Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles with different alkyl chain lengths

Article abstract of DOI:10.1007/s00706-010-0255-y

General syntheses of novel symmetrical, single-chain, diacetylene-modified bolaphospholipids have been carried out in five steps. For the ω-alkynols, which have an important role as key intermediates, three different synthetic approaches were comprehensively investigated. For the final synthesis it is suggested that (1) alkylation of lithium (trimethylsilyl)acetylide with tetrahydropyranyl-protected ω-bromoalcohols, followed by (2) cleavage of the trimethylsilyl moiety and the tetrahydropyranyl protecting group, and (3) copper(II)-catalyzed Eglinton coupling is the best strategy for obtaining diacetylene-modified alkane-1,ω-diols, because higher yields were obtained while avoiding the formation of by-products. Moreover, conversion of the diols into bipolar phospholipids was achieved by bis-phosphorylation with β-bromoethylphosphoric acid dichloride and subsequent quaternization with trimethylamine or dimethylamine. Finally, spectral data are presented for novel single-chain, diacetylene-modified bolaphospholipids with promising potential as starting molecules in the formation of polymerizable and, thus, thermostable nanofibers.

Full text of DOI:10.1007/s00706-010-0255-y

Monatsh Chem (2010) 141:339–349
DOI 10.1007/s00706-010-0255-y
ORIGINAL PAPER
Synthesis of novel symmetrical, single-chain, diacetylene-modified
bolaamphiphiles with different alkyl chain lengths
•
•
•
Simon Drescher Katrin Helmis Andreas Langner
Bodo Dobner
Received: 24 September 2009 / Accepted: 15 January 2010 / Published online: 13 February 2010
Ó Springer-Verlag 2010
Abstract General syntheses of novel symmetrical, sin-
gle-chain, diacetylene-modified bolaphospholipids have
been carried out in five steps. For the x-alkynols, which
have an important role as key intermediates, three different
synthetic approaches were comprehensively investigated.
For the final synthesis it is suggested that (1) alkylation of
lithium (trimethylsilyl)acetylide with tetrahydropyranyl-
protected x-bromoalcohols, followed by (2) cleavage
of the trimethylsilyl moiety and the tetrahydropyranyl
protecting group, and (3) copper(II)-catalyzed Eglinton
coupling is the best strategy for obtaining diacetylene-
modified alkane-1,x-diols, because higher yields were
obtained while avoiding the formation of by-products.
Moreover, conversion of the diols into bipolar phospholipids
was achieved by bis-phosphorylation with b-bromoethyl-
phosphoric acid dichloride and subsequent quaternization
with trimethylamine or dimethylamine. Finally, spectral data
are presented for novel single-chain, diacetylene-modified
bolaphospholipids with promising potential as starting
molecules in the formation of polymerizable and, thus,
thermostable nanofibers.
Introduction
In recent years, many symmetrical and unsymmetrical
bipolar amphiphiles (bolaamphiphiles, BAs) have been
synthesized, enabling the study of their outstanding self-
assembly properties in aqueous media [1, 2]. BAs were
originally observed in the membrane lipids of some species
of Archaea [1]. Those bipolar molecules are composed
of two polar headgroups attached to one or two long
hydrophobic spacers, often alkyl chains. The membrane-
spanning and thus membrane-stabilizing properties of these
BAs are responsible for the outstanding stability of the
Archaea—even under hostile conditions, for example
anaerobic milieu or high temperatures (hot springs) in
combination with low pH. The qualities summarized above
make the BAs attractive candidates for use in vesicular
drug-delivery systems or for the stabilization of supported
biosensor devices [3, 4]. Because well characterized com-
plex BAs are difficult to isolate from natural Archaea
membranes, much effort has been devoted to their syn-
thesis, and that of novel and simplified bipolar amphiphiles
[2, 5]. Unexpectedly, simplification of the Archaea model
compounds to bipolar lipids with only one long alkyl chain
resulted in the formation of novel aggregate structures, e.g.
nanofibers and nanoparticles of self-assembled BAs [6, 7].
Recently, we reported the synthesis and aggregation
behavior of symmetrical single-chain polymethylene-1,x-
bis(phosphocholines) with alkyl chain lengths of 22–32
carbon atoms and two phosphocholine headgroups attached
at each end [8]. The simplified archaeal model lipids
resulting from that work self-assemble at room temperature
into long and flexible nanofibers, forming a dense network,
which gels water very efficiently [9, 10]. Within these
fibers, the bola molecules are arranged side by side, but
twisted relative to each other, because of the bulky
Keywords Alkynes Á Diacetylenes Á Lipids Á
Nanostructures Á Phosphates Á Phospholipids
S. Drescher (&) Á K. Helmis Á A. Langner Á B. Dobner
Department of Biochemical Pharmacy, Institute of Pharmacy,
Martin-Luther-University Halle-Wittenberg,
Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany
e-mail: simon.drescher@pharmazie.uni-halle.de
123

340
S. Drescher et al.
headgroups, leading to a helical superstructure of the
nanofibers [11]. Thereby, the self-assembly process is
exclusively driven by van-der-Waals interactions between
the long alkyl chains, because the phosphocholine head-
groups are not able to form intermolecular hydrogen bonds.
Above a certain transition temperature, which is solely
dependent on the lengths of the alkyl spacers, the nanofi-
bers reversibly transform into smaller aggregates—for
example spherical micelles or discs. However, the gel
character of the aqueous suspension is completely lost after
this transformation.
O
P
N
p O
O
O
O
P
O
O
N
p
O
H
HO
p
Fig. 1 Diacetylene-modified bolaamphiphiles as target molecules
and x-alkynols as key intermediates (p = 13–16)
Stabilization can be achieved by changing the headgroup
structure from a phosphocholine to a phosphodimethyl-
ethanolamine one while implementing a stabilization
process performed by hydrogen bonds [12]. Insertion of
dissociable H-atoms furnished pH-sensitive bolaform
hydrogelators, which are important for drug-delivery sys-
tems. Nevertheless, the heat stability of these nanofibers is
also limited to a fiber–micelle transformation in which the
nanofibers are completely destroyed and a liquefaction of
the hydrogel is observed [12, 13].
Retro-synthetic analysis of the target BA arrived at the
conclusion that alkyn-1-ols with a terminal triple bond
could be regarded as the key intermediates for synthesis of
symmetrical and polymerizable BAs. Herein, three differ-
ent approaches for the synthesis of terminal alkyn-1-ols
will be discussed:
1. the formaldehyde pathway starting from terminal,
long-chain alkynes and paraformaldehyde;
2. the propargyl alcohol pathway using tetrahydropyranyl
(THP)-protected propargyl alcohol which was alkyl-
ated with different alkyl bromides; and
One possible means of overcoming this temperature-
dependent fiber–micelle transformation and associated gel
liquefaction is covalent bonding among the bola molecules
within the fiber. Therefore, the insertion of diacetylene
groups, which can be polymerized to polydiacetylenes
(PDA) by UV irradiation, is seen to be the predestined
strategy. The formation of PDAs is well described in the
literature and the applications of this conjugated polymer
widely range from materials science [14–16] to a huge
number of various biosensing devices [17–21]. Hence, the
combination of nanofiber-forming BAs and PDAs might be
one promising approach to novel aggregates, e.g. thermo-
stable nanofibers forming a hydrogel with adjustable gel
strength.
3. the acetylide pathway, the direct alkylation of lithium
acetylide or lithium (trimethylsilyl)acetylide with
THP-protected x-bromoalcohols.
Results showed that the first and second strategies
involved a base-induced acetylene zipper reaction which
turned out to be the limiting factor in the synthesis of long-
chain alkynols above 18 carbon atoms. The above men-
tioned synthetic approaches are summarized in Scheme 1.
Formaldehyde pathway
The formaldehyde pathway started with commercially
available terminal, long-chain alkynes, e.g., tetradec-1-yne
(1a) and pentadec-1-yne (1b), which were transformed into
the corresponding pentadec-2-yn-1-ol (3a) or hexadec-2-
yn-1-ol (3b) by applying a Grignard-analogue reaction
using ethyl magnesium chloride and paraformaldehyde
[23–25]. In contrast with the work of Takano et al., the
mixtures had to be heated for at least for 3 h to 45 °C in
order to obtain moderate yields (30–57%). The alkynols 3a
and 3b were then converted by means of an acetylene zipper
reaction—a base-induced alkene–alkyne rearrangement
[26]—affording the analogous pentadec-14-yn-1-ol (4a)
and hexadec-15-yn-1-ol (4b) in isolated yields of 32–40%.
