O. Schwardt et al. / Bioorg. Med. Chem. 18 (2010) 7239–7251
7249
[
a
]
ꢀ19.2 (c 1.00, CHCl3); IR (film) 3328 (s, br, OH, NH), 2930
23.1 (COCH3), 28.2 (C(CH3)3), 37.2 (C-2), 38.4 (C-6), 49.0 (C-5),
51.0 (C-20), 52.6 (OMe), 57.4 (C-4), 66.9 (CH2Ph), 68.5 (C-10), 76.7
(C-3), 78.1 (C-1), 79.8 (C(CH3)3), 127.6, 127.8, 128.4, 137.5 (6C,
C6H5), 157.2 (NCO), 170.1, 172.6 (2CO); HRMS Calcd for
D
(s), 1731 (s, CO), 1690 (vs, CO), 1662 (s, CO), 1537 (s), 1455 (m),
1367 (s), 1305 (s), 1250 (m), 1206 (m), 1162 (s), 1099 (s) cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 1.42 (s, 9H, C(CH3)3), 1.64–1.69 (m,
2H, H-2a, H-6a), 1.91 (s, 3H, COCH3), 2.45 (s, 1H, OH), 2.62 (d,
J = 12.5 Hz, 1H, H-6b), 2.82 (d, J = 11.5 Hz, 1H, H-2b), 3.47 (dt,
J = 3.9, 10.2 Hz, 1H, H-3), 3.51–3.57 (m, 2H, H-4, H-10a), 3.67 (m,
2H, H-20), 3.73 (m, 1H, H-10b), 3.78 (s, 3H, OMe), 3.84 (m, 1H, H-
5), 4.36, 4.47 (A, B of AB, J = 10.8 Hz, 2H, PhCH2), 5.00 (d,
J = 8.0 Hz, 1H, 4-NH), 6.51 (s br, 1H, 5-NH), 7.27–7.34 (m, 5H,
C
24H35N5NaO7 [M+Na]+: 528.2429. Found: 528.2430.
4.1.21. Methyl (1R,3R,4R,5S)-5-acetamido-1-benzyloxy-4-(tert-
butoxycarbonylamino)-3-[2-(4-chlorobenzamido)ethoxy]-
cyclohexane-1-carboxylate (27)
Compound 26 (29.0 mg, 57.5
lmol) and Pd/C (10%, 10 mg) were
C6H5); 13C NMR (125 MHz, CDCl3):
d
23.1 (COCH3), 28.3
suspended in MeOH (2.5 mL). NEt3 (150 lL) was added and the
(C(CH3)3), 37.4 (C-2), 38.7 (C-6), 48.6 (C-5), 52.7 (OMe), 58.0 (C-
4), 62.1 (C-20), 66.9 (CH2Ph), 70.9 (C-10), 76.9 (C-3), 78.1 (C-1),
80.0 (C(CH3)3), 127.6, 127.8, 128.4, 137.5 (6C, C6H5), 157.4 (NCO),
170.2, 172.5 (2CO); HRMS Calcd for C24H36N2NaO9 [M+Na]+:
503.2364. Found: 503.2358.
suspension was hydrogenated (1 atm H2) at rt for 1 h. The mixture
was filtered over Celite and concentrated. To a solution of the res-
idue in DCM (2 mL) were subsequently added NEt3 (31.8
0.230 mmol), DMAP (5 mg), and p-chlorobenzoyl chloride
(14.7 L, 0.115 mmol) at 0 °C under argon. The solution was stirred
at rt for 2.5 h, then NEt3 (50 L) and MeOH (0.5 mL) were added
lL,
l
l
4.1.19. Methyl (1R,3R,4R,5S)-5-acetamido-1-benzyloxy-4-(tert-
butoxycarbonylamino)-3-(2-tosyloxyethoxy)-cyclohexane-1-
carboxylate (25)
and stirring was continued for 15 min. The solvents were evapo-
rated and the residue was purified by MPLC on silica (1% gradient
of MeOH in DCM) to yield 27 (23.4 mg, 66%) as a colorless solid.
To a solution of 24 (117 mg, 0.243 mmol) in DCM were subse-
[
a
]
D ꢀ37.9 (c 0.51, CHCl3); IR (KBr) 3319 (m, br, NH), 2926 (m),
quently added NEt3 (10.1
l
L, 0.729 mmol), DMAP (10 mg) and p-
1732 (s, CO), 1690 (vs, CO), 1659 (vs, CO), 1537 (vs), 1486 (m),
toluenesulfonyl chloride (69.8 mg, 0.365 mmol) at 0 °C under ar-
gon. The mixture was stirred at rt for 4 h and then quenched by
the addition of MeOH (0.3 mL). After evaporation of the solvents
the residue was purified by MPLC on silica (1% gradient of MeOH
in DCM) to yield 25 (130 mg, 84%) as a colorless oil.
