The Journal of Organic Chemistry
Article
Cbz-L-Pro-Aib3-AibCH2OH (5c). According to general procedure 1,
Cbz-L-Pro-OH (157 mg, 0.63 mmol), H-Aib3-AibCH2OH (216 mg,
0.63), PyBOP (328 mg, 0.63 mmol), and i-Pr2NEt (0.27 mL, 204 mg,
1.58 mmol) in CH2Cl2 (6.5 mL) were used. After purification by
column chromatography (EtOAc), peptide Cbz-L-Pro-Aib3-Aib-
CH2OH was obtained as a white solid (243 mg, 67%): Rf (SiO2/
(s, 3H), 1.39 (s, 6H), 1.37 (s, 6H), 1.31 (s, 6H), 1.05 (s, 9H) ppm;
13C NMR (100 MHz, CD3OD) δ 177.4, 176.7, 176.4, 173.0, 158.6,
139.0, 138.2, 136.8, 136.7, 136.6, 134.1, 134.0, 131.2, 131.0, 130.9,
130.5, 130.0, 129.6, 129.3, 129.2, 129.0, 128.9, 128.8, 128.6, 69.5, 67.9,
64.5, 58.4, 58.3, 57.92, 57.9, 56.4, 27.4, 26.8, 26.3, 26.2, 25.0, 24.6,
24.5, 24.1, 23.9 ppm; IR (film) 3310, 2976, 2940, 1665, 1530, 1460,
1384, 1365, 1270, 1230, 1170, 1069 cm−1; MS (ES+, MeOH) 804
[M + H]+ (100); HRMS (ES+, MeOH) calcd for C43H61N5O8Si + H
804.4368, found 804.4372.
p-BrBz-L-Phe-Aib3-AibCH2OH (5g). From a solution of the peptide
Cbz-L-Phe-Aib3-AibCH2OH (5a) (88 mg, 0.14 mmol) and Pd/C
(8.8 mg, 10%) in EtOH (1.4 mL) under H2 atmosphere following
general procedure 2 (2 h) was obtained the deprotected peptide H-L-
Phe-Aib3-AibCH2OH (69 mg, 100%). From a solution of H-L-Phe-
Aib3-AibCH2OH (54 mg, 0.11 mmol), i-Pr2NEt (38 μL, 28 mg,
0.22 mmol), and p-BrBzCl (26 mg, 0.12 mmol) in dry CH2Cl2 (1.1 mL)
following general procedure 1 (3 h) and after purification by column
chromatography (EtOAc/petroleum ether, 80:20), peptide p-BrBz-L-
Phe-Aib3-AibCH2OH was obtained as a white solid (46 mg, 64%): Rf
EtOAc) = 0.16; mp = 88−90 °C; [α]20 = −28.2 (c = 1.05, CHCl3);
D
1H NMR (500 MHz, CD3OD) δ 7.67 (brs, 1H), 7.36 (s, 2H), 7.35 (s,
2H), 7.24 (m, 1H), 7.12 (brs, 1H), 7.05 (brs, 1H), 5.16 (A of AB, J =
12.5 Hz, 1H), 5.09 (B of AB, J = 12.5 Hz, 1H), 4.63 (s, 1H), 4.20 (dd,
J = 8.0, 6.0 Hz, 1H), 3.66 (A of AB, J = 11.5 Hz, 1H), 3.57 (t, J =
6.5 Hz, 2H), 3.51 (B of AB, J = 11.5 Hz, 1H), 2.21−2.33 (m, 1H),
2.00−2.09 (m, 1H), 1.88−1.95 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H),
1.40 (s, 3H), 1.393 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.31 (s, 6H)
ppm; 13C NMR (125 MHz, CD3OD) δ 177.3, 176.8, 176.6, 175.0,
156.8, 138.0, 129.7, 129.2, 128.7, 69.5, 68.2, 58.2, 57.9, 57.6, 56.4, 48.2,
31.2, 26.8, 26.3, 26.1, 25.6, 25.0, 24.3, 24.2, 24.1, 23.8 ppm; IR (film)
3323, 2984, 2938, 1671, 1532, 1450, 1422, 1385, 1361, 1218, 1167,
1126 cm−1; MS (ES+, MeOH) 598 [M + Na]+ (100), 576 ([M + H]+,
80). HRMS (ES+, MeOH) calcd for C29H45N5O7 + Na 598.3211,
found 598.3193.
