Synthesis and Structure of a/d-Hybrid Peptides
FULL PAPER
CaH(pro-S)-4), 2.08 (m, 1H; CaH(pro-S)-2), 1.73 (m, 2H; CbH-4), 1.70 (m,
2H; CbH-2), 1.58 (m, 1H; CgH(pro-S)-4), 1.50 (m, 1H; CgH(pro-S)-2), 1.49 (s,
6H; 2ꢃMe), 1.46 (s, 3H; Me), 1.43 (s, 9H; Boc), 1.42 (d, 3H, J=7.3 Hz;
CH3-5), 1.40 (m, 1H; CgH(pro-R)-4), 1.37 (d, 3H, J=7.0 Hz; CH3-3), 1.36
(d, 3H, J=6.9 Hz; CH3-1), 1.31 (m, 1H; CgH(pro-R)-2), 1.30 (s, 6H; 2ꢃ
Me); 13C NMR (CDCl3, 100 MHz): d=175.6, 174.3, 173.9, 173.7, 173.4
(2), 156.2, 111.3, 104.7 (3), 84.2, 84.0, 81.8, 81.7, 81.2, 79.7, 57.5, 57.3, 52.4,
50.5, 49.8, 48.2, 47.7, 47.6, 47.5, 34.8, 29.7, 29.2, 28.9, 28.3 (3), 26.7, 26.6,
26.2, 21.9, 21.6, 17.6, 17.1, 17.0 ppm; 1H NMR (CD3OH, 600 MHz): d=
8.32 (d, 1H, J=5.9 Hz; NH-5), 8.08 (d, 1H, J=5.8 Hz; NH-3), 7.91 (d,
1H, J=9.3 Hz; NH), 7.87 (d, 1H, J=9.2 Hz; NH), 6.68 (d, 1H, J=
7.2 Hz; NH-1), 5.79 (d, 1H, J=3.4 Hz; C1H), 5.77 (d, 1H, J=3.8 Hz;
C1H), 4.61 (brs, 1H; C2H-2, 4), 4.41–4.35 (m, 1H; CaH-5), 4.32–4.27 (m,
1H; CaH-3), 4.20–4.14 (m, 2H; CdH-2,4), 4.07 (m, 1H; CaH-1), 4.06 (dd,
2H, J=3.4, 8.8 Hz; C4H-2, 4), 3.68 (d, 2H, J=3.3 Hz; C3H-2, 4), 3.65 (s,
3H; COOMe), 3.36 (s, 6H; 2ꢃOMe), 2.29 (m, 2H; CaH-2, 4), 2.21 (m,
2H; CaH-2, 4), 1.72 (m, 2H; CbH-2, 4), 1.65 (m, 2H; CgH-2, 4), 1.56 (m,
2H; CgH-2, 4), 1.42 (s, 9H; Boc), 1.40 (m, 2H; CgH-2, 4), 1.38 (d, 3H,
J=7.4 Hz; CH3-5), 1.34 (d, 3H, J=7.0 Hz; CH3-3), 1.31 (d, 3H, J=
7.0 Hz; CH3-1), 1.28 (s, 6H; 2ꢃMe), 1.27 ppm (s, 6H; 2ꢃMe); IR (KBr):
n˜ =3312, 2984, 2937, 1744, 1655, 1539, 1454, 1382, 1219, 1167, 1079, 1025,
854, 782, 679 cmꢀ1; HRMS (ESI): m/z calcd for C41H69N5O16Na [M+
+Na]: 910.4637; found: 910.4632.
7.3 Hz; CH3-3, 5), 1.31 (d, 3H, J=7.0 Hz; CH3-1), 1.30 (s, 3H; Me),
1.29 ppm (s, 9H; 3ꢃMe); IR (KBr): n˜ =3362, 2984, 2934, 1738, 1642,
1537, 1453, 1381, 1247, 1168, 1079, 1024, 855, 698, 651 cmꢀ1; HRMS
(ESI): m/z calcd for C54H90N6O21Na [M++Na]: 1181.6056; found:
1181.6021.
Boc-d-Caa(x)-l-Ala-d-Caa(x)-l-Ala-OMe (6): As described for the synthe-
sis of 9, a solution of 13 (0.18 g, 0.22 mmol) on treatment with a 4n aque-
ous solution of NaOH (0.8 mL) and workup gave 14 (0.172 g, 97%),
which was used without further purification. A solution of 13 (0.154 g,
0.32 mmol) and CF3COOH (0.2 mL) in CH2Cl2 (1.5 mL) was stirred at
room temperature as described for 8 to give 15, which was used without
any further purification. According to the procedure described for 12, a
mixture of 14 (0.15 g, 0.32 mmol), HOBt (0.052 g, 0.39 mmol), and EDCI
(0.074 g, 0.39 mmol) in CH2Cl2 (3 mL) was stirred at 08C for 15 min and
treated with 15 and DIPEA (0.08 mL, 0.48 mmol) under an N2 atmo-
AHCTUNGTREGsNNUN phere for 8 h. Workup and purification by column chromatography
(silica gel, 2% MeOH in CHCl3) gave 6 as a white solid (0.147 g, 55%).
