Journal of Medicinal Chemistry
Article
(quin, J = 7.6 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 141.8, 139.6, 139.6, 139.0, 138.9, 138.5, 138.4, 138.2, 129.3,
128.6, 128.5, 128.5, 128.4, 128.4, 128.1, 128.0, 127.9, 127.9, 127.8,
127.7, 127.6, 117.8, 98.8, 80.7, 79.1, 77.4, 76.5, 75.3, 75.0, 74.9, 74.6,
73.7, 73.4, 73.3, 70.5, 69.9, 69.2, 68.0, 62.3, 52.4, 35.5, 31.2, 30.4, 28.6,
26.5, 15.8; LRMS (ESI+) m/z calcd for C68H76N5O8 [M + H]+
1090.57, found 1090.59.
4-((1R,2S,3S)-3-Azido-1,2-bis(benzyloxy)-4-(((2S,3R,4S,5S,6R)-
3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)oxy)butyl)-1-(6-(p-tolyl)hexyl)-1H-pyrazole (18f). 92% yield; [α]D25
+10.7 (c = 0.25, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H),
7.38−7.15 (m, 31H), 7.06 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz,
2H), 4.93 (d, J = 11.5 Hz, 1H), 4.86 (d, J = 3.0 Hz, 1H), 4.82 (d, J =
11.5 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H),
4.67 (d, J = 12.0 Hz, 1H), 4.61−4.54 (m, 3H), 4.47−4.42 (m, 2H),
4.35 (d, J = 12.0 Hz, 1H), 4.30 (d, J = 12.0 Hz, 1H), 4.06−4.02 (m,
2H), 3.97 (dd, J = 10.0, 2.5 Hz, 1H), 3.94−3.90 (m, 3H), 3.69 (dd, J =
10.5, 7.0 Hz, 1H), 3.51−3.45 (m, 2H), 2.52 (t, J = 7.8 Hz, 2H), 2.30
(s, 3H), 1.81 (quin, J = 7.3 Hz, 2H), 1.56 (quin, J = 7.5 Hz, 2H),
1.36−1.24 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 139.6, 138.9,
138.9, 138.5, 138.4, 138.2, 129.1, 128.6, 128.5, 128.4, 128.1, 128.0,
128.0, 127.9, 127.8, 127.7, 127.6, 117.9, 98.8, 80.7, 79.1, 77.4, 76.8,
76.5, 75.2, 75.0, 74.9, 74.6, 73.6, 73.4, 73.3, 70.5, 70.0, 69.2, 68.0, 62.2,
52.5, 35.5, 31.6, 30.5, 28.9, 26.7, 21.2; LRMS (ESI+) m/z calcd for
C68H76N5O8 [M + H]+ 1090.57, found 1090.77.
4-((1R,2S,3S)-3-Azido-1,2-bis(benzyloxy)-4-(((2S,3R,4S,5S,6R)-
3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-
yl)oxy)butyl)-1-(7-phenylheptyl)-1H-pyrazole (18g). 91% yield; [α]D25
+8.2 (c = 0.85, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H),
7.38−7.21 (m, 31H), 7.18−7.14 (m, 5H), 4.93 (d, J = 11.5 Hz, 1H),
4.87 (d, J = 3.5 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0
Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.62−
4.54 (m, 4H), 4.47−4.42 (m, 2H), 4.35 (d, J = 12.0 Hz, 1H), 4.29 (d, J
= 12.0 Hz, 1H), 4.06−4.02 (m, 3H), 3.98 (dd, J = 10.3, 2.8 Hz, 1H),
3.94−3.91 (m, 4H), 3.69 (dd, J = 10.8, 6.8 Hz, 1H), 3.50−3.46 (m,
3H), 2.56 (t, J = 7.8 Hz, 2H), 1.81 (quin, J = 7.4 Hz, 2H), 1.33−1.23
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 142.9, 139.5, 139.0, 138.9,
138.8, 138.5, 138.4, 138.2, 129.3, 128.6, 128.5, 128.5, 128.1, 128.0,
127.9, 127.9, 127.8, 127.7, 127.7, 125.8, 117.8, 98.8, 80.7, 79.1, 77.4,
76.5, 75.2, 75.0, 74.9, 74.6, 73.7, 73.4, 73.3, 70.5, 69.9, 69.2, 67.9, 62.2,
52.6, 36.1, 31.6, 30.5, 29.3, 29.2, 26.8; LRMS (ESI+) m/z calcd for
C68H76N5O8 [M + H]+ 1090.57, found 1090.71.
General Procedure for the N-Acylation for Compounds
19b−19g. Compound 18 and PPh3 (2 equiv) were dissolved in
benzene (0.01 M concentration) and H2O (0.1 mM concentration).
