Journal of Medicinal Chemistry
Article
(s, 3H), 3.56 (dd, J = 3.20, 9.10 Hz, 1H), 2.95 (dd, J = 5.46, 13.87 Hz,
1H), 2.85 (dd, J = 6.94, 13.88 Hz, 1H), 2.64 (td, J = 6.72, 13.14 Hz,
2H), 2.28 (t, J = 7.61 Hz, 2H), 1.98−1.85 (m, 2H), 1.63−1.54 (m,
2H), 1.44 (s, 9H), 1.30−1.21 (m, 24H), 1.13 (s, 9H), 0.86 (t, J = 6.96
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 173.95, 170.59, 155.32,
80.33, 73.62, 62.70, 61.78, 53.79, 53.27, 52.53, 34.70, 34.39, 32.04,
29.80, 29.77, 29.73, 29.59, 29.48, 29.40, 29.29, 29.01, 28.73, 28.41,
27.40, 25.06, 22.81, 14.25. MS (ESI) calculated for C35H66N2O8S, m/z
674.45, found 697.45 (M + Na)+.
Synthesis of Compound 47: 3-(((R)-2-Amino-3-(((S)-3-hy-
droxy-1-methoxy-1-oxopropan-2-yl)amino)-3-oxopropyl)-
thio)propyl Palmitate, Trifluoroacetate. Compound 46 (50 mg,
0.07 mmol) was deprotected with trifluoroacetic acid as described
earlier in the general procedure for one-step deprotection of N-Boc
and O-tert-butyl (see synthesis of compound 11) to obtain compound
1
47 as trifluoroacetate salt (47 mg, quantitative yield). H NMR (500
MHz, CDCl3) δ 8.35 (d, J = 6.83 Hz, 1H), 4.66 (s, 1H), 4.15 (t, J =
6.35 Hz, 2H), 4.01−3.87 (m, 3H), 3.79 (s, 3H), 3.05 (dd, J = 3.85,
13.59 Hz, 1H), 2.93−2.85 (m, 1H), 2.62 (t, J = 7.07 Hz, 2H), 2.30
(dd, J = 6.35, 13.88 Hz, 2H), 1.91 (p, J = 6.69 Hz, 2H), 1.59 (dd, J =
7.17, 14.37 Hz, 2H), 1.45−1.09 (m, 26H), 0.88 (t, J = 6.96 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 174.33, 170.57, 62.72, 62.67, 55.17,
53.43, 52.97, 35.43, 34.42, 32.07, 29.85, 29.81, 29.81, 29.78, 29.65,
29.51, 29.44, 29.32, 28.75, 28.57, 25.08, 22.84, 14.28. MS (ESI)
calculated for C26H50N2O6S, m/z 518.33, found 541.33 (M + Na)+.
Synthesis of Compound 48: 2-(((R)-3-(((S)-3-(tert-Butoxy)-1-
methoxy-1-oxopropan-2-yl)amino)-2-((tert-butoxycarbonyl)-
amino)-3-oxopropyl)thio)acetic Acid. To a solution of compound
41 (100 mg, 0.26 mmol) in DMF were added triethylamine (73 μL,
0.52 mmol) and iodoacetic acid (60 mg, 0.31 mmol). The reaction
mixture was stirred at 90 °C for 2 h. After completion of the reaction,
the solvent was removed under reduced pressure to obtain the residue.
The residue was dissolved in ethyl acetate, followed by washing with
10% HCl. The organic layer was dried over anhydrous sodium sulfate,
filtered, and evaporated under reduced pressure to obtain the crude
product, which was purified using column chromatography (10%
1
MeOH/CH2Cl2) to obtain compound 48 (80 mg, 71%). H NMR
(500 MHz, CDCl3) δ 7.38 (d, J = 4.79 Hz, 1H), 5.69 (d, J = 5.36 Hz,
1H), 4.66 (dt, J = 3.11, 7.67 Hz, 1H), 4.43 (d, J = 4.09 Hz, 1H), 3.80
(dd, J = 3.19, 9.23 Hz, 1H), 3.73 (s, 3H), 3.59 (dd, J = 3.20, 9.19 Hz,
1H), 3.44−3.26 (m, 2H), 3.03 (d, J = 4.67 Hz, 2H), 1.44 (s, 9H), 1.13
(s, 9H). 13C NMR (126 MHz, CDCl3) δ 173.53, 170.96, 170.63,
155.70, 80.65, 73.91, 61.73, 53.59, 53.39, 52.63, 35.21, 34.08, 28.39,
27.39, 27.35. MS (ESI) calculated for C18H32N2O8S, m/z 436.18,
found 459.18 (M + Na)+.
Figure 3. CD11b (Top) and p38MAPK upregulation in human
granulocytes. Whole human blood was stimulated ex vivo with
lipopeptides and assayed by flow cytometry. Representative experi-
ment of three independent experiments are shown.
168.27, 62.63, 61.83, 55.40, 52.98, 52.83, 34.32, 33.06, 32.08, 30.90,
29.86, 29.84, 29.82, 29.67, 29.52, 29.45, 29.31, 24.99, 22.84, 14.27.
