A new synthetic approach to phosphatidylethanolamine

Article abstract of DOI:10.1016/j.cclet.2011.10.020

A new synthetic method for phosphatidylethanolamine head group was developed via ring-opening of cyclic dioxaphospholane 2 with sodium azide and subsequent hydrogenation. The advantage of this strategy included short reaction steps, readily available materials and good yields.

Full text of DOI:10.1016/j.cclet.2011.10.020

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 154–156
www.elsevier.com/locate/cclet
A new synthetic approach to phosphatidylethanolamine
b
a
Yang Song , Wei Yuan , Yu Luo , Wei Lu
a
a,
*
a
Department of Chemistry, East China Normal University, Shanghai 200062, China
b
Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, China
Received 23 August 2011
Available online 21 December 2011
Abstract
A new synthetic method for phosphatidylethanolamine head group was developed via ring-opening of cyclic dioxaphospholane
with sodium azide and subsequent hydrogenation. The advantage of this strategy included short reaction steps, readily available
2
materials and good yields.
2011 Yu Luo. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
#
Keywords: Phosphatidylethanolamine; Synthesis
Phosphatidylethanolamine (PE), also known as cephalin, is a phospholipid found in biological membranes [1–3],
particularly in nervous tissue. PE has also been implied to be directly involved in a number of biological events, such as
in blood coagulation [4], in the regulation of blood pressure [5] and in the visual process [6]. In addition, the presence
of the reactive amino group offers the possibility of preparing phosphatidylcholine (PC) and head group modified
lipids, such as PEG-lipids and other functionalized lipids (Fig. 1).
Up to now, several synthetic methods have been developed to prepare phosphatidylethanolamine [7,8]. The key
steps include the construction of phosphate head group, using a proper phosphorus reagent.
2
-Choro-2-oxo-1,3,2-dioxaphospholane (1, Scheme 1), a commercially available phosphorus reagent, is commonly
used to prepare phosphatidylcholine (PC). Condensation of a diacylglycerol with reagent 1 produce a cyclic phosphate
intermediate 2, which is treated with trimethylamine to give PC with fairly good yields (Scheme 1). The advantage of
this dioxaphospholane method lies in the fact that, in contrast to most other chlorophosphates, the cyclic reagent 2 has
only one reactive group and therefore the formation of by-products is minimized.
Recently, Roodsari et al. [9] reported that treatment of cyclic phosphate 2 with ammonia could afford
phosphatidylethanolamine directly. However, it was found by us that the yield of this procedure was very low since
ester groups could be easily ammonolyzed. In addition, other literatures reported that cyclic phosphate 2 could react
with NaBr to give a bromide compound [10]. All of these reports suggest that the reactivity of this cyclic phosphate 2 is
so high that treatment of 2 with a variety of nucleophiles can result in ring-opening. Thus, it was surmised that
treatment of the cyclic phosphate 2 with sodium azide may also result in a ring-opened intermediate, which may afford
phosphatidylethanolamine by subsequent reduction. Herein, we report a novel strategy to produce phosphatidy-
lethanolamine.
*
Corresponding author.
E-mail address: yluo@chem.ecnu.edu.cn (Y. Luo).
1001-8417/$ – see front matter # 2011 Yu Luo. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.10.020

Y. Song et al. / Chinese Chemical Letters 23 (2012) 154–156
155
O
R
O
O
O
P
NH3+
R
O
O
O-
O
PE
R = linear alkyl
O
O
R
O
O
O
P
ONa
H
N
OH
R
O
O
O
P
O-
R
O
O
n
O
N+
R
O
O
O
O
O
O
PC
O
R
O
O
O
P
O-
H
N
R
O
O
nNH3+
R
O
O
O
P
ONa
H
N
O
O
R
O
O
mPEG
O
O
O
O
O
R
O
O
O
P
H
N
R
O
O
Link N
ONa
O
O
O
Fig. 1. Phosphatidylethanolamine and its derivatives.
As illustrated in Scheme 2, the starting material dipalmitoylglycerol 3, prepared according to reported literatures
11–13], was treated with 1 and triethylamine to produce cyclic phosphate 2. However, it was found that this cyclic
phosphate 2 was very unstable and could not be purified by recrystallization or column chromatography. After the
[
reaction was completed, the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated to
dryness to give crude 2, which was directly used in the next step. Treatment of crude 2 with NaN in DMF proceeded
3
smoothly to give an azide compound 4 as a white solid with a two-step yield of 85% after column chromatography.
With compound 4 available, we screened different reduction conditions to reduce the azide into an amine. It was found
that hydrogenation with Pd/C gave a yield of 80% after purification by column chromatography, while other reaction
conditions, such as Raney-Ni catalyzed hydrogenation and reduction with Na S or NaBH resulted in poor yields or
2
4
complications. At last, the prepared compounds 4 and 5 gave satisfactory analytical data [14].
O
R
O
O
O
P
N+
Me N
R
R
O
O
O
3
O-
O
O
PC
O
O
P
O
O
O
R
O
O
O
Cl
+
R
O
O
O
NH
3
NH
3
R
O
O
O
P
O-
O
P
R
OH
1
R
O
ref. 9
O
Et N
PE
O
3
O
O
2
O
NaBr
R
O
O
Br
R
O
O
P O
ref. 10
ONa
O
Scheme 1. Ring-opening of 2.

