Synthesis of Fluorine-Containing Analogues of 1-Lysoglycerophospholipids via Horner-Wadsworth-Emmons Reaction

Article abstract of DOI:10.1055/s-0036-1588826

An efficient method of synthesizing fluorine-containing analogues of 1-lysoglycerophospholipids (1-LPLs) by introducing a palmitoyl moiety starting from bis(2,2,2-trifluoroethyl)phosphonoacetate (Still-Gennari reagent) is described. The method effectively

Full text of DOI:10.1055/s-0036-1588826

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
M. Nakao et al.
Paper
Synthesis
Synthesis of Fluorine-Containing Analogues of 1-Lysoglycero-
phospholipids via Horner–Wadsworth–Emmons Reaction
F
Michiyasu Nakao
(S)
(S)
O
P
BnO
Kazue Tanaka
Syuji Kitaike
Shigeki Sano*
CF3CH2O
CF3CH2O
F
OH
CO2Me
+
O
P
H
BnO
H
O
CO2Me
CF3CH2O
"deprotection via
HWE reaction"
F
F
Graduate School of Pharmaceutical Sciences, Tokushima
University, Sho-machi, Tokushima 770-8505, Japan
ssano@tokushima-u.ac.jp
(S)
(S)
C15H31CO2
C15H31CO2
O
O
O
O
H
H
P
CO2Me
P
ZO
XO
"1-LPL analogues"
1-F-LPA: X = H, Y = OH
Y
"masked 1-LPL analogues"
1-F-LPE: X = CH2CH2NH2, Y = OH
1-F-LPC: X = CH2CH2N Me3, Y = O
Received: 06.03.2017
Accepted after revision: 10.04.2017
Published online: 18.05.2017
sn-1
sn-2
sn-3
RCO2
(R)
HO
HO
(R)
1,2-acyl migration
RCO2
DOI: 10.1055/s-0036-1588826; Art ID: ss-2017-f0142-op
O
O
P
H
H
O
O
XO
Abstract An efficient method of synthesizing fluorine-containing ana-
logues of 1-lysoglycerophospholipids (1-LPLs) by introducing a palmi-
toyl moiety starting from bis(2,2,2-trifluoroethyl)phosphonoacetate
(Still–Gennari reagent) is described. The method effectively employs
Horner–Wadsworth–Emmons reagents as masked 1-LPL derivatives to
prepare a series of analogues of 1-lysophosphatidic acid (1-LPA), 1-lyso-
phosphatidylethanolamine (1-LPE), and 1-lysophosphatidylcholine (1-
LPC).
P
Y
XO
Y
2-LPL
1-LPL
F
BnO
F
(S)
(S)
RCO2
O
P
O
P
H
H
O
O
Key words lysoglycerophospholipid, Horner–Wadsworth–Emmons
reaction, fluorine, lysophosphatidic acid, lysophosphatidylethanol-
amine, lysophosphatidylcholine
CO2Me
CF3CH2O
XO
Y
key intermediate 6
fluorine-containing
1-LPL analogues
1-F-LPA (1): X = H, Y = OH
1-F-LPE (2): X = CH2CH2NH2,
Y = OH
Lysoglycerophospholipids (LPLs), in which only one acyl
chain is attached to the glycerol moiety at the sn-2 position
(1-LPL) or sn-1 position (2-LPL), are of considerable current
interest as important signaling molecules in living biologi-
cal systems.1 Intramolecular acyl chain migration is known
to give an equilibrium mixture of 1-LPL and 2-LPL under
physiological conditions; the equilibrium generally favors
2-LPL, as shown in Scheme 1.2 On the other hand, fluorine
is the most electronegative element of the periodic table
and can be considered a reasonable surrogate of a hydroxy
group.3 Thus, replacement of a hydroxy group of 1-LPL by a
fluorine atom is an important strategy for blocking the acyl
migration of 1-LPL to 2-LPL.4 In this context, we have been
intrigued with sn-2 palmitoyl 1-F-LPA (1), 1-F-LPE (2), and
1-F-LPC (3), which are fluorine-containing analogues of 1-
lysophosphatidic acid (1-LPA), 1-lysophosphatidylethanol-
amine (1-LPE), and 1-lysophosphatidylcholine (1-LPC), re-
spectively. However, the literature contains only one report
on the synthesis of 1, by Prestwich et al.,4b and there are no
reports on the synthesis of 2 or 3.
O
CF3CH2O
P
CO2Me
1-F-LPC (3): X = CH2CH2N Me3,
Y = O
CF3CH2O
4
+
R = C15H31
(S)
F
OH
BnO
H
5
Scheme 1 Synthesis of fluorine-containing analogues 1–3 of 1-LPLs
Recently, we reported a novel approach to synthesize
glycerophospholipids (PLs) based on the Horner–
Wadsworth–Emmons (HWE) reaction of easily handled
mixed phosphonoacetate, which serves as a masked precur-
sor of PLs.5 Herein we describe the facile synthesis of fluo-
rine-containing analogues 1–3 using HWE reagent 6 as a
key intermediate, which was derived from methyl bis(2,2,2-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
M. Nakao et al.
Paper
Synthesis
trifluoroethyl)phosphonoacetate (Still–Gennari reagent,
4)6,7 and fluorine-containing chiral alcohol 5 as shown in
Scheme 1.
ene (DBU) and molecular sieves (type 3A) furnished the key
intermediate 6 as an inseparable diastereomeric mixture
(ca. 1:1) in 87% yield as shown in Scheme 3.5,11
For the synthesis of 5, (S)-2,2-dimethyl-1,3-dioxolane-
4-methanol [(S)-solketal, 7]8 was chosen as the starting ma-
terial (Scheme 2). The p-methoxybenzylation of 7 with p-
methoxybenzyl chloride (PMBCl) in the presence of sodium
hydride in DMF provided 8 in 96% yield. Deprotection of the
acetonide of 8 under acidic conditions afforded diol 9 in
99% yield. Selective protection of the primary hydroxy
group of diol 9 with triphenylchloromethane (TrCl) in the
presence of triethylamine and N,N-dimethylaminopyridine
(DMAP) gave secondary alcohol 10 in 93% yield. Benzyla-
tion of 10 with benzyl bromide in the presence of sodium
hydride in DMF resulted in the formation of 11 in 94% yield.
