How the stereochemistry of a central cyclopentyl ring influences the self-assembling properties of archaeal lipid analogues: Synthesis and cryoTEM observations

Article abstract of DOI:10.1021/jo201827h

The relative stereochemistry (cis or trans) of a 1,3-disubstituted cyclopentane unit placed in the middle of tetraether archaeal bipolar lipid analogues was found to have a dramatic influence on their supramolecular self-assembling properties. The synthes

Full text of DOI:10.1021/jo201827h

Article
pubs.acs.org/joc
How the Stereochemistry of a Central Cyclopentyl Ring Influences
the Self-Assembling Properties of Archaeal Lipid Analogues:
Synthesis and CryoTEM Observations
,†,‡
Alicia Jacquemet,†,‡ Loıc Lemiegre,* Olivier Lambert,§ and Thierry Benvegnu*,†,‡
̈
̀
†Ecole Nationale Super
́ ́ ́
ieure de Chimie de Rennes, CNRS, UMR 6226, Avenue du General Leclerc, CS 50837, 35708 Rennes Cedex
7, France
‡Universite
́ ́
Europeenne de Bretagne, France
§Chimie et Biologie des Membranes UMR CNRS 5248 − Universite
́ ́
Bordeaux 1-IPB, IECB, Allee Geoffroy Saint-Hilaire, 33600
Pessac, France
S
* Supporting Information
ABSTRACT: The relative stereochemistry (cis or trans) of a 1,3-disubstituted cyclopentane unit placed in the middle of
tetraether archaeal bipolar lipid analogues was found to have a dramatic influence on their supramolecular self-assembling
properties. The synthesis of two diastereomers varying only by the stereochemistry of the cyclopentyl unit was achieved following
a multistep diastereoselective route. The corresponding lipid films were hydrated and were observed by cryoTEM. The
micrographs showed several types of unilamellar nano-objects such as lamellas or irregular vesicles for the cis-isomer, whereas the
trans-isomer exhibited exclusively multilamellar vesicles with a regular spherical shape. Even if the cyclopentyl ring takes part of a
long alkyl chain (32 carbon atoms), the pseudorotation of the carbocycle would influence the global conformation of the bipolar
lipid and consequently would modify the orientation of the lactosyl polar headgroups.
represent an ideal model of study of the stereochemical
influence on the self-assembling properties of amphiphiles in
general.
INTRODUCTION
■
Physicochemical and theoretical studies of lipid self-assembling
are extensively described in the literature, which allows at some
points to predict the global behavior of some novel amphiphilic
structures.1 However, the impact of stereochemical features is
still difficult to assess and still requires the physical study of
well-defined stereoisomers. The stereochemistry is known to
undergo clear changes in the self-assembly of amphiphilic
molecules. Several research groups described, for instance,
chirality transfer from molecular to supramolecular level or
physicochemical comparative studies of diastereomers.2 These
latter examples usually illustrate stereochemical effects between
diastereomeric compounds in which the variable stereogenic
centers are relatively close one to each other and mainly near
the polar domain. This is probably a consequence of the
structure of the common natural lipids that almost do not bear
stereogenic centers in their hydrophobic parts. By contrast,
some organisms such as archaea developed membrane lipids
containing a relatively high number of stereogenic centers,
which might play a role on the self-assembling properties of
their cell-membranes. These lipids or analogues may therefore
Archaea organisms represent the third phyla of life with
bacteria and eukarya. They are known as extreme organisms
that grow under harsh conditions such as low pH, extreme
temperature, highly salted media, and anaerobia.3 These
unusual conditions, compared to that of mesophiles, coerced
the archaea to develop the required tools to circumvent what
can be considered as hostile media. Among the differences
between mesophiles and archaea, the lipid composition of
archaeal membranes is of particular interest, as it involves both
atypical hydrophobic cores and hydrophilic polar head groups.4
The most remarkable hydrophobic structures involve two
glyceryl units linked one to the other by two isoprenoid chains
leading to a 70 atom macrocycle tetraether (Figure 1).5,6 The
particular features of these archaeal lipids are related to (1) the
ability of these tetraethers to adopt a transmembrane
Received: September 9, 2011
Published: October 31, 2011
© 2011 American Chemical Society
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Figure 1. Example of natural archaeal tetraether lipid structure (hydrophobic domain).
Figure 2. Structure of synthetic archaeal lipid analogues bearing a cis- or trans-1,3-disubstituted cyclopentane ring.