156
Y. Song et al. / Chinese Chemical Letters 23 (2012) 154–156
O
O
O
R
O
O
R
O
O
2
R
O
O
O
P
a
b
O
R
OH
R
O
R
O
O
N3
P
O
ONa
O
O
O
O
3
4
O
R
O
O
O
c
NH3+
R
O
P
O-
O
R = CH (CH )
3
2 16
O
DPPE 5
3 3 2
Scheme 2. A new synthetic approach to phosphatidylethanolamine. (a) 1, Et N, THF; (b) NaN , DMF, 80 8C, 85% yield (two steps); (c) Pd/C, H ,
methanol, AcOH, 80% yield.
In conclusion, a novel three-step synthetic method for phosphatidylethanolamine is developed, using 2-choro-2-
oxo-1,3,2-dioxaphospholane (1) as a phosphorus reagent. The key steps include sodium azide involved ring-opening
and subsequent hydrogenation. This synthetic method has a great deal of flexibility, providing a convenient route to a
wide range of structurally related phosphatidylethanolamine.
Acknowledgments
We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No.
05722321) and Shanghai Municipal Natural Science Foundation (No. 10ZR1409600). We also thank Lab of Organic
3
Functional Molecules, the Sino-French Institute of ECNU for supports.
References
[
[
[
[
[
[
[
[
[
1] A. Colbeau, J. Nachbaur, P.M. Vignais, Biochim. Biophys. Acta 249 (1971) 462.
2] P. Sitte, Ber. Deut. Bot. Ges. 182 (1969) 329.
3] M.K. Jain, The Biomolecular Lipid Membrane: A System, van Nostrand Reinhold Company, New York, 1972.
4] M.J. Silver, D.L. Turner, Am. J. Physiol. 190 (1957) 8.
5] S. Sen, R.R. Smeby, F.M. Bumpus, Am. J. Physiol. 216 (1969) 499.
6] R.P. Poincelot, P.G. Millar, R.L. Kimbel, E.W. Abrahamson, Nature 221 (1969) 256.
7] H. Eibl, Chem. Phys. Lipids 26 (1980) 405.
8] F. Paltauf, A. Hermetter, Prog. Lipid Res. 33 (1994) 239.
9] F.S. Roodsari, D.P. Wu, G.S. Pum, J. Org. Chem. 64 (1999) 7727.
[
[
[
[
[
10] H. Eibl, Proc. Natl. Acad. Sci. U.S.A. 75 (1978) 4074.
11] K. Burgress, K.K. Ho, C.Y. Ke, J. Org. Chem. 58 (1993) 3767.
12] N. Hebert, A. Beck, R.B. Lennox, J. Org. Chem. 57 (1992) 1777.
13] J. Xia, Y.Z. Hui, Chem. Pharm. Bull. 47 (1999) 1659.
1
14] 4: H NMR (CDCl
3
, 500 MHz): d 0.88 (t, 6H, J = 6.5 Hz), 1.25–1.29 (m, 48H), 1.58 (d, 4H, J = 7.0 Hz), 2.30 (m, 4H), 3.48 (d, 2H, J = 4.5 Hz),
1
.99 (d, 2H, J = 6.5 Hz), 4.02 (d, 2H, J = 5 Hz), 4.18 (m, 1H), 4.40 (d, 1H, J = 10 Hz), 5.25 (s, 1H). 5: H NMR (CDCl
3
3
, 500 MHz): d 0.88 (t,
6H, J = 6.5 Hz), 1.25–1.29 (m, 48H), 1.58 (d, 4H, J = 6.0 Hz), 2.30 (m, 4H), 3.16 (s, 2H), 3.96 (m, 2H), 4.11 (m, 2H), 4.16 (m, 1H), 4.37 (d, 1H,
J = 11.5 Hz), 5.22 (s, 1H), 8.50 (br, 2H).