Design, synthesis, and self-assembly of parallel cyclobolaphile that contains four amide groups as a linkage between polar head groups and hydrocarbon chain: A mimetic of archaeal membrane lipid

Article abstract of DOI:10.1055/s-2003-37126

Chiral 52-membered macrocyclic compound has been synthesized by utilizing intramolecular cyclization under Eglinton conditions [Cu(OAc)₂, pyridine]. Three structural features include: (i) two hydrocarbon chains containing diacetylene, (ii) a li

Full text of DOI:10.1055/s-2003-37126

LETTER
349
Design, Synthesis, and Self-Assembly of Parallel Cyclobolaphile that Contains
Four Amide Groups as a Linkage between Polar Head Groups and Hydro-
carbon Chain: A Mimetic of Archaeal Membrane Lipid
A
Mimetic of Arc
h
a
aeal
M
emb
z
rane Lipiduhiro Miyawaki, Atsuhiro Harada, Toshiyuki Takagi, Motonari Shibakami*
Institute for Materials and Chemical Process, Institute of Advanced Industrial Science and Technology (AIST), Central 5th, 1-1-1 Higashi,
Tsukuba, Ibaraki 305-8565, Japan
Fax +81(298)614547; E-mail: moto.shibakami@aist.go.jp
Received 29 December 2002
OH
Abstract: Chiral 52-membered macrocyclic compound has been
synthesized by utilizing intramolecular cyclization under Eglinton
conditions [Cu(OAc)2, pyridine]. Three structural features include:
(i) two hydrocarbon chains containing diacetylene, (ii) a linkage
that is composed of amide group, and (iii) two polar head groups.
Self-assembly of this compound in a mixture of chloroform–meth-
anol (1:1) produced organogel. Transmission electron micrograph
revealed that UV-irradiated gel is featured by nanosize helicity.
HO
O
O
O
O
Figure 1 Backbone of typical caldarchaeol.
Key words: archaeal lipid, diacetylene, mimetic, amide, helical
ribbon, nanostructure, polymerization, organogel
The design and synthesis of well-defined nanoscale archi-
tecture via self-assembly is of great interest in materials
research.1 Biological cells that exemplify the assembly of
nano- and microstructures of different sizes and functions
provide inspiration for devising fundamentally new ap-
proaches toward nanoarchitecture design. Our own efforts
in this area are based on the structural mimicry of macro-
cyclic membrane lipids found in archaea (Figure 1).2 The
reason that we have chosen to employ the lipids as a mod-
el involves their considerable resistance to extreme envi-
ronment. We have recently synthesized bolaamphiphilic
lipids (parallel and antiparallel cyclobolaphiles)3,4 as a
component of self-assemblies that have potential thermo-
stability.5 Three general features that are common to our
lipids include: (i) two hydrocarbon chains that contain di-
acetylene group, (ii) a linkage that is composed of ether
bond, and (iii) two polar head groups. An intriguing ex-
tension of the nanoarchitectural aspect of our assemblies
can be envisaged, if the ether linkage would be replaced
with amide. An amide group possessing the ability of hy-
drogen bond formation has been implicated as a driving
force for self-assembly in the nanoarchitecture chemistry6
as well as raft formation in biomembranes.7 Thus one
might imagine the combination of rigidity and noncova-
lent bonding that provided by diacetylene and amide
group, respectively, should lead to well-defined nanofab-
rication. With this idea in mind, we have designed a novel
cyclobolaphile that contains these structural elements 1
(Figure 2). In this paper, we report the synthesis of such a
macrocyclic structure by adopting intramolecular cycliza-
Figure 2 Structure of 1.
tion under Eglinton conditions [Cu(OAc)2, pyridine], the
formation of organogel, and the helical structure of poly-
merized gel.
Scheme 1 outlines the synthetic approach to prepare cy-
clobolaphile 1. In brief, protection of L-serine methyl ester
hydrochloride with Boc2O, followed by silylation of the
free hydroxyl group and reduction of methyl ester group
with lithium aluminum hydride (LiAlH4) produced the de-
sired alcohol 2 in 65% overall yields for the three steps.8
Treatment of 2 with methanesulfonyl chloride (MsCl)/tri-
ethylamine, followed by displacement of the resulting me-
sylate with azide ion, afforded azide 3 in 66% overall
yields for the two steps.9 Reduction of 3 with Pd/C, fol-
lowed by condensation of the resulting amine with
HOOC(CH2)8CCH, gave terminal acetylene 4 in 87%
overall yields for the two steps.10 Subsequent subjection
of 4 to a classical Glaser acetylene coupling method af-
forded diacetylene 5 in 91% yield. Removal of the Boc
group using trifluoroacetic acid (TFA),11 followed by con-
densation of the resulting amine with HOOC(CH2)8CCH
gave terminal acetylene 6 in 75% overall yields for the
two steps. A significant task which remained was the con-
struction of macrocyclic structure. Unfortunately, our first
attempt that employed high-dilution Glaser acetylene
coupling5 resulted in failure. In the modified procedure,12
a solution of 6 in pyridine was added to a stirred solution
of Cu(OAc)2 in pyridine over 4 hours at 120 °C, which
successfully led to the formation of 7 in 55% yield.13
Synlett 2003, No. 3, Print: 19 02 2003.
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

