25
(2H, d, J = 12.0 Hz, Bn), 5.19 (2H, d, J = 12.0 Hz, Bn), 4.64
(2H, dt, J = 8.1, 4.2 Hz, CH), 3.07 (4H, d, J = 4.2 Hz, CH2),
1.45 (18H, s, tBu).
as a colorless oil; Rf 0.30 (hexane/EtOAc = 1:2); ½ꢀꢀD +148.6
(c 0.1, CHCl3); IR (neat, cm¹1): 3431, 3345, 2979, 2934,
2876, 2359, 2251, 2230, 1746, 1705, 1499, 1454, 1379, 1261,
1171, 1103, 1054, 914, 844, 735, 698, 580, 542; 1H NMR
(300 MHz, CDCl3): ¤ 8.49 (1H, s, H2/6), 7.44-7.30 (5H, m,
Bn), 5.22 (1H, d, J = 12.3 Hz, Bn), 5.15 (2H, d, J = 12.3
Hz, Bn/NH), 4.95-4.81 (2H, m, H20/20¤), 4.57 (1H, m, H16),
4.11 (4H, m, H21/21¤), 3.15-3.00 (2H, m, H15), 1.66 (6H, s,
Me), 1.53 (6H, s, Me), 1.48 (18H, s, tBu), 1.44 (9H, s, tBu);
13C NMR (75 MHz, CDCl3): ¤ 170.4, 155.2, 151.4, 150.9,
135.3, 128.3, 121.4, 97.9, 95.5, 94.3, 80.9, 80.4, 78.8, 68.7,
67.3, 65.9, 52.2, 49.3, 28.4, 27.1, 25.9, 25.2, 24.5; ESI-HRMS
(m/z) calcd for C46H58N4NaO10 [M + Na]+ 849.4051, found
849.4053.
(S)-2-(tert-Butoxycarbonyl)amino-5-[3,5-bis(2-{[(S)-2,2-
dimethyl-3-tert-butoxycarbonyl-1,3-oxazolidin-4-yl]ethyl})-
pyridin-4-yl]pentanoic Acid (18). A solution of 3 (66.7 mg,
80.7 ¯mol, 1.0 equiv) in MeOH (2.9 mL) was treated with 10%
Pd/C (53.8 mg, 50.5 ¯mol, 63 mol %) and hydrogenated at
balloon pressure at room temperature. After stirring for 4 days
at room temperature, the insoluble material was separated by
filtration through neutral silica gel and Celite eluting with
MeOH. The filtrate was then concentrated in vacuo. Concen-
tration of the filtrate yielded carboxylic acid 18 (62.9 mg, 84.0
¯mol, quant) as a colorless solid; 1H NMR (500 MHz,
CD3OD): ¤ 8.16 (2H, s, H2/6), 4.05-3.90 (8H, m, NH, H16/
20/20¤), 2.84-2.63 (6H, m, H13/18/18¤), 1.97-1.95 (2H, m,
H14), 1.86-1.79 (4H, m, H19/19¤), 1.57-1.43 (41H, m, H15/
Me/tBu); ESI-MS (m/z): calcd for C39H65N4O10 [M + H]+
749.47, found 749.48.
3,5-Bis{[(S)-2,2-dimethyl-3-tert-buthoxycarbonyl-1,3-
oxazolidin-4-yl]ethynyl}-4-iodopyridine (17).
A solution
of 6 (14.8 mg, 32.4 ¯mol, 1.0 equiv), 7 (27.6 mg, 122.5 ¯mol,
3.8 equiv), [Pd(PPh3)4] (7.4 mg, 6.40 ¯mol, 20 mol %), and CuI
(2.6 mg, 13.7 ¯mol, 42 mol %) in DMF (1.6 mL, 20 ¯M to 6)
was degassed by freeze/pump/thaw techniques. iPr2NEt (320
¯L) was added to the resulting solution. After stirring at 45 °C
for 30 h, the reaction mixture was diluted with EtOAc, and
quenched with saturated NH4Cl solution. The aqueous layer
was then extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Purification on silica gel column chromatography
(hexane/Et2O = 1:1) afforded 17 (19.1 mg, 29.3 ¯mol, 90%) as
25
a colorless solid; Rf 0.40 (hexane/EtOAc = 1:2); ½ꢀꢀD +148.6
(c 0.1, CHCl3); IR (neat, cm¹1): 3530, 3385, 2980, 2925, 2873,
2234, 1698, 1541, 1475, 1457, 1373, 1262, 1208, 1169, 1095,
1
1057, 945, 845, 806, 768, 672, 538, 513; H NMR (300 MHz,
CDCl3): ¤ 8.34 (1H, s, H2/6), 4.89-4.78 (2H, m, H20/20¤),
4.19-4.11 (4H, m, H21/21¤), 1.70 (6H, s, Me), 1.54 (6H,
s, Me), 1.43 (18H, s, tBu); 13C NMR (75 MHz, CDCl3): ¤
151.1, 150.0, 127.4, 95.5, 94.6, 94.1, 80.6, 68.7, 65.9, 49.2,
28.6, 27.2, 26.1, 25.3, 24.4; ESI-HRMS (m/z) calcd for
C29H38IN3NaO6 [M + Na]+ 674.1703, found 674.1693.
