Synthesis of Ureidopeptides and Oligourea/Peptide Hybrids
Boc-Ile-gVal-CO-Val-OBn (6g): Carbamate
FULL PAPER
5c (170 mg, (C), 172.9 (C) ppm. MALDI-TOF MS: m/z 598.46 [M + Na]+,
0.384 mmol) was treated with HCl·H-Val-OBn (103 mg,
0.423 mmol) and Hünig’s base (80 µL, 0.461 mmol) according to
the general procedure B to yield 6g (180 mg, 81%): white solid,
614.68 [M + K]+.
Boc-Ile- -gVal-CO-Pro-OMe (6k): Carbamate epi-5c (603 mg,
D
1.36 mmol) was treated with HCl·H-Pro-OMe (248 mg, 1.50 mmol)
and Hünig’s base (278 µL, 1.64 mmol) in MeCN according to the
general procedure B to yield 6k (497 mg, 80%): white solid, m.p.
170 °C. [α]2D0 = –20.6 (c = 1.0, DMF). HPLC: tR = 8.86 min (linear
gradient, 30–100% solvent B, 20 min). 1H NMR ([D6]DMSO,
500 MHz): δ = 0.76–0.81 (m, 12 H, 4 CH3), 1.01–1.10 (m, 1 H,
m.p. 180 °C (dec.). [α]2D5 = Ϫ 5.5 (c = 1.0, DMF). HPLC: tR
=
1
13.24 min (linear gradient, 30–100% solvent B, 20 min). H NMR
([D6]DMSO, 200 MHz): δ = 0.65–0.95 (m, 18 H, CH3CHCH3,
CH3CHCH2CH3), 0.95–1.18 (m, 1 H, CH3CHCH2CH3), 1.18–1.49
[m, 10 H, C(CH3)3, CH3CHCH2CH3], 1.49–1.71 (m,
CH3CHCH2CH3), 1.75–2.10 (m, 2 H, CH3CHCH3), 3.78 [br. t, J
7.3 Hz, H, CHCH(CH3)CH2CH3], 4.04–4.11 [m, H,
1 H,
CHCHCH2), 1.36 [s,
CHCHCH2), 1.61–1.69 (m, 1 H, CHCHCH2), 1.76–1.82 (m, 1 H,
CHCH2CH2), 1.82–1.88 (CHCH2CH2), 1.88–1.94 [m, H,
9 H, C(CH3)3], 1.32–1.40 (m, 1 H,
=
1
1
COCHCH(CH3)2], 4.99–5.23 [m, 3 H, OCH2OPh, NHCHNH),
6.38 [br. d, J = 9 Hz, 1 H, NHCO2C(CH3)3], 6.46–6.57 (m, 2 H,
CONHCHNHCONH), 7.22–7.44 (m, 5 H, arom. H), 8.01 (br. d,
J = 7.3 Hz, 1 H, CONHCHNHCONH) ppm. 13C NMR ([D6]-
DMSO, 50 MHz): δ = 10.9 (CH3), 15.2 (CH3), 17.6 (CH3), 18.1
(CH3), 18.9 (CH3), 24.1 (CH2), 28.0 (CH3), 30.2 (CH), 31.8 (CH),
36.7 (CH), 57.2 (CH) 57.7 (CH), 58.6 (CH), 65.6 (CH2), 77.8 (C),
127.8 (CH), 128.3 (CH), 135.9 (C), 155.1 (C), 156.8 (C), 170.3 (C),
172.3 (C) ppm. HRMS: calcd. for C28H47N4O6 [M + H]+ 535.3490;
found 535.3483.
1
CHCH(CH3)2], 2.05–2.12 (m, 1 H, CHCHCH2), 3.20–3.25 (m, 1
H, NCH2), 3.32–3.38 (m, 1 H, NCH2), 3.56 (s, 3 H, OMe), 3.71 (t,
J = 7.47 Hz, 1 H, CHCHCH2), 4.21 (dd, J = 8.60, 3.69 Hz, 1 H,
NCH), 5.00 [q, J = 8.12 Hz, 1 H, CH(CH3)2], 6.25 (d, J = 8.31 Hz,
1 H, NHCON), 6.64 (d, J = 8.34 Hz, 1 H, BocNH), 7.68 (d, J =
8.39 Hz, 1 H, CHCONH) ppm. 13C NMR ([D6]DMSO, 125 MHz):
δ = 10.9 (CH3), 15.1 (CH3), 18.1 (CH3), 18.3 (CH3), 23.8 (CH2),
24.0 (CH2), 27.9 (3 CH3), 28.9 (CH2), 31.9 (CH), 36.2 (CH), 45.2
(CH2), 51.3 (CH3), 58.2 (CH), 58.8 (CH), 61.6 (CH), 77.8 (C),
154.8 (C), 155.1 (C), 170.0 (C), 173.0 (C) ppm. HRMS: calcd. for
C22H40N4O6 [M + Li]+ 463.3103; found 463.3106.