The sodium salt of 1,3-diaminopropane (DAP), suggested
by Macaulay [27], and the lithium potassium salt of DAP,
employed by Oppolzer et al. [28], were applied as base.
However, both syntheses showed no differences concerning
reaction procedures and resulted in comparable yields.
In this work, we examined synthetic approaches to novel
symmetrical, single-chain, diacetylene-modified BAs with
an overall chain length of 30–36 carbon atoms and phos-
phocholine or phosphodimethylethanolamine headgroups.
Results and discussion
In general, the synthesis of covalently bridged single-
chain BAs can be achieved by insertion of polymerizable
functionality either in the headgroup region or within the
long alkyl chain. However, since modifications of the
headgroups have a distinct effect on the aggregation
behavior of bipolar amphiphiles [22], the choline moieties
of the BAs should be unmodified and, hence, polymeriz-
able diacetylenic groups were inserted in the middle of
the alkyl spacer leading to target molecules as shown in
Fig. 1.
123

Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles
341
Formaldehyde-pathway:
H
i
H3C
30-57%
m
1a,
1b,
m=11
m=12
H
v
OH
HO
H3C
32-40%
p
o
Propargyl-alcohol-pathway:
4a,
4b,
4c,
4d,
3a, o=11
3b, o=12
p=13 (from 3a via v)
p=14 (from 3b via v)
p=15 (from 6a via ix)
p=16 (from 6b via ix)
H3C
Br
ii-iv
o=17
o=21
3c,
3d,
7-14%
n
2a,
n=12
2b, n=17
n=21
2c,
ix
75-79%
Acetylide-pathway:
H
O
O
Br
O
O
vi 58-63%
r
r
vii
viii
6a,
6b,
5a,
5b,
r=15 (from 5a via vi or
r=15 (from 7 via viii)
r=16 (from 5b via vi)
r=15
r=16
TMS
81%
71%
O
O
r
7,
r=15
i) EtMgCl, THF, 0°C; then paraformaldehyde, rt, 24 h; ii) propargyl alcohol, DHP, CH2Cl2, PPTS, rt, 24 h;
iii) n-BuLi, THF, 2, DMPU, 40°C, 24 h; iv) PPTS, MeOH, 40°C, 12 h; v) NaH, DAP, 55°C, 5 h;
vi) Li-acetylide·H2NCH2CH2NH2, DMSO, 65°C, 24 h; vii) Li(trimethylsilyl)acetylide, THF, -35°C, DMPU, 12 h;
viii) TBAF, THF, rt, 48 h; ix) PPTS, MeOH, reflux, 12 h.
Scheme 1
Propargyl alcohol pathway
(3b), heneicos-2-yn-1-ol (3c), and pentacos-2-yn-1-ol (3d)
in 7–14% isolated yields. The low solubility of the long-
chain alkyl bromides in DMPU–THF could be a plausible
reason for the marginal yields. Extension of the reaction
time and an increase of the reaction temperature had no
positive effect on product composition. In fact, high tem-
peratures induced the formation of by-products. The final
conversion of the alkynols 3b–3d into the x-alkynols was
realized using the acetylene zipper reaction described
above. However, only 3b could be transferred to the
hexadec-15-yn-1-ol (4b), whereas formation of heneicos-
20-yn-1-ol and pentacos-24-yn-1-ol failed. In our hands
and in contrast with the work of Godt et al. [30], the base-
induced alkene–alkyne rearrangement was limited by the
length of the alkyl chain while using the procedures
employed by Macaulay [27] or Oppolzer et al. [28].
A second strategy for synthesis of terminal alkyn-1-ols was
the alkylation of THP-protected propargyl alcohols with
long-chain alkyl bromides, e.g., tridecyl bromide (2a),
octadecyl bromide (2b), and docosyl bromide (2c). In
accordance with the work of Schwarz and Waters [29] and
Oppolzer et al. [28], the alcohol moiety of the propargyl
alcohol was protected with 3,4-dihydro-2H-pyran (DHP) in
the presence of pyridinium p-toluene sulfonate (PPTS).
The alkyne group was deprotonated with n-BuLi. Alkyl-
ation with the above mentioned alkyl bromides in dry 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone
(DMPU)
and tetrahydrofuran (THF) at 40 °C, and subsequent
deprotection of the THP group with catalytic amounts of
PPTS in MeOH led to the formation of hexadec-2-yn-1-ol
123

342
S. Drescher et al.
Acetylide pathway
triethylamine (TEA) and toluene (2:1, v/v) for oxidative
coupling of the alkyn-1-ols 4c and 4d, respectively. This
change of solvent resulted in the formation of tetratria-
conta-16,18-diyn-1,34-diol (8c) and hexatriaconta-17,19-
diyn-1,36-diol (8d) in elevated isolated yields (55–60%).
The third procedure for preparation of terminal alkyn-1-ols
was the direct alkylation of lithium acetylene implementing
THP-protected x-bromoalcohols. The lithium acetylide–
ethylenediamine complex was dissolved in THF under
argon atmosphere. Subsequent addition of 2-(15-bromo-
pentadec-1-yloxy)tetrahydro-2H-pyran (5a) or 2-(16-
bromohexadec-1-yloxy)tetrahydro-2H-pyran (5b), diluted
in THF, and stirring for 48 h at 25 °C yielded in no
observable formation of the product. However, after this
reaction we could isolate small amounts (3–5%) of the bis-
alkylated 1,x-bis[(tetrahydro-2H-pyran-2-yl)oxy]alkyne.
When the solvent was changed to DMSO and the reaction
temperature increased to 65 °C, 2-(heptadec-16-yn-1-
yloxy)tetrahydro-2H-pyran (6a) and 2-(octadec-17-yn-1-
yloxy)tetrahydro-2H-pyran (6b) were obtained in 58–63%
isolated yields. In this reaction procedure we also observed
formation of the bis-alkylated by-product, which could be
separated by column chromatography. In contrast, use of
the versatile reagent lithium (trimethylsilyl)acetylide in
THF [31] avoided this side reaction and resulted in efficient
formation of 2-(17-trimethylsilylheptadec-16-yn-1-yloxy)
tetrahydro-2H-pyran (7) in 81% yield. Deprotection of the
terminal trimethylsilyl group with tetrabutylammonium
fluoride (TBAF) afforded 6a in 71% yield. Finally,
deprotection of the THP group with PPTS in MeOH
under reflux for 12 h provided heptadec-16-yn-1-ol (4c)
and octadec-17-yn-1-ol (4d) in 75–79% isolated yield.
Comparing all three approaches for the synthesis of
terminal alkyn-1-ols 4, the acetylide pathway using lithium
(trimethylsilyl)acetylide is the most efficient synthetic
strategy, because higher yields were obtained while
avoiding the formation of by-products.
Phosphorylation and quaternization
The final conversion of 8 to the respective bis(pho-
sphodimethylethanolamines) 9 or bis(phosphocholines) 10
was achieved using a bis-phosphorylation reaction with b-
bromoethylphosphoric acid dichloride in TEA–CHCl3 and
subsequent quaternization with an ethanolic solution of
Me2NH or Me3N, respectively (Scheme 2). In contrast
with the procedures described previously [8] excess phos-
phorylating reagent was minimized because of the
susceptibility of the diacetylenic groups. Moreover, the
reaction was carried out avoiding light irradiation. This
final reaction resulted in the formation of the desired al-
kadiyn-1,x-diylbis[2-(dimethylammonio)ethylphosphates]
9b–9d and the alkadiyn-1,x-diylbis[2-(trimethylammo-
nio)ethylphosphates] 10a–10d in 17–63% isolated yields.
Summary and outlook
In conclusion, we have examined a general synthetic
approach for synthesis of novel symmetrical, single-chain,
diacetylenic BAs with an over-all chain length of 30–36
carbon atoms. For the x-alkynols, which have an essential
role as key intermediates, the acetylide pathway using the
alkylation of lithium (trimethylsilyl)acetylide with THP-
protected x-bromoalcohols followed by cleavage of the
trimethylsilyl group and the THP protecting group is the
best synthetic strategy among the other approaches inves-
tigated in this work. The synthetic methodology presented
herein is also well transferrable to the preparation of
symmetrical, diacetylenic BAs with shorter or longer alkyl
chains. These novel single-chain bipolar amphiphiles have
promising potential as starting molecules for the design of
polymerizable nanofibers which form thermostable hydro-
gels with adjustable gel strength. Further investigations
including differential scanning calorimetry, transmission
electron microscopy, and rheology measurements are under
way.
