Efficient synthesis of parallel cyclobolaphiles having two diacetylenes: Mimetics of archaeal membrane lipids

Article abstract of DOI:10.1055/s-2002-32987

Chiral 48-membered parallel cyclobolaphiles and their diastereomer having two diacetylenes were efficiently synthesized by utilizing both the selective deprotection and the cross-coupling method of two distinct acetylenic compounds.

Full text of DOI:10.1055/s-2002-32987

1326
LETTER
Efficient Synthesis of Parallel Cyclobolaphiles Having Two Diacetylenes:
Mimetics of Archaeal Membrane Lipids
M
imetic
s
of Archa
a
eal
M
embr
z
ane Lipids uhiro Miyawaki, 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)614698; E-mail: moto.shibakami@aist.go.jp
Received 22 May 2002
tive deprotection and the acetylenic cross-coupling
Abstract: Chiral 48-membered parallel cyclobolaphiles and their
method for the construction of macrocyclic structure.6
diastereomer having two diacetylenes were efficiently synthesized
by utilizing both the selective deprotection and the cross-coupling
method of two distinct acetylenic compounds.
Scheme 1 outlines the synthetic approach to prepare
(2R,27R)-1 and (2S,27S)-1. In brief, alcohol (–)-2 was ob-
Key words: archaeal lipid, diacetylene, chirality, parallel cyclo- tained from D-1,2-O-isopropylidene-sn-glycerol accord-
ing to the method described in the literature.7 Alkylation
bolaphile, mimetics
of the resultant alcohol (–)-2 with MsO(CH2)8CCH8 gave
terminal acetylene (–)-3 in quantitative yield.9 Subsequent
subjection of (–)-3 to a classical Glaser acetylene coupling
method afforded diacetylene 4 in 93% yield. The synthet-
ic strategy that we have used for the stereoselective con-
struction of the cyclobolaphiles features selective removal
of the protective groups of 4 without reduction of diacet-
ylene unit. Removal of the trityl groups was accomplished
using p-toluenesulfonic acid (p-TsOH) to give diol 5 in
86% yield, while selective deprotection of the p-methox-
ybenzyl (PMB) groups with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) afforded the desired alcohol 6
Unusual resistance to harsh environmental conditions dis-
played by the archaea has received much attention in the
synthesis and properties of macrocyclic and bola-
amphiphilic membrane lipids similar to those found in the
bacterial membranes.1 Many groups have focused on
physicochemical properties of their membrane, such as
fluidity, permeability and stability.2 While interest in their
lipids within our group has centered on a new challenge
aiming at making self-assembled nanostructures that are
composed of the lipids, since the nanostructures, especial-
ly tubules, would have much promise as advanced materi-
als.3 Based on the report that both chirality and
diacetylene are essential to tubule formation,3a we
hypothesized that the formation of tubules might be ac-
complished via incorporation of two diacetylenes into a
chiral archaeal lipid analogue and subsequent self-assem-
bly process. With the hypothesis in mind, we have de-
signed novel cyclobolaphiles4 having two diacetylenes
[(2R,27R)-1, (2S,27S)-1 and (2R,27S)-1], mimics of
parallel caldarchaeol5 (Figure). Here, we report the ac-
complishment of the stereoselective construction of such
parallel cyclobolaphiles by firstly adopting both the selec-
in 88% yield.10 Alkylation of
5
and
6
with
MsO(CH2)8CCH gave alkylated products, which were the
precursors for intramolecular cyclization, in 93 and 58%
yields, respectively. A significant task which remained
was the construction of macrocyclic structure. Our first
attempt employed high-dilution Glaser acetylene coup-
ling (1 mM solution in acetone, 60 °C), resulting in
failure. In the modified procedure, a solution of the pre-
cursor in acetone was added to a stirred solution of CuCl–
TMEDA complex in p-xylene over 7 hours at 130 °C. The
procedure successfully led to the formation of 7 and 9 in
43 and 46% yields, respectively. Thus a critical point in
the present synthesis has been passed. Debenzylation of 7
O(CH2)8
O(CH2)8
OPC
X
X
(CH2)8O
(CH2)8O
PCO
O(CH2)8
O(CH2)8
OPC
X
X
(CH2)8O
(CH2)8O
PCO
O(CH2)8
O(CH2)8
OPC
X
X
(CH2)8O
(CH2)8O
PCO
27
2
(2R, 27R)-1
(2S, 27S)-1
(2R, 27S)-1
O
P
+
X =
PC =
O(CH2)2NMe3
-
O
Figure Structures of parallel cyclobolaphiles (2R,27R)-1, (2S,27S)-1, and (2R,27S)-1.