Selective removal of the triphenylmethyl group of 11 was
easily performed with p-toluenesulfonic acid in methanol
to afford primary alcohol 12 in 96% yield. Deoxyfluorina-
tion of alcohol 12 by a combination of perfluoro-1-butane-
sulfonyl fluoride (PBSF), triethylamine, and triethylamine
trihydrofluoride provided the corresponding fluoride 13 in
96% yield.9 The desired chiral alcohol 5 was obtained in 93%
yield by oxidative cleavage of the PMB ether of 13 using 1,2-
dichloro-4,5-dicyanobenzoquinone (DDQ) as an oxidant in
a dichloromethane/water mixed solvent system.10
F
5 (1 equiv)
(S)
BnO
DBU (1.37 equiv)
MS 3A [200% (w/w)]
O
P
H
O
4
CO2Me
toluene
r.t., 1.5 h
(1.1 equiv)
CF3CH2O
87%
6
Scheme 3 Synthesis of key intermediate 6
1-F-LPA (1), the fluorine-containing analogue of 1-lyso-
phosphatidic acid (1-LPA), was prepared using an HWE re-
action of mixed phosphonoacetate 17 with benzaldehyde
as the key reaction as shown in Scheme 4. The nucleophilic
substitution of 2-(trimethylsilyl)ethanol (14)12 at the phos-
phorus center of the key intermediate 6 in the presence of
excess amounts of 14 and DBU gave phosphonoacetate 15
in 76% yield. After removal of the benzyl group of 15 by hy-
drogenolysis using a palladium on carbon (Pd/C) catalyst,
palmitic acid was incorporated into the resultant secondary
alcohol 16 with 2-methyl-6-nitrobenzoic anhydride
(MNBA)13,14 and DMAP to afford 17 in 71% yield (two steps).
The HWE reaction of 17 with benzaldehyde in the presence
of lithium hexamethyldisilazide (LHMDS) provided the ex-
pected phosphodiester 18, then deprotection of the 2-
(trimethylsilyl)ethyl group of the resultant 18 furnished 1-
NaH (1 equiv)
(S)
(S)
O
OPMB
O
OH PMBCl (1.07 equiv)
H
O
H
O
Me
Me
DMF
r.t., 2 h
Me
Me
8
7
96%
F
TrCl (1.7 equiv)
Et3N (3 equiv)
DMAP (0.05 equiv)
14 (3 equiv)
1 N HCl
(R)
(S)
BnO
DBU (2.5 equiv)
H2, Pd/C
HO
OPMB
(2.77 equiv)
MS 3A [100% (w/w)]
O
(0.2 equiv)
H
HO
H
TMS
THF
r.t., 2 h
DMF
r.t., 21 h
O
O
6
9
P
CO2Me
MeOH
r.t., 30 min
toluene
99%
93%
r.t., 17 h
76%
15
NaH (2 equiv)
BnBr (1.2 equiv)
(S)
(S)
F
TrO
OPMB
TrO
OPMB
C15H31CO2H (2 equiv)
MNBA (2 equiv)
DMAP (3 equiv)
H
H
BnO
HO
(S)
DMF
r.t., 18 h
HO
10
11
O
P
94%
H
O
O
TMS
CO2Me
CH2Cl2
PBSF (6 equiv)
Et3N (12 equiv)
Et3N•(HF)3 (6 equiv)
r.t., 40 min
p-TsOH•H2O
(1.1 equiv)
(R)
71% (2 steps)
16
HO
OPMB
F
H
BnO
MeOH
r.t., 3 h
THF
r.t., 3 h
12
(S)
C15H31CO2
96%
96%
LHMDS (1.2 equiv)
O
P
PhCHO (1.2 equiv)
H
TMS
O
O
DDQ
(1.1 equiv)
(S)
(S)
CO2Me
THF
r.t., 50 min
F
OPMB
F
OH
H
H
BnO
BnO
17
CH2Cl2/H2O (47:3)
r.t., 8 h
13
5
F
93%
(S)
C15H31CO2
Scheme 2 Synthesis of chiral alcohol 5
TFA
O
P
(41 equiv)
H
TMS
O
O
1-F-LPA (1)
CH2Cl2
r.t., 1 h
OH
Nucleophilic substitution of the chiral alcohol 5 at the
phosphorus center of Still–Gennari reagent (4) in the pres-
ence of 1.37 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-
79% (2 steps)
18
Scheme 4 Synthesis of 1-F-LPA (1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
M. Nakao et al.
Paper
Synthesis
F-LPA (1) in 79% yield (two steps). In the synthetic strategy,
HWE reagent 17 should be regarded as the masked precur-
sor of sn-2 palmitoyl 1-F-LPA (1). Compounds 15–17 were
all obtained as inseparable diastereomeric mixtures (ca.
1:1), similar to the key intermediate 6.
tion with the key intermediate 6 to afford the correspond-
ing phosphonoacetate 25 in 72% yield in a manner similar
to that described for the reaction of 6 with 14 and 19. After
hydrogenolysis of 25 using a Pd/C catalyst, condensation of
the resultant 26 with palmitic acid using MNBA and DMAP
provided 27 in 72% yield (two steps). The HWE reaction of
27 with benzaldehyde in the presence of LHMDS gave phos-
phodiester 28, then amination of the resultant 28 in the
presence of excess amounts of trimethylamine in ethanol
furnished 1-F-LPC (3) in 65% yield (two steps).15
Subsequently, we explored the preparation of 1-F-LPE
(2) and 1-F-LPC (3) based on the synthetic route of 1-F-LPA
(1) through 6 as the common key intermediate. The diver-
gent synthesis of 1-F-LPE (2), fluorine-containing ana-
logues of 1-lysophosphatidylethanolamine (1-LPE), is
shown in Scheme 5. The substitution of tert-butyl (2-hy-
droxyethyl)carbamate (N-Boc-ethanolamine, 19) instead of
14 at the phosphorus center of 6 afforded phosphonoace-
tate 20 in 67% yield. Hydrogenolysis of 20 using a Pd/C cata-
lyst, followed by condensation of 21 with palmitic acid in
the presence of MNBA and DMAP, gave 22 in 56% yield (two
steps). The HWE reaction of 22 with benzaldehyde in the
presence of LHMDS, followed by deprotection of the Boc
group of the resultant phosphodiester 23 under acidic
conditions using hydrogen chloride in 1,4-dioxane, afforded
1-F-LPE (2) as hydrochloride salt in 48% yield (two steps).
F
24 (1.5 equiv)
DBU (1.5 equiv)
(S)
BnO
H2, Pd/C
O
P
(0.2 equiv)
MS 3A [100% (w/w)]
H
Br
O
O
6
CO2Me
MeOH
r.t., 15 min
toluene
0 °C, 7 h
72%
25
F
C15H31CO2H (2 equiv)
MNBA (2 equiv)
(S)
HO
O
P
DMAP (3 equiv)
H
Br
O
O
CO2Me
CH2Cl2
r.t., 15 min
72% (2 steps)
26
F
F
19 (3 equiv)
DBU (3 equiv)
MS 3A [200% (w/w)]
(S)
BnO
MeOH
(100 equiv)
(S)
C15H31CO2
O
P
LHMDS (1.2 equiv)
PhCHO (1.2 equiv)
H
O
O
6
O
P
BocHN
H
Br
CO2Me
toluene
r.t., 20 h
O
O
r.t., 15 min
CO2Me
THF
0 °C, 15 min
67%
20
27
F
F
(S)
HO
H2, Pd/C
(0.2 equiv)
(S)
C15H31CO2
Me3N in EtOH
(ca. 50 equiv)
O
P
H
O
O
O
BocHN
H
CO2Me
O
O
MeOH
r.t., 30 min
1-F-LPC (3)
Br
P
r.t., 5 d
OH
21
65% (2 steps)
28
F
Scheme 6 Synthesis of 1-F-LPC (3)
C15H31CO2H (2 equiv)
MNBA (2 equiv)
(S)
C15H31CO2
O
DMAP (3 equiv)
H
O
O
BocHN
P
CO2Me
CH2Cl2
In conclusion, we have described a novel and efficient
method of synthesizing sn-2 palmitoyl 1-F-LPA (1), 1-F-LPE
(2), and 1-F-LPC (3) as 1,2-acyl migration-blocked ana-
logues of 1-LPLs. Considering the operational ease based on
the use of HWE reagents as fluorine-containing masked an-
alogues of 1-LPLs via the common key intermediate 6, we
believe this synthetic strategy will be valuable for the
chemistry and biochemistry of phospholipids classified as
glycerophospholipids (PLs) and sphingophospholipids
(SPLs).
