Convergent synthesis of antiparallel cyclobolaphiles having two diacetylenes: Mimetics of membrane components that are found in archaea

Article abstract of DOI:10.1055/s-2002-33504

Chiral 48-membered antiparallel cyclobolaphiles and their diastereomer having two diacetylenes were convergently synthesized utilizing both cross-coupling method (Cul, pyrrolidine) and Glaser intramolecular cyclization, starting from commercially available D- and L-1, 2-O-isopropylidene-sn-glycerol as chiral sources.

Full text of DOI:10.1055/s-2002-33504

LETTER
1467
Convergent Synthesis of Antiparallel Cyclobolaphiles Having Two Diacetyl-
enes: Mimetics of Membrane Components That are Found in Archaea
Convergent
S
ynthe
a
sis of Anti
z
parallel Cyc
u
lobolaphiles
h
H
aving Tw
o
i
D
iace
r
tylenes o Miyawaki, Rie Goto, 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 5 July 2002
Such naturally-occurring membrane system stimulates us
Abstract: Chiral 48-membered antiparallel cyclobolaphiles and
to explore the feasibility of adopting a 1:1 mixture of the
parallel-antiparallel caldarchaeol analogues as an ideal
their diastereomer having two diacetylenes were convergently syn-
thesized utilizing both cross-coupling method (CuI, pyrrolidine)
and Glaser intramolecular cyclization, starting from commercially
composition when we turn our attention to the preparation
available D- and L-1,2-O-isopropylidene-sn-glycerol as chiral of thermostable self-assembled lipid nanostructures.3 At
sources.
present, to our knowledge, there is only one report on the
synthesis of totally artificial antiparallel analogue that
contains saturated long alkyl chains,4 although several
synthetic schemes of parallel caldarchaeol analogues have
previously been established.5 Moreover, possible factors
contributing to the stability in the bacterial membrane in-
clude stereospecific interactions between caldarchaeols
due to inherent chirality at syn-2 position of their glycerol
moieties. Thus, understanding how stereochemistry has
an effect on molecular packing has theoretical implica-
tions.6 With these backgrounds in mind, we have started a
program for synthesizing three stereoisomers of antiparal-
lel caldarchaeol analogues (2R,27R)-1, (2S,27S)-1 and
(2R,27S)-1 that contain two diacetylene units within a
long alkyl chain and phosphatidylcholine as a polar head
group (Figure 2). We term such analogues antiparallel cy-
clobolaphiles.7 Our construction of the thermostable cy-
clobolaphiles partyl hinges on the use of diacetylene units
besides macrocyclic structure.8 The expected effects of di-
acetylenes were 2-fold: (i) the stiffing effect of diacetyl-
enes on alkyl chains is expected to reduce the mobility of
the macrocycles to raise gel-to-liquid phase transition
temperature compared to lipids having no diacetylenes,
and (ii) diacetylene units have a potential of polymeriza-
tion on UV-irradiation to form polymerized membranes.
Key words: caldarchaeol, diacetylene, antiparallel cyclobolaphile,
convergent synthesis, mimetics
The recent finding that several thermostable archaeal
membranes contain parallel and antiparallel caldarchaeol1
with a molar ratio of ca 1:1 is of considerable interest
(Figure 1).2
HO
O C40H80
O C40H80
OH
O
O
O C40H80
O C40H80
O
O
OH
HO
parallel caldarchaeol
antiparallel caldarchaeol
C40H80=
3
3
Figure 1 Backbones of typical parallel and antiparallel caldar-
chaeol
PCO
PCO
(CH2)8O
(CH2)8O
PCO
(CH2)8O
(CH2)8O
O(CH2)8
O(CH2)8
OPC
X
X
(CH2)8O
(CH2)8O
O(CH2)8
O(CH2)8
OPC
X
X
O(CH2)8
O(CH2)8
OPC
X
X
27
2
(2R, 27R)-1
(2S, 27S)-1
(2R, 27S)-1
O
+
X =
PC =
P O(CH2)2NMe3
-
O
Figure 2 Structures of antiparallel cyclobolaphiles (2R,27R)-1, (2S,27S)-1, and (2R,27S)-1
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1467,1470,ftx,en;U01802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1468
