The Journal of Organic Chemistry
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cm−1; 1H NMR (500 MHz, CDCl3) δ 7.36−7.29 (m, 5H), 5.43 (d, J =
5.0, 1H), 4.61−4.58 (m, 1H), 4.24−4.21 (m, 1H), 3.90−3.88 (m, 2H),
3.72 (s, 3H), 3.71 (s, 2H), 2.78 (d, J = 10.0, 2H), 1.40 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 171.8, 171.3, 156.3, 138.4, 129.5, 129.1,
127.7, 80.8, 62.7, 55.0, 52.7, 42.33, 36.5, 33.6, 28.2; HRMS (ESI-TOF)
m/z: [M + Na]+ calculated for C19H28N2O6SNa 435.1560, found
435.1556.
general procedure C on a 0.13 mmol scale of 12 using DAST (50 μL,
0.38 mmol) at −78 °C and warming up to rt in CH2Cl2 (2 mL), the
desired product (41 mg, 0.11 mmol, 85%) was isolated by silica gel
column chromatography (hexane/EtOAc, 3:1): Rf (hexane/EtOAc,
1:1) 0.62; [α]2D5 +63.2 (c = 1.0, CHCl3); IR (neat) ν = 2971, 2360,
2334, 1741, 1713, 1664, 1498, 1458, 1366, 1249, 1203, 1164, 1024,
1
971, 918, 862, 734, 698 cm−1; H NMR (400 MHz, CDCl3) δ 7.28−
N-Boc-Cys(Tr)-Ser-OMe (14). Following general procedure A on a
3.15 mmol scale of HCl·Ser-OMe using Boc-Cys(Tr)-OH (1.50 g,
3.25 mmol), EDC (742.32 mg, 3.78 mmol), NMM (762 μL, 6.93
mmol), and HOBt (65.20 mg, 0.47 mmol) in EtOH (20 mL), the
desired product (1.59 g, 2.81 mmol, 89%) was isolated as a white solid
by silica gel column chromatography (hexane/EtOAc, 3:1): Rf
(hexane/EtOAc, 1:1) 0.43; IR (neat) ν = 3392, 3319, 3055, 2974,
2358, 2335, 1745, 1671, 1491, 1444, 1391, 1367, 1248, 1166, 1030,
7.20 (m, 5H), 5.41 (d, J = 7.5, 1H), 4.71−4.69 (m, 1H), 4.55−4.37 (m,
6H), 3.72−3.63 (m, 5H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 171.3, 168.6, 155.4, 138.0, 128.5, 127.9, 127.7, 80.1, 73.3, 70.3, 70.1,
68.2, 52.9, 49.5, 28.5; HRMS (ESI-TOF) m/z: [M + H]+ calculated
for C19H27N2O6 379.1864, found 379.1863.
2-[(1S)-1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-(thio-
benzyl)ethyl]2-(4S)-oxazoline Methyl Ester (19). Following
general procedure C on a 0.1 mmol scale of 13 using DAST (41
μL, 0.31 mmol) at −45 °C and warming up to rt in CH2Cl2 (2 mL),
the desired product (25 mg, 0.061 mmol, 61%) was isolated by silica
gel column chromatography (hexane/EtOAc, 3:1): Rf (hexane/EtOAc,
5:1) 0.21; [α]2D5 +45.4 (c = 1.0, CHCl3); IR (neat) ν = 3391, 2979,
2920, 1742, 1713, 1662, 1496, 1454, 1366, 1332, 1247, 1208, 1167,
1047, 1017, 766, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.24−7.16
(m, 5 H), 5.35 (d, J = 7.5, 1H), 4.73−4.68 (m, 1H), 4.62−4.59 (m,
1H), 4.51−4.47 (m, 1H), 4.41 (dd, J1 = 8.8, J2 = 10.6, 1H), 3.71 (s,
3H), 3.66 (d, J = 1.5, 2H), 2.82 (dd, J1 = 5.3, J2 = 14.1, 1H), 2.73 (dd,
J1 = 5.6, J2 = 14.0, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.1, 169.0, 155.1, 138.0, 129.1, 128.7, 127.3, 80.2, 70.4, 68.1, 52.9,
48.7, 36.8, 34.5, 28.5; HRMS (ESI-TOF) m/z: [M + Na]+ calculated
for C19H26N2O5SNa 417.1455, found 417.1459.