r.t., 30 min
56% (2 steps)
22
F
(S)
C15H31CO2
LHMDS (1.2 equiv)
PhCHO (1.2 equiv)
O
H
O
O
BocHN
P
THF
r.t., 15 min
OH
23
4 N HCl/1,4-dioxane
(20 equiv)
1-F-LPE (2) • HCl
CH2Cl2
r.t., 1.5 h
48% (2 steps)
All melting points were determined on a Yanagimoto micro melting
point apparatus and are uncorrected. IR spectra were obtained using
a JASCO FT/IR-6200 IR Fourier transform spectrophotometer. 1H NMR
(500 MHz) and 13C NMR (125 MHz) spectra were recorded on a
Bruker AV500 spectrometer. Chemical shifts are given in δ values
(parts per million) using TMS as an internal standard. Mass spectra
Scheme 5 Synthesis of 1-F-LPE (2)
Furthermore, Scheme 6 shows the synthesis of 1-F-LPC
(3), a fluorine-containing analogue of 1-lysophosphatidyl-
choline (1-LPC). 2-Bromoethanol (24) was used in the reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
M. Nakao et al.
Paper
Synthesis
(ESI) were recorded on a Waters LCT Premier spectrometer. Elemental
combustion analyses were performed using a J-SCIENCE LAB JM10
analyzer. Optical rotations were recorded using a P-2200 JASCO digi-
tal polarimeter. All reactions were monitored by TLC employing 0.25
mm silica gel plates (Merck 5715; 60 F254). Column chromatography
was carried out on silica gel [Silica Gel 60N (Kanto Chemical) or COS-
MOSIL 75 SL-II-PREP (Nacalai Tesque)]. Anhydrous THF, CH2Cl2, DMF,
and toluene were used as purchased from Kanto Chemical. DBU and
Et3N were distilled prior to use. All other reagents were used as pur-
chased.
stirred for 21 h. Then, H2O (10 mL) was added to the mixture and ex-
tracted with EtOAc–n-hexane (1:1) (3 × 50 mL). The combined organ-
ic layers were washed with H2O (30 mL), dried (anhyd MgSO4), fil-
tered, and concentrated in vacuo. The oily residue was purified by
column chromatography [Silica Gel 60N: n-hexane–EtOAc (3:1 to
28
4:1)] to afford 10 (2.67 g, 93%) as a yellow oil; [α]D –0.6 (c 1.01,
CHCl3).
IR (neat): 3454, 3058, 3032, 2932, 2870, 1612, 1513, 1448, 1249 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.43–7.41 (m, 6 H), 7.30–7.20 (m, 11
H), 6.86 (d, J = 8.7 Hz, 2 H), 4.46 (s, 2 H), 3.96 (sept, J = 5.6 Hz, 1 H),
3.80 (s, 3 H), 3.57 (dd, J = 9.7, 4.3 Hz, 1 H), 3.52 (dd, J = 9.6, 6.2 Hz, 1
H), 3.22 (dd, J = 9.4, 5.7 Hz, 1 H), 3.19 (dd, J = 9.4, 5.3 Hz, 1 H), 2.39 (d,
J = 4.8 Hz, 1 H).
(S)-4-{[(4-Methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxol-
ane (8)16
To a suspension of NaH (50–72% in mineral oil, 187 mg, 3.90–5.61
mmol) in anhyd DMF (10 mL) was added 7 (0.5 mL, 4.05 mmol), and
the reaction mixture was stirred at 0 °C for 30 min under argon. After
the addition of PMBCl (0.58 mL, 4.28 mmol), the mixture was allowed
to warm to r.t. and then stirred for 2 h under argon. H2O (10 mL) was
added to the mixture, and then extracted with EtOAc–n-hexane (1:1)
(3 × 50 mL). The combined organic layers were dried (anhyd MgSO4),
filtered, and concentrated in vacuo. The oily residue was purified by
column chromatography [Silica Gel 60N: n-hexane–EtOAc (4:1)] to af-
ford 8 (986 mg, 96%) as a colorless oil; [α]D24 +22.5 (c 1.01, CHCl3).
13C NMR (125 MHz, CDCl3): δ = 159.2, 143.8, 130.0, 129.3, 128.6,
127.8, 127.0, 113.7, 86.6, 73.0, 71.2, 69.9, 64.5, 55.2.
HRMS (ESI): m/z [M + Na]+ calcd for C30H30O4Na: 477.2042; found:
477.2047.
(S)-({2-(Benzyloxy)-3-[(4-methoxybenzyl)oxy]propoxy}methane-
triyl)tribenzene (11)
To a solution of 10 (1.70 g, 3.74 mmol) and benzyl bromide (533 μL,
4.48 mmol) in anhyd DMF (8 mL) was added NaH (50–72% in mineral
oil; washed with several portions of anhyd n-pentane, 179 mg, 7.46
mmol) at 0 °C under argon. The reaction mixture was stirred at r.t. for
18 h under argon. Then, H2O (10 mL) was added to the mixture and
extracted with EtOAc–n-hexane (1:1) (3 × 50 mL). The combined or-
ganic layers were washed with H2O (2 × 30 mL), dried (anhyd MgSO4),
filtered, and concentrated in vacuo. The oily residue was purified by
column chromatography [Silica Gel 60N: n-hexane–EtOAc (8:1 to
IR (neat): 2986, 2935, 2865, 1613, 1514, 1457, 1371, 1249 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.28–7.24 (m, 2 H), 6.90–6.85 (m, 2 H),
4.52 (d, J = 11.7 Hz, 1 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.28 (quint, J = 6.2
Hz, 1 H), 4.04 (dd, J = 8.3, 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.72 (dd, J = 8.3,
6.3 Hz, 1 H), 3.53 (dd, J = 9.8, 5.6 Hz, 1 H), 3.42 (dd, J = 9.8, 5.7 Hz, 1 H),
1.41 (s, 3 H), 1.36 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 159.3, 130.1, 129.3, 113.8, 109.4, 74.8,
73.2, 70.8, 67.0, 55.3, 26.8, 25.4.
23
10:1)] to afford 11 (1.91 g, 94%) as a yellow oil; [α]D –6.8 (c 0.88,
CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H20O4Na: 275.1259; found:
275.1238.
IR (neat): 3060, 3031, 2931, 2868, 1612, 1513, 1449, 1248 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.45–7.42 (m, 6 H), 7.36–7.15 (m, 16
H), 6.85–6.81 (m, 2 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1
H), 4.44 (d, J = 11.7 Hz, 1 H), 4.42 (d, J = 11.7 Hz, 1 H), 3.77 (s, 3 H),
3.79–3.72 (m, 1 H), 3.63 (dd, J = 10.2, 4.6 Hz, 1 H), 3.59 (dd, J = 10.2,
5.8 Hz, 1 H), 3.29–3.22 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 159.1, 144.1, 138.7, 130.5, 129.1,
128.7, 128.3, 127.7, 127.4, 126.9, 113.7, 86.6, 77.7, 72.9, 72.2, 70.3,
63.6, 55.2.
Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.35; H, 8.08.
(R)-3-[(4-Methoxybenzyl)oxy]propane-1,2-diol (9)16,17
A mixture of 8 (912 mg, 3.61 mmol), aq 1 M HCl (10 mL, 10 mmol),
and THF (10 mL) was stirred at r.t. for 2 h. Then, sat. aq NaHCO3 (10
mL) was added to the reaction mixture and extracted with EtOAc (3 ×
70 mL). The combined organic layers were dried (anhyd MgSO4), fil-
tered, and concentrated in vacuo. The oily residue was purified by
column chromatography [Silica Gel 60N: CHCl3–MeOH (15:1)] to af-
ford 9 (760 mg, 99%) as a white solid; mp 37.5–39 °C (white powder,
CHCl3–n-hexane); [α]D25 –2.2 (c 1.23, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C37H36O4Na: 567.2511; found:
567.2511.
(R)-2-(Benzyloxy)-3-[(4-methoxybenzyl)oxy]propan-1-ol (12)18
IR (KBr): 3330, 2934, 2870, 1612, 1514, 1250 cm–1
.
To a solution of 11 (100 mg, 0.184 mmol) in MeOH (1.8 mL) was add-
ed p-TsOH·H2O (39 mg, 0.205 mmol) at r.t. The reaction mixture was
stirred for 3 h. Then, aq 5 N NaOH (1 mL) was added to the mixture
and extracted with CHCl3 (3 × 10 mL). The combined organic layers
were dried (anhyd MgSO4), filtered, and concentrated in vacuo. The
oily residue was purified by column chromatography [Silica Gel 60N:
n-hexane–EtOAc (3:1)] to afford 12 (53.2 mg, 96%) as a colorless oil;
[α]D23 +17.8 (c 0.98, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.26–7.22 (m, 2 H), 6.90–6.86 (m, 2 H),
4.47 (s, 2 H), 3.90–3.84 (m, 1 H), 3.80 (s, 3 H), 3.71–3.65 (m, 1 H),
3.63–3.57 (m, 1 H), 3.55–3.48 (m, 2 H), 2.85 (br s, 1 H), 2.41 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 159.4, 129.8, 129.5, 113.9, 73.3, 71.5,
70.7, 64.1, 55.3.
HRMS (ESI): m/z [M + Na]+ calcd for C11H16O4Na: 235.0946; found:
235.0924.
IR (neat): 3440, 3031, 2868, 1612, 1514, 1455, 1248 cm–1
.
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 61.95; H, 7.61.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H), 7.26–7.22 (m, 2 H),
6.89–6.85 (m, 2 H), 4.69 (d, J = 11.8 Hz, 1 H), 4.60 (d, J = 11.8 Hz, 1 H),
4.47 (d, J = 11.6 Hz, 1 H), 4.46 (d, J = 11.6 Hz, 1 H), 3.80 (s, 3 H), 3.77–
3.71 (m, 1 H), 3.70–3.63 (m, 2 H), 3.62–3.54 (m, 2 H), 2.16 (br t, 1 H).
(S)-1-[(4-Methoxybenzyl)oxy]-3-(trityloxy)propan-2-ol (10)17
To a solution of 9 (1.34 g, 6.31 mmol) in anhyd DMF (10 mL) were
added Et3N (2.63 mL, 18.9 mmol), DMAP (38 mg, 0.311 mmol), and
TrCl (3.06 g, 11.0 mmol) at r.t. under argon. The reaction mixture was
13C NMR (125 MHz, CDCl3): δ = 159.2, 138.2, 130.0, 129.3, 128.4,
127.8, 113.8, 78.0, 73.2, 72.1, 69.9, 62.9, 55.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
M. Nakao et al.
Paper
Synthesis
HRMS (ESI): m/z [M + Na]+ calcd for C18H22O4Na: 325.1416; found:
325.1416.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 4.70 (dd, J = 11.6,
1.5 Hz, 1 H), 4.67 (dd, J = 11.6, 2.3 Hz, 1 H), 4.53 (ddd, 2JH,F = 46.9 Hz,
3
2
2
2JH,H = 9.9 Hz, JH,H = 4.9 Hz, 1 H), 4.51 (ddd, JH,F = 46.9 Hz, JH,H = 9.9
3
Hz, JH,H = 5.2 Hz, 1 H), 4.43–4.31 (m, 3 H), 4.25–4.15 (m, 1 H), 3.89–
(S)-1-{[2-(Benzyloxy)-3-fluoropropoxy]methyl}-4-methoxyben-
zene (13)
3.81 (m, 1 H), 3.74/3.73 (2 s, 3 H), 3.08 (br dd, 0.94 H for one diaste-
reomer), 3.06 (d, 2JH,P = 21.4 Hz, 1.06 H for one diastereomer).
To a solution of 12 (1.14 g, 3.77 mmol) in anhyd THF (10 mL) were
added Et3N (6.24 mL, 45.0 mmol), Et3N·(HF)3 (3.66 mL, 22.5 mmol),
and PBSF (3.96 mL, 22.5 mmol) at r.t. under argon. The reaction mix-
ture was stirred for 3 h. Then, H2O (10 mL) was added to the mixture
and extracted with CHCl3 (3 × 50 mL). The combined organic layers
were dried (anhyd MgSO4), filtered, and concentrated in vacuo. The
oily residue was purified by column chromatography [Silica Gel 60N:
n-hexane–EtOAc (7:1)], then again by column chromatography [n-
hexane–EtOAc (10:1)] to afford 13 (1.10 g, 96%) as a colorless oil;
[α]D24 +13.4 (c 1.02, CHCl3).
2
13C NMR (125 MHz, CDCl3): δ = 165.5 (d, JC,P = 5.4 Hz), 137.4, 137.3,
128.6, 128.13, 128.10, 128.00, 127.96, 122.7 (qd, 1JC,F = 277.6 Hz, 3JC,P
=
8.3 Hz), 81.6 (d, 1JC,F = 172.3 Hz), 75.66, 75.65, 75.62, 75.6, 75.5, 75.49,
2
75.46, 75.44, 72.44, 72.43, 64.65, 64.59, 64.53, 64.47, 62.7 (qd, JC,F
=
37.8 Hz, 2JC,P = 5.3 Hz), 52.82, 52.8, 33.9 (d, 1JC,P = 141.8 Hz for one dia-
stereomer), 33.8 (d, 1JC,P = 141.5 Hz for one diastereomer).
HRMS (ESI): m/z [M + Na]+ calcd for C15H19F4O6PNa: 425.0753; found:
425.0747.
IR (neat): 2865, 1613, 1514, 1455, 1249 cm–1
.
Methyl 2-{[(S)-2-(Benzyloxy)-3-fluoropropoxy][(2-trimethylsi-
1H NMR (500 MHz, CDCl3): δ = 7.36–7.25 (m, 5 H), 7.25–7.21 (m, 2 H),
6.89–6.85 (m, 2 H), 4.68 (d, J = 12.0 Hz, 1 H), 4.67 (d, J = 12.0 Hz, 1 H),
lyl)ethoxy]phosphoryl}acetate (15)
DBU (283 μL, 1.90 mmol) was added to a solution of 6 (300 mg, 0.746
mmol), 2-(trimethylsilyl)ethanol (14; 319 μL, 2.24 mmol), and molec-
ular sieves 3A (300 mg) in anhyd toluene (10 mL) at r.t. under argon.
After stirring the reaction mixture at r.t. for 17 h, aq 1 M HCl (10 mL)
was added and then extracted with CHCl3 (3 × 50 mL). The combined
organic layers were dried (anhyd MgSO4), filtered, and concentrated
in vacuo. The oily residue was purified by column chromatography
[Silica Gel 60N: n-hexane–EtOAc (3:2)] to afford 15 (diastereomeric
mixture, 240 mg, 76%) as a colorless oil.
2
2
3
4.55 (ddd, JH,F = 47.3 Hz, JH,H = 9.8 Hz, JH,H = 3.7 Hz, 1 H), 4.47–4.45
2
2
3
(m, 2 H), 4.51 (ddd, JH,F = 47.5 Hz, JH,H = 9.9 Hz, JH,H = 5.5 Hz, 1 H),
3.80 (s, 3 H), 3.86–3.78 (m, 1 H), 3.60–3.53 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 159.3, 138.2, 130.0, 129.3, 128.4,
1
2
127.8, 127.7, 113.8, 83.5 (d, JC,F = 170.8 Hz), 76.6 (d, JC,F = 19.0 Hz),
73.2, 72.4, 68.4 (d, 3JC,F = 8.0 Hz), 55.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H21FO3Na: 327.1372; found:
327.1374.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 4.72 (d, J = 11.8 Hz,
1 H), 4.68 (d, J = 11.8 Hz, 1 H), 4.56 (ddd, 2JH,F = 47.0 Hz, 2JH,H = 9.9 Hz,
(S)-2-(Benzyloxy)-3-fluoropropan-1-ol (5)19
2
2
3
3JH,H = 4.6 Hz, 1 H), 4.53 (ddd, JH,F = 47.0 Hz, JH,H = 9.9 Hz, JH,H = 5.3
Hz, 1 H), 4.36–4.29 (m, 1 H), 4.26–4.13 (m, 3 H), 3.90–3.81 (m, 1 H),
3.723/3.715 (2 s, 3 H), 3.05–2.93 (m, 2 H), 1.12–1.06 (m, 2 H),
0.03/0.02 (2 s, 9 H).
To a solution of 13 (1.40 g, 4.60 mmol) in CH2Cl2 (47 mL)/H2O (3 mL)
was added DDQ (1.15 g, 5.07 mmol) at 0 °C. The reaction mixture was
stirred at r.t. for 8 h. Then, sat. aq Na2CO3 (10 mL) was added to the
mixture and extracted with CHCl3 (3 × 50 mL). The combined organic
layers were dried (anhyd MgSO4), filtered, and concentrated in vacuo.
The oily residue was purified by column chromatography [Silica Gel
60N: n-hexane–EtOAc (3:1)] to afford 5 (791 mg, 93%) as a colorless
oil; [α]D24 +14.8 (c 1.01, CHCl3).
13C NMR (125 MHz, CDCl3): δ = 166.1 (d, 2JC,P = 4.7 Hz), 137.62, 137.59,
128.5, 127.96, 127.95, 127.9, 127.8, 82.0 (d, JC,F = 171.7 Hz), 76.0,
1
75.9, 75.81, 75.76, 72.34, 72.32, 65.62, 65.56, 65.5, 65.4, 64.13, 64.08,
64.03, 63.97, 63.91, 63.85, 52.58, 52.55, 34.2 (d, 1JC,P = 136.1 Hz for one
1
diastereomer), 34.1 (d, JC,P = 135.3 Hz for one diastereomer), 19.80,
IR (neat): 3416, 2953, 2885, 1455, 1348, 1209, 1119, 1060 cm–1
.
19.76, –1.52, –1.53.
HRMS (ESI): m/z [M + Na]+ calcd for C18H30FO6PSiNa: 443.1431;
found: 443.1431.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 4.72 (d, J = 11.7 Hz,
1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.53 (ddd, 2JH,F = 47.2 Hz, 2JH,H = 9.9 Hz,
2
2
3
3JH,H = 4.4 Hz, 1 H), 4.51 (ddd, JH,F = 47.3 Hz, JH,H = 9.9 Hz, JH,H = 5.2
Hz, 1 H), 3.78–3.70 (m, 2 H), 3.67–3.60 (m, 1 H), 2.12 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 137.9, 128.6, 128.0, 127.9, 82.8 (d,
1JC,F = 170.8 Hz), 77.9 (d, 2JC,F = 19.1 Hz), 72.5, 61.4 (d, 3JC,F = 7.4 Hz).
(2S)-1-Fluoro-3-({(2-methoxy-2-oxoethyl)[2-(trimethylsi-
lyl)ethoxy]phosphoryl}oxy)propan-2-yl Palmitate (17)
A mixture of 15 (43 mg, 0.102 mmol) and 10% Pd/C (21 mg, 0.0197
mmol) in MeOH (1 mL) was stirred at r.t. for 30 min under H2 atmo-
sphere. The reaction mixture was filtered and concentrated in vacuo
to afford 16. A solution of 16 in anhyd CH2Cl2 (3 mL) was added to a
solution of palmitic acid (52 mg, 0.203 mmol), 2-methyl-6-nitroben-
zoic anhydride (70 mg, 0.203 mmol), and DMAP (37 mg, 0.303 mmol)
in anhyd CH2Cl2 (10 mL) at r.t. under argon. The mixture was stirred
for 40 min. Aq 1 M HCl (2 mL) was added to the mixture and then ex-
tracted with CHCl3 (3 × 10 mL). The combined organic layers were
dried (anhyd MgSO4), filtered, and concentrated in vacuo. The residue
was purified by column chromatography [Silica Gel 60N: n-hexane–
EtOAc (3:2)] to afford 17 (diastereomeric mixture, 41 mg, 71%, two
steps) as a colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C10H13FO2Na: 207.0797; found:
207.0784.
Methyl 2-{[(S)-2-(Benzyloxy)-3-fluoropropoxy](2,2,2-trifluoro-
ethoxy)phosphoryl}acetate (6)
A solution of alcohol 5 (607 mg, 3.30 mmol) in anhyd toluene (120
mL) was added to a solution of methyl bis(2,2,2-trifluoroethyl)phos-
phonoacetate (4; 773 μL, 3.62 mmol), DBU (673 μL, 4.51 mmol), and
molecular sieves 3A (1.28 g) in anhyd toluene (44 mL) at r.t. under ar-
gon. After stirring the reaction mixture at r.t. for 1.5 h, aq 1 M HCl (10
mL) was added and then extracted with CHCl3 (3 × 50 mL). The com-
bined organic layers were dried (anhyd MgSO4), filtered, and concen-
trated in vacuo. The oily residue was purified by column chromatog-
raphy [Silica Gel 60N: n-hexane–EtOAc (3:2)] to afford 6 (diastereo-
meric mixture, 1.16 g, 87%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ = 5.26–5.16 (m, 1 H), 4.64–4.60 (m, 1 H),
2
4.55–4.51 (m, 1 H), 4.38–4.16 (m, 4 H), 3.74 (s, 3 H), 3.00 (d, JH,P
=
21.6 Hz, 1 H for one diastereomer), 2.98 (d, 2JH,P = 21.5 Hz, 1 H for one
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
M. Nakao et al.
Paper
Synthesis
2
diastereomer), 2.37 (br td, 2 H), 1.67–1.59 (m, 2 H), 1.34–1.22 (m, 24
H), 1.11 (t, J = 8.6 Hz, 2 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.047/0.045 (2 s, 9
13C NMR (125 MHz, CDCl3): δ = 166.1 (d, JC,P = 3.6 Hz for one diaste-
2
reomer), 166.0 (d, JC,P = 2.9 Hz for one diastereomer), 155.8, 137.42,
H).
137.41, 128.5, 128.07, 128.05, 127.95, 127.94, 81.7 (d, 1JC,F = 171.7 Hz),
79.6, 75.81, 75.76, 75.75, 75.70, 75.65, 75.60, 75.59, 75.54, 72.4, 72.3,
66.21, 66.17, 64.5, 64.4, 64.38, 64.35, 64.30, 64.2, 52.74, 52.71, 41.0,
33.9 (d, 1JC,P = 137.3 Hz for one diastereomer), 33.8 (d, 1JC,P = 137.1 Hz
for one diastereomer), 28.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H31FNO8PNa: 486.1669; found:
486.1647.
13C NMR (125 MHz, CDCl3): δ = 172.83, 172.82, 165.9 (d, 2JC,P = 6.2 Hz),
80.8 (d, 1JC,F = 172.8 Hz for one diastereomer), 80.7 (d, 1JC,F = 173.4 Hz
for one diastereomer), 70.3, 70.23, 70.18, 70.13, 70.07, 70.0, 65.7,
1
65.6, 63.33, 63.28, 63.22, 63.17, 52.6, 34.14, 34.11 (d, JC,P = 136.1 Hz
for one diastereomer), 34.07 (d, 1JC,P = 135.4 Hz for one diastereomer),
31.9, 29.7, 29.69, 29.66, 29.6, 29.5, 29.4, 29.3, 29.1, 24.8, 22.7, 19.83,
19.82, 19.79, 19.77, 14.1, –1.51.
HRMS (ESI): m/z [M + Na]+ calcd for C27H54FO7PSiNa: 591.3258;
(2S)-1-[({2-[(tert-Butoxycarbonyl)amino]ethoxy}(2-methoxy-2-
oxoethyl)phosphoryl)oxy]-3-fluoropropan-2-yl Palmitate (22)
found: 591.3248.
A mixture of 20 (54.3 mg, 0.117 mmol) and 10% Pd/C (24.9 mg, 0.0234
mmol) in MeOH (1 mL) was stirred at r.t. for 30 min under H2 atmo-
sphere. The reaction mixture was filtered and concentrated in vacuo
to afford 21, which was used in the next reaction without further pu-
rification. To a solution of palmitic acid (60 mg, 0.234 mmol), 2-meth-
yl-6-nitrobenzoic anhydride (80.6 mg, 0.234 mmol), and DMAP (42.9
mg, 0.351 mmol) in anhyd CH2Cl2 (3 mL) was added a solution of 21
in anhyd CH2Cl2 (2 mL) at r.t. under argon. The mixture was stirred for
30 min. A 1/15 M phosphate buffer (pH 7.4, 3 mL) was added to the
mixture, and then extracted with CHCl3 (3 × 10 mL). The combined
organic layers were dried (anhyd MgSO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography [Silica
Gel 60N: n-hexane–EtOAc (1:1)] to afford 22 (diastereomeric mixture,
40.2 mg, 56%, two steps) as a colorless oil.
(S)-1-Fluoro-3-(phosphonooxy)propan-2-yl Palmitate [1-F-LPA
(1)]4b
To a solution of 17 (70 mg, 0.123 mmol) in anhyd THF (1.26 mL) was
added LHMDS (1.1 mol/L in n-hexane, 137 μL, 0.151 mmol) and the
solution was stirred at 0 °C for 5 min under argon. After the addition
of benzaldehyde (15 μL, 0.147 mmol), the reaction mixture was al-
lowed to warm to r.t. and then stirred for 50 min under argon. Aq 1 M
HCl (2 mL) was added to the mixture and then extracted with CHCl3
(3 × 10 mL). The combined organic layers were dried (anhyd MgSO4),
filtered, and concentrated in vacuo. The crude 18 was dissolved in an-
hyd CH2Cl2 (1.25 mL), and TFA (385 μL, 5.03 mmol) was added. After
stirring at r.t. for 1 h, the mixture was concentrated in vacuo. The res-
idue was purified by column chromatography [COSMOSIL 75 SL-II-
PREP: CHCl3–MeOH (100:1 to 6:1)] to afford 1-F-LPA (1) (39.9 mg,
1H NMR (500 MHz, CDCl3): δ = 5.26–5.14 (m, 2 H), 4.65–4.59 (m, 1 H),
27
79%, two steps) as a white solid; mp 80–93 °C; [α]D +4.8 (c 0.79,
4.55–4.49 (m, 1 H), 4.38–4.10 (m, 4 H), 3.76 (s, 3 H), 3.48–3.35 (m, 2
2
CHCl3).
H), 3.04 (d, JH,P = 21.6 Hz, 0.97 H for one diastereomer), 3.02 (br dd,
1.03 H for one diastereomer), 2.37 (t, J = 7.6 Hz, 2 H), 1.67–1.60 (m, 2
H), 1.45 (s, 9 H), 1.34–1.23 (m, 24 H), 0.88 (t, J = 7.1 Hz, 3 H).