K. Miyawaki et al.
LETTER
OTr
OH
OTr
OH
c
a, b
e, b
d
O(CH2)8
H
O(CH2)8
H
O
OPMB
3
OPMB
OPMB
2
4
O
OH
OTr
OH
OTr
OH
f
D-1,2-O-isopropylidene
-sn-glycerol
O(CH2)8
O(CH2)8
H
I
5
6
OTr
OH
OTr
OH
c
a, b
e, b
d
O(CH2)8
OPMB
8
H
O(CH2)8
OPMB
9
H
O
OPMB
7
O
OH
OTr
OH
OTr
f
L
-1,2-O-isopropylidene
OH
-sn-glycerol
O(CH2)8
10
O(CH2)8
11
H
I
Scheme 1 Reagents and conditions: (a) (i) KOH, PMBCl, DMSO, r.t., 24 h; (ii) p-TsOH, MeOH, r.t., 36 h, 78–80%; (b) TrCl, DMAP, py-
ridine, 80 °C, 13 h, 80–89%; (c) MsO(CH2)8CCH, NaH, TBAI, DMF, r.t., 19 h, 92–99%; (d) p-TsOH, CHCl3/MeOH (2:1, v/v), r.t., 4 h, 89–
90%; (e) (i) MsO(CH2)8CCH, KOH, DMSO, r.t., 20 h; (ii) p-TsOH, MeOH, r.t., 17 h, 92%; (f) NIS, AgNO3, acetone, 0 °C, 4 h, 89–99%.
PMBCl = p-methoxybenzyl chloride, p-TsOH = p-toluenesulfonic acid, DMAP = 4-(dimethylamino)pyridine, TBAI = tetrabutylammonium
iodide, NIS = N-iodosuccinimide, TrCl = trityl chloride
25
Here we report the accomplishment of the synthesis of the 0.61, CHCl3), 17, [ ]D +7.8 (c 0.85, CHCl3), and 20,
diacetylene-containing antiparallel cyclobolaphiles by [ ]D28 0.0 (c 0.50, CHCl3), in 50%, 69% and 55% overall
firstly adopting cross-coupling method of alkynes with 1- yields for two steps, respectively. Finally, Phosphoryla-
iodoalkynes for the construction of macrocyclic struc- tion, followed by replacement of bromine with trimethy-
ture.9
lamine yielded the desired products (2R,27R)-1, (2S,27S)-
1, and (2R,27S)-1 in 67%, 60% and 59% yields for two
steps, respectively.16,17 The structures of the cyclobo-
Chiral building blocks 4, 6, 9 and 11 were synthesized
via the reaction sequence shown in Scheme 1. In brief,
detritylation (p-TsOH) of terminal acetylene 3 that was
prepared according to the method described in the litera-
1
laphiles were confirmed on the basis of H, 13C and 31P
NMR spectra, mass spectra and elemental analyses.18
ture,10–12 afforded the desired alcohol 4 in 90% yield. To examine thermal stability of the cyclobolaphiles, the
Next, iodination (N-iodosuccinimide, AgNO3) of 5, pre- thermotropic phase behavior of (2S,27S)-1 was examined
pared by use of procedures described in the literature,4 by high-sensitive differential scanning calorimetry (hs-
provided the desired iodide 6 in 89% yield. Finally, the DSC) (data not shown).19 This compound exhibited a
synthesis of 9 and 11 followed the same strategy that was substantially broadened endotherm at 65 °C with a peak
employed for the preparation of 4 and 6, respectively.