M.p. 171–1738C; [a]D =ꢀ22.85 (c=0.17 in CHCl3); 1H NMR (CDCl3,
600 MHz): d=7.62 (d, 1H, J=7.7 Hz; NH-4), 6.85 (d, 1H, J=9.5 Hz;
NH-3), 6.84 (d, 1H, J=7.3 Hz; NH-2), 5.92 (d, 1H, J=3.9 Hz; C1H-1),
5.91 (d, 1H, J=3.9 Hz; C1H-3), 4.95 (d, 1H, J=9.0 Hz; NH-1), 4.65–4.60
(m, 1H; CaH-4), 4.58 (d, 2H, J=3.9 Hz; C2H-1, 3), 4.36 (m, 1H; CaH-2),
4.35 (m, 1H; CdH-3), 4.01 (dd, 1H, J=3.4, 7.4 Hz; C4H-1, 3), 3.98–3.93
(m, 1H; CdH-1), 3.75 (s, 3H; COOMe), 3.62 (d, 1H, J=3.4 Hz; C3H-1),
3.60 (d, 1H, J=3.4 Hz; C3H-3), 3.36 (s, 6H; 2ꢃOMe), 2.48 (ddd, 1H,
J=6.4, 7.8, 13.8 Hz; CaH(pro-R)-3), 2.32 (ddd, 1H, J=6.4, 8.3, 14.5 Hz;
CaH(pro-R)-1), 2.20 (ddd, 1H, J=7.2, 8.2, 14.5 Hz; CaH(pro-S)-1), 2.13 (ddd,
1H, J=7.9, 7.6, 13.8 Hz; CaH(pro-S)-3), 1.75 (m, 1H; CbH-1), 1.73 (m, 1H;
CbH-3), 1.68 (m, 1H; Cb’H-1), 1.60 (m, 1H; Cb’H-3), 1.50 (m, 1H;
CgH-3), 1.48 (m, 2H; CgH-1), 1.49 (s, 12H; 4ꢃMe), 1.43 (s, 9H; Boc),
1.41 (m, 1H; CgH-3), 1.40 (d, 3H, J=7.3 Hz; CH3-4), 1.35 ppm (d, 3H,
J=6.9 Hz; CH3-2); 13C NMR (CDCl3, 150 MHz): d=175.2, 173.6, 173.3,
172.9, 156.1, 111.5, 111.4, 104.8, 104.7, 84.3, 84.1, 81.5, 81.3, 81.2, 81.1,
79.0, 57.7, 57.6, 57.5, 52.5, 49.1, 48.9, 47.8, 47.5, 47.3, 47.2, 35.5, 34.9, 31.9,
30.2, 28.4 (3), 26.7, 26.2, 26.1, 21.9, 21.6, 17.7, 17.0 ppm; IR (KBr): n˜ =
3335, 2984, 2935, 1742, 1699, 1644, 1455, 1382, 1218, 1171, 1079, 1025,
Boc-l-Ala-d-Caa(x)-l-Ala-d-Caa(x)-l-Ala-d-Caa(x)-OMe (5): As described
for the synthesis of 9, a solution of 3 (0.14 g, 0.17 mmol) on treatment
with a 4n aqueous solution of NaOH (0.68 mL) and workup gave 19
(0.132 g, 96%), which was used without further purification. A solution
of 12 (0.065 g, 0.13 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.7 mL)
was stirred at room temperature as described for 8 to give 18, which was
used without any further purification. As described for the synthesis of
12, a mixture of 19 (0.11 g, 0.13 mmol), HOBt (0.022 g, 0.16 mmol), and
EDCI (0.031 g, 0.16 mmol) in CH2Cl2 (2 mL) was stirred at 08C for
15 min followed by the addition of 18 and DIPEA (0.03 mL, 0.2 mmol).