Then, the mixture was stirred at 60 °C for 10 h. After completion of
the reaction as monitored by TLC, the reaction mixture was
condensed under reduced pressure and redissolved in anhydrous
THF (10 mM concentration). Cerotic acid (1.5 equiv), 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDCI, 3 equiv), and 4-dimethy-
laminopyridine (DMAP, catalytic amount) were added to the
corresponding mixture and stirred at room temperature for 24 h.
After reaction completion, the resulting mixture was diluted with
EtOAc and washed with brine. The combined organic layer was dried
over anhydrous Na2SO4 (s). The filtrate was condensed under reduced
pressure and purified by silica gel flash column chromatography
(EtOAc:Hex = 1:3, v/v) to provide the desired product 19 as a
colorless oil.
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-
hexacosanamide (19c). 57% yield; [α]2D5 −3.2 (c = 0.88, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 7.42 (s, 1H), 7.37−7.20 (m,
30H), 7.08−7.04 (m, 4H), 6.17 (d, J = 9.5 Hz, 1H), 4.91 (d, J = 11.5
Hz, 1H), 4.80−4.71 (m, 5H), 4.64−4.55 (m, 2H), 4.49−4.44 (m, 3H),
4.34 (d, J = 12.0 Hz, 1H), 4.22 (d, J = 12.0 Hz, 1H), 4.07−3.86 (m,
9H), 3.52 (dd, J = 11.0, 3.5 Hz, 1H), 3.48 (dd, J = 9.2, 6.8 Hz, 1H),
3.33 (dd, J = 9.3, 5.7 Hz, 1H), 2.57−2.53 (m, 4H), 2.14 (quin, J = 7.1
Hz, 2H), 1.96−1.87 (m, 2H), 1.60−1.54 (m, 2H), 1.48 (quin, J = 7.1
Hz, 2H), 1.33 (quin, J = 7.4 Hz, 2H), 1.28−1.24 (m, 46H), 0.93−0.86
(m, 6H); LRMS (ESI+) m/z calcd for C94H128N3O9 [M + H]+
1442.97, found 1442.87.
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(4-(4-propylphenyl)butyl)-
1H-pyrazol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-
hexacosanamide (19d). 59% yield; [α]2D5 −2.6 (c = 0.85, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.40 (s, 1H), 7.37−7.21 (m,
30H), 7.06−7.02 (m, 4H), 6.15 (d, J = 9.0 Hz, 1H), 4.91 (d, J = 11.5
Hz, 1H), 4.80−4.71 (m, 5H), 4.62 (d, J = 12.0 Hz, 1H), 4.57−4.55
(m, 2H), 4.48−4.44 (m, 3H), 4.35 (d, J = 12.0 Hz, 1H), 4.21 (d, J =
12.0 Hz, 1H), 4.07−4.00 (m, 4H), 3.96 (dd, J = 11.0, 4.0 Hz, 1H),
3.92 (dd, J = 8.0, 3.5 Hz, 1H), 3.89−3.86 (m, 3H), 3.52 (dd, J = 11.0,
3.5 Hz, 1H), 3.48 (dd, J = 9.2, 6.8 Hz, 1H), 3.33 (dd, J = 9.2, 5.8 Hz,
1H), 2.57 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.8 Hz, 2H), 1.97−1.83 (m,
4H), 1.62−1.56 (m, 5H), 1.48 (quin, J = 7.0 Hz, 2H), 1.28−1.24 (m,
48H), 0.95−0.86 (m, 6H); LRMS (ESI+) m/z calcd for C94H128N3O9
[M + H]+ 1442.97, found 1443.21.
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(5-(4-ethylphenyl)pentyl)-
1H-pyrazol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-
hexacosanamide (19e). 61% yield; [α]2D5 −1.9 (c = 1.10, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.37−7.23 (m,
30H), 7.09 (d, J = 7.5 Hz, 2H), 7.05 (d, J = 7.5 Hz, 2H), 6.16 (d, J =
9.0 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.80−4.71 (m, 5H), 4.63 (d, J
= 12.0 Hz, 1H), 4.58−4.55 (m, 2H), 4.49−4.45 (m, 3H), 4.35 (d, J =
12.0 Hz, 1H), 4.22 (d, J = 12.0 Hz, 1H), 4.09−3.87 (m, 9H), 3.54 (dd,
J = 11.0, 3.0 Hz, 1H), 3.48 (dd, J = 9.0, 6.5 Hz, 1H), 3.35 (dd, J = 9.3,
5.8 Hz, 1H), 2.60 (q, J = 7.5 Hz, 2H), 2.53 (t, J = 7.8 Hz, 2H), 1.96−
1.82 (m, 4H), 1.65−1.57 (m, 4H), 1.48 (quin, J = 7.0 Hz, 2H), 1.28−
1.24 (m, 49H), 0.88 (t, J = 6.8 Hz, 3H); LRMS (ESI+) m/z calcd for
C94H128N3O9 [M + H]+ 1442.97, found 1442.93.