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1326,1328,ftx,en;Y07402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Mimetics of Archaeal Membrane Lipids
1327
28
with DDQ gave diol 8, [ ]D –9.80 (c 0.60, CHCl3), in Diastereomer (2R,27S)-1 was synthesized as shown in
64% yield, and detritylation of 9 with p-TsOH gave diol Scheme 2. Iodide 11 was obtained, in 91% yield, by iodi-
10, [ ]D28 +9.67 (c 0.30, CHCl3), in 77% yield. As expect- nation of (+)-3 that was prepared from L-1,2-O-isopropyl-
ed, the spectral data of 8 were identical with those of 10, idene-sn-glycerol according to the same synthetic method
and their specific rotation values were very close in abso- as (–)-3, while terminal acetylene 12 was obtained by de-
lute values but with opposite sign.11 Finally, phosphoryla- tritylation of (–)-3 in 90% yield. Cross-coupling of 12
tion of 8 and 10, followed by exchange of the bromine with 11, followed by detritylation, gave diol 13 in 69%
with trimethylamine, afforded (2R,27R)-1 and (2S,27S)-1 overall yield for the two steps.13 The resultant diol 13 was
in 62 and 76% yields, respectively.12 The structures of converted to (2R,27S)-1 in four steps according to the
(2R,27R)-1 and (2S,27S)-1 were confirmed on the basis of same synthetic method as (2R,27R)-1. The structure of
1H, 13C and 31P NMR spectra, mass spectra and elemental (2R,27S)-1 was confirmed on the basis of 1H, 13C and 31P
analyses.11
NMR spectra, mass spectra and elemental analyses by
comparing with the spectral data of (2R,27R)-1.11
O
OTr
TrO
(CH2)8O
PMBO
OTr
OTr
c
a, b
d
O
O(CH2)8
OPMB
X
OH
O(CH2)8
OPMB
(-)-3
H
OH
OPMB
(-)-2
D-1,2-O-isopropylidene
-sn-glycerol
4
OH
HO
(CH2)8O
PMBO
O(CH2)8 X (CH2)8O
g, h
e
27
2
O(CH2)8
OPMB
X
O(CH2)8
OR
X
(CH2)8O
RO
5
7: R = PMB
8: R = H
f
4
j
(2R,27R)-1: R = PC
OTr
TrO
(CH2)8O
HO
O(CH2)8 X (CH2)8O
i, h
f
O(CH2)8
OH
X
O(CH2)8
OR
X
(CH2)8O
RO
6
9: R = Tr
e
j
10: R = H
(2S,27S)-1: R = PC
Scheme 1 Reagents and conditions: (a) (i) KOH, PMBCl, DMSO, r.t., 24 h; (ii) p-TsOH, MeOH, r.t., 36 h, 80%; (b) TrCl, DMAP, pyridine,
80 °C, 13 h, 80%; (c) MsO(CH2)8CCH, NaH, TBAI, DMF, r.t., 19 h, 99%; (d) CuCl, O2, acetone, TMEDA, 60 °C, 15 h, 93%; (e) p-TsOH,
CHCl3/MeOH (2:1, v/v), r.t., 4 h, 77–86%; (f) DDQ, CH2Cl2/phosphate buffer solution (pH 7.2) (18:1, v/v), 0 °C, 1.5 h, 64–88%; (g)
MsO(CH2)8CCH, NaH, DMSO, r.t., 14 h, 93%; (h) CuCl, TMEDA, O2, p-xylene, 130 °C, 43–46%; (i) MsO(CH2)8CCH, NaH, DMSO, 60 °C,
6 h, 58%; (j) (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, 62–76%. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TMEDA = tetramethylethylenediamine, PMBCl = p-me-
thoxybenzyl chloride, p-TsOH = p-toluenesulfonic acid, DMAP = 4-(dimethylamino)pyridine, TBAI = tetrabutylammonium iodide,
TrCl = trityl chloride.