Boc-Pro-gAla-CO-Leu-OMe
(6i):
Carbamate
5g
(1.0 g,
2.508 mmol) was treated with HCl·H-Leu-OMe (501 mg,
2.76 mmol) and Hünig’s base (640 µL, 3.67 mmol) according to the
general procedure B to yield 6i (790 mg, 74%): white solid, m.p.
167 °C. [α]2D5 = –32.5 (c = 0.9, DMF). HPLC: tR = 7.57 min (linear
gradient, 30–100% solvent B, 20 min). 1H NMR ([D6]DMSO,
300 MHz): δ = 0.79 (d, J = 6.1 Hz, 3 H, CH3), 0.83 (d, J = 6.5 Hz,
Z-gPhe-CO-Val-OMe (6n): Carbamate 4h (520 mg, 1.26 mmol)
was treated with HCl·H-Val-OMe (317 mg, 1.89 mmol) and
Hünig’s base (324 µL, 1.89 mmol) according to the general pro-
cedure B to yield 6n (467 mg, 86%): white solid, m.p. 181 °C.
[α]2D5 = –3.6 (c = 1.0, DMF). HPLC: tR = 10.74 min (linear gradient,
1
3 H, CH3), 1.21 (d, J = 6.5 Hz, 3 H, CH3), 1.27–1.61 [m, 12 H, 30–100% solvent B, 20 min). H NMR ([D6]DMSO, 300 MHz): δ
C(CH3)3, CH2CH(CH3)2], 1.55–1.84 (m, 3 H, CH2CH2CH2CH), = 0.76 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 0.77 [d, J = 6.8 Hz, 3 H,
1.91–2.10 (m,
NCH2CH2), 3.56 (s, 3 H, OCH3), 3.87–4.01 (m, 1 H, NHCHCO), H, CHCH2Ph), 3.58 (s,
4.08–4.21 (m, 1 H, NHCHCO), 5.11–5.28 (m, 1 H, NHCHNH), CHCH(CH3)2], 4.95 (s, 2 H, OCH2Ph), 5.15 (br. t, J = 7.5 Hz, 1
3
H, CH2CH2CH2CH), 3.15–3.42 (m,
2
H, CH(CH3)2], 1.78–2.01 [m, 1 H, CH(CH3)2], 2.87 (d, J = 5.9 Hz, 2
3
H, OCH3), 4.00–4.06 [m, H,
1
6.31 (br. d, J = 7.7 Hz, 1 H, NHCONH), 6.44 (br. d, J = 8.0 Hz,
1 H, NHCONH), 8.16 (br. d, J = 7.4 Hz, 1 H, NHCOCH) ppm.
H, CHCH2Ph), 6.39 (br. d, J = 8.6 Hz, 1 H, NHCO), 6.52 (br. d,
J = 8.1 Hz, 1 H, NHCO), 7.14–7.32 (m, 10 H, arom. H), 7.74 (br.
13C NMR ([D6]DMSO, 75 MHz): δ = 21.4 (CH3), 21.6 (CH3), 22.6 d, J = 7.2 Hz, 1 H, NHCO) ppm. 13C NMR ([D6]DMSO, 75 MHz):
(CH3), 23.1 (CH2), 24.2 (CH), 27.9 (CH), 28.1 (CH3), 30.9 (CH2), δ = 17.7 (CH3), 18.9 (CH3), 30.5 (CH), 40.9 (CH2), 51.5 (CH3),
41.1 (CH2), 46.4 (CH2), 50.6 (CH2), 51.6 (CH), 53.1 (CH), 59.5
(CH3), 78.3 (C), 153.2 (C), 156.0 (C), 171.7 (C), 173.8 (C) ppm.
MALDI-TOF MS: m/z 451.08 [M + Na]+, 467.51 [M + K]+.
57.3 (CH), 65.0 (CH2), 126.2 (C), 127.6(C), 127.7 (C), 128.0 (C),
128.3 (C), 129.1 (C), 129.2 (C), 137.0 (C), 137.6 (C), 155.0 (C),
156.2 (C), 173.0 (C) ppm. MALDI-TOF MS: m/z 378.1 [M +
Na]+, 394.0 [M + K]+.
Boc-Pro-gLeu-CO-Ala-Phe-OMe (6j): Carbamate 5f (300 mg,
0.68 mmol) was treated with TFA·H-Ala-Phe-OMe (273 mg,
0.75 mmol) and Hünig’s base (142 µL, 0.82 mmol) in MeCN ac-
cording to the general procedure B to yield 6j (274 mg, 70%): white
Z-Ala-gLeu-CONHiPr (6p): Carbamate 5s (0.50 g, 1.11 mmol) was
treated with isopropylamine (0.28 mL, 3.35 mmol) according to the
general procedure B to yield 6p (0.38 g, 88%): white solid, m.p.
