Synthesis of a pH-independent bifurcated amphiphile

Article abstract of DOI:10.1016/j.tetlet.2008.01.132

An efficient synthetic method for preparing bifurcated amphiphiles has been developed such that the functionality for attachment is located at the interface between the lipophilic and hydrophilic side chains. Attachment of the amphiphile to the repeat uni

Full text of DOI:10.1016/j.tetlet.2008.01.132

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2091–2094
Synthesis of a pH-independent bifurcated amphiphile
Kaitlin A. Willham, Boyd A. Laurent, Scott M. Grayson *
Department of Chemistry, Tulane University, New Orleans, LA 70118, United States
Received 11 December 2007; revised 29 January 2008; accepted 30 January 2008
Available online 6 February 2008
Abstract
An efficient synthetic method for preparing bifurcated amphiphiles has been developed such that the functionality for attachment is
located at the interface between the lipophilic and hydrophilic side chains. Attachment of the amphiphile to the repeat units of polymeric
substrates enables the rapid preparation of amphiphilic homopolymers.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Amphiphile; Amphiphilic monomer; Amphiphilic polymer; Amphiphilic homopolymer
The human production and use of amphiphilic com-
pounds dates to prehistory, when triacylglycerides were
hydrolyzed in alkaline solution affording soaps to enable
the aqueous dispersion of lipids. Since that time, amphi-
philes have seen widespread use owing to their unique abi-
lity to modulate the surface properties of molecules,
particles, or solid surfaces with respect to their environ-
ment. Amphiphilic materials also can be used to enhance
medical technologies, from their encapsulation of potent
but insoluble drugs in micellar carriers to their disruption
of fungal cell walls. Much effort has been focused on the
synthesis and applications of amphiphilic block copoly-
mers; however, equally promising but relatively under-
explored architectures include amphiphilic homopolymers1
and dendrimers,2 in which each repeat unit bears both lipo-
philic and hydrophilic side chains. If amphiphilic homo-
polymers can organize into discrete nanoscale reverse
micelles, they offer promise as carriers to transport polar
therapeutics through the lipophilic stratum corneum,
thereby enhancing transdermal drug delivery.
efforts have shifted to investigate technologies that would
allow the transdermal administration of these materials.
While the lipids within the skin are permeable to small,
lipophilic molecules, most therapeutics are required to be
hydrophilic to permit their distribution throughout the
body via the bloodstream. However, only a handful of
therapeutics exhibits the amphiphilic character that affords
both permeability through the skin and systemic delivery
through the bloodstream. Amphiphilic carriers can be
designed to compatibilize polar drugs with the skin lipids
to enable their transdermal transport, while allowing their
release once they reach the bloodstream.
To probe the efficacy of amphiphilic homopolymers for
improving transdermal drug delivery, a broad range of
polymer sizes and architectures should be explored. The
first step toward this goal is the development of an efficient
synthetic method for preparing bifurcated amphiphiles.
The amphiphilic unit can then be attached either to the
monomer before polymerization or to each repeat unit
after polymerization (Scheme 1).
The traditional oral route for delivering drugs is incom-
patible with many therapeutics due to the harshly acidic
and enzymatically active gastric environment, therefore,
The bifurcated amphiphile 1 was designed so that the
hydrophilic and hydrophobic chains had the same proxi-
mity to the attachment point. A dodecyl unit was selected
as the lipophilic side chain because its length is comparable
to the average length of hydrocarbon chains found among
the lipids in the dermal extracellular matrix. A triethylene
glycol hydrophilic side chain was selected because it
*
Corresponding author. Tel.: +1 504 862 8135; fax: +1 504 865 5596.
E-mail address: sgrayson@tulane.edu (S. M. Grayson).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.132

