BODP - A versatile reagent for phospholipid synthesis

Article abstract of DOI:10.1055/s-0030-1258427

Benzyloxydichlorophosphine (BODP) has been found to be a convenient reagent for the synthesis of phospholipids. A series of artificial ether and ester phospholipids have been prepared in good to high yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258427

778
PAPER
BODP – A Versatile Reagent for Phospholipid Synthesis
B
O
D
P
–
A Ve
i
rsatile
e
R
eagent for
r
Phosph
r
olipid Sy
e
nthesis -Léonard Zaffalon, Andreas Zumbuehl*
Department of Organic Chemistry, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
Fax +41(22)3793215; E-mail: andreas.zumbuehl@unige.ch
Received 11 January 2011
PCl3) are readily available, cheap, and can be used without
purification or drying. Furthermore, the benzyl group can
be easily removed under various mild conditions.
Abstract: Benzyloxydichlorophosphine (BODP) has been found to
be a convenient reagent for the synthesis of phospholipids. A series
of artificial ether and ester phospholipids have been prepared in
good to high yields.
BODP has been used as a reactive intermediate for the
Key words: ethers, esters, phospholipids, phosphorylation, protect- synthesis of ribonucleotides,9 phosphoramidates,10 poly-
phosphates,11 and in cyclization reactions.12 When being
ing group
reacted with phosphonates and amides BODP – like other
phosphorus(III) reagents – presumably primarily formed
the monochlorophosphine intermediate and not the dou-
bly substituted phosphine,9b,11b making it less useful for
symmetrical double substitution, but more interesting for
stepwise addition of different nucleophiles. The reactivity
is strongly dependent on the solvent used, with tetrahy-
drofuran being preferred over acetonitrile and dichlo-
romethane.13
Despite over 80 years of synthetic efforts, the preparation
of phospholipids remains a challenge.1 We have recently
initiated a program for the synthesis of artificial phospho-
lipids and found it necessary to investigate new reactive
intermediates for the introduction of a phosphate head
group.2 Here, we report on a convenient reagent, benzyl-
oxydichlorophosphine (BODP, 1), that was successfully
used for the synthesis of various artificial choline phos-
pholipids.
Here, BODP was successfully used in the synthesis of 3
phospholipids: miltefosine (4), Pet-PC-Pet (7), and Pes-
PC-Pes (10). Others and we have recently suggested
amendments to the existing IUPAC recommendation for
phospholipid nomenclature.2,14 The new classification fo-
cuses on the type of chemical linkage between the phos-
pholipid tails and the lipid backbone. ‘Pes’ thus
designates a C16 alkyl chain (P = palmitic) connected to
the lipid backbone with an ester functionality. In ‘Pet’, the
chemical linker is an ether. The order in which the substit-
uents are attached to the glycerol backbone is represented
by the order of the groups in the abbreviation: Pes-PC-Pes
is a 1,3-substituted, and Pes-Pes-PC a natural, sn-1,2-sub-
stituted phospholipid.
Typical ways to introduce a phosphocholine head group
include both phosphorus(V) and phosphorus(III) re-
agents: for example, bromoethylphosphoric acid dichlo-
ride readily reacts with primary alcohols to give a stable
intermediate that can be substituted to the choline using
trimethylamine.3 Dioxophospholanes can be opened to
the corresponding choline.4 Successful phosphorus(III)
intermediates include H-phosphonates5 and reagents such
as methyl dichlorophosphite6 and phosphoramidites,7
which allow a stepwise addition of two different alcohols.
On attempting to phosphorylate a secondary alcohol, we
found that phosphorus(V) reagents are generally too unre-
active and phosphorus(III) reagents lead to oxidation after
the addition of the first alcohol. This and the cost of phos-
phoramidite reagents led us to look for an alternative, a
middle way using a reagent that at the same time was sta-
ble towards oxidation, but also reactive enough to allow
the stepwise addition of two different alcohols in one pot.
Benzyloxydichlorophosphine fulfills these criteria and, to
our knowledge, was never before used for the synthesis of
phospholipids. The reagent was initially synthesized un-
der rudimentary conditions that lead to explosions during
the distillation.8 However, the reagent can be used without
this purification step, is safe to handle,9 and requires only
moderately dry working conditions under nitrogen gas
(BOPD is routinely used by undergraduate students in our
laboratory). The starting materials (benzyl alcohol and
Our nomenclature allows easy classification of artificial
phospholipids based on their chemical linkage and is
complementary to the impressive nomenclature of the
International Lipid Classification and Nomenclature
Committee.15
Benzyloxydichlorophosphine (1) was synthesized opti-
mizing a reported procedure:12b benzyl alcohol was react-
ed with phosphorus trichloride in diethyl ether. Upon
completion of the reaction, the excess of diethyl ether was
evaporated leaving the BODP that was used without fur-
ther purification.