MS (ESI) calculated for C25H48N2O6S, m/z 504.32, found 505.34
(M + H)+.
Synthesis of Compound 49: (S)-Methyl 3-(tert-Butoxy)-2-
((R)-2-((tert-butoxycarbonyl)amino)-3-((2-(hexadecyloxy)-2-
oxoethyl)thio)propanamido)propanoate. To a solution of 48
(60 mg, 0.13 mmol) in anhydrous DMF were added 1-hexadecanol
(50 mg, 0.20 mmol), HOBt (35 mg, 0.26 mmol), and triethylamine
(36 μL, 0.26 mmol). The reaction mixture was stirred at 0 °C for 30
min, followed by addition of EDCI (50 mg, 0.26 mmol) at 0 °C. The
reaction mixture was stirred at room temperature for 16 h, followed by
evaporation of the solvent under reduced pressure. The residue was
then dissolved in ethyl acetate and washed with water. The organic
solvent was dried over anhydrous sodium sulfate, filtered, and
evaporated under reduced pressure to obtain the crude product,
which was purified using column chromatography (25% EtOAc/
hexanes) to obtain compound 49 (77 mg, 85%). 1H NMR (500 MHz,
CDCl3) δ 7.30 (d, J = 7.84 Hz, 1H), 5.55 (d, J = 7.44 Hz, 1H), 4.65
(dt, J = 2.98, 7.95 Hz, 1H), 4.41 (d, J = 6.59 Hz, 1H), 4.12 (t, J = 6.86
Hz, 2H), 3.82 (dd, J = 3.03, 9.05 Hz, 1H), 3.73 (d, J = 3.35 Hz, 3H),
3.57 (dd, J = 3.27, 9.06 Hz, 1H), 3.37 (q, J = 15.34 Hz, 2H), 2.99
(ddd, J = 6.30, 14.18, 33.64 Hz, 2H), 1.67−1.59 (m, 2H), 1.43 (s, 9H),
1.38−1.22 (m, 26H), 1.13 (d, J = 4.63 Hz, 9H), 0.87 (t, J = 6.95 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 170.97, 170.63, 170.46, 155.41,
80.23, 73.61, 66.00, 61.73, 53.39, 53.25, 52.53, 35.86, 34.34, 32.05,
29.82, 29.81, 29.79, 29.78, 29.72, 29.65, 29.50, 29.37, 28.61, 28.41,
27.38, 25.94, 22.83, 14.28. MS (ESI) calculated for C34H64N2O8S, m/z
660.43, found 683.44 (M + Na)+.
Synthesis of Compound 45: (S)-Methyl 3-(tert-Butoxy)-2-
((R)-2-((tert-butoxycarbonyl)amino)-3-((3-hydroxypropyl)thio)-
propanamido)propanoate. Compound 41 (60 mg, 0.16 mmol)
was S-alkylated with 3-iodo-1-propanol (18 μL, 0.19 mmol) as
described in the general procedure for S-alkylation (see synthesis of
compound 42) to obtain compound 45 (50 mg, 72%). 1H NMR (500
MHz, CDCl3) δ 7.23 (d, J = 7.64 Hz, 1H), 5.53 (s, 1H), 4.67 (dt, J =
3.01, 8.20 Hz, 1H), 4.34 (d, J = 4.72 Hz, 1H), 3.83 (dd, J = 2.96, 9.14
Hz, 1H), 3.80−3.70 (m, 5H), 3.58 (dd, J = 3.18, 9.14 Hz, 1H), 2.96
(dd, J = 5.42, 14.04 Hz, 1H), 2.87 (dd, J = 7.03, 14.04 Hz, 1H), 2.80
(d, J = 5.68 Hz, 1H), 2.75−2.69 (m, 1H), 2.24 (s, 1H), 1.91−1.82 (m,
2H), 1.46 (s, 9H), 1.15 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
170.69, 155.50, 80.42, 73.73, 61.82, 60.92, 53.49, 53.25, 52.58, 34.86,
32.04, 28.49, 28.42, 27.40. MS (ESI) calculated for C19H36N2O7S, m/z
436.22, found 459.23 (M + Na)+.
Synthesis of Compound 46: 3-(((R)-3-(((S)-3-(tert-Butoxy)-1-
methoxy-1-oxopropan-2-yl)amino)-2-((tert-butoxycarbonyl)-
amino)-3-oxopropyl)thio)propyl Palmitate. Compound 45 (40
mg, 0.09 mmol) was palmitoylated using the general procedure for
palmitoylation (see synthesis of compound 28) to obtain compound
46 (50 mg, 81%). 1H NMR (500 MHz, CDCl3) δ 7.16 (d, J = 7.75 Hz,
1H), 5.44 (s, 1H), 4.65 (dt, J = 3.02, 8.14 Hz, 1H), 4.29 (d, J = 4.64
Hz, 1H), 4.18−4.09 (m, 2H), 3.81 (dd, J = 2.94, 9.10 Hz, 1H), 3.73
8155
dx.doi.org/10.1021/jm201071e|J. Med. Chem. 2011, 54, 8148−8160