Oxidative coupling
Several reaction conditions were studied for oxidative
coupling of the terminal alkyn-1-ols 4 to the corresponding
compounds 8 (Scheme 2) using reaction procedures
employed by Menger et al. [32] or Eglinton and Galbraith
[33]. In a first attempt, the alkyn-1-ols 4a and 4b were
dissolved in xylene containing CuCl and tetra-
methylethylenediamine (TMEDA). While heating to
140 °C, oxygen was gently passed into the mixture through
a gas inlet tube [32]. This reaction conditions led to
numerous by-products associated with the complete
decomposition of the molecule. In a second approach, an
excess of copper(II) acetate monohydrate dissolved in
pyridine was utilized [33], affording triaconta-14,16-diyn-
1,30-diol (8a) and dotriaconta-15,17-diyn-1,32-diol (8b) in
14–30% isolated yields. Because of problems during the
work-up, the pyridine was replaced by a mixture of
Experimental
All substances were purchased from Sigma–Aldrich and
were used without further purification. 2-(x-Bromoalkane-
1-yloxy)tetrahydro-2H-pyrans 5a and 5b [8] and b-
bromoethylphosphoric acid dichloride [34] were prepared
according to the literature. All organic solvents used were
123

Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles
343
O
P
N
OH
p O
O
R
p
H
O
ii, iii
i
O
P
HO
HO
R
O
O
17-63%
14-60%
N
p
p
p
O
(9a,
10a,
p=13, R=H)
p=13, R=CH3
4a, p=13
4b, p=14
4c, p=15
8a, p=13
8b, p=14
8c, p=15
9b, p=14, R=H
10b, p=14, R=CH3
p=15, R=H
p=16, R=H
p=15, R=CH
p=16, R=CH
9c,
9d,
10c,
10d,
3
3
p=16
p=16
8d,
4d,
i) Cu(OAc)2, pyridine or triethylamine/toluene (2/1, v/v), MeOH, 70 °C, 12 h; ii) CHCl3, β-bromoethylphosphoric acid dichloride, 40 °C;
then THF/H2O, rt, 2 h; iii) CHCl3, CH3CN, EtOH, N(CH3)2R, 50 °C, 72 h
Scheme 2
Pentadec-2-yn-1-ol (3a)
purified and dried. The purity of all compounds was
checked by thin-layer chromatography (TLC, plates
obtained from Merck) using the following mobile phases:
A = CHCl3–heptane (3:2, v/v), B = CHCl3, C = CHCl3–
Et2O (1:1, v/v), D = CHCl3–MeOH–NH3 (10:10:1, v/v/v),
E = CHCl3–MeOH–NH3 (10:10:2, v/v/v), F = CHCl3–
MeOH–NH3 (10:10:3, v/v/v). Purification of the final BAs
was carried out by medium-pressure liquid chromatogra-
phy (MPLC, Bu¨chi) using silica gel (Merck, 0.032–
0.060 mm). Melting points were determined with a Boetius
apparatus. 1H NMR and 13C NMR analysis was performed
on a Varian Inova 500 or Gemini 2000 NMR spectrometer
using CDCl3 or CD3OD as internal standard. Mass spec-
trometric data were obtained with a Finnigan MAT model
SSQ 710 C mass spectrometer (ESI–MS) or were recorded
on an AMD 402 (70 eV) spectrometer. Elemental analysis
(C, H, N) was conducted using a Leco CHNS-932; results
were in good agreement ( 0.4%) with calculated values.
Compound 3a was obtained as a white solid in 30% yield
(1.62 g) from reaction of 4.66 g 1a (24 mmol) with 1.44 g
paraformaldehyde (48 mmol) according to the general
procedure described above. M.p.: 41 °C (Ref. [35]
38–41 °C, Ref. [28] 43–45 °C); Rf = 0.13 (solvent A),
1
0.54 (solvent C); H NMR (400 MHz, CDCl3): d = 0.87
(t, 3J = 6.6 Hz, 3H, –CH3), 1.20–1.54 (m, 20H,
–(CH2)10CH3), 2.19 (tt, 3J = 7.1 Hz, 5J = 2.1 Hz, 2H,
–C:CCH2CH2–), 4.31 (t, 5J = 2.1 Hz, 2H, HOCH2–)
ppm; MS (70 eV): m/z (%) = 224 (1) [M?], 206 (4)
[M? – H2O].
Hexadec-2-yn-1-ol (3b)
Compound 3b was obtained as a white solid in 57% yield
(3.26 g) from reaction of 5.00 g 1b (24 mmol) with 1.44 g
paraformaldehyde (48 mmol) according to the general
procedure described above. M.p.: 52 °C (Ref. [36] 49.5–
50.0 °C, Ref. [37] 54.2–55.0 °C); Rf = 0.13 (solvent A),
1
0.57 (solvent C); H NMR (400 MHz, CDCl3): d = 0.87
Formaldehyde pathway: general procedure for reaction
of long-chain alkynes with formaldehyde
(t, 3J = 6.6 Hz, 3H, –CH3), 1.24–1.37 (m, 20H,
–(CH2)10CH3), 1.51–1.54 (m, 2H, –C:CCH2CH2–), 2.19
3
5
(tt, J = 7.1 Hz, J = 2.1 Hz, 2H, –C:CCH2CH2–), 4.23
(t, 5J = 2.1 Hz, 2H, HOCH2–) ppm; MS (70 eV): m/z
(%) = 237 (2) [M?], 220 (2) [M? – H2O].
A solution of ethyl magnesium chloride in THF (12 cm3,
2 M) was added dropwise to a cold solution of either 1a or
1b (24 mmol) in 30 cm3 dry THF, adjusting the rate so the
temperature remained below 0 °C. After addition the
mixture was kept at 45 °C for 3 h. After cooling to 25 °C
1.44 g solid paraformaldehyde (48 mmol) was added
stepwise and the mixture was stirred for 24 h at this tem-
perature. For work-up the resulting mixture was diluted
with 60 cm3 H2O, acidified with HCl, and then extracted
with 100 cm3 Et2O (49). The combined organic phases
were washed with 100 cm3 brine and 100 cm3 H2O, dried
over Na2SO4, and concentrated to dryness in vacuo,
affording 1.62–3.26 g (30–57% yield) of either 3a or 3b.
The final purification of 3a and 3b was carried out by flash
chromatography on silica gel (0.032–0.060 mm) using
gradient elution and heptane–Et2O as eluent.
Propargyl alcohol pathway: general procedure
for reaction of long-chain alkyl bromides
with propargyl alcohol
A solution of 5.6 g propargyl alcohol (0.1 mol), 15.1 g
freshly distilled DHP (0.18 mol), and catalytic amounts of
PPTS in 50 cm3 dry CH2Cl2 was stirred at 25 °C. After
24 h 100 cm3 H2O was added to the mixture and the
organic layer was separated. The aqueous residue was
extracted with 25 cm3 CH2Cl2 (29). The combined
organic layers were washed with H2O, dried over
Na2SO4, and concentrated to dryness in vacuo. The crude
123

344
S. Drescher et al.
5J = 2.1 Hz, 2H, HOCH2–) ppm; MS (70 eV): m/z
(%) = 364 (1) [M?], 346 (9) [M? – H2O].
residue was passed through a silica gel column using
gradient elution with heptane–Et2O as eluent to obtain 2-
(prop-2-yn-1-yloxy)tetrahydro-2H-pyran as a colorless oil.
A solution of n-BuLi in hexane (5.5 cm3, 1.6 M) was
added slowly to a solution of 2.94 g 2-(prop-2-yn-1-
yloxy)tetrahydro-2H-pyran (20 mmol) in 20 cm3 dry THF
at 0 °C. After 2 h a solution of 2a, 2b, or 2c (23 mmol)
in dry DMPU was introduced dropwise and the mixture
was stirred for 24 h at 40 °C. For work-up 50 cm3 of a
cold saturated solution of NH4Cl was added and the
organic layer was separated. The aqueous residue was
extracted with 25 cm3 heptane (29). The combined
organic phases were washed with H2O, dried over
Na2SO4, and concentrated to dryness in vacuo. For
cleavage of the THP protecting groups the crude alkyne
THP ethers were dissolved in 50 cm3 dry MeOH and
stirred at 40 °C with catalytic amounts of PPTS. After
12 h the solution was poured into ice water and the
mixture obtained was extracted with 50 cm3 CHCl3 (39).