172 °C. [α]2D0 = +6.0 (c = 0.5, DMF). HPLC: tR = 8.67 min (linear
gradient, 30–100% solvent B, 20 min). 1H NMR ([D6]DMSO,
300 MHz): δ = 0.84 [d, J = 5.88 Hz, 6 H, CH2CH(CH3)2], 0.98–
1.02 [m, 6 H, NHCH(CH3)2], 1.17 (d, J = 7.14 Hz, 3 H, CHCH3),
137–1.59 [m, 3 H, CH2CH(CH3)2, CH2CH(CH3)2], 3.56–3.72 [m,
1 H, NHCH(CH3)2], 3.97 [quint., J = 7.12 Hz, 1 H, NHCH-
(CH3)2], 4.98 (d, J = 12.46 Hz, 1 H, CH2Phe), 5.03 (d, J =
12.47 Hz, 1 H, CH2Phe), 5.14–5.23 (m, 1 H, NHCHNH), 5.94 [d,
J = 7.51 Hz, 1 H, NHCH(CH3)2], 6.07 [d, J = 8.53 Hz, 1 H,
NHCONHCH(CH3)2], 7.29–7.35 (m, 5 H, arom. H), 7.39 (d, J =
7.78 Hz, 1 H, NHCHCO), 8.10 (d, J = 7.82 Hz, 1 H, NHCHNH)
ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 23.4 (CH3), 27.4 (CH3),
27.6 (CH3), 28.3 (CH3), 28.4 (CH3), 29.4 (CH), 46.0 (CH), 48.9
(CH), 55.2 (CH), 60.4 (CH), 70.5 (CH2), 132.9 (2 CH), 133.0 (CH),
133.5 (2 CH), 142.2 (C), 160.8 (C), 161.4 (C), 177.2 (C) ppm.
HRMS: calcd. for C20H32N4O4 [M + Li]+ 399.2579; found
399.2572.
solid, m.p. 185 °C. [α]2D5 = –15.9 (c = 1.0, DMF). HPLC: tR
=
7.57 min (linear gradient, 30–100% solvent B, 20 min). 1H NMR
([D6]DMSO, 500 MHz): δ = 0.83–0.86 [m, 7 H, CH(CH3)2,
CH(CH3)2], 1.11 (d, J = 6.86 Hz, 3 H, CHCH3), 1.26 [s, 9 H,
C(CH3)3], 1.36–1.41 [m, 1 H, CH2CH(CH3)2], 1.48–1.57 [m, 1 H,
CH2CH(CH3)2], 1.68–1.79 (m, 3 H, CHCH2CH2, CHCH2CH2),
1.94–2.10 (m, 1 H, CHCH2CH2), 2.90 (dd, J = 13.85, 9.37 Hz, 1
H, CH2Ph), 3.02 (dd, J = 13.90, 5.35 Hz, 1 H, CH2Ph), 3.21–3.26
(m, 1 H, NCH2), 3.30–3.36 (m, 1 H, NCH2), 3.58 (s, OCH3), 3.99
(dd, J = 25.19, 7.97 Hz, 1 H, NCH), 4.15–4.21 (m, 1 H,
NHCHCH3), 4.41–4.45 (m, 1 H, CHCOOMe), 5.21 (quint, J =
7.60 Hz, 1 H, NHCHNH), 6.25 (br. s, 1 H, NHCHCH3), 6.43 (d,
J = 8.44 Hz, 1 H, NHCONHCHCH3), 7.18–7.29 (m, 5 H, arom.
H), 7.97 (br. s, 1 H, NCHCONH), 8.35 (d, J = 7.37 Hz, 1 H,
NHCHCOOMe) ppm. 13C NMR ([D6]DMSO, 125 MHz): δ = 21.9
(CH3), 22.2 (CH3), 22.7 (CH2), 23.9 (CH3), 27.6 (3 CH3), 27.9
(CH), 30.8 (CH2), 36.3 (CH2), 43.5 (CH2), 46.2 (CH2), 47.8 (CH3),
51.6 (CH), 53.4 (CH), 54.9 (CH), 59.3 (CH), 78.1 (C), 126.3 (CH),
Peptidyl Hydantoin (7a): Ureidopeptide ester 6f (100 mg,
128.0 (2 CH), 128.8 (2 CH), 136.9 (C), 153.1 (C), 155.6 (C), 171.6 0.22 mmol) was stirred with a solution of 10% Et3N in MeOH.
Eur. J. Org. Chem. 2007, 2511–2525
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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