(SiO2/EtOAc/petroleum ether 90:10) = 0.16; mp = 124−128 °C;
1
[α]20 = −24.3 (c = 1.2, CHCl3); H NMR (500 MHz, CD3OD) δ
D
Cbz-L-Leu-Aib3-AibCH2OH (5d). According to general procedure 1,
Cbz-L-Leu-OH (85 mg, 0.32 mmol), H-Aib3-AibCH2OH (110 mg,
0.32), PyBOP (166 mg, 0.32 mmol), and i-Pr2NEt (0.11 mL, 83 mg,
0.64 mmol) in CH2Cl2 (3.2 mL) were used. After purification by
column chromatography (EtOAc), peptide Cbz-L-Leu-Aib3AibCH2OH
7.75 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.58 (brs, 1H), 7.32
(m, 5H), 7.27−7.25 (m, 2H), 6.99 (brs, 1H), 4.54 (t, J = 8.0 Hz, 1H),
3.69 (A of AB, 1 H, J = 11.5 Hz, 1H), 3.45 (B of AB, J = 11.5 Hz, 1H),
3.17 (d, J = 14.0 Hz, 1H), 3.12 (d, J = 14.0 Hz, 1H), 1.41 (s, 3H), 1.34
(s, 3H), 1.33 (s, 3H), 1.30 (s, 6H), 1.29 (s, 3H), 1.26 (s, 3H), 1.24 (s,
3H) ppm; 13C NMR (75 MHz, CD3OD) δ 177.4, 176.6, 174.2, 169.4,
138.1, 133.0, 132.9, 130.6, 130.5, 129.6, 128.0, 127.6, 69.5, 58.2, 57.9,
57.7, 56.5, 37.9, 27.5, 27.0, 26.6, 24.2, 23.82, 23.8, 23.6 ppm; IR (film)
3331, 2986, 2927, 1653, 1534, 1420, 1381, 1363, 1228, 1070,
1011 cm−1; MS (ES+ MeOH) 698 [M + Na]+ (100); HRMS (ES+,
MeOH) calcd for C32H44N5O679Br + Na 696.2367, found 696.2357.
p-BrBz-L-Val-Aib3-AibCH2OH (5h). From a solution of the peptide
Cbz-L-Val-Aib3-AibCH2OH (5b) (108 mg, 0.19 mmol) and Pd/C
(10.8 mg, 10%) in EtOH (1.8 mL) under H2 atmosphere following
general procedure 2 (3 h) was obtained the deprotected peptide H-L-
Val-Aib3-AibCH2OH (84 mg, 100%). From a solution of H-L-Val-Aib3-
AibCH2OH (84 mg, 0.19 mmol), i-Pr2NEt (66 μL, 49 mg, 0.38 mmol),
and p-BrBzCl (46 mg, 0.21 mmol) in dry CH2Cl2 (1.9 mL) following
general procedure 2 (3 h) and after purification by column chro-
matography (EtOAc/petroleum ether, 80:20), peptide p-BrBz-L-Val-
Aib3-AibCH2OH was obtained as a white solid (141 mg, 90%): Rf
was obtained as a white solid (170 mg, 91%): Rf (SiO2/EtOAc) = 0.24;
1
mp = 138−140 °C; [α]20 = −17.4 (c = 1.0, CHCl3); H NMR (500
D
MHz, CD3OD) δ 7.73 (brs, 1H), 7.36−7.29 (m, 6H), 7.09 (brs, 1H),
5.10 (s, 2H), 4.00 (dd, J = 9.0, 6.0 Hz, 1H), 3.64 (A of AB, J = 11.5 Hz,
1H), 3.54 (B of AB, J = 11.5 Hz, 1H), 1.78−1.67 (m, 2H), 1.60−1.48
(m, 2H), 1.43 (s, 3H), 1.40 (s, 6H), 1.38 (s, 6H), 1.34 (s, 3H), 1.32 (s,
6H), 0.97 (d, J = 17.0 Hz, 3H), 0.95 (d, J = 17.0 Hz, 3H) ppm; 13C
NMR (75 MHz, CD3OD) δ 177.5, 177.4, 176.6, 176.5, 158.8, 138.3,
129.6, 129.1, 128.6, 69.5, 67.7, 58.3, 57.8, 57.6, 56.5, 55.4, 41.2, 26.6,
26.0, 25.9, 25.7, 25.2, 24.7, 24.5, 24.1, 23.9, 23.3, 22.1 ppm; IR (film)
3318, 3323, 2959, 2483, 1660, 1531, 1470, 1454, 1417, 1380, 1362,
1260, 1049 cm−1; MS (ES+, MeOH) 614 [M + Na]+ (100); HRMS
(ES+, MeOH) calcd for C30H49O7N5 + Na 614.3524, found 614.3502.