The organic layers were dried over Na2SO4 and concen-
trated to dryness in vacuo, affording 0.33–0.86 g 3b, 3c,
or 3d, respectively, in 8–14% isolated yields. The final
purification of 3b–3d was carried out by flash chroma-
tography on silica gel (0.032–0.060 mm) using gradient
elution with heptane–Et2O as eluent.
General procedure for the acetylene zipper reaction
NaH (0.41 g, 17 mmol) was suspended in 15 cm3 dry DAP
under argon atmosphere and the mixture was kept at 70 °C
for 2 h. After cooling to 25 °C a solution of either 3a or 3b
(2.1 mmol) in 8 cm3 dry DAP was added and the mixture
obtained was stirred for further 3–5 h at 55 °C. For work-
up the solution was poured into ice water and extracted
several times with Et2O. The organic layers were washed
with H2O, dilute HCl, and cold saturated brine, dried over
Na2SO4, and concentrated to dryness in vacuo, affording
0.16–0.19 g of either 4a or 4b in 32–40% isolated yields.
The final purification was carried out by MPLC using
CHCl3 as eluent.
Pentadec-14-yn-1-ol (4a)
Compound 4a was obtained in 40% yield (0.19 g) from
the acetylene zipper reaction of 0.47 g 3a (2.1 mmol)
following the general procedure described above. M.p.:
39 °C (Ref. [39] 35–36 °C); Rf = 0.42 (solvent C);
1H NMR (400 MHz, CDCl3): d = 1.17–1.58 (m, 22H,
–(CH2)11CH2C:CH), 1.92 (t, 4J = 2.5 Hz, 1H, –C:CH),
2.16 (td, 3J = 7.1 Hz, 4J = 2.5 Hz, 2H, –CH2C:CH),
3.62 (t, 3J = 6.6 Hz, 2H, HOCH2–) ppm; MS (70 eV): m/z
(%) = 224 (1) [M?].
Hexadec-2-yn-1-ol (3b)
Compound 3b was obtained as a white solid in 7% yield
(0.33 g) from reaction of 6.05 g 2a (23 mmol) with 2.94 g
THP-protected propargyl alcohol (20 mmol) according to
the general procedure described above. For spectral data
see section above.
Hexadec-15-yn-1-ol (4b)
Compound 4b was obtained in 32% yield (0.16 g) from the
acetylene zipper reaction of 0.50 g 3b (2.1 mmol) follow-
ing the general procedure described above. M.p.: 48 °C
(Ref. [32] 49.5–50.5 °C); Rf = 0.10 (solvent A), 0.43
Heneicos-2-yn-1-ol (3c)
1
(solvent C); H NMR (400 MHz, CDCl3): d = 1.15–1.58
Compound 3c was obtained as a white solid in 14% yield
(0.86 g) from reaction of 7.67 g 2b (23 mmol) with 2.94 g
THP-protected propargyl alcohol (20 mmol) according to
the general procedure described above. M.p.: 62 °C (Ref.
[38] 65–66 °C); Rf = 0.17 (solvent A), 0.59 (solvent C);
4
(m, 24H, –(CH2)12CH2C:CH), 1.92 (t, J = 2.5 Hz, 1H,
–C:CH), 2.16 (td, 3J = 7.1 Hz, 4J = 2.5 Hz, 2H,
3
–CH2C:CH), 3.62 (t, J = 6.6 Hz, 2H, HOCH2–) ppm;
MS (70 eV): m/z (%) = 238 (1) [M?].
3
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz,
Acetylide pathway: general procedure for alkylation
of lithium acetylide with long-chain THP-protected
x-bromoalcohols
3H, –CH3), 1.19–1.52 (m, 32H, –(CH2)16CH3), 2.19 (tt,
5
3J = 7.1 Hz, J = 2.1 Hz, 2H, –C:CCH2CH2–), 4.23 (t,
5J = 2.1 Hz, 2H, HOCH2–) ppm; MS (70 eV): m/z
(%) = 308 (2) [M?].
A solution of 0.92–5.0 g lithium acetylide–ethylenedia-
mine complex (90%, 9.0–48.9 mmol) in 5–10 cm3 DMSO
(freshly distilled over CaH2) was stirred under argon
atmosphere at 0 °C for 10 min. After this time, 3.66–
19.11 g 5a or 5b (9.0–48.9 mmol) in 5–10 cm3 DMSO was
added slowly and the mixture was heated to 65 °C for a
further 24 h. For work-up the reaction was quenched with
50 cm3 H2O and the resulting mixture was extracted with
50 cm3 heptane (29), washed with 50 cm3 H2O, dried over
Na2SO4, and concentrated to dryness in vacuo, affording
Pentacos-2-yn-1-ol (3d)
Compound 3d was obtained a as white solid in 8% yield
(0.58 g) from reaction of 8.96 g 2c (23 mmol) with 2.94 g
THP-protected propargyl alcohol (20 mmol) according to
the general procedure described above. M.p.: 70 °C (Ref.
[30] 77–79 °C); Rf = 0.18 (solvent A), 0.60 (solvent C);
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 6.6 Hz,
3
3H, –CH3), 1.24–1.52 (m, 40H, –(CH2)20CH3), 2.19 (tt,
5
3J = 7.1 Hz, J = 2.1 Hz, 2H, –C:CCH2CH2–), 4.23 (t,
123

Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles
345
Acetylide pathway: general procedure
for the alkylation of lithium (trimethylsilyl)acetylide
1.84–10.33 g of either 6a or 6b in 58–63% isolated yields.
The final purification was carried out by chromatography
using a heptane–Et2O gradient (?0.5% TEA) as eluent.
with long-chain THP-protected x-bromoalcohols
2-(Heptadec-16-yn-1-yloxy)tetrahydo-2H-pyran
(6a, C22H40O2)
2-(17-Trimethylsilylheptadec-16-yn-1-yloxy)tetrahydro-
2H-pyran (7, C25H48O2Si)
Compound 6a was obtained as a white waxy solid in 63%
yield (10.33 g) from the reaction of 19.11 g 5a
(48.9 mmol) with a solution of 5.0 g lithium acetylide–
ethylenediamine complex (90%, 48.9 mmol) in 10 cm3
DMSO following the general procedure described above.
Rf = 0.51 (solvent B); 1H NMR (400 MHz, CDCl3):
d = 1.23–1.38 (m, 22H, –CH2–), 1.46–1.60 (m, 8H,
–CH2–), 1.65–1.72 (m, 1H, –OCH2CH2(CH2)13–), 1.75–
A 250-cm3 round-bottomed flask was filled with 0.5 M
lithium (trimethylsilyl)acetylide solution in 50 cm3 THF
under argon atmosphere and cooled to -35 °C. Dry DMPU
was added, and the mixture was stirred at this temperature.