width of ca. 30 °C (four scans). Such breadth of the endo-
therm is an intrinsic property of cyclobolaphiles, i.e., sym-
metric cyclobolaphile does not allow the lipid to pack
tightly in the curved vesicle membrane, resulting in the
lack of cooperative melting process.20 Thus, comparison
of Tm value for (2S,27S)-1 with ‘untethered’ 1,2-dialkyl-
phosphatidylcholine suggests that both cyclic structure
and two diacetylene units contribute to the raise of ther-
mostability.21
(2R,27R)-1, (2S,27S)-1 and (2R,27S)-1 were synthesized
as shown in Scheme 2. Terminal acetylene 4 was coupled
with iodide 11 by Alami procedure employing CuI-pyr-
26
rolidine,13 to furnish diacetylene 12, [ ]D +6.7 (c 0.45,
CHCl3), in 79% yield. By use of the same procedure for
the preparation of 12, coupling of 9 and 4 with 6 provided
26
diacetylenes 15, [ ]D –6.7 (c 0.48, CHCl3), and 18,
[ ]D26 +2.5 (c 0.57, CHCl3), in 64 and 73% yields, respec-
tively. Subsequent alkylation of 12, 15 and 18 with In conclusion, we have developed a convergent synthetic
MsO(CH2)8CCH, followed by intramolecular cyclization route for cyclobolaphiles (2R,27R)-1, (2S,27S)-1 and
by applying high dilution Glaser protocol,4,14 afforded (2R,27S)-1. This strategy also could be wide applicable to
23
macrocyclic compounds 13, [ ]D +6.1 (c 3.0, CHCl3), the stereoselective construction of antiparallel cyclobo-
16, [ ]D26 –6.9 (c 2.0, CHCl3), and 19, [ ]D28 –4.1 (c 1.7, laphiles containing the same functional group at each end
CHCl3), in 26%, 27% and 27% overall yields for the two of a macrocyclic segment. Work is currently in progress
steps, respectively. Detritylation (p-TsOH), followed by to develop their thermostable self-assembled lipid nano-
25
debenzylation (DDQ)15 afforded diols 14, [ ]D –9.0 (c structures and will be reported elsewhere.
Synlett 2002, No. 9, 1467–1470 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Convergent Synthesis of Antiparallel Cyclobolaphiles Having Two Diacetylenes
1469
R2O
TrO
27
O(CH2)8
O(CH2)8
OR1
X
X
(CH2)8O
(CH2)8O
OH
HO
b, c
a
2
O(CH2)8
OPMB
X
(CH2)8O
4 + 11
12
13: R1 = PMB, R2 = Tr
d
e
14: R1 = R2 = H
(2R, 27R)-1: R1 = R2 = PC
R2O
TrO
HO
O(CH2)8
O(CH2)8
OR1
X
X
(CH2)8O
(CH2)8O
OH
b, c
a
6 + 9
O(CH2)8
OPMB
X
(CH2)8O
15
16: R1 = PMB, R2 = Tr
17: R1 = R2 = H
d
e
(2S, 27S)-1: R1 = R2 = PC
R2O
TrO
HO
O(CH2)8
O(CH2)8
OR1
X
X
(CH2)8O
(CH2)8O
OH
a
b, c
4 + 6
O(CH2)8
OPMB
X
(CH2)8O
19: R1 = PMB, R2 = Tr
18
d
e
20: R1 = R2 = H
(2R, 27S)-1: R1 = R2 = PC
Scheme 2 Reagents and conditions: (a) CuI, pyrrolidine, –20 °C, 10 min, 64–79%; (b) MsO(CH2)8CCH, NaH, DMSO, r.t., 14 h, 57–64%;
(c) CuCl, TMEDA, O2, p-xylene, 130 °C, 42–45%; (d) (i) p-TsOH, CHCl3/MeOH (2:1, v/v), r.t., 4 h; (ii) DDQ, CH2Cl2/phosphate buffer solu-
tion (pH 7.2) (18:1, v/v), 0 °C, 1.5 h, 50–69%; (e) (i) 2-bromoethyl dichlorophosphate, benzene, Et3N, r.t., 12 h, and then H2O, r.t., 9 h; (ii)
Me3N (aq), CHCl3/i-PrOH/MeCN (3:5:5, v/v/v), 60 °C, 15 h, 59–67%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
TMEDA = N,N,N ,N -tetramethylethylenediamine
considerably thermostable nanostructure that is robuster
Acknowledgement
than the natural one. Our ultimate goal is to find such
optimal combinations. Note that the applicability of
Kakinuma’s strategy to the construction of all stereoisomers
and diacetylene-containing derivatives (see in text) remains
unclear, although they did not refer to such possibility (see
ref. 4a and 5a). As a first step toward this goal, therefore,
alternative strategy that is applicable to the synthesis of all
stereoisomers is required.
We are grateful to S. Shibasaki and M. Usui (the Technical Center,
AIST) for valuable technical assistance. We are also greatful to Dr.