4-Bromo-3,5-bis{[(S)-2,2-dimethyl-3-tert-butoxycarbon-
yl-1,3-oxazolidin-4-yl]ethynyl}pyridine (16). A solution of
5 (13.6 mg, 33.1 ¯mol, 1.0 equiv), 7 (28.6 mg, 126.9 ¯mol, 3.8
equiv), [Pd(PPh3)4] (7.5 mg, 6.49 ¯mol, 20 mol %), and CuI
(2.4 mg, 12.6 ¯mol, 38 mol %) in DMF (1.6 mL, 20 ¯M to 5)
was degassed by freeze/pump/thaw techniques. iPr2NEt (320
¯L) was added to the resulting solution. After stirring at 45 °C
for 8 h, the reaction mixture was diluted with EtOAc, and
quenched with saturated NH4Cl solution. The aqueous layer
was then extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Purification on silica gel column chromatography
(hexane/Et2O = 1:1) afforded 16 (17.3 mg, 28.6 ¯mol, 86%) as
Benzyl (S)-2-(tert-Butoxycarbonyl)amino-5-[3,5-bis(2-
{[(S)-2,2-dimethyl-3-tert-butoxycarbonyl-1,3-oxazolidin-4-
yl]ethyl})pyridin-4-yl]pentanoate (19). To a solution of the
obtained 18 (20.2 mg, 27.0 ¯mol, 1.0 equiv) and Cs2CO3 (29.2
mg, 8.94 mmol, 3.3 equiv) in DMF (0.27 mL) was added TBAI
(11.6 mg, 31.4 ¯mol, 1.2 equiv) and BnBr (3.4 ¯L, 28.6 ¯mol,
1.06 equiv) at ¹20 °C. After stirring for 4 h at ¹20 °C followed
by 12 h at room temperature, the mixture was diluted with
EtOAc, and quenched with saturated NH4Cl solution. The
aqueous layer was then extracted with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification on silica gel column chro-
matography (hexane/EtOAc = 1:3) afforded 19 (14.6 mg, 17.4
¯mol, 65%) as a colorless oil; Rf 0.48 (hexane/EtOAc = 1:5);
1
a colorless solid; H NMR (300 MHz, CDCl3): ¤ 8.44 (1H, s,
H2/6), 4.88-4.78 (2H, m, H20/20¤), 4.14 (4H, m, H21/21¤),
1.68 (6H, s, Me), 1.54 (6H, s, Me), 1.42 (18H, s, tBu); ESI-MS
(m/z) calcd for C29H38BrN3NaO6 [M + Na]+ 626.16, found
626.24.
25
Benzyl (S)-2-(tert-Butoxycarbonyl)amino-5-(3,5-bis{[(S)-
2,2-dimethyl-3-tert-butoxycarbonyl-1,3-oxazolidin-4-yl]-
ethynyl}pyridin-4-yl)pent-4-ynoate (3). A solution of 17
(16.8 mg, 25.8 ¯mol, 1.0 equiv), 8 (23.7 mg, 78.1 ¯mol, 3.0
equiv), [Pd2(dba)3] (3.2 mg, 2.62 ¯mol, 10 mol %), P(2-furyl)3
(2.5 mg, 10.8 ¯mol, 42 mol %) and CuI (2.0 mg, 10.5 ¯mol,
41 mol %) in DMF (1.29 mL, 20 ¯M to 17) was degassed by
freeze/pump/thaw techniques. iPr2NEt (22.6 ¯L) was added
to the resulting solution. After stirring at room temperature
for 8.5 h, the reaction mixture was diluted with EtOAc, and
quenched with saturated NH4Cl solution. The aqueous layer
was then extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Purification by silica gel column chromatography
(hexane/Et2O = 1:1) afforded 3 (18.3 mg, 22.1 ¯mol, 86%)
½ꢀꢀD ¹28.5 (c 0.07, CHCl3); IR (neat, cm¹1): 2979, 2933,
2873, 2357, 1739, 1696, 1389, 1365, 1253, 1166, 1094, 858,
1
681; H NMR (500 MHz, CDCl3): ¤ 8.20 (2H, s, H2/6), 7.33-
7.29 (5H, m, Bn), 5.25 (1H, s, NH), 5.18 (1H, d, J = 12.0 Hz,
Bn), 5.19 (1H, d, J = 12.5 Hz, Bn), 4.33 (1H, m, H16), 3.98-
3.78 (6H, H20/20¤/21/21¤), 2.54 (6H, H13, H18/18¤), 2.00-
1.94 (2H, m, H14), 1.79 (4H, m, H19/19¤), 1.59-1.44 (41H,
H15/Me/tBu); ESI-HRMS (m/z): calcd for C46H71N4O10
[M + H]+ 839.5170, found 839.5151.
4-[(S)-4-Benzyloxycarbonyl-4-(tert-butoxycarbonyl)amino-
butyl]-1-[(S)-5-benzyloxycarbonyl-5-(tert-butoxycarbonyl)-
aminopentyl]-3,5-bis(2-{[(S)-2,2-dimethyl-3-tert-butoxycar-
bonyl-1,3-oxazolidin-4-yl]ethyl})pyridinium Iodide (20).
mixture of 19 (14.6 mg, 17.4 ¯mol, 1.0 equiv) and benzyl (S)-2-
(tert-butoxycarbonyl)amino)-6-iodohexanoate (4)14 (15.6 mg,
A
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