1454 (m), 1366 (m), 1305 (s), 1250 (m), 1206 (m), 1161 (m),
1092 (s) cmꢀ1 1H NMR (500 MHz, CDCl3): d 1.33 (s, 9H, C(CH3)3),
;
1.66 (t, J = 11.3 Hz, 1H, H-2a), 1.68 (t, J = 12.4 Hz, 1H, H-6a), 1.93
(s, 3H, COCH3), 2.62 (ddd, J = 2.8, 3.4, 12.0 Hz, 1H, H-6b), 2.80
(ddd, J = 2.6, 3.9, 11.4 Hz, 1H, H-2b), 3.43 (ddd, J = 4.4, 9.9,
10.7 Hz, 1H, H-3), 3.53 (m, 2H, H-20), 3.56 (q, J = 10.0 Hz, 1H, H-
4), 3.64 (m, 1H, H-10a), 3.75–3.80 (m, 4H, H-10b, OMe), 3.89 (m,
1H, H-5), 4.35, 4.43 (A, B of AB, J = 10.7 Hz, 2H, PhCH2), 4.94 (d,
J = 8.9 Hz, 1H, 4-NH), 6.41 (d, J = 8.1 Hz, 1H, 5-NH), 6.78 (t,
J = 5.2 Hz, 1H, 20-NH), 7.24–7.31 (m, 5H, C6H5), 7.37, 7.74 (AA0,
BB0 of AA0BB0, J = 8.6 Hz, 4H, C6H4); 13C NMR (125 MHz, CDCl3): d
23.2 (COCH3), 28.2 (C(CH3)3), 37.6 (C-2), 38.7 (C-6), 40.1 (C-20),
48.0 (C-5), 52.7 (OMe), 58.6 (C-4), 67.0 (CH2Ph), 68.4 (C-10), 76.6
(C-3), 78.2 (C-1), 79.8 (C(CH3)3), 127.7, 128.0, 128.4, 128.6, 128.6,
132.6, 137.1, 137.5 (12C, C6H4, C6H5), 157.2 (NCO), 166.3, 170.2,
[
a]D ꢀ14.2 (c 1.04, CHCl3); IR (film) 3326 (m, br, NH), 3066 (w),
2926 (s), 1731 (vs, CO), 1690 (vs, CO), 1532 (s), 1455 (m), 1366 (vs),
1304 (s), 1248 (m), 1206 (m), 1189 (s), 1177 (vs), 1097 (s) cmꢀ1; 1H
NMR (500 MHz, CDCl3): d 1.42 (s, 9H, C(CH3)3), 1.64–1.69 (m, 2H,
H-2a, H-6a), 1.89 (s, 3H, COCH3), 2.43 (s, 3H, PhCH3), 2.61 (d,
J = 12.4 Hz, 1H, H-6b), 2.72 (d, J = 11.5 Hz, 1H, H-2b), 3.44 (m, 1H,
H-3), 3.49 (q, J = 9.4 Hz, 1H, H-4), 3.69 (m, 1H, H-10a), 3.76 (m,
1H, H-10b), 3.78–3.81 (m, 4H, H-5, OMe), 4.12 (m, 2H, H-20), 4.33,
4.46 (A, B of AB, J = 10.7 Hz, 2H, PhCH2), 4.70 (d, J = 8.0 Hz, 1H, 4-
NH), 6.49 (d, J = 7.7 Hz, 1H, 5-NH), 7.27–7.34 (m, 7H, 2H of C6H4,
C6H5), 7.78 (BB0 of AA0BB0, J = 8.3 Hz, 2H of C6H4); 13C NMR
(125 MHz, CDCl3): d 21.6 (PhCH3), 23.2 (COCH3), 28.2 (C(CH3)3),
36.8 (C-2), 38.4 (C-6), 48.9 (C-5), 52.6 (OMe), 57.1 (C-4), 66.9,
67.0 (C-10, CH2Ph), 69.2 (C-20), 76.5 (C-3), 78.0 (C-1), 80.0
(C(CH3)3), 127.6, 127.8, 127.9, 128.4, 129.9, 132.9, 137.5, 144.9
(12C, C6H4, C6H5), 157.3 (NCO), 170.0, 172.6 (2CO); HRMS Calcd
for C31H42N2NaO10S [M+Na]+: 657.2452. Found: 657.2450.
