234
R. K. Anchoori et al. / Bioorg. Med. Chem. 18 (2010) 229–235
at 400 MHz on a Bruker Avance spectrometer and are reported in
parts per million downfield relative to tetramethylsilane (TMS).
EI-MS profiles were obtained using a Bruker Esquire 3000 plus.
The HPLC method was set up on a Waters System equipped with
4.2.4. (4R,5R)-4-(2-(Benzyloxy)ethyl)-2,2-dimethyl-5-octyl-1,3-
dioxane (6)
To a solution of compound 1 (0.7 g, 2.2 mmol) in CH2Cl2 (10 mL)
was added 2,2-dimethoxy propane (1.2 g, 11 mmol) and catalytic
amount of p-Toluene-sulfonic acid and stirred the reaction mixture
for 4 hours at ambient temperature. To the crude compound ob-
tained after removal of the solvents was added water (10 mL)
and extracted with ethyl acetate twice (2 Â 30 mL). Combined or-
ganic layers were washed with brine (20 mL), dried over Na2SO4
and concentrated in vacuo. Purification by column chromatogra-
phy (SiO2, EtOAc/hexanes 3:7) afforded 6 as a syrup. 1H NMR
(400 MHz, CDCl3): 7.35–7.38 (m, 5H), 4.51 (d, 2H, J = 3.6 MHz),
4.17–4.22 (m, 1H), 3.95–4.01 (m, 1H), 3.77–3.81 (m, 1H),
3.51–3.58 (m, 2H), 1.80–1.90 (m, 1H), 1.60–1.76 (m, 2H), 1.44
(s, 3H), 1.38 (s, 3H), 1.25–1.35 (m, 14H), 0.90 (t, 3H, J = 6.8,
13.6 MHz); MS: 362 (M++1).
a PDA detector 2996, using C18 column (5
with water and acetonitrile as mobile phase and the flow rate of
l
m, 250 Â 4.6 mm)
1 mL/min. The wavelengths were obtained at 214 nm.
4.2. General procedure for the preparation of compounds 1–10
4.2.1. (S)-4-Benzyl-3-decanoyloxazolidin-2-one (3)
To a solution of decanoic acid (0.2 g, 1.0 mmol) in THF (5 mL)
at À20 °C was added triethylamine (0.18 mL, 1.3 mmol), LiCl (cat-
alytic amount) and pivaloyl chloride (0.13 mL, 1.1 mmol). The
reaction mixture was stirred at À78 °C for 1 h and the resulting
pivaloyl anhydride was used without purification. To this reaction
mixture a solution of oxazolidinone 7 (0.212 g, 1.2 mmol) in THF
(5 mL) was added at À78 °C. The reaction mixture was stirred at
this temperature for 1 h, quenched with satd NH4Cl (2 mL), and
washed with Et2O (2 Â 10 mL). The combined organic phases
were washed with satd NaHCO3 (5 mL), brine (5 mL), dried
(MgSO4) and concentrated. Purification by flash chromatography
(SiO2, EtOAc/hexane 1:4) gave 0.276 g (78%) of 3 as a yellow
oil; 1H NMR (400 MHz, CDCl3): 7.23–7.42 (m, 5H), 4.67–4.73
(m, 1H), 4.17–4.24 (m, 2H), 3.34 (dd, 1H, J = 3.2, 13.2 MHz),
2.88–3.03 (m, 2H), 2.79 (ab q, 1H, J = 9.6, 13.2 MHz), 1.68–1.76
(m, 2H), 1.23–1.46 (m, 12 H), 0.91 (t, 3H, J = 6.4, 13.6 MHz);
MS: 332 (M++1).
4.2.5. (2R,3R)-5-(Benzyloxy)-2-heptylpentane-1,3-diol (SK2009)
SK2009 was synthesized based on the synthesis of 5 using cor-
responding acid CH3 (CH2)7COOH.
1H NMR (400 MHz, CDCl3): 7.30–7.40 (m, 5H), 4.56 (s, 2H), 4.11
(d, 1H, J = 10.8 MHz), 3.76–3.86 (m, 2H), 3.67–3.73 (m, 2H),
1.87–2.10 (m, 1H), 1.19–1.42 (m, 12H), 0.90 (t, 3H, J = 6.4,
13.2 MHz); MS: 309 (M++1).
4.2.6. (4R,5S)-Tetrahydro-4-hydroxy-5-tetradecylpyran-2-one
(4)
Compound 4 was synthesized using the Ref. 7.
1H NMR (400 MHz, CDCl3): 4.5 (dd, 1H, J = 4.4, 11.6 MHz), 3.94–
4.0 (m, 2H), 2.90 (dd, 1H, J = 6.0, 17.6 MHz), 2.56 (dd, 1H, J = 6.0,
17.6 MHz), 1.81–1.97 (m, 2H), 1.54–1.66 (m, 2H), 1.25–1.31 (m,
24H), 0.90 (t, 3H, J = 6.8, 13.6 MHz); MS: 647 (dimmer), 313
(M++1).