O
OTr
OTr
OTr
c
a, b
d
O
O(CH2)8
OPMB
I
OH
O(CH2)8
OPMB
(+)-3
H
OH
OPMB
(+)-2
L-1,2-O-isopropylidene
-sn-glycerol
11
OH
e
OH
HO
O(CH2)8 X (CH2)8O
g, h
f, e
(-)-3
O(CH2)8
OPMB
12
H
O(CH2)8
OPMB
X
(CH2)8O
PMBO
O(CH2)8
OR
X
(CH2)8O
RO
13
14: R = PMB
15: R = H
i
j
(2R,27S)-1: R = PC
Scheme 2 Reagents and conditions: (a) (i) KOH, PMBCl, DMSO, r.t., 24 h; (ii) p-TsOH, MeOH, r.t., 36 h, 78%; (b) TrCl, DMAP, pyridine,
80 °C, 13 h, 89%; (c) MsO(CH2)8CCH, NaH, TBAI, DMF, r.t., 19 h, 92%; (d) I2, morpholine, benzene, 40 °C, 11 h, 91%; (e) TsOH, CHCl3/
MeOH (2:1, v/v), r.t., 19 h, 90–95%; (f) 11, CuI, pyrrolidine, –20 °C, 62%; (g) MsO(CH2)8CCH, NaH, DMSO, r.t., 14 h, 53%; (h) CuCl, TME-
DA, O2, p-xylene, 130 °C, 19%; (i) DDQ, CH2Cl2/phosphate buffer solution (pH 7.2) (18:1, v/v), 0 °C, 1.5 h, 59%; (j) (i) 2-bromoethyl dich-
lorophosphate, 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, 79%.
Synlett 2002, No. 8, 1326–1328 ISSN 0936-5214 © Thieme Stuttgart · New York

1328
K. Miyawaki et al.
LETTER
(5) (a) We term caldarchaeol with a parallel arrangement of
In conclusion, the synthetic strategy that highlights both
the selective deprotection of compound 4 and cross-coup-
ling of intermediates 11 and 12 should permit the efficient
construction of chiral cyclobolaphiles and the diastere-
omer having two diacetylenes. This strategy also could be
wide applicable to the synthesis of the analogous com-
pounds. Work is currently in progress to develop their
self-assemblies and will be reported elsewhere.
glycerol units ‘parallel caldarchaeol’, and that with an
antiparallel arrangement ‘antiparallel caldarchaeol’:
Gräther, O.; Arigoni, D. J. Chem. Soc., Chem. Commun.
1995, 405. (b) Nishihara, M.; Morii, H.; Koga, Y. J.
Biochem. 1987, 101, 1007.
(6) Intense examination of macrocyclic synthetic methods that
have been previously reported indicates that only our
strategy has the potential to provide three stereoisomers of
parallel cyclobolaphiles that contain diacetylene units (see
Ref.1c,d,2).
Acknowledgement
(7) Qin, D.; Byun, H.; Bittman, R. J. Am. Chem. Soc. 1999, 121,
662.
(8) Carvalho, J. F.; Prestwich, G. D. J. Org. Chem. 1984, 49,
1251.
(9) Hirth, G.; Barner, R. Helv. Chim. Acta 1982, 65, 1059.
(10) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
We are grateful to S. Shibasaki and M. Usui (the Technical Center,
AIST) for valuable technical assistance. This research was suppor-
ted by Industrial Technology Research Grant Program in 2001 from
New Energy and Industrial Technology Development Organization
(NEDO) of Japan.
