 3H, J=7.5 Hz, Me), 1.34 (d, 6H,
1
H, J=3.6 Hz, C H-1), 5.81 (d, 1H, J=3.6 Hz, C H-3), 4.70 (d, 1H,
1
1
13
J=3.6 Hz, C H-1), 4.70 (d, 1H, J=3.6 Hz, C H-3), 4.70 (d, 1H, J=
J=7.3 Hz, 2ꢂMe), 1.31 ppm (s, 3H, Me); C NMR (CDCl , 150 MHz):
2
2
3
3
.6 Hz, C H-7), 4.36 (qd, 1H, J=6.5, 7.4 Hz, C H-8), 4.35 (dddd, 1H,
d=175.41, 173.35, 173.17, 172.66, 170.77, 155.79, 111.66, 104.85,
83.24, 81.20, 80.22, 79.80, 57.35, 52.61, 51.01, 50.75, 48.55, 47.96,
46.57, 38.12, 28.23, 26.66, 26.32, 17.52, 17.16, 16.82, 16.22 ppm;
2
a
J=8.5, 5.1, 4.8, 9.3 Hz, C H-7), 4.34 (qd, 1H, J=8.2, 7.0 Hz, C H-5),
4
b
a
.31 (dd, 1H, J=3.2, 9.3 Hz, C H-7), 4.27 (dd, 1H, J=3.0, 7.0 Hz,
4
Chem. Eur. J. 2014, 20, 11428 – 11438
11436
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim