G. Arthur, R. Bittman, et al.
MED
which was rinsed with 100 mL hexane/EtOAc (10:1). The filtrate
was concentrated to give a residue, which was purified by column
chromatography on silica gel (elution with hexane/EtOAc 25:1) to
provide bromide 8 (5.36 g, 87%) as a pale-yellow oil; [a]2D5 =À24.9
(c=6.7, CHCl3); 1H NMR (CDCl3): d=0.88 (t, 3H, J=6.6 Hz), 1.26
(brs, 26H), 1.50–1.56 (m, 2H), 2.31–2.41 (m, 2H), 3.42–3.50 (m, 4H),
3.62–3.65 (m, 2H), 5.35–5.41 (m, 1H), 7.42–7.46 (m, 2H), 7.54–7.59
(m, 1H), 8.05 ppm (dd, 2H, J=1.4, 8.4 Hz); 13C NMR (CDCl3): d=
14.1, 22.6, 26.0, 28.7, 29.3, 29.4, 29.5, 29.6, 31.9, 34.5, 71.2, 71.7,
71.7, 128.3, 129.6, 130.0, 133.0, 165.9 ppm; MS (ES) [M+H]+ m/z
calcd for C27H46BrO3: 497.2, found: 497.2.
10 mmol), and hydroxyphosphonate 10 (2.12 g, 5.02 mmol) in
25 mL THF/DMF (10:1). The mixture was stirred until compound 10
was completely consumed. The reaction mixture was diluted with
CHCl3 and washed with brine solution. The organic layer was dried
over Na2SO4 and concentrated. The product was purified by
column chromatography on silica gel (elution with a gradient of
CHCl3, CHCl3/MeOH 100:1, CHCl3/MeOH 50:1, then CHCl3/MeOH
25:1) to give carbamoyl phosphonate 11 (265 mg, 11%) and dicar-
bamoyl phosphonate 12 (1.43 g, 53%) as colorless oils. Data for
compound 11: [a]2D5 =À5.82 (c=5.5, CHCl3); 1H NMR (CDCl3): d=
0.88 (t, 3H, J=6.4 Hz), 1.26 (brs, 26H), 1.48–1.62 (m, 2H), 1.15–2.00
(m, 4H), 2.87 (d, 3H, J=4.8 Hz), 3.25–3.50 (m, 6H), 3.75 (d, 6H, J=
10.8 Hz), 4.90–5.00 (m, 1H), 7.60–7.70 ppm (brs, 1H); 13C NMR
(CDCl3): d=14.1, 20.7 (d, J=151 Hz), 22.6, 24.0 (d, J=5.0 Hz), 26.0,
26.1, 26.4, 29.3, 29.4, 29.5, 29.6, 31.9, 52.4, 67.8, 74.4 ppm (d, J=
6.0 Hz), 153.7; 31P NMR (CDCl3): d=35.5; MS (ES) [M+H]+ m/z calcd
3(R)-Benzoyl-4-hexadecyloxy-1-bromobutane. The enantiomer of
bromide 8 was prepared in 85% yield from (3R)-4-O-hexadecyl-1,3-
O-benzylidine-1,3,4-butanediol by the procedure described above;
[a]2D5 =+20.5 (c=6.9, CHCl3).
for C24H51NO6P: 480.3, found: 480.3. Data for compound 12: [a]D25
=
Diethyl 3(S)-benzoyl-4-hexadecyloxy-1-butanephosphonate (9).
A solution of bromide 8 (4.98 g, 10.0 mmol) in 25 mL (EtO)3P
(150 mmol) was heated at 1508C (oil bath temperature) overnight.
After excess (EtO)3P was removed by using a stream of air, the resi-
due was purified by column chromatography on silica gel (elution
with CHCl3/MeOH 25:1) to give benzoyl phosphonate 9 (4.39 g,
79%) as a colorless oil; [a]2D5 =À6.88 (c=5.8, CHCl3); 1H NMR
(CDCl3): d=0.88 (t, 3H, J=6.7 Hz), 1.26 (brs, 26H), 1.28–1.33 (m,
6H), 1.70–2.00 (m, 2H), 3.43–3.62 (m, 4H), 4.06–4.12 (m, 4H), 5.23–
5.27 (m, 1H), 7.42–7.46 (m, 2H), 7.54–7.59 (m, 1H), 8.04 ppm (d,
2H, J=7.0 Hz); 13C NMR (CDCl3): d=14.1, 16.4 (d, J=5.8 Hz), 22.2
(d, J=143.2 Hz), 22.6, 24.3 (d, J=4.0 Hz), 29.3, 29.4, 29.6, 29.7, 31.9,
61.6, 71.3, 71.7, 72.8 (d, J=18.1 Hz), 127.7, 128.3, 129.6, 130.1,
133.0, 166.0 ppm; MS (ES) [M+H]+ m/z calcd for C31H56O6P: 555.4,
found: 555.3.
À4.70 (c=5.6, CHCl3); 1H NMR (CDCl3): d=0.88 (t, 3H, J=6.0 Hz),
1.25 (brs, 26H), 1.50–1.62 (m, 2H), 1.75–1.86 (m, 2H), 1.90–2.10 (m,
2H), 2.87 (d, 3H, J=4.4 Hz), 3.22 (s, 3H), 3.42–3.52 (m, 4H), 3.51 (t,
2H, J=5.2 Hz), 3.75 (d, 6H, J=10.8 Hz), 4.90–5.00 (m, 1H), 8.40–
8.50 ppm (brs, 1H); 13C NMR (CDCl3): d=14.1, 20.7 (d, J=143 Hz),
22.4, 24.0 (d, J=4.3 Hz), 26.0, 27.1, 29.3, 29.4, 29.5, 29.6, 30.7, 31.9,
52.5, 71.1, 71.7, 75.0 (d, J=17.5 Hz), 155.2, 155.9 ppm; 31P NMR
(CDCl3): d=33.6; ESI-HRMS [M+H]+ m/z calcd for C26H54N2O7P:
537.3663, found: 537.3667.
Dimethyl
phosphonate and dimethyl 4-hexadecyloxy-3(R)-[N-(N’-methyl-
carbamoyl)-N-methylcarbamoyl]-1-butanephosphonate. The
4-hexadecyloxy-3(R)-N-methylcarbamoyl-1-butane-
enantiomers of carbamoyl phosphonate 11 and dicarbamoyl phos-
phonate 12 were prepared in 12 and 50% yields, respectively, from
4-hexadecyloxy-3(R)-hydroxy-1-butanephosphonate by the proce-
dure described above. Data for the enantiomer of 11: [a]2D5 =+5.49
(c=5.6, CHCl3); MS (ES) [M+H]+ m/z calcd for C24H51NO6P: 480.3,
found: 480.3. Data for the enantiomer of 12: [a]2D5 =+4.55 (c=5.7,
CHCl3); ESI-HRMS [M+H]+ m/z calcd for C26H54N2O7P: 537.3663,
found: 537.3659.
Diethyl 3(R)-benzoyl-4-hexadecyloxy-1-butanephosphonate. The
enantiomer of benzoyl phosphonate 9 was prepared in 80% yield
from 3(R)-benzoyl-4-hexadecyloxy-1-bromobutane by the proce-
dure described above; [a]2D5 =+6.71 (c=6.0, CHCl3).
Dimethyl
4-hexadecyloxy-3(S)-hydroxy-1-butanephosphonate
(10).[25] Na0 (0.18 g, 7.83 mmol) was added to 100 mL dry MeOH.
After complete disappearance of Na0, a solution of phosphonate 9
(3.91 g, 7.05 mmol) in 10 mL dry MeOH was added. After the mix-
ture was stirred overnight, the reaction was quenched by the addi-
tion of 500 mL HOAc (8.73 mmol) and then concentrated under re-
duced pressure to give a residue, which was purified by column
chromatography on silica gel (elution with CHCl3/MeOH 10:1) to
provide hydroxyphosphonate 10 (2.56 g, 86%) as a colorless oil;
[a]2D5 =À5.20 (c=5.0, C6H6); 1H NMR (CDCl3): d=0.88 (t, 3H, J=
6.8 Hz), 1.26 (brs, 26H), 1.54–1.58 (m, 2H), 1.70–1.90 (m, 4H), 2.78
(brs, 1H), 3.29 (dd, 1H, J=7.1, 9.4 Hz), 3.40–3.48 (m, 3H), 3.74 (d,
6H, J=10.8 Hz), 3.70–3.85 ppm (m, 1H); 13C NMR (CDCl3): d=14.0,
20.7 (d, J=142.1 Hz), 22.6, 26.0, 26.1 (d, J=4.7 Hz), 29.3, 29.4, 29.5,
29.6, 31.9, 52.3, 69.8 (d, J=14.8 Hz), 71.6, 74.4; ESI-HRMS [M+H]+
m/z calcd for C22H48O5P: 423.3234, found: 423.3242.
2’-(Trimethylammonio)ethyl 4-hexadecyloxy-3(S)-N-methylcarba-
moyl-1-butanephosphonate (1). Me3SiBr (500 mL, 3.79 mmol) was
added to a solution of carbamoyl phosphonate 11 (512 mg,
1.07 mmol) in 25 mL CH2Cl2. After the mixture was allowed to
stand overnight at room temperature, volatile materials were re-
moved under reduced pressure to give a residue. Choline toluene-
sulfonate (1.45 g, 3.01 mmol) was added to the residue, and the
mixture was dried overnight under high vacuum. After the dry mix-
ture was dissolved in pyridine (50 mL), Cl3CCN (1.5 mL, 15.0 mmol)
was added, and the reaction mixture was heated for 48 h at 508C
(oil bath temperature). Upon removal of most of the pyridine by
rotary evaporation, a brown residue was formed, which was dis-
solved in THF/H2O (10 mL, 9:1 v/v) and passed through a column
of TMD-8 resin (previously equilibrated with the same solvent mix-
ture). The product was purified by silica gel chromatography (elu-
tion with CHCl3/MeOH/H2O 65:25:4). The fractions containing the
product were pooled and concentrated under reduced pressure.
The residue was dissolved in CHCl3 (15–25 mL) and passed through
an Osmonics filter three times to remove the suspended silica gel.
The filtrate was concentrated to give a residue, which was lyophi-
lized from benzene to afford phosphonate 1 (395 mg, 69%) as a
white powder; [a]2D5 =À2.53 (c=0.21, CHCl3/MeOH 1:1); 1H NMR
(CDCl3/CD3OD): d=0.89 (t, 3H, J=6.4 Hz), 1.26 (brs, 26H), 1.32–
1.35 (m, 2H), 1.44–1.62 (m, 4H), 1.86–1.95 (m, 2H), 2.86 (d, 3H, J=
4.8 Hz), 3.24 (s, 9H), 3.30–3.70 (m, 8H), 4.90–5.00 ppm (m, 1H);
Dimethyl 4-hexadecyloxy-3(R)-hydroxy-1-butanephosphonate.
The enantiomer of hydroxyphosphonate 10 was prepared in 88%
yield from diethyl 3(R)-benzoyl-4-hexadecyloxy-1-butanephospho-
nate by the procedure described above; [a]2D5 =+5.22 (c=5.1,
C6H6).
Dimethyl
phosphonate (7) and dimethyl 4-hexadecyloxy-3(S)-[N-(N’-meth-
ylcarbamoyl)-N-methylcarbamoyl]-1-butanephosphonate (11).
4-hexadecyloxy-3(S)-N-methylcarbamoyl-1-butane-
MeI (3.2 mL, 51.4 mmol) and (iPr)2NEt (1.8 mL, 10.4 mmol) were
added to a mixture of KNCO (8.11 g, 100 mmol), nBu4NBr (3.22 g,
1050
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2010, 5, 1045 – 1052