Miltefosine (hexadecylphosphocholine, 4) is an impres-
sive example for an interdisciplinary collaboration be-
tween basic and clinical research. Miltefosine was
initially identified for its antitumor potency and is now
used clinically for the treatment of visceral and cutaneous
leishmaniasis.16 Miltefosine was synthesized by phospho-
rylation of hexadecan-1-ol with phosphorus oxychloride,
ring closure with ethanolamine, and opening of the oxaza-
SYNTHESIS 2011, No. 5, pp 0778–0782
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x
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x
x
.2
0
1
1
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1258427; Art ID: T10811SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
BODP – A Versatile Reagent for Phospholipid Synthesis
779
O
Br
O
P
1
O
P
O
13
+
O
O
P
1)
Et3N, THF
1) TFA, CH2Cl2
Cl
Cl
NMe3
OH
O
O
2) Me3N, MeCN
CHCl3, i-PrOH
42%
13
2) bromoethanol
3) MCPBA
88%
13
–
O
2
4
3
Scheme 1 Synthesis of miltefosine (hexadecylphosphocholine, 4)
phospholane ring under acidic conditions. The alkylphos- 1,3-Diacyl phosphocholines were introduced in order to
phoethanolamine was reacted to form the choline with study the differences between natural 1,2- and artificial
dimethyl sulfate.17
1,3-diacyl phospholipids.18,19
Here, BODP (1) was reacted stepwise with hexadecan-1- The starting alcohol 8 was available from a reaction of
ol (2), followed by bromoethanol, and oxidation to the palmitoyl chloride with glycerol.21 Reaction with BODP
protected phosphate triester 3. Deprotection with trifluo- led to the reactive intermediate 9 that was deprotected and
roacetic acid and substitution with trimethylamine3 lead to further substituted to Pes-PC-Pes (10) (Scheme 3). The
the choline derivative 4 in two steps and an overall yield compound was obtained in 26% yield which is compara-
of 37% (Scheme 1).
ble to earlier syntheses of Les-PC-Les (L = lauric).22
Surprisingly, changing from a natural 1,2-diacyl phospho- In conclusion, we have presented a rapid and high-yield-
lipid to a symmetrical 1,3-diacyl phospholipid does not ing approach leading to alkylphosphocholines, 1,3-di-
significantly alter the physical properties of the molecule alkyl-, and 1,3-diacylphosphocholines. The synthesis is
in a membrane.18 Similarly, changing between diacyl- and based on benzyloxydichlorophosphine, a reagent rarely
dialkylphosphocholines also does not introduce big alter- used for phosphorylations, but with many advantages over
ations in the physical characteristics of the molecules.19 phosphoramidite reagents such as cost, stability and ease
These facts should allow new possibilities to produce of handling. The presented approach for phospholipid
membrane probes at more reasonable prices and an effi- synthesis is flexible, allowing the introduction of various
cient synthesis is certainly appreciated.
head groups. Synthetic efforts in this direction are current-
ly ongoing in our group.
Pet-PC-Pet (7) had previously been accessed using bro-
moethyl dichlorophosphate that was substituted with tri-
methylamine.19 Here, we started from the corresponding
1,3-dialkylpropan-2-ol 5 that was obtained from the reac-
tion of hexadecan-1-ol with epichlorohydrin.20 The inter-
mediate was reacted with BODP (1) and bromoethanol to
give the protected phosphate triester 6. Again, substitution
with trimethylamine led to the product 7 (Scheme 2) in
48% overall yield.
Starting compounds and solvents were purchased from Sigma-
Aldrich/Fluka or Acros and were used without further purification.
