Journal of Medicinal Chemistry
Article
was extracted three times with CH2Cl2 (10 mL × 3). The combined
organic layer was washed with brine, dried over Na2SO4, and
evaporated. The residue was column-chromatographed (n-hexane/
ethyl acetate/Et3N = 35:4:1) to yield 17 (704.1 mg, 1.516 mmol, 92%,
yellow oil). In the purification with column chromatography, Et3N-
deactivated silica gel was used, that is, eluents containing 3% (v/v)
Et3N. 1H NMR (CD2Cl2): δ = 5.500 (1/2H, d, J = 8.28 Hz), 5.332 (1/
2H, d, J = 8.28 Hz), 4.218−4.138 (1H, m), 3.895 (1H, m), 3.747−
3.650 (1H, m), 3.569 (2H, m), 1.447 (9/2H, s), 1.439 (9/2H, s),
1.419 (9/2H, s), 1.412 (9/2H, s), 1.344 (9/2H, s), 1.308 (9/2H, s),
1.140 (12H, m). 13C NMR (CD2Cl2): δ = 169.61, 155.25, 155.16,
81.46, 81.31, 79.10, 79.05, 74.97, 74.89, 74.78, 63.67, 63.53, 63.26,
63.12, 55.26, 55.20, 55.13, 43.12, 43.06, 42.99, 42.93, 30.65, 30.62,
30.56, 30.54, 28.07, 28.05, 27.74, 24.46, 24.38, 24.34, 24.27, 23.97,
23.89, 23.86, 23.79. 31P NMR (CD2Cl2): δ = 138.847, 138.325. HRMS
(ESI, [M + Na]+) calcd for C22H45N2NaO6P+: 487.2907. Found:
487.2927.
77%, white powder). The AcOH salt was dissolved in TFA and
evaporated to yield 9-o-C11 as the TFA salt (white powder). Mp:
151.5−153.0 °C. 1H NMR (CDCl3/TFA-d = 4:1): δ = 7.201 (1H, t, J
= 7.54 Hz), 7.078 (1H, m), 6.887 (2H, m), 4.641 (2H, m), 4.533 (1H,
m), 4.239 (2H, m), 4.061 (2H, m), 4.013 (2H, t, J = 6.68 Hz), 2.951
(2H, t, J = 6.96 Hz), 2.747 (2H, t, J = 7.00 Hz), 1.993 (2H, m), 1.798
(2H, m), 1.448 (2H, m), 1.274 (14H, m), 0.878 (3H, t, J = 6.74 Hz).
31P NMR (CDCl3/TFA-d = 4:1): δ = −1.404. HRMS (ESI, [M −
H]−) calcd for C26H43NO9P−: 544.2681. Found: 544.2700. Anal.
Calcd For C26H44NO9P·0.7CF3COOH: C, 52.62; H, 7.20; N, 2.24.
Found: C, 52.66; H, 7.43; N, 2.29.
tert-Butyl (tert-Butoxycarbonyl)-L-allothreoninate (22). L-allo-
Threonine 20 (997.3 mg, 8.372 mmol) was dissolved in 1 N aqueous
NaOH (10 mL), H2O (10 mL) and dioxane (20 mL) at 0 °C with
stirring. After di-tert-butyl dicarbonate (2.763 g, 12.66 mmol) was
added to the solution at 0 °C with stirring over 10 min, the reaction
mixture was stirred at room temperature for 24 h. Then 5% aqueous
KHSO4 was added to the reaction mixture to adjust to pH 3. The
solution was extracted three times with AcOEt (40 mL × 3). The
combined organic layer was washed with brine, dried with Na2SO4,
and evaporated to yield the crude N-Boc-L-allo-threonine (21, 2.016 g,
colorless oil). The crude N-Boc-L-allo-threonine was dissolved in
anhydrous dichloromethane (150 mL), and O-tert-butyl-N,N′-
diisopropylisourea (5.872 g, 29.31 mmol) was added. The solution
was stirred for 18 h at room temperature. Hexane was added in the
mixture and stirred for 10 min. The mixture was filtered through
Celite, and the filtrate was evaporated. The residue was column-
chromatographed (hexane/AcOEt = 4:1) to yield 22 (1.581 g, 5.741
3-Hydroxypropyl 3-(2-(Undecyloxy)phenyl)propanoate (18).