Cbz-L-Ser-Aib3-AibCH2OH (5e). According to general procedure 1,
Cbz-L-Ser-OH (189 mg, 0.79 mmol), H-Aib3-AibCH2OH (274 mg,
0.79), PyBOP (414 mg, 0.79 mmol), and i-Pr2NEt (0.34 mL, 255 mg,
1.97 mmol) were used. After purification by column chromatography
(CH2Cl2/EtOH, 98:2), peptide Cbz-L-Ser-Aib3-AibCH2OH was
obtained as a white solid (125 mg, 28%): Rf (SiO2/CH2Cl2/EtOH
98:2) = 0.17; mp = 104−106 °C; [α]20D = −12.0 (c = 0.9, CHCl3); 1H
NMR (500 MHz, CD3OD) δ 7.91 (brs, 1H), 7.67 (brs, 1H), 7.38−
7.29 (m, 7H), 7.07 (brs, 1H), 5.10 (s, 2H), 4.13 (t, J = 5.5 Hz, 1H),
3.83 (dd, J = 11.0, 5.5 Hz, 1H), 3.76 (dd, J = 11.0, 5.5 Hz, 1H), 3.60
(A of AB, J = 12.0 Hz, 1H), 3.58 (B of AB, J = 12.0 Hz, 1H), 1.43 (s,
3H), 1.42 (s, 6H), 1.40 (s, 3H), 1.36 (s, 3H), 1.36 (s, 3H), 1.32 (s,
6H) ppm; 13C NMR (125 MHz, CDCl3) δ 176.0, 175.1, 174.3, 171.5,
156.6, 136.1, 128.4, 128.3, 128.0, 69.0, 67.1, 62.4, 57.4, 57.1, 56.9, 56.7,
55.6, 25.5, 25.3, 25.2, 25.1, 24.9, 23.9 ppm; IR (film) 3320, 2986, 2940,
1659, 1531, 1457, 1385, 1364, 1266, 1229, 1167, 1059 cm−1; MS (ES+,
MeOH) 588 [M + Na]+ (100), 566 [M + H]+ (85); HRMS (ES+,
MeOH) calcd for C27H43N5O8 + H 566.3184, found 566.3180.
Cbz-L-Ser(OTBDPS)-Aib3-AibCH2OH (5f). Cbz-L-Ser-Aib3-Aib-
CH2OH (31 mg, 0.06 mmol), imidazole (5.0 mg, 0.07 mmol), and
DMAP (one crystal) were dissolved in CH2Cl2 (1.0 mL). TBDPSCl
(17 μL, 0.07 mmol) was then added and the mixture stirred for 2 days.