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K. A. Willham et al. / Tetrahedron Letters 49 (2008) 2091–2094
O
OMe
OMe
pTSA,
HO
HO
O
O
O
O
HO
HO
O
O
O
+
OH
r.t., 5 hr
98%
2
CrO3, aq. H2SO4
acetone
chloroform
77%
O
O
O
O
O
O
OH
4
1
acryloyl chloride
Et3N, THF
70 oC, 48 hr
97%
dodecyl bromide,
NaH, THF
97%
O
O
O
O
O
O
O
O
O
3
5
Scheme 1. Target amphiphiles.
r.t., 12 hr
90%
DIBAL,
hexanes
provides a pH-independent hydrophilic moiety (as opposed
to amines or carboxylic acids) that has an analogous length
to the dodecyl chain. Finally, a third functionality was
included as a means of attachment to the polymer. Because
of the large number of natural and synthetic biocompatible
polymers with alcohol functionalities, such as carbo-
hydrates, poly(vinyl alcohol), poly(hydroxyethyl acrylate),
and poly(hydroxyethyl methacrylate), the third functiona-
lity was converted to carboxylic acid 2 for attachment. This
carboxylic acid can be easily attached to the hydroxyl side
chains via the conversion of 2 to the acid chloride or
through carbodiimide couplings using either N,N0-dicyclo-
hexylcarbodiimide (DCC) or 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide methiodide (EDC). In addition, the
alcohol of 1 can be esterified with acryloyl chloride to yield
the polymerizable amphiphile 3.
O
OH
O
6
O O
70 oC, 72 hr
73%
S
O
O
O
O
7
NaH, THF
O
O
O
O
O
O
8
methanol, r.t., 24 hr
H2, Pd/C
HO
95%
O
O
O
O
O
1
1,1,1-Tris(hydroxymethyl)ethane was selected as the
core for our amphiphile largely because of its low cost
and commercial availability. To carry out selective func-
tionalizations on each of the three hydroxyl groups, a ketal
protecting group was selected to mask two of the alcohols.3
Ketal protecting groups have seen extensive use for the
protection of 1,2- and 1,3-diols for a wide range of applica-
tions including the selective modification of carbo-
hydrates,4 the synthesis of natural products,5 the
production of deep UV photoresists,6 and the preparation
of hydroxylated dendrimers.7 The benzylidene ketal was
chosen specifically because of its unique ability to be par-
tially cleaved, exposing one of the alcohols, and leaving
the other one protected as a benzyl ether.8 This partial
deprotection reaction is quite useful for selective function-
alization of diols, and has demonstrated high regioselectiv-
ity with appropriate substrates.9 For our synthesis, the
benzylidene protecting group enables selective and high
yielding modifications of each of the three hydroxyls of
1,1,1-tris(hydroxymethyl)ethane. The protection, selective
modification, and deprotection of the hydroxyl groups
were carried out over five synthetic steps outlined in
Scheme 2 to produce amphiphile 1 in high yields.
Scheme 2. Preparation of bifurcated amphiphile.
Protection of two alcohols of 1,1,1-tris(hydroxy-
methyl)ethane with the dimethyl acetal of benzaldehyde
was achieved by using p-toluenesulfonic acid as a catalyst.
The substituted 1,3-dioxane product 4 is isolated as a mix-
ture of two isomers in which the phenyl substituent can
either be cis (4a) or trans (4b) to the hydroxymethyl substi-
tutuent (Scheme 3). Both stereoisomers are expected to
exist predominantly in the conformation where the bulky
phenyl ring is in the equatorial position due to 1,3-diaxial
interactions (4a and 4b).
As both isomers were predicted to have similar, but not
identical, kinetic and thermodynamic parameters for
formation, a mixture of products was expected.3 Well
1
resolved differences in their H NMR spectra, particularly
of the acetal hydrogen (5.42 ppm for cis vs 5.39 ppm for
trans) and the methyl hydrogens (0.80 ppm for cis vs
1.31 ppm for trans), enabled the product ratios to be easily
determined using 1H NMR. NMR integration studies con-
firm that the polarity of the reaction solvent significantly