Workup and purification by column chromatography (silica gel, 2.5%
MeOH in CHCl3) afforded 5 as a white solid (0.073 g, 46%). M.p. 160–
1628C; [a]D =ꢀ29.2 (c=0.32 in CHCl3); 1H NMR (CDCl3, 500 MHz and
600 MHz): d=7.88 (d, 1H, J=7.5 Hz; NH-5), 7.80 (d, 1H, J=7.1 Hz;
NH-3), 7.32 (d, 1H, J=9.7 Hz; NH-2), 7.19 (d, 1H, J=9.4 Hz; NH-4),
6.26 (d, 1H, J=8.1 Hz; NH-6), 5.89 (d, 1H, J=3.8 Hz; C1H-6), 5.87 (d,
2H, J=3.9 Hz; C1H-2, 4), 5.50 (d, 1H, J=7.2 Hz; NH-1), 4.59 (d, 1H,
J=3.9 Hz; C2H-6), 4.54 (d, 2H, J=4.0 Hz; C2H-4, 6), 4.52 (d, 1H, J=
3.9 Hz; C2H-2), 4.37 (m, 2H; CaH-3, 5), 4.32 (m, 1H; CdH-2), 4.30 (m,
1H; CdH-4), 4.25 (m, 1H; CdH-6), 4.20–4.14 (m, 1H; CaH-1), 4.08 (dd,
1H, J=3.3, 6.8 Hz; C4H-6), 4.01 (dd, 1H, J=3.4, 7.3 Hz; C4H-2), 3.99
(dd, 1H, J=3.4, 8.1 Hz; C4H-4), 3.68 (s, 3H; COOMe), 3.65 (d, 1H, J=
3.3 Hz; C3H-6), 3.62 (d, 1H, J=3.4 Hz; C3H-4), 3.57 (d, 1H, J=3.4 Hz;
C3H-2), 3.37 (s, 6H; 2ꢃOMe), 3.36 (s, 3H; OMe), 2.42 (m, 1H; CaH-2),
2.41 (m, 1H; CaH-4), 2.33 (m, 2H; CaH-6), 2.11 (m, 1H; Ca’H-4), 2.10
(m, 1H; Ca’H-2), 1.73 (m, 2H; CbH-6), 1.70 (m, 4H; CbH-2, 4), 1.55 (m,
2H; CgH-6), 1.52 (m, 1H; CgH-4), 1.49 (m, 1H; CgH-2), 1.43 (s, 9H;
Boc), 1.45 (s, 9H; 3ꢃMe), 1.39 (d, 3H, J=7.0 Hz; CH3-3), 1.36 (d, 3H,
J=7.1 Hz; CH3-1), 1.34 (m, 2H; CgH-2, 4), 1.33 (m, 3H; CH3-5), 1.30 (s,
6H; 2ꢃMe), 1.28 (s, 3H; Me); 13C NMR (CDCl3, 150 MHz): d=174.1,
174.0, 173.9, 173.6, 173.5, 156.1, 111.4, 111.3, 111.2, 105.0, 104.7, 84.5,
84.1, 83.9, 81.9, 81.8, 81.3, 81.2, 80.9, 79.7, 57.5, 57.3, 51.5, 50.5, 49.8, 49.5,
47.9, 47.7, 35.1, 34.9, 33.6, 31.9, 29.1, 28.3, 26.8, 26.7, 26.6, 26.3, 26.2, 26.1,
22.0, 21.9, 20.8, 17.9, 17.3, 17.0 ppm; 1H NMR (CD3OH, 600 MHz): d=
8.22 (d, 1H, J=7.0 Hz; NH-5), 8.20 (d, 1H, J=6.5 Hz; NH-3), 8.15 (d,
1H, J=9.7 Hz; NH-2), 8.01 (d, 1H, J=9.2 Hz; NH), 8.00 (d, 1H, J=
9.4 Hz; NH), 6.78 (d, 1H, J=7.2 Hz; NH-1), 5.82–5.79 (m, 3H; C1H-2, 4,
6), 4.67 (d, 1H, J=3.9 Hz; C2H-2), 4.66 (d, 2H, J=3.9 Hz; C2H-4, 6),
4.33–4.28 (m, 2H; CaH-3, 5), 4.21 (m, 1H; CdH-2), 4.19 (m, 2H; CdH-4,
6), 4.08 (m, 1H; CaH-1), 4.06 (dd, 2H, J=3.3, 9.1 Hz; C4H-4, 6), 4.03
(dd, 1H, J=3.3, 9.4 Hz; C4H-2), 3.69 (d, 1H, J=3.3 Hz; C3H-2), 3.67 (d,
2H, J=3.3 Hz; C3H-4, 6), 3.65 (s, 3H; COOMe), 3.38 (s, 3H; OMe), 3.37
(s, 6H; 2ꢃOMe), 2.39–2.28 (m, 3H; CaH-2, 4, 6), 2.21 (m, 1H; CaH-4,
6), 2.16 (m, 1H; CaH-6), 1.70 (m, 6H; CbH-2, 4, 6), 1.54 (m, 2H; CgH-4,
6), 1.53 (m, 1H; CgH-2), 1.45 (s, 3H; Me), 1.44 (s, 3H; Me), 1.43 (s, 9H;
Boc), 1.39 (m, 2H; CgH-4, 6), 1.34 (m, 1H; CgH-2), 1.35 (d, 1H, J=
856 cmꢀ1
;
HRMS (ESI): m/z calcd for C38H64N4O15Na [M++Na]:
839.4265; found: 839.4281.