To a solution of 1,3-propandiol (287.1 mg, 3.773 mmol), acid 15
(301.9 mg, 0.942 mmol), and DMAP (10.9 mg, 0.0907 mmol) in
CH2Cl2 (5 mL), EDCI (199.5 mg, 1.041 mmol) was added at 0 °C.
Then the whole was stirred for 16 h at room temperature. After
quenching with H2O (10 mL), the whole was extracted three times
with CH2Cl2 (10 mL × 3), washed with brine, and dried over Na2SO4
and evaporated. The residue was column-chromatographed (hexane/
AcOEt = 4:1) to yield 18 (322.7 mg, 0.852 mmol, 90%, colorless oil).
1H NMR (CDCl3): δ = 7.173−7.126 (2H, m), 6.871−6.815 (2H, m),
4.221 (2H, t, J = 6.10 Hz), 3.961 (2H, t, J = 6.48 Hz), 3.610 (2H, t, J =
6.02 Hz), 2.946 (2H, t, J = 7.68 Hz), 2.638 (2H, t, J = 7.66 Hz), 1.827
(2H, m), 1.470 (2H, m), 1.272 (14H, m), 0.884 (3H, t, J = 6.84 Hz)
(no −OH peak). 13C NMR (CDCl3): δ = 174.86, 157.00, 129.95,
128.80, 127.57, 120.16, 111.06, 67.80, 61.14, 59.17, 34.19, 31.91,
31.78, 29.62, 29.37, 29.33, 26.32, 26.16, 22.67, 14.09. HRMS (ESI, [M
1
mmol, 69%, white solid). Mp: 62.1−63.0 °C. H NMR (CDCl3): δ =
5.226 (1H, m), 4.224 (1H, s), 4.123 (1H, m), 1.960 (1H, d, J = 6.00
Hz), 1.486 (9H, s), 1.455 (9H, s), 1.234 (3H, d, J = 6.40 Hz). 13C
NMR (CDCl3): δ = 169.29, 156.49, 82.72, 80.28, 69.22, 59.45, 28.16,
+
27.88, 18.15. HRMS (ESI, [M + Na]+) calcd for C13H25NNaO5 :
+
+ Na]+) calcd for C23H38NaO4 : 401.2662. Found: 401.2639.
298.1630. Found: 298.1609. Anal. Calcd for C13H25NO5: C, 56.66; H,
9.01; N, 5.11. Found: C, 56.76; H, 9.05; N, 5.39.
tert-Butyl O-(tert-Butoxy(3-((3-(2-(undecyloxy)phenyl)-
propanoyl)oxy)propoxy)phosphoryl)-N-(tert-butoxycarbonyl)-
L-serinate (19). In order to eliminate traces of water, phosphoamidite
17 (204.1 mg, 0.440 mmol) was dissolved in CH2Cl2 (5 mL) and
toluene (0.5 mL), and the solvent was evaporated under vacuum. To
this residue, alcohol 18 (201.5 mg, 0.532 mmol), CH2Cl2 (5 mL), and
toluene (0.5 mL) were added, and the solvent was evaporated under
vacuum. This residue was dissolved in CH2Cl2 (2 mL) under an argon
atmosphere, and the solution of 1H-tetrazole (92.3 mg, 1.318 mmol)
in THF (2 mL) was added at room temperature. In a few minutes, a
white solid was precipitated. The reaction mixture was stirred for 11 h
at room temperature, and a solution of TBHP in decane (5.0−6.0 M)
(0.1761 mL, 0.881 mmol) was added at room temperature, and the
whole was stirred for 5 h at room temperature. The solution was
diluted with water (10 mL), and the whole was extracted three times
with CH2Cl2 (10 mL × 3). The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated. The residue was
column-chromatographed (hexane/AcOEt = 4:1) to yield 19 (307.0
tert-Butyl O-(tert-Butoxy(diisopropylamino)phosphanyl)-N-
(tert-butoxycarbonyl)-L-allothreoninate (23). Bis(diisopropyl-
amino)-tert-butylphosphine (303.1 mg, 1.101 mmol) was dissolved
in CH2Cl2 (5 mL) and toluene (0.5 mL). To this solution, N-Boc-L-
allo-threonine tert-butyl ester 22 (508.2 mg, 1.669 mmol) was added.