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LETTER
Scheme 1 Reagents and conditions: (a) (i) Boc2O, pyridine, Et3N, CH2Cl2, r.t., 2 h; (ii) TBDPSCl, imidazole, DMF, r.t., 11 h; (iii) LiAlH4,
THF, r.t., 20 min, 65% from L-serine methyl ester hydrochloride; (b) (i) MsCl, Et3N, CH2Cl2, 0 °C, 3 h; (ii) NaN3, DMSO, 80 °C, 1 h, 66%
from 2; (c) (i) H2, Pd-C; (ii) 10-undecynoic acid, EDCI, HOBt⋅H2O, Et3N, CH2Cl2, r.t., 3 h, 87% from 3; (d) TMEDA, CuCl, O2, acetone, 60 °C,
11 h, 91%; (e) (i) TFA, CH2Cl2; (ii) 10-undecynoic acid, EDCI, HOBt⋅H2O, Et3N, CH2Cl2, r.t., 15 h, 75% from 5; (f) Cu(OAc)2, pyridine,
120 °C, 55%; (g) TBAF, CHCl3, r.t., 6 d, 64%. MsCl = methanesulfonyl chloride, TBDPSCl = tert-butylchlorodiphenylsilane, HOBt = 1-hy-
droxybenzotriazole, TMEDA = tetramethylethylenediamine, TFA = trifluoroacetic acid, TBAF = tetrabutylammonium fluoride, Boc2O = di-
tert-butyl dicarbonate, EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
Finally, desilylation of 7 with tetrabutylammonium fluor-
ide (TBAF) gave diol 1 in 64% yield.13,14
In order to construct molecular assembly, we adopted ge-
lation process.6a In brief, 1 (3.7 mg) was placed in a test
tube, and dissolved in a 1:1 mixture of chloroform–meth-
anol (0.3 mL) at 50–60 °C. The resulting transparent solu-
tion was then cooled to 25 °C, and white gel was formed.
Once the gel is formed, it is stable and the test tube can be
inverted without changing the shape of the gel. The gel
was thermoreversible, i.e., it turned into clear, low-viscos-
ity solution upon heating (50–60 °C) and gelation re-
turned after cooling (25 °C). In view of the rigid
framework and four amide groups that act simultaneously
as hydrogen bond donor and acceptor, the diacetylene
groups were expected to be aligned in a highly ordered
state. With this assumption in mind, we exposed the orga-
nogel to short-wave UV (254 nm) at 25 °C, and observed
the immediate colorless-to-purple transition in the gel.
UV/Vis absorption spectra of the gel before and after UV
irradiation are shown in Figure 3. The absorbance approx-
Figure 3 UV/Vis absorption spectra of the gel that was made from
1 (UV irradiation at 254 nm for 3 min at 25 °C). The solvent was a
imately at 579 nm indicated that photo-polymerization
took place.6b These polymerization points to the existence mixture of chloroform /methanol (1/1, v/v). The concentration of 1
was 12.0 mM (before irradiation). Cell width was 2.0 mm. All spectra
were recorded at 25 °C.
of perfectly packed ordered structure of 1 capable of re-
acting topochemically.15
The TEM micrograph of the polymerized gel showed the
formation of helical ribbons (Figure 4, a). Interestingly,
only left-handed ribbons (width of 27 nm, pitch of 186
In conclusion, we have developed an efficient approach to
the synthesis of chiral parallel cyclobolaphile 1 that has
both, two diacetylene and four amide groups. We also
have demonstrated that the UV-irradiated gel formed
nm) are observed. Currently, we consider that this helicity
stems from chirality of 1.6e The TEM image also shows
that the ribbons join at ‘junction zones’ to form networks
three-dimensional network structures composing of heli-
(Figure 4, b).6f Such three-dimensional networks may ex-
cal ribbons. Efforts aimed at exploiting the stereoisomers
plain the physical gelation of 1.6g
of 1 with a view toward synthesis and self-assembly are
now under intense investigation in our laboratory.
Synlett 2003, No. 3, 349–352 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Mimetic of Archaeal Membrane Lipid
