Demonstration of a convergent approach to UV-polymerizable lipids bisDenPC and bisSorbPC

Article abstract of DOI:10.1016/j.tetlet.2010.11.090

Lipids containing UV-polymerizable diene moieties, such as BisDenPC 1 and BisSorbPC 2, have been extremely useful for the construction of micelles and lipid bilayers. The published syntheses have yielded lipids with only a trimethylamine head group. We have improved the syntheses of these monomers by a convergent method employing the Chabrier reaction of trimethylamine with a cyclic phospholane. This method can be extended to a variety of dialkylamine derivatives.

Full text of DOI:10.1016/j.tetlet.2010.11.090

Tetrahedron Letters 52 (2011) 3699–3701
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Demonstration of a convergent approach to UV-polymerizable lipids
bisDenPC and bisSorbPC
⇑
Ian W. Jones , H. K. Hall Jr.
Department of Chemistry and Biochemistry, University of Arizona, Tucson 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Lipids containing UV-polymerizable diene moieties, such as BisDenPC 1 and BisSorbPC 2, have been
extremely useful for the construction of micelles and lipid bilayers. The published syntheses have yielded
lipids with only a trimethylamine head group. We have improved the syntheses of these monomers by a
convergent method employing the Chabrier reaction of trimethylamine with a cyclic phospholane. This
method can be extended to a variety of dialkylamine derivatives.
Received 12 October 2010
Revised 15 November 2010
Accepted 16 November 2010
Available online 4 December 2010
Published by Elsevier Ltd.
1. Introduction
after PCC oxidation of tetradecanol, subjecting the resulting
tetradecanal to Horner–Wadsworth–Emmons (HWE) reaction con-
For the past 25 years, the synthetic lipids bisDenPC 1 and bis-
SorbPC 2 have been utilized by a number of groups, including
our own, to form vesicles which undergo polymerization to impart
stability.1 Polymerization of the conjugated dienes in 1 and 2 via
UV and/or redox techniques yields a poly[lipid] covalently bonded
via poly-olefin chains. For a time, 1 was commercially available
from Wako Chemicals and Nippon Oil & Fats Co.;2 unfortunately,
these companies are no longer suppliers. Previously published
syntheses of 1 coupled the appropriate dienoic fatty acids to the
commercially available syn-glycero-3-phosphocholine cadmium
chloride adduct.3–5 These procedures can only yield lipids with a
trimethylamine head group. We decided to try the convergent
methodology6 to construct the phosphocholine head group onto
the glycerol backbone already containing the fatty acid compo-
nents. The Chabrier reaction7 involving displacement on a cyclic
phospholane by dialkylamine derivatives has been demonstrated
to be very general by Nakaya and Li6 for the synthesis of other lin-
ear-polymerizable lipids; however, this method has not been ex-
tended to vesicle-forming monomers. While this Letter is a
preliminary report on the successful synthesis of two known lipids,
this methodology is envisioned to be used to synthesize related lip-
ids with potentially polymerizable hydrophilic head groups.8 Var-
ious improvements in the synthesis of the required intermediates
are included in our Letter.
ditions with triethylphosphonocrotonate led to a variable ratio of
desired (E,E) and unusable (E,Z) isomers;13 similar results were ob-
tained with either commercially available or freshly prepared
methyl or ethyl HWE reagent. Urea inclusion had been the pre-
ferred separation method to isolate the pure (E,E) isomer.14 We
have now observed that saponification of the intermediate methyl
or ethyl ester in refluxing alkali overnight gave only the desired
(E,E) dienoic acid 3, presumably due to base-catalyzed olefin isom-
erization (Scheme 1).
Attention then turned to diacylation of commercially avai-
lable (R)-(+)-3-benzyloxy-1,2-propanediol 4 with dienoic acid 3
(Scheme 2). When the coupling reagent DCC was used, even under
reflux, only the primary monoacylated product 5 and the unre-
acted DCC-fatty acid adduct were isolated. With the acid chloride
or acid bromide15 from 3, only 5 was observed, even when 4 was
first treated with 2.2 equiv of nBuLi. When the acid was activated
with carbonyl-diimidazole,16 again only 5 was isolated. Some
mixed success was achieved using a catalytic amount of scan-
dium(III) triflate,17 with both monoacyated 5 and diacylated 6
being isolated from the reaction mixture.
Finally, Yamaguchi esterification conditions18 yielded the one-
pot diacylation product 6 with no observed 5; addition of 2,4,6-tri-
chlorobenzoyl chloride to acid 3 in toluene with triethylamine
followed by addition of 4 with DMAP gave the diacylated 6 in
acceptable yield (Scheme 3). Following careful deprotection with
BCl3, the installation of the phosphocholine head group was
achieved in two-steps using 2-chloro-2-oxo-1,3,2-dioxaphospho-
lane followed by trimethylamine in acetonitrile.19 This model reac-
tion improved the synthesis of our ‘‘workhouse’’ bisDenPC by a
convergent method which can be extended to a variety of dialkyl-
amine derivatives.
2. Results/discussion
The first improvement in the synthesis of bisDenPC 1 concerned
the synthesis and purification of dienoic acid 3.9–12 Previously,
⇑
Corresponding author. Address: Department of Chemistry and Biochemistry,
California Polytechnic State University, San Luis Obispo, CA 93407, United States.
As to bisSorbPC 2, the synthesis of the fatty acid component
turned out to be the difficult step. The more recent approach of
E-mail address: iwjones@calpoly.edu (I.W. Jones).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.11.090