4.2.2. (S)-3-((S)-2-((R)-3-(Benzyloxy)-1-hydroxypropyl)
decanoyl)-4-benzyloxazolidin-2-one (5)
To a solution of oxazolidinone 3 (0.9 g, 3.6 mmol) in CH2Cl2
(10 mL) at 0 °C, Dibutyl boron triflate (0.79 mL, 7.2 mmol) was
added dropwise. The reaction mixture turned into yellowish slurry.
It was stirred for 5 min at 0 °C and then diisopropylethylamine
(0.7 mL, 3.96 mmol) was added dropwise. The reaction mixture
now turned deep reddish in color. Stirring was continued for an-
other 20 min at 0 °C. It was cooled to À78 °C and aldehyde 10
(0.5 mL, 3.96 mmol) in CH2Cl2 (3 mL) was added dropwise, during
which the yellow color appeared again. Then it was stirred at
À78 °C for 1 h, warmed to 0 °C and quenched by the addition of
cold saturated NH4Cl solution. It was then extracted with EtOAc
(20 mL) and washed with brine (10 mL), dried (Na2SO4) and con-
centrated in vacuo. Purification by column chromatography (SiO2,
EtOAc/hexanes 2:4) afforded 5 (12.25 g, 88%) as a colorless solid.
1H NMR (400 MHz, CDCl3): 7.23–7.40 (m, 10H), 4.65–4.72 (m,
1H), 4.53 (s, 2H), 4.11–4.19 (m, 5H), 3.66–3.73 (m, 2H),
3.30–3.37 (m, 1H), 3.15–3.19 (m, 1H), 2.69–2.75 (dd, 1H, J = 10.4,
13.2 MHz), 1.83–1.87(m, 2H), 1.26–1.40 (m, 12H), 0.88 (t, 3H,
J = 6.8, 13.6 MHz); MS: 518 (M++Na), 497 (M++1).
4.2.7. 3-Benzyloxy-1-propionaldehyde (10)
DMSO (1.6 mL, 22 mmol) was added to a solution of (COCl)2
(1.0 mL, 11 mmol) in CH2Cl2 (100 mL) at À78 °C. The reaction
mixture was stirred for 10 min at which time 3-benzyl-1-propyl
alcohol (9, 1.66 g, 10.0 mmol) was added dropwise in CH2Cl2
(5 mL). After 15 min, triethylamine (7.0 mL, 50 mmol) was added,
the solution was stirred for 5 min at which time the reaction
mixture was warmed to room temperature. After stirring for
30 min the reaction was quenched with saturated NH4Cl
(10 mL), and the aqueous phase was washed with CH2Cl2
(2 Â 20 mL). The combined organic phase was washed with satu-
rated NaHCO3 (2 Â 10 mL), brine (10 mL), dried (Na2SO4) and
concentrated. Purification by flash chromatography (EtOAc/hex-
ane 1:4) gave aldehyde 10 as a clear oil (1.63 g, 99%); 1H NMR
(CDCl3)
d 7.2–7.4 (m, 5H), 4.5 (s, 2H), 3.8–3.9 (t, 2H,
J = 6.1 MHz), 2.6–2.7 (m, 2H).
5. Conclusion
4.2.3. (2R,3R)-5-(Benzyloxy)-2-octylpentane-1,3-diol (1)
To a solution of compound 5 (1.0 g, 2 mmol) in THF (5 mL) was
added sodium borohydride (0.1 g, 2.4 mmol) and two drops of
water at 0 °C and the reaction mixture was stirred for 1 h at the
same temperature. Reaction progress was monitored by TLC and
quenched the reaction mixture with saturated NH4Cl solution
(5 mL) and extracted with ethyl acetate twice (2 Â 10 mL). Com-
bined organic layers were washed with brine (20 mL), dried over
Na2SO4 and concentrated in vacuo. Purification by column chroma-
tography (SiO2, EtOAc/hexanes 6:4) afforded diol 1 as a pure thick
syrup. 1H NMR (400 MHz, CDCl3): 7.28–7.39 (m, 5H), 4.55 (s, 2H),
4.07–4.15 (m, 1H), 3.64–3.83 (m, 5H), 3.07–3.11 (m, 1H),
1.97–2.03 (m, 2H), 1.58–1.65 (m, 2H), 1.22–1.33 (m, 10H), 0.90
(t, 3H, J = 6.4, 13.2 MHz); MS: 322 (M++1).
In summary, we report the synthesis and biological evaluation
of novel promising candidates that are able to inhibit TNF-in-
duced NF-jB activation in KBM-5 cells in a dose- and time-
dependent manner. The results showed that SK2009 (branched
aliphatic alcohol) which is a precursor of simplactone analog
suppressed TNF-induced I
intrinsic activity on TNF-induced I
j
Ba
kinase (IKK) activation but no
kinase (IKK) activation in
jBa
in vitro experiments. Interestingly, SK2009 showed a potential
suppression on the expression of TNF-induced cyclin D1, Bcl-2,
and VEGF in KBM-5 cells. Detail studies of molecular modeling
based drug design are underway of SK2009 in order to obtain
improved activity at a lower dose.