351
Figure 4 Transmission electron micrographs of the polymerized gel that was prepared by UV-irradiation (10 min) of the organogel.
(5) (a) Miyawaki, K.; Takagi, T.; Shibakami, M. Synlett 2002,
1326. (b) Miyawaki, K.; Goto, R.; Takagi, T.; Shibakami,
M. Synlett 2002, 1467.
Acknowledgment
We are grateful to Y. Sato (JEOL) for providing technical assistance
with the electron microscopy. This research was supported by In-
dustrial Technology Research Grant Program in 2001 from New
Energy and Industrial Technology Development Organization
(NEDO) of Japan.
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mmol) and pyridine (56 mL) was stirred at 120 °C. To the
reaction was then added a solution of 6 (100 mg, 0.076
mmol) in pyridine (5 mL) over 4 h at 120 °C. After cooling
to r.t., pyridine was removed under reduced pressure. The
resulting solution was allowed to stand at 120 °C for 11 h
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acid (50 mL), and then extracted with CHCl3 (300 mL × 2).
The organic phase was washed with brine, dried (Na2SO4),
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CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.63–7.60 (m, 8
H), 7.45–7.41 (m, 12 H), 6.27 (d, J = 7.6 Hz, 2 H), 5.93 (t,
J = 5.5 Hz, 2 H), 4.10–4.00 (m, 2 H), 3.79 (dd, J = 10.3, 3.7
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(3) (a) Amphiphilic molecules containing a polar head group at
the end of a hydrophobic segment have been termed;
‘bolaamphiphiles’ or ‘bolaphile’. While amphiphiles having
a macrocyclic ring as a hydrophobic segment have been
termed ‘macrocyclic bolaamphiphiles’ (see ref.2f), we prefer
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antiparallel arrangement of glycerol units, respectively, we
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LETTER
H]+. Because compounds 7 and 1 were easy to be poly-
merized by light, their elemental analyses could not be
obtained as seen in analogous diacetylene compounds.
(b) Wang, G.; Hollingsworth, R. I. Langmuir 1999, 15, 3062.
(14) Our synthetic scheme should provide optically pure
compound 1. Our reason for this is 2-fold. First, the first
step8a that can lead to racemization retained the
Hz, 2 H), 3.62–3.53 (m, 4 H), 3.33–3.29 (m, 2 H), 2.22 (t,
J = 6.9 Hz, 8 H), 2.12–2.20 (m, 8 H), 1.60–1.43 (m, 16 H),
1.38–1.30 (m, 8 H), 1.29–1.20 (m, 24 H), 1.06 (s, 18 H) ppm.
13C NMR: δ = 174.53, 173.98, 135.54, 133.07, 132.74,
130.01, 127.92, 127.89, 77.43, 65.35, 63.59, 51.45, 41.94,
36.76, 36.60, 29.22, 29.18, 28.91, 28.76, 28.29, 26.90,
25.64, 25.59, 19.26, 19.17 ppm. LRMS (FAB): m/z = 1310
[M + H]+, 1252 [M – (CH3)3C]+. Compound 1: Stage
colorless solid. 1H NMR [500 MHz, CDCl3/CD3OD (1:1,
v/v)]: δ = 7.37 (t, J = 5.9 Hz, 2 H), 7.10 (t, J = 7.9 Hz, 2 H),
3.73–3.65 (m, 2 H), 3.38 (dd, J = 11.6, 4.0 Hz, 2 H), 3.25
(dd, J = 11.6, 5.5 Hz, 2 H), 3.21–3.13 (m, 2 H), 3.12–3.04
(m, 2 H), 2.03 (t, J = 7.0 Hz, 8 H), 1.97 (t, J = 7.0 Hz, 8 H),
1.42–1.34 (m, 8 H), 1.33–1.26 (m, 8 H), 1.21–1.13 (m, 8 H),
1.12–1.05 (brs, 24 H) ppm. LRMS (FAB): m/z = 834 [M +
stereochemical configuration of L-serine methyl ester
hydrochloride {2: [α]D21 +4.99 (c 3.55, CHCl3), Lit.8a [α]D
+4.7 (c 1.2, CHCl3)}. Second, intermediates (2–7) and the
desired product (1) do not include carbonyl group that can
cause epimerization at the chiral center.
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Synlett 2003, No. 3, 349–352 ISSN 0936-5214 © Thieme Stuttgart · New York