Boc-d-Caa(x)-l-Ala-d-Caa(x)-l-Ala-d-Caa(x)-l-Ala-OMe (7): As described
for the synthesis of 9, a solution of 6 (0.08 g, 0.09 mmol) on treatment
with a 4n aqueous solution of NaOH (0.4 mL) and workup gave 20
(0.073 g, 94%), which was used without further purification. A solution
of 13 (0.029 g, 0.062 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.5 mL)
was stirred at room temperature as described for 8 to give 15, which was
used without any further purification. As described for the synthesis of
12, a mixture of 20 (0.05 g, 0.062 mmol), HOBt (0.01 g, 0.074 mmol), and
EDCI (0.014 g, 0.074 mmol) in CH2Cl2 (1.5 mL) was stirred at 08C for
15 min and treated with 15 and DIPEA (0.02 mL, 0.09 mmol). Workup
and purification by column chromatography (Silica gel, 3.4% MeOH in
CHCl3) afforded 7 as a white solid (0.034 g, 48%). M.p. 195–1978C;
[a]D =ꢀ28.33 (c=0.3 in CHCl3); 1H NMR (CDCl3, 500 MHz and
600 MHz): d=8.12 (d, 1H, J=7.5 Hz; NH-6), 7.7 (d, 1H, J=7.1 Hz; NH-
4), 7.23 (d, 1H, J=7.5 Hz; NH-2), 7.16 (d, 1H, J=9.7 Hz; NH-3), 6.97
(d, 1H, J=9.5 Hz; NH-5), 5.89 (d, 1H, J=3.9 Hz; C1H-5, 1), 5.88 (d, 1H,
J=3.9 Hz; C1H-3), 4.90 (d, 1H, J=8.3 Hz; NH-1), 4.64–4.59 (m, 1H;
CaH-6), 4.56 (d, 1H, J=3.9 Hz; C2H-5), 4.54 (d, 2H, J=3.9 Hz; C2H-1,
3), 4.53–4.48 (m, 1H; CaH-2), 4.34 (m, 1H; CdH-3), 4.27 (m, 1H; CdH-5),
4.23 (m, 1H; CaH-4), 4.02 (m, 1H; C4H-1), 4.00 (m, 2H; C4H-3, 5), 3.95–
3.90 (m, 1H; CdH-1), 3.74 (s, 3H; COOMe), 3.63 (d, 1H, J=3.3 Hz;
C3H-1), 3.60 (d, 1H, J=3.4 Hz; C3H-5), 3.58 (d, 1H, J=3.4 Hz; C3H-3),
3.36 (s, 3H; OMe), 3.35 (s, 3H; OMe), 3.34 (s, 3H; OMe), 2.48 (ddd,
1H, J=5.2, 8.6, 14.8 Hz; CaH-3), 2.40 (ddd, 1H, J=5.9, 7.4, 14.8 Hz;
CaH-5), 2.34–2.21 (m, 2H; CaH-1), 2.17 (ddd, 1H, J=6.4, 8.2, 14.4 Hz;
Ca’H-5), 2.03 (ddd, 1H, J=7.4, 8.4, 14.8 Hz; Ca’H-3), 1.81 (m, 2H; CgH-
1), 1.74 (m, 1H; CbH-5), 1.71 (m, 2H; CbH-1), 1.70 (m, 2H; CbH-3), 1.67
(m, 1H; Cb’H-5), 1.57 (m, 1H; CgH-5), 1.56 (s, 9H; Boc), 1.51 (m, 1H;
Cg’H-3), 1.49 (s, 3H; Me), 1.48 (s, 3H; Me), 1.47 (s, 6H; 2ꢃMe), 1.44 (s,
3H; Me), 1.43 (m, 1H; Cg’H-3), 1.42 (s, 3H; Me), 1.40 (d, 3H, J=7.2 Hz;
CH3-6), 1.39 (m, 1H; Cg’H-5), 1.37 (d, 3H, J=7.1 Hz; CH3-4), 1.35 ppm
Chem. Eur. J. 2009, 15, 5552 – 5566
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5563