After 30 min a solution of 5a (15 mmol) in 30 cm3 dry THF
was added at such a rate that the temperature remained
below -15 °C and stirring was continued for a further 12 h
at 25 °C. For work-up the reaction was quenched by slowly
adding of 30 cm3 H2O, and the organic product obtained
was extracted with 50 cm3 Et2O (29). The organic layer
was dried over Na2SO4 and concentrated to dryness in
vacuo, affording 4.98 g (81% yield) of 7. The final
purification was carried out by chromatography using a
heptane–Et2O gradient (?0.5% TEA) as eluent. Rf = 0.52
(solvent B); 1H NMR (400 MHz, CDCl3): d = 0.11 (s, 9H,
39 –CH3), 1.23–1.35 (m, 22H, –CH2–), 1.44–1.60 (m, 8H,
–CH2–), 1.65–1.72 (m, 1H, –OCH2CH2(CH2)13–), 1.76–
4
1.84 (m, 1H, –OCH2CH2(CH2)13–), 1.90 (t, J = 2.5 Hz,
1H, –C:CH), 2.15 (td, 3J = 7.1 Hz, 4J = 2.5 Hz, 2H,
–CH2C:CH), 3.35 (dt, 2J = 9.5 Hz, 3J = 6.6 Hz, 1H,
–OCH2(CH2)14–), 3.44–3.49 (m, 1H, –OCH2(CH2)3CH–),
2
3
3.70 (dt, J = 9.5 Hz, J = 6.8 Hz, 1H, –OCH2(CH2)14–),
3.81–3.87 (m, 1H, –OCH2(CH2)3CH–), 4.53–4.55 (m, 1H,
–CH–) ppm; 13C NMR (100 MHz, CDCl3): d = 18.42
and 19.71 (–CH2C:CH and –O(CH2)2CH2CH2CH–),
25.56 and 26.27 (–O(CH2)2CH2(CH2)12C:CH and
–OCH2CH2(CH2)2CH–), 28.52, 28.77, 29.12, 29.51, 29.61,
29.66, and 29.79 (–CH2–), 30.82 (–CH2CH–), 62.27
(–OCH2(CH2)3CH–), 67.66 (–OCH2(CH2)14–), 67.99
(–C:CH), 84.72 (–C:CH), 98.76 (–CH–) ppm; MS
(70 eV): m/z (%) = 335 (10) [M? – H], 311 (5) [M?
– C:CH], 101 (95) [THPO], 85 (100) [THP].
3
1.84 (m, 1H, –OCH2CH2(CH2)13–), 2.17 (t, J = 7.1 Hz,
2H, –CH2C:C–), 3.35 (dt, 2J = 9.5 Hz, 3J = 6.6 Hz, 1H,
–OCH2(CH2)14–), 3.44–3.49 (m, 1H, –OCH2(CH2)3CH–),
2
3
3.70 (dt, J = 9.5 Hz, J = 6.8 Hz, 1H, –OCH2(CH2)14–),
3.81–3.87 (m, 1H, –OCH2(CH2)3CH–), 4.53–4.55 (m, 1H,
–CH–) ppm; 13C NMR (100 MHz, CDCl3): d = 0.30 (39
–CH3), 19.78 and 19.99 (–CH2C:C– and –O(CH2)2
CH2CH2CH–), 25.63 and 26.34 (–O(CH2)2CH2(CH2)12
C:C– and –OCH2CH2(CH2)2CH–), 28.72, 28.87, 29.15,
29.56, 29.66, 29.67, 29.69, 29.72, 29.74, and 29.85 (–CH2–),
30.88 (–CH2CH–), 62.29 (–OCH2(CH2)3CH–), 67.67
(–OCH2(CH2)14–), 84.17 (–CH2C:C–Si), 98.76 (–CH–),
107.68 (–CH2C:C–Si) ppm; MS (70 eV): m/z (%) = 408
(5) [M?], 393 (6) [M? – CH3], 335 (6) [M? – Si(CH3)3],
307 (5) [M? – OTHP], 234 (4) [M? – Si(CH3)3 – OTHP],
128 (18) [THPOCH2CH2], 101 (23) [THPO], 85 (100)
[THP], 73 (34) [Si(CH3)3].
2-(Octadec-17-yn-1-yloxy)tetrahydro-2H-pyran
(6b, C23H42O2)
Compound 6b was obtained as a white waxy solid in 58%
yield (1.84 g) from the reaction of 3.66 g 5b (9.0 mmol)
with a solution of 0.92 g lithium acetylide–ethylenedia-
mine complex (90%, 9.0 mmol) in 5 cm3 DMSO following
the general procedure described above. Rf = 0.57 (solvent
1
B); H NMR (400 MHz, CDCl3): d = 1.23–1.37 (m, 24H,
–CH2–), 1.46–1.58 (m, 8H, –CH2–), 1.66–1.72 (m, 1H,
–OCH2CH2(CH2)14–), 1.76–1.83 (m, 1H, –OCH2CH2
4
(CH2)14–), 1.90 (t, J = 2.5 Hz, 1H, –C:CH), 2.15 (td,
3J = 7.1 Hz, 4J = 2.5 Hz, 2H, –CH2C:CH), 3.35 (dt,
2J = 9.5 Hz, 3J = 6.6 Hz, 1H, –OCH2(CH2)15–), 3.44–
2
Acetylide pathway: general procedure for the removal
of the trimethylsilyl protecting group
3.49 (m, 1H, –OCH2(CH2)3CH–), 3.70 (dt, J = 9.5 Hz,
3J = 7.1 Hz, 1H, –OCH2(CH2)15–), 3.81–3.86 (m, 1H,
–OCH2(CH2)3CH–), 4.54–4.55 (m, 1H, –CH–) ppm; 13C
NMR (100 MHz, CDCl3): d = 18.49 and 19.78 (–CH2C:
CH and –O(CH2)2CH2CH2CH–), 25.62 and 26.33
(–O(CH2)2CH2(CH2)13C:CH and –OCH2CH2(CH2)2CH–),
28.59, 28.84, 29.18, 29.57, 29.67, 29.72, and 29.85 (–CH2–),
30.88 (–CH2CH–), 62.29 (–OCH2(CH2)3CH–), 67.68
(–OCH2(CH2)15–), 68.00 (–C:CH), 84.72 (–C:CH), 98.76
(–CH–) ppm; MS (70 eV): m/z (%) = 349 (2) [M? – H], 101
(98) [THPO], 85 (100) [THP].
2-(Heptadec-16-yn-1yloxy)tetrahydro-2H-pyran (6a)
To a solution of 3.93 g 7 (9.6 mmol) in 30 cm3 dry THF
was added dropwise 10 cm3 TBAF solution in THF (1 M)
at -5 °C. After 48 h at 25 °C the reaction was quenched
with HCl (2 M), and the resulting mixture was extracted
with 50 cm3 heptane (29). The organic layer was washed
with 50 cm3 brine, dried over Na2SO4, and concentrated to
dryness in vacuo, affording 2.29 g (71% yield) of 6a. The
123

346
S. Drescher et al.
product was used for the next reaction without further
purification. For spectral data see section above.
After 12 h, the mixture was cooled to 25 °C and the
reaction was quenched with 50 cm3 half-concentrated
HCl. The organic product was extracted with 50 cm3
CHCl3 (29); the organic layer was washed with brine,
dried over Na2SO4, and concentrated to dryness in vacuo.
The crude product was recrystallized from petroleum ether
(50–70), affording 0.22–1.38 g of 8a-d in 14–60% isolated
yields.
Acetylide pathway: general procedure for the removal
of the THP protecting group
THP ethers 6 (0.91–6.21 g, 2.6–18.5 mmol) were heated
under reflux in 15–30 cm3 dry MeOH with catalytic
amounts of PPTS. After 12 h, the solvent was removed in
vacuo, and the crude product was recrystallized from
petroleum ether (50–70), affording 0.52–3.68 g of either 4c
or 4d in 75–79% isolated yield.
Triaconta-14,16-diyn-1,30-diol (8a, C30H54O2)
Compound 8a was obtained as white crystals in 30% yield
(1.38 g) from the dimerization reaction of 4.60 g 4a
(20.5 mmol) using a solution of 15.0 g copper(II) acetate
monohydrate (75 mmol) in 50 cm3 pyridine, following the
general procedure described above. M.p.: 93 °C; Rf = 0.19
Heptadec-16-yn-1-ol (4c, C17H32O)
Compound 4c was obtained as white crystals in 79% yield
(3.68 g) from the deprotecting reaction of 6.21 g 6a
(18.5 mmol) following the general procedure described
above. M.p.: 54.5–56.0 °C; Rf = 0.27 (solvent B), 0.47
1
(solvent C); H NMR (400 MHz, CDCl3): d = 1.24–1.58
(m, 44H, 29 HOCH2(CH2)11CH2C:C–), 2.22 (t,
3
3J = 7.1 Hz, 4H, 29 –CH2C:C–), 3.62 (t, J = 6.6 Hz,
4H, 29 HOCH2–) ppm; MS (70 eV): m/z (%) = 446 (10)
1
(solvent C); H NMR (400 MHz, CDCl3): d = 1.24–1.38
[M?].