K. A. Willham et al. / Tetrahedron Letters 49 (2008) 2091–2094
2093
the cleavage of the 1,3-dioxane ring is not stereoselective,
the product was obtained as a racemic mixture of R and
S isomers. Without further purification, the unmasked
alcohol of 6 was functionalized with a hydrophilic triethyl-
ene glycol chain via a second Williamson ether coupling.
The mesylate-functionalized triethyleneglycol monomethyl-
ether 7 was prepared10 from the addition of methylsulfonyl
chloride to triethyleneglycol monomethylether and reacted
with the alkoxide of 6 to yield the benzyl protected amphi-
phile 8. The remaining benzyl ether was removed by
palladium catalyzed hydrogenation to afford the desired
amphiphile 1, in nearly quantitative yields. The racemic
product was isolated from the metal catalyst by simple
filtration over Celite.
CH3
OCH3
OCH3
Ph
+
HO
HO
OH
H
p-TsOH
OH
Ph
H
O
O
CH3
O
OH
O
Ph
Ph
(4a)
CH3
H
+
+
CH3
Ph
O
OH
H
O
O
CH3
OH
O
(4b)
H
Several methods of oxidizing the primary alcohol to a
carboxylic acid were attempted. Use of potassium perman-
ganate as the oxidant caused degradation of the starting
material, while use of TEMPO as the oxidant with a phos-
phate buffer11 failed to oxidize the alcohol in sufficient
yields. However, an excess of Jones reagent (2.67 M) in
acetone achieved a clean oxidation of the primary alcohol
to carboxylic acid 2 without significant degradation of
the molecule. This reaction was easily monitored by the
disappearance of the starting material by TLC and the
appearance of the 13C NMR carbonyl signal of the carb-
oxylic acid at 178 ppm. Partial oxidation to the aldehyde
was not observed as long as an excess of Jones reagent
was used. The amphiphilic carboxylic acid 2 could be
isolated by a series of extractions in a 77% yield.
Scheme 3. Diastereomeric products (and conformers) of the acid cata-
lyzed benzylidene protection of two of the three alcohols of 1,1,1-
tris(hydroxymethyl)ethane.
affects the ratio of isomers. When acetone is used as the sol-
vent, the cis isomer is favored 3 to 1 over the trans isomer.
Only negligible changes in product ratio were observed
when the reaction temperatures were varied from ꢀ70 to
56 °C using acetone solvent. However, polar, hydrogen-
bonding solvents, such as acetonitrile, reduced the cis/trans
ratio to 2:1 while less polar solvents, such as chloroform,
increased the ratio to 5:1. It is presumed that the preference
toward the cis isomer in non-polar solvents results from
hydrogen bonding between the hydroxyl group and the
two oxygens of the dioxane ring. The stereochemistry
was confirmed by the isolation of the major isomer (4a)
by column chromatography, followed by X-ray crystallo-
graphic characterization (Fig. 1) and was in agreement with
previously reported studies.3 Because the stereochemistry
was not a critical factor in our studies, the synthesis was
continued with the sample as a mixture of isomers.
Next, the primary alcohol of 4 was converted to the
alkyl ether 5, via a Williamson ether coupling. Sodium
hydride was used to generate the alkoxide, which carried
out a nucleophilic substitution of the bromide of 1-bromo-
dodecane. Higher yields were obtained when the reaction
mixture was heated to 70 °C, but an excess of 1-bromo-
decane was required, presumably a result of the competing
elimination reaction.
The amphiphilic monomer 3 was prepared by the reac-
tion of the primary alcohol 1 with acryloyl chloride.
Triethylamine was added to the tetrahydrofuran solvent
to quench the hydrochloric acid produced as a bi-product
of the esterification reaction. The product was purified by
flash chromatography in a 97% yield and the attachment
of the acrylate group confirmed by the presence of the
1
distinct vinyl resonances in the H NMR.
In summary, we have developed an efficient synthesis for
the preparation of a bifurcated amphiphile. Amphiphile 1
could be obtained in a 60% overall yield from the starting
material with only two chromatographic purifications.
Amphiphilic homopolymers can be prepared readily by
either attachment of this molecule to a monomer before
polymerization (compound 3) or the attachment of an acti-
vated ester (compound 2) after polymerization. The latter
has been demonstrated with polymers bearing alcohols
on each repeat unit, and is expected to be equally effective
for amine bearing polymers. Both pre- and post-polymeri-
zation attachment approaches are being fully investigated
in our labs, and more complicated polymer architectures,
such as cyclic and star polymers will be explored in the near
future.
Reduction of benzylidene protected diol 5, with diiso-
butylaluminumhydride (DIBAL) yielded compound 6,
with one unprotected alcohol and a benzyl ether.9 Because
Acknowledgments
The authors would like to thank Kristi Lebkowsky for
assistance acquiring ESI-MS data and Professor Joel T.
Fig. 1. Crystal structure of the major isomer 4a from the benzylidene
protection reaction.

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K. A. Willham et al. / Tetrahedron Letters 49 (2008) 2091–2094
Kim, T.; Arnt, L.; Atkins, E.; Tew, G. N. Chem. Eur. J. 2006, 12,
2423.
Mague for crystal structure determination. The authors
also would like to acknowledge Tulane University, the
Louisiana Board of Regents Research Competitive-
ness Subprogram, the National Institute of Health
(5R01EB006493-02), and the National Aeronautics and
Space Administration (NNC06AA18A) for support of this
research, as well as the National Science Foundation,
Major Research Instrumentation Program (0619770) for
enabling mass spectral characterization. In addition, the
Board of Regents Graduate Fellowship program is
acknowledged for support (B.A.L.).
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