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861, 743, 701, 627 cm−1; H NMR (500 MHz, CDCl3) δ 7.29−7.21
(m, 15H), 6.79 (d, J = 8.1, 1H), 4.77 (d, J = 5.7, 1H), 4.76−4.54 (m,
1H), 4.03 (dd, J1 = 2.7, J2 = 9.9, 1H), 3.94 (m, 1H), 3.76 (dd, J1 = 3.0,
J2 = 10.1, 1H), 3.69 (s, 3H), 2.78 (dd, J1 = 5.7, J2 = 13.2, 1H), 2.54 (dd,
J1 = 4.8, J2 = 12.6, 1H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
170.8, 170.6, 144.5, 129.8, 128.4, 128.3, 127.2, 80.3, 67.5, 62.7, 55.3,
54.2, 52.9, 34.2, 28.5; HRMS (ESI-TOF) m/z: [M + Na]+ calculated
for C31H36N2O6SNa 587.2186, found 587.2189.
N-Boc-Ser(Bn)-Ser(TES)-OMe (15). Following general procedure
B on a 0.63 mmol scale of 12 using TES-Cl (316 μL, 1.89 mmol) and
imidazole (129 mg, 1.89 mmol) in DMF (1 mL), the desired product
(294 mg, 0.58 mmol, 91%) was isolated as a colorless oil by silica gel
column chromatography (hexane/EtOAc, 9:1): Rf (hexane/EtOAc,
7:1) 0.25; IR (neat) ν = 3333, 2954, 2876, 2359, 2333, 1749, 1717,
1680, 1497, 1456, 1366, 1247, 1206, 1167, 1109, 1047, 1017, 858, 743,
698 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.34−7.29 (m, 5H), 5.39 (s,
1H), 4.67−4.64 (m, 1H), 4.58 (s, 2H), 4.35 (br s, 1H), 4.08 (dd, J1 =
3.0, J2 = 10.3, 1H), 3.89 (dd, J1 = 5.0, J2 = 9.3, 1H), 3.80 (dd, J1 = 3.5, J2
= 10.0, 1H), 3.72 (s, 3H), 3.59 (dd, J1 = 6.5, J2 = 9.3, 1H), 1.45 (s, 9H),
0.90 (t, J = 7.5, 9H), 0.54 (q, J = 7.5, 6H); 13C NMR (75 MHz,
CDCl3) δ 170.7, 170.5, 155.6, 137.7, 128.6, 128.0, 127.9, 80.3, 73.7,
70.1, 63.4, 54.6, 54.0, 52.5, 28.5, 6.8, 4.4; HRMS (ESI-TOF) m/z: [M
+ Na]+ calculated for C25H42N2O7SiNa 533.2654, found 533.2653.
N-Boc-Cys(Bn)-Ser(TES)-OMe (16). Following general procedure
B on a 0.49 mmol scale of 13 using TES-Cl (108 μL, 0.64 mmol) and
imidazole (168 mg, 2.46 mmol) in DCM (5 mL), the desired product
(167 mg, 0.32 mmol, 65%) was isolated as a white solid by silica gel
column chromatography (hexane/EtOAc, 7:1): Rf (hexane/EtOAc,
7:1) 0.30; IR (neat) ν = 3286, 2953, 2874, 1743, 1710, 1673, 1650,
1508, 1452, 1366, 1241, 1164, 1105, 1045, 1019, 1005, 869, 746, 733,
2-[(1S)-1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-
((triphenylmethyl)thio)ethyl]2-(4S)-oxazoline Methyl Ester
(20). Following general procedure C on a 0.09 mmol scale of 14
using DAST (37 μL, 0.28 mmol) at −78 °C and warming up to rt in
CH2Cl2 (2 mL), the desired product (40 mg, 0.07 mmol, 79%) was
isolated by silica gel column chromatography (hexane/EtOAc, 3:1): Rf
(hexane/EtOAc, 3:1) 0.27; [α]2D5 +48.5 (c = 1.0, CHCl3); IR (neat) ν
= 2976, 2361, 1743, 1715, 1661, 1491, 1444, 1366, 1265, 1248, 1209,
1
1165, 1035, 981, 964, 849, 767, 738, 700, 676, 620 cm−1; H NMR
(400 MHz, CDCl3) δ 7.33−7.30 (m, 6H), 7.21−7.11 (m, 9H), 5.09
(br s, 1H), 4.68−4.64 (m, 1H), 4.48−4.31 (m, 2H), 3.67 (s, 3H),
2.52(d, J = 5.4, 2H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
171.2, 168.9, 154.9, 144.6, 129.7, 128.1, 127.0, 80.1, 70.4, 68.1, 66.9,
52.8, 48.1, 35.2, 28.5; HRMS (ESI-TOF) m/z: [M + Na]+ calculated
for C31H34N2O5SNa 569.2081, found 569.2086.
N-Boc-Ser(Bn)-Ser-Ser-OMe (21). To a stirring solution of 12
(1.72 g, 4.35 mmol) at rt in MeOH (30 mL) was added a solution of
LiOH (625.20 mg, 26.09 mmol) in H2O (15 mL) and stirred for 4 h.