Shinya Honda (AIST) for valuable discussions. This research was
supported by Industrial Technology Research Grant Program in
2001 from New Energy and Industrial Technology Development
Organization (NEDO) of Japan.
(7) Amphiphilic molecules that contain a polar head group at the
end of a hydrophobic segment have been termed;
‘bolaamphiphiles’ (Fuhrhop, J.-H.; Mathiewu, J. Angew.
Chem., Int. Ed. Engl. 1984, 23, 100) or ‘bolaphile’
(Jayasuriya, N.; Bosak, S.; Regen, S. L. J. Am. Chem. Soc.
1990, 112, 5844). While amphiphiles having a macrocyclic
ring as a hydrophobic segment have been termed ‘macro-
cyclic bolaamphiphiles’ (see Ref. 5b), we prefer to adopt the
abbreviated and more readily pronounceable term,
‘cyclobolaphile’.
(8) Ladika, M.; Fisk, T. E.; Wu, W. W.; Jons, S. D. J. Am. Chem.
Soc. 1994, 116, 12093.
(9) Intense examination of macrocyclic synthetic methods that
have been previously reported indicate that only our strategy
has the potential to provide antiparallel cyclobolaphiles that
contain diacetylene units (see ref. 5).
References
(1) (a) We term caldarchaeol with a parallel arrangement of
glycerol units ‘parallel caldarchaeol’, and that with an
antiparallel arrangement ‘antiparallel caldarchaeol’.
(b) Nishihara, M.; Morii, H.; Koga, Y. J. Biochem. 1987,
101, 1007.
(2) Gräther, O.; Arigoni, D. J. Chem. Soc., Chem. Commun.
1995, 405.
(3) Arakawa, K.; Eguchi, T.; Kakinuma, K. Chem. Lett. 2001,
440.
(4) Eguchi, T.; Kano, H.; Kakinuma, K. J. Chem. Soc., Chem.
Commun. 1996, 365.
(5) (a) Eguchi, T.; Ibaragi, K.; Kakinuma, K. J. Org. Chem.
1998, 63, 2689. (b) Menger, F. M.; Chen, X. Y. Tetrahedron
Lett. 1996, 37, 323. (c) Patwarahan, A. P.; Thompson, D. H.
Org. Lett. 1999, 1, 241. (d) Wang, G.; Hollingsworth, R. I.
Langmuir 1999, 15, 3062.
(6) Our working hypothesis has been that each stereochemical
combination of parallel-antiparallel caldarchaeol analogues
provides a nanostructure with various degrees of thermo-
stability, and that some optimal combinations give a
(10) Qin, D.; Byun, H.; Bittman, R. J. Am. Chem. Soc. 1999, 121,
662.
(11) Hirth, G.; Barner, R. Helv. Chim. Acta 1982, 65, 1059.
(12) Carvalho, J. F.; Prestwich, G. D. J. Org. Chem. 1984, 49,
1251.
(13) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
Synlett 2002, No. 9, 1467–1470 ISSN 0936-5214 © Thieme Stuttgart · New York

1470
K. Miyawaki et al.
LETTER
(14) A solution of the precursor of 13 (0.10 g, 0.10 mmol) in
acetone (5 mL) was added to a stirred solution of CuCl (0.20
g, 2.1 mmol) and TMEDA (310 L, 2.1 mmol) in p-xylene
(36 mL) under oxygen over 7 h at 130 °C.
(15) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
[(M – (Me)3N)+]. Anal. Calcd for C56H100N2O12P2 2 H2O: C,
61.63; H, 9.60; N, 2.57%. Found: C, 61.62; H, 9.50; N,
2.42%. (2S,27S)-1: [ ]D27 –4.9 (c 0.49, MeOH). (2R,27S)-1:
[ ]D28 0.0 (c 0.70, MeOH). The spectral data of (2R,27S)-1
and (2S,27S)-1 were identical with those of (2R,27R)-1
except the optical rotations.
(16) Hansen, W. J.; Murari, R.; Wedmid, Y.; Baumann, W. J.
Lipids 1982, 17, 453.
(17) (2R, 27R)-1, (2S, 27S)-1, and (2R, 27S)-1 were successfully
purified by flash chromatography (SiO2, CHCl3/MeOH/
H2O, 65:25:4, v/v/v).