(m, 22H, HO(CH2)2(CH2)11(CH2)2C:CH), 1.46–1.58
(m, 4H, HOCH2CH2(CH2)11CH2CH2C:CH), 1.91 (t, 4J =
2.7 Hz, 1H, –C:CH), 2.15 (td, 3J = 7.1 Hz, 4J = 2.7 Hz,
2H, –CH2C:CH), 3.61 (t, 3J = 6.6 Hz, 2H, HOCH2–)
ppm; 13C NMR (100 MHz, CDCl3): d = 18.43 (–CH2C:
CH), 25.77 (HO(CH2)2CH2–), 28.53, 28.79, 29.13, 29.46,
29.51, 29.62, and 29.66 (–CH2–), 32.83 (HOCH2CH2–),
63.08 (HOCH2–), 68.00 (–C:CH), 84.78 (–C:CH) ppm;
MS (70 eV): m/z (%) = 252 (1) [M?].
Dotriaconta-15,17-diyn-1,32-diol (8b, C32H58O2)
Compound 8b was obtained as white crystals in 14% yield
(0.68 g) from the dimerization reaction of 4.89 g 4b
(20.5 mmol) using a solution of 15.0 g copper(II) acetate
monohydrate (75 mmol) in 50 cm3 pyridine, following the
general procedure described above. M.p.: 92 °C; Rf = 0.23
1
(solvent C); H NMR (400 MHz, CDCl3): d = 1.24–1.57
(m, 48H, 29 HOCH2(CH2)12CH2C:C–), 2.22 (t,
3
3J = 7.1 Hz, 4H, 29 –CH2C:C–), 3.62 (t, J = 6.6 Hz,
4H, 29 HOCH2–) ppm; MS (70 eV): m/z (%) = 474 (10)
Octadec-17-yn-1-ol (4d)
Compound 4d was obtained as white crystals in 75% yield
(0.52 g) from the deprotecting reaction of 0.91 g 6b
(2.6 mmol) following the general procedure described
above. M.p.: 58.0–58.5 °C (Ref. [32] 59.0–60.5 °C);
Rf = 0.28 (solvent B), 0.51 (solvent C); 1H NMR
(400 MHz, CDCl3): d = 1.24–1.39 (m, 24H, HO(CH2)2
(CH2)12(CH2)2C:CH), 1.47–1.57 (m, 4H, HOCH2CH2
[M?].
Tetratriaconta-16,18-diyn-1,34-diol (8c, C34H62O2)
Compound 8c was obtained as white crystals in 60% yield
(0.59 g) from the dimerization reaction of 1.0 g 4c
(3.96 mmol) using a solution of 2.34 g copper(II) acetate
monohydrate (11.9 mmol) in 15 cm3 TEA–toluene (2:1,
v/v), following the general procedure described above. M.p.:
95 °C; Rf = 0.22 (solvent C); 1H NMR (400 MHz, CDCl3):
d = 1.22–1.57 (m, 52H, 29 HOCH2(CH2)13CH2C:C–)
2.22 (t, 3J = 7.1 Hz, 4H, 29 –CH2C:C–), 3.63 (t,
3J = 6.6 Hz, 4H, 29 HOCH2–) ppm; 13C NMR:
(100 MHz, CDCl3): d = 19.27 (29 –CH2C:C–), 25.79
(29 HO(CH2)2CH2–), 28.41, 28.90, 29.13, 29.47,
29.51, 29.62, 29.65, 29.66, and 29.67 (HO(CH2)3
(CH2)11CH2C:C–), 32.89 (29 HOCH2CH2–), 63.12 (29
HOCH2–), 65.29 (29 –CH2C:C–), 77.56 (29 –CH2C:
C–) ppm; MS (70 eV): m/z (%) = 502 (63) [M?].
4
(CH2)12CH2CH2C:CH), 1.92 (t, J = 2.3 Hz, 1H, –C:
3
4
CH), 2.16 (td, J = 6.9 Hz, J = 2.3 Hz, 2H, –CH2C:
3
CH), 3.62 (t, J = 6.6 Hz, 2H, HOCH2–) ppm; 13C NMR
(100 MHz, CDCl3): d = 18.51 (–CH2C:CH), 25.85
(HO(CH2)2CH2–), 28.61, 28.86, 29.19, 29.52, 29.58,
29.69, and 29.73 (–CH2–), 32.92 (HOCH2CH2–), 63.13
(HOCH2–), 68.01 (–C:CH), 84.80 (–C:CH) ppm; MS
(70 eV): m/z (%) = 266 (1) [M?].
Eglinton coupling: general procedure for the copper-
catalyzed dimerization of alkynols to alkadiyndiols
To a solution of 0.9–15.0 g copper(II) acetate monohy-
drate (4.5–75 mmol) in 50 cm3 pyridine or 7–15 cm3
TEA–toluene (2:1, v/v) was added the corresponding x-
alkynol 4a–4d (1.5–20.5 mmol) dissolved in 2–30 cm3
MeOH. The mixture was kept at 70 °C while stirring.
Hexatriaconta-17,19-diyn-1,36-diol (8d)
Compound 8d was obtained as white crystals in 55% yield
(0.22 g) from the dimerization reaction of 0.4 g 4d
(1.5 mmol) using a solution of 0.9 g copper(II) acetate
monohydrate (4.5 mmol) in 7 cm3 TEA–toluene (2:1, v/v),
123

Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles
347
following the general procedure described above. M.p.:
1
96 °C (Ref. [40] 94 °C); Rf = 0.31 (solvent C); H NMR
Triaconta-14,16-diyn-1,30-diylbis[2-(dimethylammo-
nio)ethylphosphate] (9a)
(400 MHz, CDCl3): d = 1.24–1.57 (m, 56H, 29
HOCH2(CH2)14CH2C:C–), 2.22 (t, J = 7.1 Hz, 4H, 29
Compound 9a was obtained from the phosphorylation
reaction of 8a and subsequent quaternization with an
ethanolic solution of Me2NH following the general proce-
dure described above. ESI–MS: m/z = 747.6 [M? – H],
749.5 [M? ? H], 776.5 [M? ? Na]. Because of problems
during the purification procedures no additional spectral
data could be obtained.
3
–CH2C:C–), 3.62 (t, 3J = 6.6 Hz, 4H, 29 HOCH2–)
ppm; 13C NMR (100 MHz, CDCl3): d = 19.26
(29 –CH2C:C–), 25.79 (29 HO(CH2)2CH2–), 28.40,
28.90, 29.13, 29.47, 29.50, 29.62, and 29.67 (29
HO(CH2)3(CH2)12CH2C:C–), 32.87 (29 HOCH2CH2–),
63.11 (29 HOCH2–), 65.28 (29 –CH2C:C–), 77.56 (29
–CH2C:C–) ppm; MS (70 eV): m/z (%) = 530 (16)
[M?].
Dotriaconta-15,17-diyn-1,32-diylbis[2-(dimethylammo-
nio)ethylphosphate] (9b, C40H78N2O8P2)
Compound 9b was obtained as a white solid in 35% yield
(136 mg) from the phosphorylation reaction of 0.24 g 8b
(0.5 mmol) and subsequent quaternization with an ethanolic
solution of Me2NH following the general procedure
described above. Rf = 0.43 (solvent D); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 1.24–1.39 (m, 40H, 29
–O(CH2)2(CH2)10(CH2)2C:C–), 1.46–1.53 (m, 4H, 29
–CH2CH2C:C–), 1.57–1.64 (m, 4H, 29 –OCH2CH2
General procedure for phosphorylation
and quaternization reaction
The reaction procedure is based on the general synthesis
of polymethylene-1,x-diylbis(phosphocholines) described
previously [8]. b-Bromoethylphosphoric acid dichloride
(0.24–0.97 g, 1–4 mmol) was poured into 5–15 cm3 dry
CHCl3 under argon atmosphere and cooling with ice–
water. A solution of 0.20–0.81 g dry TEA (2–8 mmol) in
5–15 cm3 CHCl3 was added slowly with stirring, which
was continued for further 30 min at 0 °C. After this
time, the corresponding diacetylene-modified 1,x-diol
8a–8d (0.25–1.0 mmol) was added as solid substance in
one portion, avoiding light irradiation. The suspension
was heated for 10 min to 40 °C (until the solid was
completely dissolved), then rapidly cooled to 25 °C, and
stirring was continued for a further 24–48 h at this
temperature. After TLC showed complete conversion of
the 1,x-diol 8a–8d, 5–15 cm3 crushed ice was added to
the solution and the mixture was stirred vigorously for
2 h. The organic layer was separated, and the aqueous
phase was diluted with 25 cm3 of a cold saturated
solution of NaCl and extracted with 30 cm3 CHCl3 (29).