3700
I. W. Jones, H. K. Hall Jr. / Tetrahedron Letters 52 (2011) 3699–3701
1) triethylphosphonocrotonate
CHO
PCC
CO2H
OH
Me
Me
Me
nBuLi, THF, 65 oC, 76%
11
11
12
CH2Cl2,
90%
3
2) NaOH/MeOH,reflux 100%
Scheme 1. Synthesis of (E,E)-2,4-octadecadienoic acid 3.
O
Various Conditions
Me
HO
(CH2)12
BnO
OH
OH
3
4
O
O
O
Me
Me
BnO
(CH2)12
BnO
O
(CH2)12
(CH2)12
OH
O
Me
5
6
O
Scheme 2. Synthesis of diacylated benzyloxy protected propanediol 6.
O
O
1) Yamaguchi Protocol
Me
Me
BnO
O
(CH2)12
(CH2)12
HO
(CH2)12
O
4
2) , DMAP, PhMe, 94%
Me
3
6
O
O
O
1) BCl3/heptanes
P
O
O
N
O
O
2) Cyclic Phospholane,Et3N, PhH
3) Me3N, MeCN
O
1
Scheme 3. Synthesis of bisDenPC 1.
Bae et al. failed in our hands; however, we did take inspiration
from their work. Sorbic acid was coupled to methyl 10-hydroxyde-
canoate under standard Yamaguchi esterification conditions to
give the mixed ester 7 (Scheme 4). We expected that saponification
should occur much faster with a methyl group as opposed to a sor-
boyl group; yet traditional saponifications with alkali in alcohol or
mixed alcohol–solvent systems were either too sluggish or not spe-
cific enough for the methyl ester. By subjecting 7 to lithium iodide
demethylation yielded the corresponding fatty acid 8. With this
saturated acid, DCC coupling of 8 to chiral diol 4 cleanly gave the
diacylated product 9. Deprotection with BCl3 gave the expected
alcohol, which was used without purification to suppress ester
group migration. Subjecting the alcohol to 2-chloro-2-oxo-1,3,
2-dioxaphospholane followed by trimethylamine in acetonitrile
gave bisSorbPC 2. Again, we have improved the synthesis of our
extensively used monomer using a convergent approach which
can be generalized with other dimethylamine derivatives.21
and potassium cyanide in refluxing pyridine20
,
an SN2-type
O
O
LiI, KCN, pyr
Sorbic Acid
HO
CO2Me
9
O
CO2Me
O
CO2H
9
9
reflux, 72%
Yamaguchi Esterfication
7
8
O
O
1) BCl3/heptanes
O
DCCCoupling
BnO
O
9
O
O
2) Cyclic Phospholane, Et3N, PhH
3) Me3N, MeCN
9
O
O
9
O
O
O
P
O
O
N
O
O
O
O
O
O
2
Scheme 4. Synthesis of bisSorbPC 2.

I. W. Jones, H. K. Hall Jr. / Tetrahedron Letters 52 (2011) 3699–3701
3701
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Acknowledgments
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Supplementary data
Supplementary data (the synthesis, characterization, and NMR
spectra of compounds 1, 2, 3, 6, 7, 8, and 9) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.090.
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