(19) Multilamellar suspension for hs-DSC measurement was
prepared as follows. First, 1 mL of methanol solution of (2S,
27S)-1 (4.7 mM) was transferred to a test tube. The methanol
was then evaporated under a stream of nitrogen, thereby
leaving the lipid as a thin film on the walls of the test tube.
The remaining solvent was removed by subjecting the lipid
film to high vacuum for at least 2 h. 3 mL of milli-Q water
was added and the mixture was sonicated for 1 h at 97±2 °C.
Calorimetric measurement was performed with a MC-2
differential scanning calorimeter purchased from Microcal,
Inc.
(18) All new compounds gave satisfactory analytical and spectral
data. Selected physical data are as follows: 14: Stage pale
25
yellow oil, Rf = 0.13 [hexane/ethyl acetate (2:1, v/v)], [ ]D
–9.0 (c 0.61, CHCl3). 1H NMR (500 MHz, CDCl3): = 3.70–
3.38 (m, 18 H), 2.23 (t, J = 6.9 Hz, 8 H), 2.17 (brs, 2 H),
1.60–1.43 (m, 16 H), 1.36–1.23 (m, 32 H) ppm. 13C NMR
(100 MHz, CDCl3): = 78.42, 72.40, 71.65, 71.11, 70.33,
65.32, 63.00, 29.97, 29.50, 29.30, 29.15, 28.98, 28.63,
28.22, 25.97, 19.16 ppm. LRMS (FAB): m/z = 725 [(M +
H)+]. Anal. Calcd for C46H76O6: C, 76.20; H, 10.56%.
Found: C, 75.91; H, 10.41%. 17: [ ]D25 +7.8 (c 0.85, CHCl3).
20: [ ]D28 0.0 (c 0.50, CHCl3). The spectral data of 17 and 20
were identical with those of 14 except the optical rotations.
(2R, 27R)-1: Stage pale yellow solid, Rf = 0.10 [CHCl3/
MeOH/H2O (65:25:4, v/v/v)], [ ]D25 +4.2 (c 0.70, MeOH).
1H NMR [500 MHz, CDCl3/CD3OD (97:3, v/v)]: = 4.21
(brs, 4 H), 3.83 (brs, 4 H), 3.60 (brs, 4 H), 3.56–3.51 (m, 8
H), 3.43–3.33 (m, 6 H), 3.19 (s, 18 H), 2.19 (t, J = 6.7 Hz, 8
(20) Fuhrhop, J.-H.; Liman, U.; Koesling, V. J. Am. Chem. Soc.
1998, 110, 6840.
(21) Menger, F. M.; Chen, X. F.; Brocchini, S.; Hopkins, H. P.;
Hamilton, D. J. Am. Chem. Soc. 1993, 115, 6600. The
‘untethered’ lipids are also archaeal membrane lipid
analogues, and include linear saturated long alkyl chains that
are connected to the glycerol backbone by means of ether
linkage. If one may take into account the “dimer-like
structure” of the cyclobolaphiles, it seems reasonable to
assume that (2S,27S)-1 is comparable to the “untethered”
lipid with chains of 10 carbons. Menger et al. have reported
the Tm values for the ‘untethered’ lipids with chains of only
14–20 carbons, ranging from 26.9 to 66.5 °C in this report.
Thus, we currently consider that the introduction of cyclic
structure and diacetylene units leads to higher
H), 1.47–1.42 (m, 16 H), 1.33–1.15 (m, 32 H) ppm. 13
C
NMR (125 MHz, CD3OD): = 79.50, 77.98, 72.50, 72.03,
71.43, 67.47, 66.60, 66.23, 60.38, 54.71, 31.13, 30.79,
30.62, 30.41, 30.26, 29.96, 29.86, 29.59, 29.52, 27.29, 19.82
ppm. 31P NMR [200 MHz, CDCl3/CD3OD (99:1, v/v)]:
= –0.69 (s)ppm. LRMS (FAB): m/z = 1054 [M+], 995
thermostability, although exact comparison between the
cyclobolaphile and 10-carbon “untethered” lipid remains to
be made.
Synlett 2002, No. 9, 1467–1470 ISSN 0936-5214 © Thieme Stuttgart · New York