IR (KBr): 2918, 2849, 1729, 1468, 1179 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 5.23 (br d, 1 H), 4.93 (br s, 2 H), 4.58 (br
d, 2 H), 4.23–4.10 (m, 2 H), 2.44–2.31 (m, 2 H), 1.68–1.55 (m, 2 H),
1.40–1.10 (m, 24 H), 0.88 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 174.2, 80.8 (d, 1JC,F = 173.5 Hz), 70.6 (d,
2JC,F = 17.3 Hz), 64.0, 34.2, 31.9, 29.74, 29.72, 29.69, 29.68, 29.5, 29.4,
29.3, 29.1, 24.8, 22.7, 14.1.
13C NMR (125 MHz, CDCl3): δ = 172.89, 172.88, 165.9 (d, 2JC,P = 5.8 Hz),
1
1
155.8, 80.7 (d, JC,F = 173.3 Hz for one diastereomer), 80.6 (d, JC,F
=
173.4 Hz for one diastereomer), 79.6, 70.16, 70.11, 70.06, 70.00,
69.95, 69.90, 66.41, 66.36, 63.6, 63.53, 63.48, 63.43, 63.38, 52.8, 41.04,
1
41.01, 34.1, 33.8 (d, JC,P = 137.3 Hz for one diastereomer), 33.7 (d,
1JC,P = 137.1 Hz for one diastereomer), 31.9, 29.71, 29.69, 29.66, 29.62,
HRMS (ESI): m/z [M – H]– calcd for C19H37FO6P: 411.2312; found:
29.5, 29.4, 29.3, 29.1, 28.4, 24.8, 22.7, 14.1.
411.2310.
HRMS (ESI): m/z [M + Na]+ calcd for C29H55FNO9PNa: 634.3496; found:
634.3470.
Methyl 2-([(S)-2-(Benzyloxy)-3-fluoropropoxy]{2-[(tert-butoxy-
carbonyl)amino]ethoxy}phosphoryl)acetate (20)
(2S)-1-{[(2-Aminoethoxy)(hydroxy)phosphoryl]oxy}-3-fluoropro-
To a solution of 6 (53.4 mg, 0.133 mmol), tert-butyl (2-hydroxyeth-
yl)carbamate (19; 64.2 mg, 0.398 mmol), and molecular sieves 3A
(107 mg) in anhyd toluene (2 mL) was added DBU (59.4 μL, 0.398
mmol) at r.t. under argon. After stirring at r.t. for 20 h, MeOH (537 μL,
13.3 mmol) was added and the reaction mixture was stirred at r.t. for
another 15 min. The mixture was filtered, and a 1/15 M phosphate
buffer (pH 7.4, 10 mL) was added to the filtrate, and then extracted
with CHCl3 (3 × 10 mL). The combined organic layers were dried (an-
hyd MgSO4), filtered, and concentrated in vacuo. The oily residue was
purified by column chromatography [Silica Gel 60N: n-hexane–EtOAc
(1:2 to 1:3)] to afford 20 (diastereomeric mixture, 41.3 mg, 67%) as a
colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 5.15 (br s, 1 H),
4.70 (dd, J = 11.7, 2.9 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1 H), 4.61–4.54 (m,
1 H), 4.51–4.45 (m, 1 H), 4.38–4.28 (m, 1 H), 4.23–4.05 (m, 3 H), 3.89–
3.81 (m, 1 H), 3.74/3.73 (2 s, 3 H), 3.43–3.28 (m, 2 H), 3.08–2.96 (m, 2
H), 1.44 (s, 9 H).
pan-2-yl Palmitate Hydrochloride [1-F-LPE (2)·HCl]
To a solution of 22 (69.2 mg, 0.113 mmol) in anhyd THF (1 mL) was
added LHMDS (1.02 mol/L in n-hexane, 133 μL, 0.136 mmol) and the
solution was stirred at 0 °C for 5 min under argon. After adding benz-
aldehyde (13.9 μL, 0.136 mmol), the reaction mixture was allowed to
warm to r.t. and stirred for 15 min under argon. A 1/15 M phosphate
buffer (pH 7.4, 3 mL) was added to the mixture, and then concentrat-
ed in vacuo. The residue was purified by column chromatography
[COSMOSIL 75 SL-II-PREP: CHCl3–MeOH (100:1 to 2:1)] to afford 23,
which was used in the next reaction without further purification. A
mixture of 23 and 4 M HCl in 1,4-dioxane (0.57 mL, 2.26 mmol) in
CH2Cl2 (1 mL) was stirred at r.t. for 1.5 h and concentrated in vacuo.
The residue was purified by column chromatography [Silica Gel 60N:
CHCl3–MeOH (2:1)] to afford 1-F-LPE (2)·HCl (26.6 mg, 48%, two
27
steps) as a white solid; mp 188–191 °C; [α]D +9.7 [c 0.55, CHCl3–
MeOH (2:1)].
IR (KBr): 2920, 2851, 1741, 1467, 1252, 1225, 1082 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
M. Nakao et al.
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Synthesis
1H NMR [500 MHz, CDCl3–CD3OD (2:1)]: δ = 5.23–5.13 (m, 1 H), 4.61
(dd, JH,F = 47.1 Hz, JH,H = 4.1 Hz, 2 H), 4.07–3.99 (m, 4 H), 3.13–3.09
(m, 2 H), 2.39–2.34 (m, 2 H), 1.67–1.58 (m, 2 H), 1.36–1.22 (m, 24 H),
0.89 (t, J = 7.1 Hz, 3 H).
1H NMR (500 MHz, CDCl3): δ = 5.27–5.17 (m, 1 H), 4.64–4.61 (m, 1 H),
4.55–4.51 (m, 1 H), 4.45–4.24 (m, 4 H), 3.76 (s, 3 H), 3.55/3.54 (2 t, J =
2
3
2
6.2, 6.1 Hz, 2 H), 3.06 (d, JH,P = 21.5 Hz, 1 H for one diastereomer),
3.05 (d, 2JH,P = 21.5 Hz, 1 H for one diastereomer), 2.37 (t, J = 7.6 Hz, 2
H), 1.68–1.59 (m, 2 H), 1.35–1.20 (m, 24 H), 0.88 (t, J = 7.1 Hz, 3 H).
1
13C NMR [125 MHz, CDCl3–CD3OD (2:1)]: δ = 173.9, 81.5 (d, JC,F
=
171.8 Hz), 71.3 (dd, 2JC,F = 19.4 Hz, 3JC,P = 8.4 Hz), 62.8 (dd, 3JC,F = 7.4 Hz,
2JC,P = 5.2 Hz), 61.8 (d, 2JC,P = 5.2 Hz), 40.8 (d, 3JC,P = 5.4 Hz), 34.4, 32.2,
29.92, 29.89, 29.8, 29.7, 29.6, 29.5, 29.3, 25.1, 22.9, 14.2.
13C NMR (125 MHz, CDCl3): δ = 172.9, 165.7 (d, 2JC,P = 5.4 Hz), 80.7 (d,
1JC,F = 173.3 Hz for one diastereomer), 80.6 (d, 1JC,F = 172.9 Hz for one
diastereomer), 70.12, 70.08, 70.06, 70.02, 69.95, 69.91, 69.86, 66.0,
65.97, 65.95, 65.92, 63.7, 63.63, 63.58, 63.53, 63.5, 63.4, 52.8, 34.14,
HRMS (ESI): m/z [M – H – HCl]– calcd for C21H42FNO6P: 454.2734;
found: 454.2732.