(11) All new compounds gave satisfactory analytical and spectral
data. Selected physical data are as follows: 4: Stage yellow
oil, Rf = 0.55 [hexane/ethyl acetate (2:1, v/v)], [ ]D28 –1.67
(c 0.24, CHCl3). 1H NMR (500 MHz, CDCl3): = 7.45–7.39
(m, 12 H), 7.27–7.19 (m, 18 H), 7.16 (d, J = 8.8 Hz, 4 H),
6.81 (d, J = 8.5 Hz, 4 H), 4.44 (d, J = 11.6 Hz, 2 H), 4.40 (d,
J = 11.9 Hz, 2 H), 3.77 (s, 6 H), 3.56–3.49 (m, 10 H), 3.17
(d, J = 4.6 Hz, 4 H), 2.19 (t, J = 7.2 Hz, 4 H), 1.56–1.44 (m,
8 H), 1.34–1.24 (m, 16 H) ppm. 13C NMR (100 MHz,
CDCl3): = 159.06, 144.09, 130.48, 129.13, 128.72, 127.70,
126.87, 113.62, 86.48, 78.29, 77.52, 72.87, 70.60, 70.09,
65.22, 63.44, 55.24, 30.06, 29.33, 29.07, 28.82, 28.32,
26.10, 19.17 ppm. Anal. Calcd for C80H90O8: C, 81.46; H,
7.69%. Found: C, 81.43; H, 7.66%. 8: Stage pale yellow oil,
Rf = 0.13 [hexane/ethyl acetate (2:1, v/v)], [ ]D28 –9.80 (c
0.60, CHCl3). 1H NMR (500 MHz, CDCl3): = 3.72–3.48
(m, 18 H), 2.23 (t, J = 6.9 Hz, 8 H), 2.17 (brs, 2 H), 1.65–
1.42 (m, 16 H), 1.40–1.19 (m, 32 H) ppm. 13C NMR (100
MHz, CDCl3): = 78.44, 77.41, 71.60, 71.08, 70.34, 65.31,
62.90, 29.95, 29.46, 29.26, 29.10, 28.93, 28.58, 28.19,
25.93, 19.11 ppm. LRMS (FAB): m/z = 725 [(M + H)+].
Anal. Calcd for C46H76O6: C, 76.20; H, 10.56%. Found: C,
76.19; H, 10.81%. 10: [ ]D28 +9.67 (c 0.30, CHCl3). 15:
[ ]D28 0.00 (c 0.45, CHCl3). (2R,27R)-1: Stage pale yellow
References
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(4) (a) Amphiphilic molecules containing 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. (b) Also termed
‘bolaphile’: Jayasuriya, N.; Bosak, S.; Regen, S. L. J. Am.
Chem. Soc. 1990, 112, 5844. (c) While amphiphiles having
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prefer to adopt the abbreviated and more readily
28
solid, Rf = 0.1 [CHCl3/MeOH/H2O (65:25:4, v/v/v)]. [ ]D
+5.81 (c 0.75, MeOH). 1H NMR [500 MHz, CDCl3/CD3OD
(97:3, v/v)]: = 4.24 (brs, 4 H), 3.84 (t, J = 5.3 Hz, 4 H),
3.65 (brs, 4 H), 3.58–3.51 (m, 8 H), 3.43–3.37 (m, 6 H), 3.24
(s, 18 H), 2.21 (t, J = 6.7 Hz, 8 H), 1.49–1.43 (m, 16 H),
1.34–1.20 (m, 32 H) ppm. 13C NMR (125 MHz, CD3OD):
= 79.50, 77.97, 72.46, 72.01, 71.49, 67.47, 66.57, 66.20,
60.37, 54.69, 31.21, 30.78, 30.41, 30.24, 29.98, 29.83,
29.58, 27.29, 19.79 ppm. 31P NMR [200 MHz, CDCl3/
CD3OD (99:1, v/v)]: = –0.50 (s)ppm. LRMS (FAB): m/z =
1054 (M+), 995 [(M – (Me)3N)+]. Anal. Calcd for
C56H100N2O12P2·2 H2O: C, 61.63; H, 9.60; N, 2.57%. Found:
C, 61.59; H, 9.43; N, 2.56%. (2S,27S)-1: [ ]D28 –5.77 (c
0.70, MeOH). (2R,27S)-1: [ ]D28 +0.00 (c 0.37, MeOH). The
spectral data of (2R,27S)-1 and (2S,27S)-1 were identical
with those of (2R,27R)-1.
(12) Hansen, W. J.; Murari, R.; Wedmid, Y.; Baumann, W. J.
Lipids 1982, 17, 453.
pronounceable term, ‘cyclobolaphile’.
(13) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
Synlett 2002, No. 8, 1326–1328 ISSN 0936-5214 © Thieme Stuttgart · New York