The combined organic phases were concentrated in
vacuo, the oily residue was dissolved in 10–30 cm3
THF–H2O (9:1, v/v), and the mixture was stirred for
1 h. After this time, the solvent was evaporated and
the residue was added to a mixture of 15 cm3 dry
CHCl3, 15 cm3 CH3CN, and an ethanolic solution of
Me2NH (5.6 M, 4 cm3) for synthesis of the bis(phos-
phodimethylethanolamines) 9 or Me3N (4.2 M, 5 cm3)
for the synthesis of the corresponding bis(phosphocho-
lines) 10. The mixture was kept in a closed tube at
50 °C for 72 h, avoiding light irradiation. Afterwards, the
mixture was concentrated by evaporation of the solvent,
and the residue was purified by MPLC using a gradient
and CHCl3–MeOH–H2O as eluent, affording 0.07–0.48 g
of the diacetylene-modified BAs 9b–9d and 10a–10d in
17–63% isolated yields.
3
(CH2)12C:C–), 2.24 (t, J = 7.1 Hz, 4H, 29 –CH2C:
C–), 2.82 (s, 12H, 49 –CH3), 3.12–3.14 (m, 4H,
29 NCH2CH2O–), 3.89 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)13C:C–), 4.22–4.26 (m, 4H, 29 NCH2CH2O–) ppm;
13C NMR (100 MHz, CDCl3–CD3OD): d = 18.97 (29
–CH2C:C–), 25.59 (29 –O(CH2)2CH2(CH2)11C:C–),
28.18, 28.64, 28.89, 29.19, 29.27, and 29.43 (29
3
–O(CH2)3(CH2)10CH2C:C–), 30.55 (d, JC,P = 6.9 Hz,
29 –OCH2CH2(CH2)12C:C–), 43.19 (49 –CH3), 58.62
and 59.07 (2d, JC,P = 5.0 Hz, 29 NCH2CH2O–), 65.05 (29
2
–CH2C:C–), 66.01 (d, JC,P = 6.1 Hz, 29 –OCH2
(CH2)13C:C–), 77.25 (29 –CH2C:C–) ppm; ESI–MS:
m/z = 775.6 [M? – H], 778.4 [M? ? H], 799.6 [M? ? Na].
Tetratriaconta-16,18-diyn-1,34-diylbis[2-(dimethylammo-
nio)ethylphosphate] (9c, C42H82N2O8P2)
Compound 9c was obtained as a white solid in 63% yield
(0.48 g) from the phosphorylation reaction 0.48 g 8c
(0.95 mmol) and subsequent quaternization with an etha-
nolic solution of Me2NH following the general procedure
described above. Rf = 0.53 (solvent E); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 1.23–1.39 (m, 44H, 29
–O(CH2)2(CH2)11(CH2)2C:C–), 1.45–1.52 (m, 4H, 29
–CH2CH2C:C–), 1.56–1.63 (m, 4H, 29 –OCH2CH2
3
(CH2)13C:C–), 2.22 (t, J = 7.1 Hz, 4H, 29 –CH2C:
C–), 2.87 (s, 12H, 49 –CH3), 3.18–3.22 (m, 4H,
29 NCH2CH2O–), 3.86 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)14C:C–), 4.19–4.24 (m, 4H, 29 NCH2CH2O–)
ppm; 13C NMR (100 MHz, CDCl3–CD3OD): d = 18.99
(29 –CH2C:C–), 25.61 (29 –O(CH2)2CH2(CH2)12C:
C–), 28.18, 28.66, 28.91, 29.20, 29.30, and 29.46 (29
3
–O(CH2)3(CH2)11CH2C:C–), 30.54 (d, JC,P = 6.9 Hz,
29 –OCH2CH2(CH2)13C:C–), 43.14 (49 –CH3), 58.78
123

348
S. Drescher et al.
3
(d, JC,P = 4.6 Hz, 29 NCH2CH2O–), 58.86 (d, JC,P
2
=
Dotriaconta-15,17-diyn-1,32-diylbis[2-(trimethylammo-
nio)ethylphosphate] (10b, C42H82N2O8P2)
5.4 Hz, 29 NCH2CH2O–), 65.06 (29 –CH2C:C–), 66.07
2
(d, JC,P = 5.4 Hz, 29 –OCH2(CH2)14C:C–), 77.19 (29
Compound 10b was obtained as a white solid in 17% yield
(70 mg) from the phosphorylation reaction of 0.24 g 8b
(0.5 mmol) and subsequent quaternization with an etha-
nolic solution of Me3N following the general procedure
described above. Rf = 0.13 (solvent F); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 1.10–1.14 (m, 48H, 29
–CH2C:C–) ppm; ESI–MS: m/z = 804.1 [M? – H],
806.6 [M? ? H], 828.5 [M? ? Na], 1,631.9 [2M? ? Na].
Hexatriaconta-17,19-diyn-1,36-diylbis[2-(dimethylammo-
nio)ethylphosphate] (9d, C44H86N2O8P2)
Compound 9d was obtained as a white solid in 61% yield
(127 mg) from the phosphorylation reaction of 0.13 g 8d
(0.25 mmol) and subsequent quaternization with an etha-
nolic solution of Me2NH following the general procedure
described above. Rf = 0.55 (solvent E); 1H NMR (400 MHz,
CDCl3–CD3OD): d = 1.14–1.25 (m, 48H, 29 –O(CH2)2
(CH2)12(CH2)2C:C–), 1.36–1.43 (m, 4H, 29 –CH2CH2
C:C–), 1.48–1.55 (m, 4H, 29 –OCH2CH2(CH2)14C:C–),
2.12 (t, 3J = 7.1 Hz, 4H, 29 –CH2C:C–), 2.77 (s, 12H, 49
–CH3), 3.14–3.16 (m, 4H, 29 NCH2CH2O–), 3.77 (q,
J = 6.6 Hz, 4H, 29 –OCH2(CH2)15C:C–), 4.01–4.06 (m,
4H, 29 NCH2CH2O–) ppm; 13C NMR (100 MHz, CDCl3–
CD3OD): d = 19.04 (29 –CH2C:C–), 25.63 (29
–O(CH2)2CH2(CH2)13C:C–), 28.21, 28.69, 28.94, 29.23,
29.32, 29.50, and 29.53 (29 –O(CH2)3(CH2)12CH2C:C–),
3
–OCH2(CH2)12CH2C:C–), 1.95 (t, J = 7.1 Hz, 4H, 29
–CH2C:C–), 2.97 (s, 18H, 69 –CH3), 3.33–3.36 (m, 4H,
29 NCH2CH2O–), 3.62 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)13C:C–), 3.97–4.00 (m, 4H, 29 NCH2CH2O–)
ppm; 13C NMR (100 MHz, CDCl3–CD3OD): d = 19.01
(29 –CH2C:C–), 25.65 (29 –O(CH2)2CH2(CH2)11
C:C–), 28.21, 28.68, 28.93, 29.26, 29.31, and 29.48
3
(29 –O(CH2)3(CH2)10CH2C:C–), 30.65 (d, JC,P
=
6.9 Hz, 29 –OCH2CH2(CH2)12C:C–), 54.12 (t, J =
3.8 Hz, 69 –CH3), 58.60 (d, JC,P = 5.0 Hz, 29 NCH2
2
2
CH2O–), 65.09 (29 –CH2C:C–), 65.74 (d, JC,P
=
6.0 Hz, 29 –OCH2(CH2)13C:C–), 66.48 (b, 29 NCH2
CH2O–), 77.26 (29 –CH2C:C–) ppm; ESI–MS:
m/z = 805.5 [M? ? H], 828.5 [M? ? Na].