Column chromatographic separations were carried out using 230–
400 mesh silica gel. TLC plates were developed with KMnO4. 1H,
13C, and 31P NMR spectra were recorded (as indicated) on either a
Bruker 300 MHz, 400 MHz or 500 MHz spectrometer and are re-
ported as chemical shifts (d) in ppm relative to TMS (d = 0). Spin
multiplicities are reported as a singlet (s), doublet (d), or triplet (t)
O
O
O
P
O
+
O
P
O
O
Br
1) TFA, CH2Cl2
OH
O
NMe3
–
13
O
O
1) BODP 1
Et3N, THF
13
O
13
O
O
O
2) bromoethanol
3) MCPBA
89%
2) Me3N, MeCN
CHCl3, i-PrOH
54%
13
13
13
7
5
6
Scheme 2 Synthesis of Pet-PC-Pet (7)
O
O
O
O
O
P
O
P
O
OH
O
O
+
O
Br
1) BODP 1
Et3N, THF
O
O
NMe3
O
–
13
1) TFA, CH2Cl2
13
13
O
O
2) Me3N, MeCN
CHCl3, i-PrOH
50%
O
O
2) bromoethanol
3) MCPBA
O
51%
O
O
13
13
13
10
9
8
Scheme 3 Synthesis of Pes-PC-Pes (10)
Synthesis 2011, No. 5, 778–782 © Thieme Stuttgart · New York

780
P.-L. Zaffalon, A. Zumbuehl
PAPER
with coupling constants (J) given in Hz, or multiplet (m). Broad
peaks are marked as br. HRESI-MS were performed on QSTAR
Pulsar (AB/MDS Sciex) spectrometer and are reported as mass-per-
charge ratio m/z. IR spectra were recorded on a Perkin-Elmer Spec-
trum One FT-IR spectrometer (ATR, Golden Gate). MCPBA pro-
vided by Sigma was 77% pure.
mL). Then, Me3N (45% in H2O, 2 mL) was added. After 3 h, the sol-
vent was removed under vacuum. The crude product was purified
on a silica gel column (eluent: CH2Cl2–MeOH–25% NH4OH,
75:22:3); white solid; yield: 56 mg (42%); Rf = 0.1 (CH2Cl2–
MeOH–25% NH4OH, 75:22:3).
1H NMR (400 MHz, CDCl3): d = 4.27 (br, 2 H), 3.86 (br, 2 H), 3.78
(dd, J = 13.1, 6.6 Hz, 2 H), 3.41 (s, 9 H), 1.66–1.48 (m, 2 H), 1.25
(s, 26 H), 0.87 (t, J = 6.8 Hz, 3 H).
Benzyloxydichlorophosphine (BODP, 1)
The protocol was optimized from a literature procedure.12b Benzyl
alcohol (6.00 mL, 58.0 mmol) was dissolved in anhyd Et2O (120
mL) and added to PCl3 (10.1 mL, 116 mmol) in anhyd Et2O (90 mL)
over 5 h. The first 20 min of the addition was performed at 0 °C, and
then the ice bath was removed. After the addition, the stirring was
continued for 2 h at 20 °C. The solvent was evaporated by distilla-
tion at 50 °C and the excess of PCl3 was removed under reduced
pressure. The product was used without further purification; color-
less oil; yield: 11.4 g (94%).
31P NMR (162 MHz, CDCl3): d = –0.40 (s).
HRMS (ESI+): m/z [M + H]+ calcd for C21H47NO4P: 408.3237;
found: 408.3232.
1,3-Bis(hexadecyloxy)propan-2-ol (5)
NaH (60% in mineral oil, 525 mg, 13.1 mmol) was added in 3 por-
tions to hexadecan-1-ol (6.63 g, 27.3 mmol) at 100 °C. After stirring
for 30 min, epichlorohydrin (250 mL, 3.19 mmol) was added drop-
wise to the hot mixture and maintained at 100 °C overnight, after
which H2O (2 mL) was added to quench the reaction. CH2Cl2 (200
mL) was added, followed by THF to facilitate the solubility of the
product, and the organic phase was washed with H2O (3 × 150 mL).
The organic phase was dried (Na2SO4), filtered, and the solvent re-
moved under reduced pressure. Purification on a silica gel column
(eluent: pentane–EtOAc, 5:95) afforded a white solid; yield: 1.06 g
(61%); Rf = 0.16 (pentane–EtOAc, 95:5)
1H NMR (300 MHz, CDCl3): d = 7.47 (s, 5 H), 5.32 (d, J = 8.0 Hz,
2 H).
13C NMR (75 MHz, CDCl3): d = 134.8, 128.8, 128.5, 69.8.
31P NMR (162 MHz, CDCl3): d = –177.37 (s).