After completion, approximately 2/3 of the MeOH was removed by a
rotary evaporator. The solution was then acidified by adding 40 mL of
1 M NaHSO4 whereon a white precipitate was formed. The
suspension was extracted with EtOAc (3×), and the combined
organic phases were dried with MgSO4, filtered, and evaporated in
vacuo to yield the carboxylic acid (1.60 g, 4.11 mmol, 96%) as a white
solid. The crude material was directly used for peptide bond
formation. To individual stirring solutions of the carboxylic acid
(1.55 g, 4.05 mmol) and HCl·Ser-OMe (630.62 mg, 4.05 mmol),
DMF was added (each 20 mL) and NMM (each 1.23 mL, 12.16
mmol)·PyBop (3.17 g, 6.08 mmol) was added to the stirring solution
of carboxylic acid, followed by the solution of H-Ser-OMe. The
reaction solution was stirred overnight at rt. After completion, most of
the DMF was removed on a rotary evaporator; diluted with EtOAc (30
mL); washed with 0.1 M citric acid (2×), sat. NaHCO3 (2×), and
brine; dried over MgSO4; filtered; and evaporated in vacuo. The crude
material was purified by column chromatography (gradient from 0 to
10% MeOH in CHCl3) to give 21 (1.09 g, 2.25 mmol, 56%) as a
mixture of four diastereomers: Rf (CHCl3/MeOH, 9:1) 0.31; 1H NMR
(500 MHz, CDCl3) δ 7.35−7.28 (m, 20H), 5.62−5.52 (m, 4H), 4.60−
4.56 (m, 8H), 4.29 (br-s, 4H), 4.08−3.82 (m, 16H), 3.75−3.73 (m,
12H), 3.69−3.66 (m, 8H), 1.42 (s, 36H); 13C NMR (100 MHz,
CDCl3) δ 171.4, 171.3, 170.9, 170.8, 137.5, 137.4, 137.4, 137.4, 173.4,
137.3, 128.8, 128.8, 128.7, 128.4, 128.3, 128.2, 128.2, 128.1, 128.1,
1
717, 699 cm−1; H NMR (500 MHz, CDCl3) δ 7.36−7.23 (m, 5H),
7.12 (d, J = 7.5, 1H), 5.33 (br s, 1H), 4.61 (ddd, J1 = 5.5, J2 = 6.0, J3 =
8.0, 1H), 4.32 (br s, 1H), 4.09 (dd, J1 = 2.5, J2 = 10.0, 1H), 3.82 (dd, J1
= 3.0, J2 = 10.3, 1H), 3.78 (s, 2H), 3.73 (s, 3H), 2.87 (dd, J1 = 5.5, J2 =
14.0, 1H), 2.78 (dd, J1 = 7.0, J2 = 14.0, 1H), 1.46 (s, 9H), 0.93 (t, J =
8.0, 9H), 0.57 (q, J = 8.0, 6H); 13C NMR (100 MHz, CDCl3) δ 170.7,
170.6, 138.1, 129.3, 128.8, 127.4, 77.4, 63.2, 54.7, 53.0, 52.6, 36.7, 34.2,
28.5, 6.8, 4.4; HRMS (ESI-TOF) m/z: [M + Na]+ calculated for
C25H42N2O6SSiNa 549.2425, found 549.2432.
N-Boc-Cys(Tr)-Ser(TES)-OMe (17). Following general procedure
B on a 0.45 mmol scale of 14 using TES-Cl (226 μL, 1.35 mmol) and
imidazole (92 mg, 1.35 mmol) in DMF (1 mL): Rf (hexane/EtOAc,
3:1), the desired product (274 mg, 0.40 mmol, 90%) was isolated as a
white solid by silica gel column chromatography (hexane/EtOAc,
gradient from 9:1 to 3:1): 0.71; IR (neat) ν = 3412, 3334, 2954, 2912,
2876, 2361, 1748, 1716, 1672, 1490, 1444, 1366, 1248, 1207, 1167,
1110, 1047, 1016, 862, 753, 700, 676, 618 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.35−7.28 (m, 5H), 5.46 (d, J = 7.0), 4.65−4.62 (m, 1H),
4.54 (s, 2H), 4.32 (br s, 1H), 3.91−3.88 (m, 3H), 3.75 (s, 3H), 3.62
(dd, J1 = 5.5, J2 = 9.5, 1H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 170.8, 170.7, 155.8, 137.5, 128.7, 128.2, 128.1, 80.7, 73.7, 70.0, 63.0,
60.6, 55.2, 52.9, 28.5; HRMS (ESI-TOF) m/z: [M + Na]+ calculated
for C37H50N2O6SSiNa 701.3051, found 701.3054.
2-[(1S)-1-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-(phenyl-
methoxy)ethyl]2-(4S)-oxazoline Methyl Ester (18). Following
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dx.doi.org/10.1021/jo5016695 | J. Org. Chem. 2015, 80, 40−51