Scheme 1. Retrosynthesis of Bipolar Lipids 1a,b
conformation within the archaeal membrane that is responsible
for its exceptional thermostability; (2) the less hydrolyzable
ether-linkages compared to the ester-linkages commonly found
in other forms of life; and (3) the presence of cyclopentane
rings in the isoprenoid chains for which the number is
associated with the living temperature of the considered
organisms.7 In terms of stereochemistry, absolute and relative
configurations of glyceryl residues, isopranyl chains, and five-
membered rings present on natural tetraether structures have
been determined.8,9 From these studies, the stereochemistry of
the glyceryl moieties was found to be opposite of that of
conventional glycerolipids. More recently, the trans config-
uration of the 1,3-disubstituted cyclopentane rings, as well as its
absolute configuration, was determined by the synthesis of
models and the comparison of their optical rotation and NMR
spectroscopic data.8
Over the last 20 years, a considerable effort has been devoted
to the synthesis of bipolar lipids10 (also named “bolaamphi-
philes”) that retain some of the essential structural features of
archaeal membrane lipids.6 However, only a few studies
provided evidence for a crucial stereochemical impact of
branched chains and/or glyceryl units on the self-assembling
properties of bipolar lipids.11 Moreover, the precise role of the
trans-1,3-disubstituted cyclopentane remains unknown in
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archaeal lipids. Indeed, the cyclopentane is known to adopt
numerous conformations of close energies that originate from
the pseudorotation of the carbocycle.12 Ruiz del Ballesteros et
al.13 have shown by computational analysis that the energy
profiles of the two diastereomers of a 1,3-disubstituted
cyclopentane (cis or trans) are rather similar in terms of
energy level. However, the main difference lay on the distance
between the two substituents all along the pseudorotation
circuit. This distance is relatively stable for the trans-isomer
(4.5−4.8 Å) but varies from 3.2 to 4.8 Å when considering the
cis-isomer (for two methyl groups). Within a hydrophobic
structure, these differences could be at the origin of important
changes in the conformational behavior of a lipid.
(Scheme 2).8,16 The reaction proceeds through a 1,4-addition
on the unsaturated lactone, leading to the corresponding
Scheme 2. Synthesis of Diol 2b Including a trans-1,3-
Disubtituted Cyclopentane
In view of establishing the influence of stereochemical
features on both supramolecular structures and properties, we
have embarked on a program to synthesize and investigate the
lyotropic behavior of diastereomers 1a,b (Figure 2) possessing
the same chemical structure but a different relative stereo-
chemistry of the cyclopentane unit (cis or trans). These bipolar
molecules are characterized by a hydrophobic backbone
constructed around a bridging chain incorporating a central
1,3-disubtituted cyclopentane unit. On both ends, a stereo-
controlled glyceryl unit makes the tripodal link between the
bridging chain, an optically pure phytanyl chain and a lactosyl
polar headgroup. The latter brings the tetrather structures to an
adequate hydrophilic/hydrophobic balance. Additionally, the
presence of neutral sugar headgroups instead of charged
phosphorylated derivatives is expected to provide a higher
sensitivity of the self-assembling properties of these glycolipids
toward minor changes in their hydrophobic cores, such as the
stereochemical variations we describe hereafter.14
Thus, we described herein the synthesis of the two
diastereomers 1a,b (Figure 2) and the corresponding long-
range effect of this stereochemical variation through com-
parative cryogenic transmission electron microscopy (cryo-
TEM) observations of the resulting supramolecular assemblies
in water (1 mg mL−1).
carboxylic acid. One difficulty laid on the synthesis of the long
alkyl chain organomagnesium halide used for the preparation of
the required organocuprate. Conversion of the ω-tetrahydro-
pyranyloxy-α-bromopentadecane 317 into the corresponding
organomagnesium bromide 4 required freshly purified starting
materials and the heating of the reaction mixture for 3 h at 55
°C in THF.17 The Grignard reagent was then engaged in the
alkylation reaction of lactone 5 in the presence of CuBr·Me2S
in THF/Me2S. The 1,4-addition proceeded cleanly and
provided the carboxylic acid 6 with a trans configuration
(confirmed by NOE NMR experiments) in 50% yield. This acid
6 can be isolated or used without purification in the next step,
which consisted of the reduction of the carboxylic acid function
followed by a reoxidation by the Dess−Martin periodinane to
the aldehyde stage. Aldehyde 7 was obtained in 77% yield and
was engaged in a Wittig olefination step to introduce the
second arm of the bridging chain that fixed the length of the
tetraether. Indeed, treatment of phosphonium salt 8 in THF
with 1 equiv of n-BuLi gave the corresponding phosphorane,
which was treated with aldehyde 7 for 12 h to provide olefin 9
in 70% yield. The conversion of the lactone 5 into the olefin 9
was optimized by removing the purification steps at the stage of
the carboxylic acid 6 and aldehyde 7; a single careful
purification was then required after the olefination reaction to
provide compound 9 in 65% yield (from 5), compared to 27%
yield if each step was performed from pure products. The
RESULTS AND DISCUSSION
■
Synthesis of Tetraether Lipids 1a,b. The strategic plan
for the synthesis of the two diastereomers 1a and 1b is based
on the functionalization of α,ω-dihydroxylated alkanes
containing a 1,3-disubstituted cyclopentane ring at their
midpart and characterized by a cis or trans relative
configuration (2a,b) (Scheme 1). The symmetrical construc-
tion of the tetraether backbones involved the stereocontrolled
bisalkylation of diols 2a,b with two (S)-epichlorhydrins and the
regiospecific opening of the resulting epoxides that ensured the
final configuration of the glyceryl units. The introduction of
two (R,R,R)-phytanyl chains by a Williamson etherification
reaction led to the formation of tetraether structures. Finally,
the cleavage of the protecting groups permitted the
introduction of the polar head groups by a double O-
lactosylation under standard conditions.