Benzyl 2-Bromoethyl Hexadecyl Phosphate (3)
BODP (1; 1.00 mL, 6.10 mmol) and anhyd Et3N (2.00 mL, 14.0
mmol) were dissolved in anhyd THF (20 mL) under N2. Hexadecan-
1-ol (400 mg, 1.65 mmol) in anhyd THF (20 mL) was added drop-
wise to the solution under stirring at 0 °C over 3 h [completion of
the reaction was checked by TLC (MeOH–CH2Cl2, 2:98)]. Then,
bromoethanol (910 mL, 12.8 mmol) was added at 0 °C and the mix-
ture was stirred for 3 h (the reaction can be monitored by 31P NMR
spectroscopy, the signal should shift from 166 ppm to about 140
ppm). MCPBA (1.56 g, 9.60 mmol) was added to the reaction mix-
ture at 0 °C and the mixture was stirred for 1 h (oxidation can be
monitored by a signal shift from 140 ppm to about –5 ppm in 31P
NMR spectrum). The solution was treated with of aq 10% Na2S2O3
(110 mL), sat. aq NaHCO3 (30 mL), and extracted with CH2Cl2
(3 × 100 mL). The solvents from the combined organic phases were
removed under reduced pressure. The crude product was purified on
a silica gel column (eluent: pentane–EtOAc, 4:1) to give the pure
product as a brownish oil; yield: 750 mg (88%); Rf = 0.23 (pentane–
EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 3.94 (s, 1 H), 3.60–3.26 (m, 8 H),
2.45 (s, 1 H), 1.57 (s, 4 H), 1.26 (s, 52 H), 0.88 (t, J = 5.3 Hz, 6 H).
HRMS (ESI+): m/z [M + H]+ calcd for C35H73O3: 541.5554; found:
541.5565.
Benzyl 1,3-Bis(hexadecyloxy)propan-2-yl 2-Bromoethyl Phos-
phate (6)
A solution of 5 (400 mg, 739 mmol) in anhyd THF (20 mL) was add-
ed dropwise to a solution of BODP (1; 405 mL, 2.44 mmol) and an-
hyd Et3N (722 mL, 5.18 mmol) in anhyd THF (25 mL) over 3 h at
0 °C. The stirring was continued at 20 °C for 12 h. After the con-
sumption of the starting material (TLC: pentane–EtOAc, 9:1), bro-
moethanol (370 mL, 5.18 mmol) was added dropwise at 0 °C. The
ice-bath was removed and the stirring continued for 45 min. MCPBA
(829 mg, 3.70 mmol) was added at 0 °C and the mixture was stirred
for 1 h at 20 °C. Then, aq 10% Na2S2O3 (110 mL) and sat. aq
NaHCO3 (50 mL) were added and the aqueous phase was extracted
with CH2Cl2 (3 × 100 mL). The organic solvent was removed under
reduced pressure and the product was purified on a silica gel column
(eluent: pentane–EtOAc, 5:2) to give a yellowish solid; yield: 536
mg (89%); Rf = 0.35 (pentane–EtOAc, 4:1).
IR (ATR): 2923, 2853, 1457, 1379, 1270, 1215, 1000, 733, 696
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37 (d, J = 7.2 Hz, 5 H), 5.10 (d,
J = 8.5 Hz, 2 H), 4.25 (dd, J = 13.0, 6.5 Hz, 2 H), 4.04 (q, J = 6.8
Hz, 2 H), 3.47 (t, J = 6.3 Hz, 2 H), 1.63 (dd, J = 13.7, 6.7 Hz, 2 H),
1.25 (s, 25 H), 0.88 (t, J = 6.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 135.7, 128.7, 128.0, 69.5, 68.3,
66.5, 32.0, 30.2, 30.2, 29.7, 29.7, 29.7, 29.6, 29.6, 29.5, 29.5, 29.4,
29.2, 25.4, 22.7, 14.2.
31P NMR (162 MHz, CDCl3): d = –0.63 (s).
IR (ATR): 2922, 2853, 1462, 1378, 1278, 1117, 1013, 734, 697
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.47–7.31 (m, 5 H), 5.14 (d,
J = 7.6 Hz, 2 H), 4.70–4.59 (m, 1 H), 4.30 (dd, J = 14.8, 6.6 Hz, 2
H), 3.65–3.53 (m, 4 H), 3.53–3.35 (m, 6 H), 1.54 (tt, J = 13.7, 6.7
Hz, 4 H), 1.26 (s, 52 H), 0.89 (t, J = 7.0 Hz, 6 H).