34.12, 33.94 (d, 1JC,P = 138.7 Hz for one diastereomer), 33.89 (d, 1JC,P
=
138.2 Hz for one diastereomer), 31.9, 29.7, 29.69, 29.66, 29.65, 29.62,
29.5, 29.4, 29.3, 29.1, 24.8, 22.7, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H45BrFO7PNa: 597.1968;
Anal. Calcd for C21H44ClFNO6P: C, 51.26; H, 9.01; N, 2.85. Found: C,
51.23; H, 8.85; N, 2.98.
found: 597.1911.
Methyl 2-{[(S)-2-(Benzyloxy)-3-fluoropropoxy](2-bromo-
ethoxy)phosphoryl}acetate (25)
(S)-3-Fluoro-2-(palmitoyloxy)propyl [2-(Trimethylammonio)eth-
To a solution of 6 (50 mg, 0.124 mmol), 2-bromoethanol (24; 13 μL,
0.186 mmol), and molecular sieves 3A (50 mg) in anhyd toluene (0.8
mL) was added DBU (28 μL, 0.186 mmol) at 0 °C under argon. After
stirring at 0 °C for 7 h, a 1/15 M phosphate buffer (pH 7.4, 3 mL) was
added to the reaction mixture. The mixture was filtered, and then ex-
tracted with CHCl3 (3 × 10 mL). The combined organic layers were
dried (anhyd MgSO4), filtered, and concentrated in vacuo. The oily
residue was purified by column chromatography [Silica Gel 60N: n-
hexane–EtOAc (2:3) to afford 25 (diastereomeric mixture, 38.4 mg,
72%) as a colorless oil.
yl] Phosphate [1-F-LPC (3)]
To a solution of 27 (68.6 mg, 0.119 mmol) in anhyd THF (1 mL) were
added LHMDS (1.02 mol/L in n-hexane, 140 μL, 0.143 mmol) and
benzaldehyde (14.6 μL, 0.143 mmol) at 0 °C under argon. The reaction
mixture was stirred for 15 min under argon. A 1/15 M phosphate buf-
fer (pH 7.4, 3 mL) was added to the mixture, and then concentrated in
vacuo. The residue was purified by column chromatography [COSMO-
SIL 75 SL-II-PREP: CHCl3–MeOH (100:1 to 3:1)] to afford 28, which
was used in the next reaction without further purification. A mixture
of 28 and Me3N (ca. 3 mol/L in EtOH, 2 mL, ca. 6 mmol) was stirred at
r.t. for 5 d and then concentrated in vacuo. The residue was purified
by column chromatography [Silica Gel 60N: CHCl3–MeOH (3:1) to
CHCl3–MeOH–H2O (5:5:1)] to afford 1-F-LPC (3) (38.7 mg, 65%, two
steps) as a white solid; mp 65–67 °C; [α]D27 +9.8 (c 1.09, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.34–7.28 (m, 5 H), 4.71 (dd, J = 11.7,
1.2 Hz, 1 H), 4.68 (dd, J = 11.7, 2.8 Hz, 1 H), 4.62–4.55 (m, 1 H), 4.53–
4.45 (m, 1 H), 4.41–4.30 (m, 3 H), 4.25–4.17 (m, 1 H), 3.91–3.81 (m, 1
H), 3.74/3.73 (2 s, 3 H), 3.50/3.48 (2 t, J = 6.2, 6.1 Hz, 2 H),
2
2
2
3.06/3.04/3.03 (dd, JH,P = 21.9 Hz, JH,H = 14.8 Hz, dd, JH,P = 21.5 Hz,
IR (KBr): 2918, 2850, 1737, 1468, 1247, 1093 cm–1
.
2JH,H = 14.8 Hz, d, 2JH,P = 21.5 Hz, 2H).
1H NMR (500 MHz, CDCl3): δ = 5.15 (br d, 1 H), 4.69–4.52 (m, 2 H),
4.35–4.26 (m, 2 H), 3.98–3.91 (m, 2 H), 3.82–3.76 (m, 2 H), 3.36 (s, 9
H), 2.35–2.28 (m, 2 H), 1.64–1.54 (m, 2 H), 1.34–1.20 (m, 24 H), 0.88
(t, J = 7.1 Hz, 3 H).
2
13C NMR (125 MHz, CDCl3): δ = 165.8 (d, JC,P = 5.9 Hz), 137.5, 128.5,
1
128.0, 127.94, 127.91, 81.8 (d, JC,F = 172.1 Hz), 75.8, 75.7, 75.63,
75.59, 72.4, 72.3, 65.9, 65.8, 65.79, 65.74, 64.47, 64.42, 64.37, 64.34,
1
64.29, 64.23, 52.72, 52.70, 34.0 (d, JC,P = 138.9 Hz for one diastereo-
1
mer), 33.9 (d, 1JC,P = 138.0 Hz for one diastereomer), 29.9, 29.83, 29.79,
13C NMR (125 MHz, CDCl3): δ = 173.5, 82.0 (d, JC,F = 171.8 Hz), 71.2
2
3
29.7.
(dd, JC,F = 19.6 Hz, JC,P = 9.1 Hz), 66.2, 62.4, 59.6, 54.6, 34.3, 32.0,
29.78, 29.77, 29.71, 29.66, 29.5, 29.4, 29.2, 25.0, 22.7, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H49FNO6PNa: 520.3179; found:
HRMS (ESI): m/z [M + Na]+ calcd for C15H21BrFO6PNa: 449.0141;
found: 449.0145.
520.3178.
(2S)-1-{[(2-Bromoethoxy)(2-methoxy-2-oxoethyl)phosphor-
yl]oxy}-3-fluoropropan-2-yl Palmitate (27)
Supporting Information
A mixture of 25 (61.2 mg, 0.143 mmol) and 10% Pd/C (30 mg, 0.0282
mmol) in MeOH (1 mL) was stirred at r.t. for 15 min under H2 atmo-
sphere. The reaction mixture was filtered and concentrated in vacuo
to afford 26, which was used in the next reaction without further pu-
rification. To a solution of palmitic acid (73 mg, 0.286 mmol), 2-meth-
yl-6-nitrobenzoic anhydride (99 mg, 0.286 mmol), and DMAP (52 mg,
0.426 mmol) in anhyd CH2Cl2 (6 mL) was added a solution of 26 in
anhyd CH2Cl2 (4 mL) at r.t. under argon. The mixture was stirred for
15 min. A 1/15 M phosphate buffer (pH 7.4, 3 mL) was added to the
mixture, and then extracted with CHCl3 (3 × 10 mL). The combined
organic layers were dried (anhyd MgSO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography [Silica
Gel 60N: n-hexane–EtOAc (1:1)] twice to afford 27 (diastereomeric
mixture, 59.6 mg, 72%, two steps) as a colorless oil.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588826.
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