A mixture of starting material and the two possible monoprotected
alcohols was obtained. This mixture was purified by column chroma-
tography (CH2Cl2/EtOH, 98:2) to yield Cbz-L-Ser(OTBDPS)-Aib3-
AibCH2OH as a colorless oil (11 mg, 25%): Rf (SiO2/CH2Cl2/EtOH
(SiO2/EtOAc/petroleum ether 90:10) = 0.21; mp = 158−160 °C;
1
[α]20 = −22.9 (c = 1.1, CHCl3); H NMR (500 MHz, CD3OD) δ
D
7.80 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 6.99 (s, 1 H), 4.01
(d, J = 8.5 Hz, 1 H), 3.69 (d, J = 11.5 Hz, 1 H), 3.45 (d, J = 11.5 Hz,
1 H), 2.17 (m, 1H), 1.47 (s, 3 H), 1.45 (s, 3 H), 1.43 (s, 3 H), 1.33 (s,
3 H), 1.30 (s, 9 H), 1.23 (s, 3 H), 1.12 (d, J = 6.5 Hz, 3H), 1.06 (d, J =
6.5 Hz, 3 H) ppm; 13C NMR (100 MHz, CD3OD) δ 177.4, 176.8,
176.7, 174.5, 169.7, 134.0, 132.9, 130.6, 127.6, 69.4, 62.6, 58.2, 57.9,
57.8, 56.4, 30.7, 27.5, 27.0, 26.6, 24.21, 24.2, 23.8, 23.6, 20.3, 19.7 ppm;
IR (film) 3333, 2963, 1652, 1538, 1471, 1385, 1362, 1260, 1218, 1055,
1012 cm−1; MS (ES+) 649 [M + Na]+ (100); HRMS (ES+, MeOH)
calcd for C28H44N5O679Br + Na+ 648.2367, found 648.2352.
p-BrBz-L-Leu-Aib3-AibCH2OH (5i). From a solution of the peptide
Cbz-L-Leu-Aib3-AibCH2OH (5d) (85 mg, 0.14 mmol) and Pd/C
(8.5 mg, 10%) in EtOH (1.4 mL) under H2 atmosphere following
general procedure 2 (5 h) was obtained the deprotected peptide H-L-
Leu-Aib3-AibCH2OH (67 mg, 100%). From a solution of H-L-Leu-
Aib3-AibCH2OH (67 mg, 0.14 mmol), i-Pr2NEt (49 μL, 36 mg,
0.28 mmol), and p-BrBzCl (34 mg, 0.15 mmol) in dry CH2Cl2 (1.4 mL)
following general procedure 2 (3 h) and after purification by column
chromatography (EtOAc/petroleum ether, 80:20) was obtained pep-
tide p-BrBz-L-Leu-Aib3-AibCH2OH as a white solid (89 mg, 100%): Rf
(SiO2/EtOAc/petroleum ether 80:20) = 0.18; mp = 220−222 °C;
98:2) = 0.36; [α]20 = −16.4 (c = 1.0, CHCl3); 1H NMR (500 MHz,
[α]20 = −20.0 (c = 1.1, CHCl3); H NMR (500 MHz, CD3OD) δ
1
D
D
CDCl3) δ 7.73−7.09 (m, 19H), 5.13 (A of AB, J = 12.5 Hz, 1H), 5.08
(B of AB, J = 12.5 Hz, 1H), 4.18 (t, J = 6.0 Hz, 1H), 3.95 (dd, J = 10.0,
6.5 Hz, 1H), 3.89 (dd, J = 10.0, 6.0 Hz, 1H), 3.65 (A of AB, J =
11.5 Hz, 1H), 3.52 (B of AB, J = 11.5 Hz, 1H), 1.403 (s, 3 H), 1.40
7.80 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 4.37
(dd, J = 9.0, 5.5 Hz, 1H), 3.68 (d, J = 11.5 Hz, 1H), 3.46 (d, J =
11.5 Hz, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.44 (s, 6H), 1.43 (s, 3H),
1.36 (s, 3H), 1.295 (s, 6H), 1.29 (s, 3H), 1.22 (s, 3H), 1.04
4668
dx.doi.org/10.1021/jo500714b | J. Org. Chem. 2014, 79, 4659−4675