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(6-(p-tolyl)hexyl)-1H-pyra-
zol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)-
methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)hexacosanamide
(19f). 53% yield; [α]2D5 −16.1 (c = 1.5, CHCl3); H NMR (500 MHz,
1
CDCl3) δ 7.54 (s, 1H), 7.41 (s, 1H), 7.37−7.21 (m, 30H), 7.06 (d, J =
8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.17 (d, J = 9.0 Hz, 1H), 4.91
(d, J = 11.5 Hz, 1H), 4.80−4.71 (m, 5H), 4.62 (d, J = 12.0 Hz, 1H),
4.57−4.55 (m, 2H), 4.48−4.45 (m, 3H), 4.35 (d, J = 12.0 Hz, 1H),
4.22 (d, J = 12.0 Hz, 1H), 4.08−4.01 (m, 4H), 3.97−3.91 (m, 2H),
3.89−3.87 (m, 5H), 3.53 (dd, J = 11.0, 3.5 Hz, 1H), 3.48 (dd, J = 9.0,
7.0 Hz, 1H), 3.35 (dd, J = 9.0, 6.0 Hz, 1H), 2.52 (t, J = 7.8 Hz, 2H),
2.30 (s, 3H), 1.96−1.88 (m, 2H), 1.81 (quin, J = 7.1 Hz, 2H), 1.55
(quin, J = 7.4 Hz, 2H), 1.48 (quin, J = 7.1 Hz, 2H), 1.31−1.25 (m,
48H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.0,
139.7, 138.8, 138.7, 138.6, 137.9, 129.1, 128.6, 128.6, 128.6, 128.5,
128.5, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 117.6, 99.7, 81.0,
79.0, 77.4, 75.0, 74.9, 74.5, 73.7, 73.7, 73.1, 70.3, 70.2, 69.4, 52.4, 36.9,
35.5, 32.1, 31.6, 30.6, 29.9, 29.8, 29.7, 29.6, 29.6, 29.0, 26.7, 25.9, 22.9,
21.2, 14.3; LRMS (ESI+) m/z calcd for C94H128N3O9 [M + H]+
1442.97, found 1443.11.
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(4-pentylphenethyl)-1H-
pyrazol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-
((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-
hexacosanamide (19b). 68% yield; [α]2D5 −1.5 (c = 0.80, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.38−7.23 (m, 31H), 7.02
(d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.13 (d, J = 9.0 Hz, 1H),
4.91 (d, J = 11.5 Hz, 1H), 4.03−3.85 (m, 7H), 3.52−3.46 (m, 2H),
3.33 (dd, J = 9.5, 6.0 Hz, 1H), 3.12−3.08 (m, 2H), 2.48 (t, J = 7.8 Hz,
2H), 1.95−1.86 (m, 2H), 1.56−1.45 (m, 2H), 1.28−1.24 (m, 48H),
0.89−0.85 (m, 6H); LRMS (ESI+) m/z calcd for C94H128N3O9 [M +
H]+ 1442.97, found 1443.13.
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(7-phenylheptyl)-1H-pyra-
zol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)-
methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)hexacosanamide
(19g). 60% yield; [α]2D5 −8.6 (c = 0.55, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.53 (s, 1H), 7.43 (s, 1H), 7.37−7.14 (m, 35H), 6.15 (d, J =
9.0 Hz, 1H), 4.91 (d, J = 11.5 Hz, 1H), 4.80−4.71 (m, 5H), 4.63 (d, J
= 11.5 Hz, 1H), 4.57−4.54 (m, 2H), 4.48−4.45 (m, 3H), 4.35 (d, J =
12.0 Hz, 1H), 4.21 (d, J = 12.0 Hz, 1H), 4.08−3.86 (m, 9H), 3.53 (dd,
J = 11.0, 3.5 Hz, 1H), 3.48 (dd, J = 9.2, 6.8 Hz, 1H), 3.34 (dd, J = 9.5,
6.0 Hz, 1H), 2.56 (t, J = 7.7 Hz, 2H), 1.98−1.86 (m, 2H), 1.81 (quin, J
N-((2S,3S,4R)-3,4-Bis(benzyloxy)-4-(1-(3-(4-butylphenyl)propyl)-
1H-pyrazol-4-yl)-1-(((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-
G
dx.doi.org/10.1021/jm400949h | J. Med. Chem. XXXX, XXX, XXX−XXX