172.3 (3CO); HRMS Calcd for
640.2396. Found: 640.2400.
C
31H40ClN3NaO8 [M+Na]+:
4.1.22. Methyl (1R,3R,4R,5S)-5-acetamido-1-benzyloxy-3-[2-(4-
chlorobenzamido)ethoxy]-4-(2-fluoroacetamido)-cyclohexane-
1-carboxylate (28)
A solution of 27 (30.5 mg, 49.3
lmol) was treated with DCM/
TFA (2:1, 0.75 mL) for 3 h at 0 °C under argon. After concentration
4.1.20. Methyl (1R,3R,4R,5S)-5-acetamido-3-(2-azidoethoxy)-1-
benzyloxy-4-(tert-butoxycarbonylamino)-cyclohexane-1-
carboxylate (26)
in vacuo the residue was dissolved in DCM (3 mL). NEt3 (68.4
0.493 mmol), DMAP (5 mg), and 2-fluoroacetyl chloride (5.6
l
l
L,
L,
74.0
lmol) were subsequently added at 0 °C under argon and the
To a solution of 25 (129 mg, 0.204 mmol) in DMF (5 mL) were
solution was stirred for 2.5 h at rt. Then NEt3 (20
l
L) and MeOH
added 15-crown-5 (20.1
l
L, 0.102 mmol) and sodium azide
(0.5 mL) were added and stirring was continued for 10 min. After
evaporation to dryness the residue was purified by MPLC on silica
(1% gradient of MeOH in DCM) to give 28 (19.7 mg, 69%) as a yel-
lowish solid.
(133 mg, 2.04 mmol). The resulting suspension was stirred for
22 h at 60 °C under argon, then diluted with EtOAc (20 mL) and fil-
tered over Celite. After co-evaporation with toluene (2 ꢁ 10 mL),
the residue was purified by MPLC on silica (1% gradient of MeOH
in DCM) to yield 26 (85.7 mg, 83%) as a colorless solid.
[a
]D ꢀ38.3 (c 0.84, CHCl3); IR (KBr) 3292 (m, br, NH), 2927 (m),
1733 (s, CO), 1660 (vs, CO), 1652 (vs, CO), 1555 (vs), 1487 (m),
[
a
]
D ꢀ21.0 (c 0.99, CHCl3); IR (KBr) 3363 (m, br, NH), 2926 (m),
1455 (m), 1367 (m), 1310 (m), 1206 (m), 1150 (m), 1093 (s)
2103 (s, N3), 1732 (vs, CO), 1688 (vs, CO), 1661 (vs, CO), 1532 (m),
cmꢀ1 1H NMR (500 MHz, CDCl3): d 1.67 (t, J = 12.1 Hz, 1H, H-2a),
;
1455 (m), 1366 (s), 1305 (vs), 1250 (m), 1206 (m), 1163 (s), 1096
1.72 (t, J = 12.7 Hz, 1H, H-6a), 1.93 (s, 3H, COCH3), 2.62 (m, 1H,
H-6b), 2.87 (m, 1H, H-2b), 3.44 (ddt, J = 3.9, 7.6, 12.0 Hz, 1H, H-
20a), 3.54–3.59 (m, 2H, H-3, H-10a), 3.65 (m, 1H, H-20b), 3.74–3.80
(m, 4H, H-10b, OMe), 3.94 (q, J = 9.8 Hz, 1H, H-4), 4.04 (m, 1H, H-
5), 4.37, 4.44 (A, B of AB, J = 10.8 Hz, 2H, PhCH2), 4.47, 4.62 (A, B
of ABX, J = 14.4, 47.2 Hz, 2H, FCH2), 6.29 (d, J = 8.5 Hz, 1H, 5-NH),
6.77 (t, J = 5.2 Hz, 1H, 20-NH), 6.94 (dd, J = 1.9, 8.9 Hz, 1H, 4-NH),
7.26–7.35 (m, 5H, C6H5), 7.38, 7.75 (AA0, BB0 of AA0BB0, J = 8.5 Hz,
4H, C6H4); 13C NMR (125 MHz, CDCl3): d 23.0 (COCH3), 37.5 (C-2),
(m) cmꢀ1 1H NMR (500 MHz, CDCl3): d 1.42 (s, 9H, C(CH3)3),
;
1.65 (t, J = 12.4 Hz, 1H, H-6a), 1.68 (t, J = 12.1 Hz, 1H, H-2a), 1.90
(s, 3H, COCH3), 2.64 (d, J = 12.7 Hz, 1H, H-6b), 2.82 (d, J = 12.2 Hz,
1H, H-2b), 3.35 (m, 2H, H-20), 3.49 (m, 1H, H-3), 3.57 (q,
J = 9.6 Hz, 1H, H-4), 3.63 (m, 1H, H-10a), 3.78 (m, 1H, H-10b), 3.79
(s, 3H, OMe), 3.83 (m, 1H, H-5), 4.36, 4.48 (A, B of AB, J = 10.8 Hz,
2H, PhCH2), 4.78 (d, J = 8.1 Hz, 1H, 4-NH), 6.58 (d, J = 7.7 Hz, 1H,
5-NH), 7.27–7.34 (m, 5H, C6H5); 13C NMR (125 MHz, CDCl3): d