D. Becker, U. Kazmaier
FULL PAPER
3 H), 2.25 (td, J = 6.9, 6.9 Hz, 2 H), 2.31 (m, 2 H), 2.43 (m, 2 H),
2.76 (dd, J = 15.6, 7.0 Hz, 1 H), 2.85 (dd, J = 16.6, 8.8 Hz, 1 H),
2.92 (s, 3 H), 3.21 (dd, J = 15.7, 10.2 Hz, 1 H), 3.45 (dd, J = 15.8,
5.8 Hz, 1 H), 3.97 (t, J = 7.2 Hz, 2 H), 4.38 (dq, J = 6.8 Hz, 1 H),
AcOH] gave rise to 16b (0.23 g, 0.26 mmol, 96%) as a pale yellow
foam. Rf = 0.29 [petroleum ether/ethyl acetate (1:1) + 1% AcOH].
83:17 Mixture of diastereomers. Major diastereomer: 1H NMR
(400 MHz, CDCl3): δ = 0.23 (s, 6 H), 0.95 (d, J = 7.5 Hz, 3 H),
4.56 (ddd, J = 5.8, 1.3, 1.3 Hz, 2 H), 5.09 (t, J = 7.0 Hz, 1 H), 1.02 (s, 9 H), 1.41 (s, 9 H), 1.64 (s, 3 H), 2.23 (m, 1 H), 2.28–2.38
5.20–5.36 (m, 4 H), 5.60 (dd, J = 9.9, 5.7 Hz, 1 H), 5.90 (ddt, J =
17.1, 10.3, 5.8 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.96–7.12 (m, 4
(m, 3 H), 2.47 (m, 2 H), 2.67 (dd, J = 15.6, 4.5 Hz, 1 H), 2.84 (dd,
J = 16.0, 9.3 Hz, 1 H), 2.99 (s, 3 H), 3.20 (dd, J = 15.6, 9.5 Hz, 1
H), 7.16 (dd, J = 8.0, 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.38 H), 3.37 (dd, J = 15.2, 6.4 Hz, 1 H), 3.98 (m, 2 H), 4.47 (dq, J =
(d, J = 1.8 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 8.16 (br. s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = –4.3, 16.0, 17.0, 18.3, 23.2, 25.7,
27.3, 28.3, 30.8, 32.9, 34.5, 40.3, 46.6, 49.0, 56.7, 64.1, 65.1, 79.8,
6.8, 6.8 Hz, 1 H), 5.19 (t, J = 7.0 Hz, 1 H), 5.29 (m, 1 H), 5.47–
5.54 (m, 2 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.92 (s, 1 H), 7.05 (dd, J
= 8.5, 2.3 Hz, 1 H), 7.09 (dd, J = 7.8, 7.8 Hz, 1 H), 7.16 (dd, J =
111.0, 111.1, 115.3, 118.2, 118.5, 119.4, 119.8, 120.0, 122.0*, 7.5, 7.5 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.36 (br. s, 1 H), 7.39
122.1*, 126.4, 127.4, 131.2, 132.2, 134.9, 136.1, 136.6, 151.9, 155.6,
169.3, 170.4, 172.9, 174.3 ppm. (* determined from CH-COSY).
Minor diastereomer (selected signals): 1H NMR (400 MHz,
(d, J = 8.0 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 8.13 (br. s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = –4.4, 15.9, 17.5, 18.3, 23.4, 25.7,
27.2, 28.3, 30.9, 32.8, 34.7, 40.1, 46.7, 49.1, 56.7, 64.2, 79.8, 110.7,
CDCl3): δ = 1.01 (s, 9 H), 1.44 (s, 9 H), 1.60 (s, 3 H), 3.14 (m, 1 111.1, 115.3, 118.5, 119.4, 120.0, 121.0, 122.0, 122.2, 126.5, 127.2,
H), 3.40 (m, 1 H), 3.91 (t, J = 7.3 Hz, 2 H), 6.80 (d, J = 8.3 Hz, 1 131.2, 135.2, 136.0, 136.1, 151.8, 155.5, 169.4, 170.4, 174.3,
H), 8.22 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.4,
49.1, 136.5, 172.9 ppm. HPLC [hexane/iPrOH (3:7) for 10 min,
175.5 ppm. Minor diastereomer (selected signals): 1H NMR
(400 MHz, CDCl3): δ = 0.22 (s, 6 H), 0.90 (d, J = 8.0 Hz, 3 H),
1.02 (s, 9 H), 1.43 (s, 9 H), 1.62 (s, 3 H), 2.80 (s, 3 H), 3.13 (m, 1
then in 5 min to 1:9, 1 mL/min]: tR = 12.88 min [(R)-15b], tR
=
30.25 min [(S)-15b]. HRMS (CI): m/z calcd. C46H66BrN4O9Si [M H), 3.43 (m, 1 H), 4.41 (m, 1 H), 5.36 (m, 1 H), 5.60 (dd, J = 9.5,
+ H]+ 925.3777; found 925.3817.