In order to eliminate traces of water, the resultant solution was
evaporated under vacuum. The residue was dissolved in CH2Cl2 (5
mL) under an argon atmosphere, and a solution of 1H-tetrazole (105.9
mg, 1.512 mmol) in THF (5 mL) was added at room temperature. In
a few minutes, a white solid was precipitated. The whole was stirred for
3 h at room temperature. The reaction was quenched with the addition
of saturated aqueous NaHCO3 (10 mL), and the whole was extracted
three times with CH2Cl2 (10 mL × 3). The combined organic layer
was washed with brine and dried over Na2SO4. The solvent was
evaporated, and the residue was chromatographed (hexane/AcOEt/
Et3N = 35:4:1) to yield 23 (445.0 mg, 0.930 mmol, 84%, yellow oil).
In the purification with column chromatography, Et3N deactivated
silica gel was used, that is, eluents containing 3% (v/v) Et3N. 1H NMR
(CD2Cl2): δ = 5.825 (1/2H, m), 5.300 (1/2H, m), 4.085−3.959 (2H,
m), 3.576 (2H, m), 1.436−1.431 (9H, m), 1.405−1.396 (9H, m),
1.360−1.308 (9H, m), 1.270 (3H, d, J = 6.56 Hz), 1.143 (12H, m).
13C NMR (CD2Cl2): δ = 169.12, 169.06, 155.51, 155.26, 81.59, 81.22,
1
mg, 0.405 mmol, 92%, colorless oil). H NMR (CDCl3): δ = 7.178−
7.112 (2H, m), 6.854−6.801 (2H, m), 5.486 (1H, m), 4.347 (1H, m),
4.212 (1H, m), 4.158 (2H, m), 4.019 (2H, m), 3.948 (2H, t, J = 6.54
Hz), 2.928 (2H, t, J = 7.88 Hz), 2.611 (2H, dt, J = 7.70, 1.04 Hz),
1.956 (2H, m), 1.788 (2H, m), 1.482−1.467 (18H, m), 1.436 (9H, s),
1.262 (14H, m), 0.874 (3H, t, J = 6.84 Hz). 13C NMR (CDCl3): δ =
173.20, 168.33, 156.93, 155.22, 129.89, 128.79, 127.50, 120.13, 110.99,
83.64, 83.57, 82.64, 82.61, 79.89, 67.74, 67.39, 64.06, 64.00, 60.36,
54.47, 54.39, 34.03, 31.87, 29.78, 29.76, 29.74, 29.72, 29.58, 29.56,
29.52, 29.33, 29.30, 28.28, 27.93, 26.13, 26.09, 22.64, 14.07. 31P NMR
(CDCl3):δ = −5.547, −5.693. HRMS (ESI, [M + Na]+) calcd for
C39H68NNaO11P+: 780.4422. Found: 780.4432.
79.19, 79.06, 75.23, 75.13, 74.98, 74.87, 70.86, 70.70, 70.67, 70.53,
59.35, 59.31, 59.10, 43.32, 43.26, 43.20, 43.13, 30.83, 30.76,30.75,
30.68, 28.24, 28.18, 27.98, 27.95, 24.49, 24.46, 24.41, 24.37, 24.12,
24.03, 23.91, 23.85, 19.73, 19.71, 19.07. 31P NMR (CD2Cl2): δ =
138.879, 137.547. HRMS (ESI, [M
C23H47N2NaO6P+: 501.3064. Found: 501.3053.
+
Na]+) calcd for
3-(3-(Undecyloxy)phenyl)propanoic Acid (26). To a solution
of phenol 24 (315.4 mg, 1.750 mmol), 11-bromoundecane (501.2 mg,
2.131 mmol), and TBAI (190.7 mg, 0.516 mmol) in DMF (5 mL) was
added Cs2CO3 (695.6 mg, 2.135 mmol), and the whole was heated at
70 °C with stirring for 27 h. To this solution was added MeOH (2
mL), and the whole was heated at 70 °C with stirring for 15 h. The
reaction mixture was diluted with H2O (10 mL) and AcOEt (20 mL),
O-(Hydroxy(3-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)-
propoxy)phosphoryl)-L-serine (9-o-C11). 19 (24.3 mg, 0.0274
mmol) was dissolved in TFA (1.0 mL) at 0 °C, and the mixture was
stirred at room temperature for 1 h. The mixture was evaporated. The
residue was column-chromatographed (CHCl3/MeOH/AcOH =
8:1:1) to yield 9-o-C11 as the AcOH-salt (14.4 mg, 0.0210 mmol,
4216
J. Med. Chem. 2015, 58, 4204−4219