HRMS (ESI+): m/z [M + H]+ calcd for C25H45BrO4P: 519.2236;
found: 519.2233.
13C NMR (126 MHz, CDCl3): d = 181.1, 175.2, 148.1, 135.9, 128.6,
128.5, 127.9, 71.7, 70.2, 69.4, 66.5, 62.8, 31.9, 29.7, 29.7, 29.6,
29.5, 29.5, 29.4, 29.3, 29.2, 26.1, 22.7, 14.1.
Hexadecylphosphocholine (4)
HRMS (Turbo Spray): m/z [M + H]+ calcd for C44H83BrO6P:
To a solution of 3 (292 mg, 0.562 mmol) in CH2Cl2 (2 mL) was add-
ed CF3CO2H (TFA, 98%, 3.00 mL, 40.3 mmol) and the mixture
was stirred at r.t. for 20 h. Excess TFA was removed by bubbling N2
through the mixture. The residue was partitioned between aq HCl
(25 mL) and CH2Cl2 (4 × 25 mL). The solvent from the combined
organic phases were removed under reduced pressure. The white
solid obtained (280 mg, 100% conversion of 3) was used without
further purification. A portion of the solid (140 mg) was dissolved
in a mixture of CH2Cl2 (1 mL), MeCN (1.6 mL), and i-PrOH (1.6
817.5105; found: 817.5113.
Pet-PC-Pet (7)
To a solution of 6 (503 mg, 615 mmol) in CH2Cl2 (7 mL) was added
TFA (98%, 7.00 mL, 93.3 mmol). After stirring the mixture for 24
h, the TFA was removed by bubbling N2 through the solution. The
residual crude oil was partitioned between aq 1 M HCl (25 mL) and
CH2Cl2 (4 × 25 mL). The solvent from the combined organic phases
was removed under reduced pressure to give 315 mg (70% conver-
Synthesis 2011, No. 5, 778–782 © Thieme Stuttgart · New York

PAPER
BODP – A Versatile Reagent for Phospholipid Synthesis
781
sion of 6) of a white solid, which was used without further purifica-
tion. A portion of the crude solid (285 mg) was dissolved in a
mixture of CHCl3 (8 mL), MeCN (5 mL), and i-PrOH (8 mL). Then,
Me3N (45% in H2O, 4 mL) was added. After stirring for 48 h, the
solvents were removed under reduced pressure and the crude prod-
uct was purified on a silica gel column (eluent: CH2Cl2–MeOH–
25% NH4OH, 75:22:3); white solid; yield: 213 mg (54%); Rf = 0.27
(CH2Cl2–MeOH–25% NH4OH, 75:22:3).
1H NMR (500 MHz, CDCl3): d = 4.33 (s, 3 H), 3.81 (s, 2 H), 3.55
(d, J = 5.1 Hz, 4 H), 3.39 (s, 13 H), 1.61–1.43 (m, 4 H), 1.25 (s, 52
H), 0.87 (t, J = 6.8 Hz, 6 H).
the crude oil obtained was used directly in the next step. The oil was
dissolved in a mixture of CHCl3 (1.5 mL), i-PrOH, MeCN (1.5 mL),
and Me3N (45% in H2O, 3 mL; 2 mL of additional Me3N were add-
ed after 24 h) and the mixture was stirred for 36 h. The solvents
were removed under reduced pressure and the crude product was
purified on a silica gel column (eluent: CH2Cl2–MeOH–25%
NH4OH, 175:22:3, then CH2Cl2–MeOH–25% NH4OH, 75:22:3) to
give the product as a white powder; yield: 24 mg (50%); Rf = 0.2
(CH2Cl2–MeOH–25% NH4OH, 75:22:3).
1H NMR (300 MHz, CDCl3): d = 4.49 (br s, 1 H), 4.33 (br s, 2 H),
4.24 (d, J = 4.9 Hz, 4 H), 3.80 (s, 2 H), 3.34 (s, 9 H), 2.29 (t, J = 7.6
Hz, 4 H), 1.71–1.46 (m, 4 H), 1.25 (s, 48 H), 0.88 (t, J = 6.7 Hz, 6
H).
HRMS (Turbo Spray): m/z [M + H]+ calcd for C40H85NO6P:
706.6109; found: 706.6126.
HRMS (ESI+): m/z [M + H]+ calcd for C40H81O8NP: 734.5694;
found: 734.5728.