6.0 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.98 (s, 1 H), 8.21 (br. s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 34.3, 49.3, 56.7, 120.1,
126.4, 175.6 ppm. HPLC/MS (H2O/ACN, 3:7, 20 min, 0.6 mL/
min): tR = 14.58 min [(R)-16b], tR = 15.15 min [(S)-16b], m/z calcd.
[C43H61BrN4O9Si + Na]+ 907; found 907. HRMS (CI): m/z calcd.
C43H62BrN4O9Si [M + H]+ 885.3464; found 885.3495
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-tryptophanyl-(R)-3-
chloro-4-(tert-butyldimethylsilyloxy)-β-phenylalanine-{[(E)-4-meth-
ylhept-4-enoic acid]-7-yl} Ester (16a): According to N,O-protected
amino acid 8b, 16a was prepared from tripeptide 15a (0.44 g,
0.50 mmol), Pd(PPh3)4 (57.0 mg, 0.05 mmol) and morpholine
(0.09 mL, 0.99 mmol) in abs. THF (10 mL). Purification by flash
chromatography [petroleum ether/ethyl acetate (6:4 to 1:1) + 1%
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-2-chlorotrypto-
phanyl-(R)-3-chloro-4-(tert-butyldimethylsilyloxy)-β-phenylalanine-
AcOH] gave rise to 16a (0.40 g, 0.48 mmol, 96%) as a pale yellow {[(E)-4-methylhept-4-enoic acid]-7-yl} Ester (16c): According to
foam. Rf = 0.26 [petroleum ether/ethyl acetate (1:1) + 1% AcOH].
N,O-protected amino acid 8b, 16c was prepared from tripeptide 14a
73:27 Mixture of diastereomers. Major diastereomer: 1H NMR (0.32 g, 0.35 mmol), Pd(PPh3)4 (40.0 mg, 35.0 μmol) and morph-
(400 MHz, CDCl3): δ = 0.21 (s, 6 H), 0.97 (d, J = 6.8 Hz, 3 H), oline (61 μL, 0.70 mmol) in abs. THF (3.5 mL). Purification by
1.02 (s, 9 H), 1.41 (s, 9 H), 1.64 (s, 3 H), 2.21–2.39 (m, 4 H), 2.48
flash chromatography [petroleum ether/ethyl acetate (7:3 to 1:1) +
(m, 2 H), 2.67 (dd, J = 17.4, 6.2 Hz, 1 H), 2.84 (dd, J = 16.0,
1% AcOH] gave rise to 16c (0.30 g, 0.34 mmol, 97%) as a colorless
9.3 Hz, 1 H), 2.99 (s, 3 H), 3.20 (dd, J = 15.3, 9.5 Hz, 1 H), 3.37 foam. Rf = 0.14 [petroleum ether/ethyl acetate (7:3) + 1% AcOH].
(dd, J = 14.8, 6.3 Hz, 1 H), 3.98 (m, 2 H), 4.48 (dq, J = 6.8, 6.8 Hz,
[α]2D0 = +7.4 (c = 1.5, CHCl3). 91:9 Mixture of diastereomers. Major
1 H), 5.19 (t, J = 7.0 Hz, 1 H), 5.31 (m, 1 H), 5.46–5.54 (m, 2 H), diastereomer: 1H NMR (400 MHz, CDCl3): δ = 0.22 (s, 6 H), 0.70
6.77 (d, J = 8.5 Hz, 1 H), 6.92 (s, 1 H), 7.01 (dd, J = 8.5, 2.3 Hz, (d, J = 6.8 Hz, 3 H), 1.02 (s, 9 H), 1.38 (s, 9 H), 1.64 (s, 3 H), 2.21
1 H), 7.09 (dd, J = 7.9, 7.9 Hz, 1 H), 7.16 (dd, J = 7.5, 7.5 Hz, 1
H), 7.21 (d, J = 2.3 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.33 (br.
s, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 8.09 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = –4.4, 15.9, 17.5, 18.3, 23.4, 25.6, 27.2, 28.3,
(m, 1 H), 2.28–2.41 (m, 3 H), 2.48 (m, 2 H), 2.68 (dd, J = 15.8,
5.5 Hz, 1 H), 2.85 (dd, J = 16.0, 9.3 Hz, 1 H), 3.01 (s, 3 H), 3.22
(dd, J = 15.1, 10.0 Hz, 1 H), 3.30 (dd, J = 15.6, 6.5 Hz, 1 H), 3.98
(m, 2 H), 4.37 (dq, J = 7.0, 7.0 Hz, 1 H), 5.18 (t, J = 7.0 Hz, 1 H),
30.9, 32.8, 34.7, 40.1, 46.8, 49.2, 56.7, 64.2, 79.8, 110.7, 111.1, 5.27–5.32 (m, 2 H), 5.63 (dd, J = 9.8, 6.0 Hz, 1 H), 6.77 (d, J =
118.5, 119.4, 120.6, 120.6, 122.1, 122.3, 125.5, 125.7, 127.2, 128.2,
134.9, 136.1, 136.2, 150.8, 155.5, 169.4, 170.4, 174.3 ppm. Minor
diastereomer (selected signals): H NMR (400 MHz, CDCl3): δ =
0.20 (s, 6 H), 0.91 (d, J = 7.0 Hz, 3 H), 1.01 (s, 9 H), 1.43 (s, 9 H),
1.62 (s, 3 H), 2.80 (s, 3 H), 3.14 (m, 1 H), 3.42 (m, 1 H), 4.40 (m,
1 H), 5.14 (t, J = 6.5 Hz, 1 H), 5.59 (dd, J = 9.5, 6.3 Hz, 1 H), 6.82
(d, J = 8.5 Hz, 1 H), 8.16 (br. s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.2, 34.3, 39.9, 46.6, 121.0, 125.5, 125.6, 127.3, 128.4,
135.0, 170.2 ppm. HPLC/MS (H2O/ACN, 3:7, 20 min, 0.6 mL/
8.3 Hz, 1 H), 7.03 (dd, J = 9.0, 2.5 Hz, 1 H), 7.07 (dd, J = 8.0,
8.0 Hz, 1 H), 7.12 (dd, J = 7.8, 7.8 Hz, 1 H), 7.19–7.23 (m, 2 H),
7.31 (d, J = 7.0 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 8.06 (br. s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.3, 15.9, 17.6, 18.3,
22.5, 25.6, 27.2, 28.3, 31.3, 32.8, 34.7, 40.2, 46.6, 49.3, 55.7, 64.2,
79.8, 107.0, 110.4, 118.3, 120.2, 120.6, 120.9, 121.7, 122.4, 125.5,
125.8, 127.3, 128.2, 134.3, 134.8, 136.1, 150.8, 155.5, 169.3, 170.3,
1
1
174.2, 175.5 ppm. Minor diastereomer (selected signals): H NMR
(400 MHz, CDCl3): δ = 1.41 (s, 9 H), 1.66 (s, 3 H), 2.21 (m, 1 H),
min): tR = 13.65 min [(R)-16a], tR = 14.40 min [(S)-16a], m/z calcd. 2.72 (s, 3 H), 2.77 (m, 1 H), 2.77 (m, 1 H), 4.06 (m, 2 H), 4.52 (m,
[C43H61ClN4O9Si + Na]+ 864; found 864. HRMS (CI): m/z calcd.
1 H), 5.02 (m, 1 H), 5.46 (m, 1 H) ppm. HPLC/MS (H2O/ACN,
2:8, 20 min, 0.6 mL/min): tR = 2.78 min [(R/S)-16c], m/z calcd.
[C43H60Cl2N4O9Si + Na]+ 897; found 897. HRMS (CI): m/z calcd.
C43H61Cl2N4O9Si [M + H]+ 875.3579; found 875.3621.
C43H60ClN4O9Si [M – H]– 839.3824; found 839.3816.
N-tert-Butoxycarbonyl-(S)-alanyl-N-methyl-(R)-tryptophanyl-(R)-3-
bromo-4-(tert-butyldimethylsilyloxy)-β-phenylalanine-{[(E)-4-meth-
ylhept-4-enoic acid]-7-yl} Ester (16b): According to N,O-protected
amino acid 8b, 16b was prepared from tripeptide 15b (0.25 g,
(4R,7R,10S,E)-7-(1H-indol-3-ylmethyl)-4-(4-tert-butyldimethylsilyl-
oxy-3-chlorophenyl)-8,10,15-trimethyl-1-oxa-5,8,11-triazacycloocta-
0.27 mmol), Pd(PPh3)4 (31.0 mg, 37.0 μmol) and morpholine dec-15-ene-2,6,9,12-tetraone (17a): To a solution of tripeptide 16a
(46.0 μL, 0.53 mmol) in abs. THF (5 mL). Purification by flash (0.25 g, 0.30 mmol) in abs. CH2Cl2 (2.6 mL) TFA (1.16 mL,
chromatography [petroleum ether/ethyl acetate (6:4 to 1:1) + 1% 15.1 mmol) was added at –20 °C and the mixture was stirred for
2600
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Eur. J. Org. Chem. 2015, 2591–2602