The synthesis of the bridging chain 2a (cis), resulting from
the oxidative cleavage of norbornene, has been already reported
by our research group.15 The preparation of the trans-isomer,
which has never been described, required a totally different
strategy. Indeed, the access to trans-1,3-disubtituted cyclo-
pentanes is not extensively described in the literature. We based
our synthetic scheme on the use of lactone 5 (rac), which is
known to be selectively opened by an organocuprate to provide
a clean reaction in favor of a trans-1,3-disubtituted cyclopentene
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Scheme 3. Preparation of Tetraethers 1a (cis) and 1b (trans)
simultaneous hydrogenation of benzyloxy groups and double
bonds was tried out in the presence of Pd/C. These conditions
were chemically efficient but resulted in a loss of the
stereochemistry of the cyclopentane ring; thus, alcohol 10
was isolated as a cis/trans 1:1 mixture. The replacement of the
Pd/C catalytic system by PtO2, which is known to proceed
without double bond isomerization,8,18 afforded pure trans-
isomer 11 in 84% yield. The cleavage of the protecting groups
was achieved by successive hydrogenolysis (H2, Pd/C, 94%)
and acidic methanolysis (PTSA, 89%). Thus, diol 2b bearing a
trans 1,3-disubtituted cyclopentane ring in a racemic form was
obtained in seven steps from lactone 5 (overall yield of 46%).
Having the diols 2a,b in hand, the next step involved the
introduction of the glyceryl moieties through the reaction of
diols 2a,b with (S)-epichlorhydrin that ensured a sn-2,3
absolute configuration of the final product (Scheme 3). The
bis-glycidyl derivatives 12a,b were isolated respectively in 51
and 45% yields, in addition to monoglycidylation products
(∼40%), which can be recycled in another glycidylation
reaction to furnish additional diepoxide products. The glycidyl
derivatives 12a,b were easily opened by an excess of benzylic
alcohol in the presence of a catalytic amount of sodium
methoxide yielding diols 13a,b (∼80%). The phytanyl chains
were next introduced from (3R,7R,11R)-phytanylbromide. The
latter was synthesized from 7R,11R-phytol by asymmetric
reduction based on Noyori’s procedure,19 followed by
bromination of the resulting alcohol in aqueous HBr.15,20
The diastereoisomeric ratio (100:3) was determined by
integrable 13C NMR experiments on the (3R,7R,11R)-phytanol.
Reaction of phytanylbromide (Br-phyt) with diols 13a,b was
carried out in the presence of sodium hydride at 130 °C, which
permitted the removal of the solvent, allowing the reaction to
proceed under solvent-free conditions for 12 h. This double
Williamson reaction led to the dibenzylated tetraethers 14a,b in
72 and 60% yields, respectively. After hydrogenolysis of the
benzyloxy groups, a glycosylation reaction of the resulting diol
15 was performed using the trichloroacetimidate lactosyl
derivative 16. A catalytic amount of trimethylsilyltriflate
promoted a stereoselective double glycosylation (92−76%
yield), and final methanolysis of the benzoate groups provided
dilactosyl-tetraethers 1a,b in 66 and 48% yields, respectively.
These modest yields are mainly due to the tricky purification
steps of such amphiphilic compounds.