2-Hydroxypropane-1,3-diyl Dipalmitate (8)18
A solution of palmitoyl chloride (1.70 mL, 5.45 mmol) in anhyd
THF (12 mL) was added dropwise to a solution of glycerol (200 mL,
2.72 mmol) and pyridine (900 mL, 11.1 mmol) in anhyd THF (18
mL) at 0 °C under N2 over 90 min. The stirring was continued at
20 °C for 1 h. Then, the solution was partitioned between aq 1 M
HCl (100 mL) and Et2O (3 × 150 mL). The product was recrystal-
lized from Et2O at 6 °C overnight. The white powder was filtered,
dried, and used without further purification; yield: 540 mg (35%);
Rf = 0.7 (CH2Cl2–MeOH, 49:1).
Acknowledgment
We would like to thank Mr. Frédéric Loosli for his help on the pro-
ject during an undergraduate student internship. The authors thank
the University of Geneva and the Swiss National Science Foundati-
on for the financial support (SNF 200021-121718) and acknow-
ledge the contributions of the Mass Spectrometry platform at the
Faculty of Sciences, University of Geneva, for mass spectrometry
services and A. Pinto for NMR measurements.
1H NMR (400 MHz, CDCl3): d = 4.20–4.11 (m, 5 H), 2.41 (s, 1 H),
2.34 (t, J = 7.3 Hz, 2 H), 1.63–1.61 (m, 4 H), 1.25 (s, 48 H), 0.88 (t,
J = 8.0 Hz, 6 H).
References
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found: 627.5205
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2-[Benzyloxy(2-bromoethoxy)phosphoryloxy]propane-1,3-diyl
Dipalmitate (9)
A solution of 8 (365 mg, 0.64 mmol) in anhyd THF (20 mL) was
added dropwise to a solution of BODP (1; 460 mL, 2.76 mmol) and
anhyd Et3N (820 mL, 5.90 mmol) in anhyd THF (10 mL) over 90
min at 0 °C. The stirring continued at 20 °C for 5 h. After the con-
sumption of the starting material (TLC: pentane–EtOAc, 5:2), bro-
moethanol (420 mL, 5.90 mmol) was added dropwise at 0 °C. Then
the ice-bath was removed and the stirring continued for 45 min.
MCPBA (733 mg, 3.27 mmol) was added at 0 °C and the solution
was stirred for 1 h at 20 °C. Aq 10% Na2S2O3 (110 mL) was added
followed by sat. aq NaHCO3 (50 mL). The aqueous phases were ex-
tracted with CH2Cl2 (4 × 100 mL). The solvents were removed from
the combined organic phases and the crude product was purified on
a silica gel column (eluent: pentane–EtOAc, 5:2) to give a yellow
solid; yield: 275 mg (51%); Rf = 0.5 (pentane–EtOAc, 4:1).
IR (ATR): 2922, 2853, 1743, 1457, 1379, 1276, 1163, 1011, 735,
697 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.45–7.31 (m, 5 H), 5.11 (dd,
J = 8.1, 1.7 Hz, 2 H), 4.81–4.74 (m, 1 H), 4.35–4.24 (m, 4 H), 4.18
(ddd, J = 12.1, 7.7, 5.9 Hz, 2 H), 3.47 (tdd, J = 6.4, 1.7, 0.5 Hz, 2
H), 2.37–2.29 (m, 2 H), 2.26 (td, J = 7.4, 1.6 Hz, 2 H), 1.78–1.40
(m, 4 H), 1.25 (s, 48 H), 0.88 (t, J = 7.0 Hz, 6 H).
13C NMR (126 MHz, CDCl3): d = 173.2, 135.4, 128.7, 128.7, 128.0,
74.2, 69.7, 66.8, 62.7, 34.0, 33.9, 31.9, 29.6, 29.3, 29.1, 24.7, 22.7,
14.1.
31P NMR (121 MHz, CDCl3): d = –2.60 (s).
HRMS (ESI+): m/z = [M + H]+ calcd for C44H79BrO8P: 845.469;
found: 845.4682.
Pes-PC-Pes (10)
To a solution of the phosphate triester 9 (55.0 mg, 65.0 mmol) in
CH2Cl2 (3 mL) was added TFA (98%, 3.00 mL, 40.0 mmol). After
36 h, the solvent was removed by bubbling N2 through the vial and
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Synthesis 2011, No. 5, 778–782 © Thieme Stuttgart · New York