3
30.57 (d, JC,P = 7.7 Hz, 29 –OCH2CH2(CH2)14C:C–),
43.25 (49 –CH3), 58.83 (d, JC,P = 6.1 Hz, 29 NCH2
Tetratriaconta-16,18-diyn-1,34-diylbis[2-(trimethylammo-
nio)ethylphosphate] (10c, C44H86N2O8P2)
3
2
CH2O–), 59.01 (d, JC,P = 3.8 Hz, 29 NCH2CH2O–),
Compound 10c was obtained as a white solid in 50% yield
(105 mg) from the phosphorylation reaction of 0.13 g 8c
(0.25 mmol) and subsequent quaternization with an etha-
nolic solution of Me3N following the general procedure
described above. Rf = 0.19 (solvent F); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 0.98–1.10 (m, 44H, 29
–O(CH2)2(CH2)11(CH2)2C:C–), 1.20–1.27 (m, 4H, 29
–CH2CH2C:C–), 1.31–1.38 (m, 4H, 29 –OCH2CH2
2
65.09 (29 –CH2C:C–), 66.19 (d, JC,P = 5.4 Hz, 29
–OCH2(CH2)15C:C–), 77.22 (29 –CH2C:C–) ppm; ESI–
MS: m/z = 832.0 [M? – H], 835.1 [M? ? H], 856.1
[M? ? Na]
Triaconta-14,16-diyn-1,30-diylbis[2-(trimethylammo-
nio)ethylphosphate] (10a, C40H78N2O8P2)
Compound 10a was obtained as a white solid in 20% yield
(78 mg) from the phosphorylation reaction of 0.22 g 8a
(0.5 mmol) and subsequent quaternization with an etha-
nolic solution of Me3N following the general procedure
described above. Rf = 0.12 (solvent F); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 1.17–1.55 (m, 44H, 29
3
(CH2)13C:C–), 1.96 (t, J = 7.1 Hz, 4H, 29 –CH2C:
C–), 2.93 (s, 18H, 69 –CH3), 3.32–3.34 (m, 4H, 29
NCH2CH2O–), 3.59 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)14C:C–), 3.94–3.99 (m, 4H, 29 NCH2CH2O–)
ppm; 13C NMR (100 MHz, CDCl3–CD3OD): d = 18.57
(29 –CH2C:C–), 25.26 (29 –O(CH2)2CH2(CH2)12C:
C–), 27.87, 28.31, 28.58, 28.91, 28.97, and 29.16 (29
3
–OCH2(CH2)11CH2C:C–), 2.16 (t, J = 7.1 Hz, 4H, 29
–CH2C:C–), 3.13 (s, 18H, 69 –CH3), 3.50–3.55 (m, 4H,
29 NCH2CH2O–), 3.77 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)12C:C–), 4.11–4.17 (m, 4H, 29 NCH2CH2O–)
ppm; 13C NMR (100 MHz, CDCl3–CD3OD): d = 19.03
(29 –CH2C:C–), 25.68 (29 –O(CH2)2CH2(CH2)10
3
–O(CH2)3(CH2)11CH2C:C–), 30.24 (d, JC,P = 7.4 Hz,
29 –OCH2CH2(CH2)13C:C–), 53.61 (t, J = 3.7 Hz, 69
–CH3), 58.60 (d, 2JC,P = 5.9 Hz, 29 NCH2CH2O–), 65.77
2
(d, JC,P = 5.2 Hz, 29 –OCH2(CH2)14C:C–), 77.19 (29
–CH2C:C–) ppm; ESI–MS: m/z = 868.0 [M? ? Cl],
834.0 [M? ? H], 867.7 [M? ? Na].
C:C–), 28.22, 28.69, 28.95, 29.27, 29.34, 29.46, and
3
29.49 (29 –O(CH2)3(CH2)9CH2C:C–), 30.68 (d, JC,P
=
6.9 Hz, 29 –OCH2CH2(CH2)11C:C–), 54.14 (t, J =
3.7 Hz, 69 –CH3), 58.66 (d, JC,P = 5.2 Hz, 29
Hexatriaconta-17,19-diyn-1,36-diylbis[2-(trimethylammo-
nio)ethylphosphate] (10d, C46H90N2O8P2)
2
NCH2CH2O–), 65.12 (29 –CH2C:C–), 65.77 (d,
2JC,P = 6.1 Hz, 29 –OCH2(CH2)12C:C–), 66.43 (b,
29 NCH2CH2O–), 77.20 (29 –CH2C:C–) ppm; ESI–
MS: m/z = 777.6 [M? ? H], 799.5 [M? ? Na].
Compound 10d was obtained as a white solid in 56%
yield (120 mg) from the phosphorylation reaction of
0.13 g 8d (0.25 mmol) and subsequent quaternization with
an ethanolic solution of Me3N following the general
123

Synthesis of novel symmetrical, single-chain, diacetylene-modified bolaamphiphiles
349
procedure described above. Rf = 0.20 (solvent F); 1H NMR
(400 MHz, CDCl3–CD3OD): d = 1.18–1.32 (m, 48H, 29
–O(CH2)2(CH2)12(CH2)2C:C–), 1.40–1.47 (m, 4H, 29
–CH2CH2C:C–), 1.51–1.58 (m, 4H, 29 –OCH2CH2
11. Meister A, Drescher S, Mey I, Wahab M, Graf G, Garamus VM,
Hause G, Mogel HJ, Janshoff A, Dobner B, Blume A (2008)
J Phys Chem B 112:4506
¨
¨
12. Kohler K, Meister A, Forster G, Dobner B, Drescher S, Ziethe F,
Richter W, Steiniger F, Drechsler M, Hause G, Blume A (2006)
Soft Matter 2:77
3
(CH2)14C:C–), 2.17 (t, J = 7.1 Hz, 4H, 29 –CH2C:
13. Meister A, Drescher S, Garamus VM, Karlsson G, Graf G,
Dobner B, Blume A (2008) Langmuir 24:6238
14. Inoue K, One Y, Kanekiyo Y, Hanabusa K, Shinkai S (1999)
Chem Lett 28:429
15. George M, Weiss RG (2003) Chem Mater 15:2879
16. Shirakawa M, Fujita N, Shinkai S (2005) J Am Chem Soc
127:4164
17. Charych D, Cheng Q, Reichert A, Kuziemko G, Stroh M, Nagy
JO, Spevak W, Stevens RC (1996) Chem Biol 3:113
18. Song J, Cheng Q, Zhu S, Stevens RC (2002) Biomed Microde-
vices 4:213
19. Song J, Cisar JS, Bertozzi CR (2004) J Am Chem Soc 126:8459
20. Reppy MA, Pindzola BA (2007) Chem Commun 4317
21. Ahn DJ, Kim JM (2008) Acc Chem Res 41:805
22. Drescher S, Meister A, Graf G, Hause G, Blume A, Dobner B
(2008) Chem Eur J 14:6796
23. Corey EJ, Katzenellenbogen JA, Gilman NW, Roman SA,
Erickson BW (1968) J Am Chem Soc 90:5618
24. Corey EJ, Katzenellenbogen JA, Roman SA, Gilman NW (1971)
Tetrahedron Lett 12:1821
25. Takano S, Sugihara T, Ogasawara K (1991) Synlett 279
26. Brown CA, Yamashita A (1975) J Am Chem Soc 97:891
27. Macaulay SR (1980) J Org Chem 45:734
C–), 3.17 (s, 18H, 69 –CH3), 3.57–3.59 (m, 4H, 29
NCH2CH2O–), 3.80 (q, J = 6.6 Hz, 4H, 29 –OCH2
(CH2)15C:C–), 4.16–4.22 (m, 4H, 29 NCH2CH2O–)
ppm; 13C NMR (100 MHz, CDCl3–CD3OD): d = 19.07
(29 –CH2C:C–), 25.66 (29 –O(CH2)2CH2(CH2)13C:
C–), 28.19, 28.66, 28.96, 29.29, 29.33, 29.45, and 29.54
3
(29 –O(CH2)3(CH2)12CH2C:C–), 30.66 (d, JC,P
=
7.4 Hz, 29 –OCH2CH2(CH2)14C:C–), 54.29 (t, J =
3.7 Hz, 69 –CH3), 58.95 (d, JC,P = 4.4 Hz, 29
2
2
NCH2CH2O–), 65.21 (29 –CH2C:C–), 66.07 (d, JC,P
=
5.9 Hz, 29 –OCH2(CH2)15C:C–), 66.36 (b, 29
NCH2CH2O–), 77.20 (29 –CH2C:C–) ppm; ESI–MS:
m/z = 862.3 [M? ? H], 884.3 [M? ? Na], 1,744.0
[2M? ? Na].
Acknowledgments We are grateful to the Deutsche Forschungs-
gemeinschaft (DFG) for financial support.
28. Oppolzer W, Radinov RN, El-Sayed E (2001) J Org Chem
66:4766
29. Schwarz M, Waters RM (1972) Synthesis 567
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