CryoTEM Observations. CryoTEM was carried out on
both tetraether lipids (1a,b), which gave access to direct
observations of their self-assemblies in aqueous media. The
samples were prepared at a concentration of 1 mg mL−1 by
hydration at 45 °C of lipid films that were obtained by
evaporation of a chloroform/methanol solution. The temper-
ature of hydration was fixed to 45 °C to ensure a fluidic state of
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Figure 3. CryoTEM observations of aqueous dispersions of tetraether 1a (1 mg mL−1). Scale bars 1 μm (A) and 50 nm (B).
Figure 4. CryoTEM observations of aqueous dispersions of tetraether 1b (1 mg mL−1). Note that the membranes of unilamellar and bilamellar
liposomes are ∼6 and ∼12 nm thick, respectively. Scale bars 1 μm (A) and 50 nm (B).
the alkyl chains (confirmed by SAXS studies, data not shown).
Macroscopically, the hydration of the cis-isomer 1a led to a
transparent aqueous solution resulting from a easy dispersion of
the lipid film in water. Conversely, the trans-isomer 1b
(following strictly the same conditions of preparation) led to
a homogeneous solution that did not appear as a clear
transparent solution. CryoTEM observations of frozen-
hydrated samples supported on carbon grids with holes were
performed under low-dose conditions. The micrographs shown
in Figure 3 (cis-isomer 1a) and Figure 4 (trans-isomer 1b) also
demonstrated contrasting behavior at a nanoscale level.
Concerning the cis-isomer 1a, the cryoTEM analysis led to
the observation of various nanostructures including lamellae,
unilamellar and irregular vesicles, or flat structures (Figure 3).
Additionally, most of the membranes involved in these
nanostructures are not pairing to one another, leading mainly
to unilamellar objects. Independent of the nature of the nano-
objects, the thickness of the membrane was estimated to be ∼6
nm.
However, the cryoTEM study of the trans-isomer 1b sample
led to the observation of regular vesicles with sizes ranging from
50 to 200 nm that have a tendency to interact with one another,
leading to a relative aggregation phenomenon (Figure 4A).
Furthermore, most of the vesicles are multilamellar structures
with strong interactions between lamellae (Figure 4B). Also,
when a vesicle contained a sufficiently smaller one, the latter
usually stacked on one side of the larger vesicles. The thickness
of the membranes are also very regular and were determined to
be more or less the same as for the cis-isomer 1a (∼ 6 nm).
The supramolecular morphologies determined by cryoTEM
experiments revealed different lyotropic self-assembling proper-
ties for the tetraether glycolipids 1a and 1b, with a significant
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(ppm) referenced to the appropriate residual solvent peak. Coupling
constants are reported in Hertz (Hz). Data are reported as follows:
chemical shift (multiplicity, coupling constants where applicable,
number of hydrogens, attribution). Abbreviations are as follows: s
(singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet),
dt (doublet of triplet), m (multiplet), bs (broad singlet), CyP
(cyclopentyl). The NMR peak assignments were determined from 2D
NMR experiments such as COSY, HSQC, and HMBC. High-
resolution mass spectra (accurate mass) were performed on a MS/
MS-TOF mass spectrometer and are reported as m/z. Accurate masses
are reported for the molecular ion [M + Na]+, [M + H]+, or [M]+.
(15-(Tetrahydro-2H-pyran-2-yloxy)pentadecyl)magnesium
Bromide 4. A solution of freshly purified ω-bromo-1-[(tetrahydro-
2H-pyran-2-yl)oxy]pentadecane 3 (6.42 g, 1 equiv, 16.40 mmol, in dry
THF (33 mL)) was added dropwise with stirring to magnesium
turnings (598 mg, 1.5 equiv, 24.60 mmol) under an argon atmosphere.
After the exothermic reaction had subsided, the mixture was stirred at
55 °C for 3 h. The Grignard solution of 4 was titrated with a sec-
butanol solution (0.5 mol/L) in the presence of ortho-phenanthroline
and was used rapidly in the next step.
dependence on the relative stereochemistry of the cyclopentane
unit. A more extensive comparative study is in progress to
confirm this stereochemical effect. As a potential interpretation,
we suggest that the trans-isomer 1b adopts a specific
conformation leading to a unique type of nano-object (vesicle).
This preferred conformation would favor the formation of a
hydrogen-bonding network between the sugar moieties, as
shown by the observation of a multilamellar system as well as
by the partial contacts of internal vesicles within larger ones.
Conversely, a wider range of nano-objects was observed from
the cis-isomer 1a. Indeed, the effect of the pseudorotation of
the cyclopentyl ring discussed before could explain a relative
conformational inconstancy of the lipid within the membrane.
Additionally, the absence of multilamellar structures seems to
reveal a low tendency for the formation of a hydrogen-bonding
network. These clear differences would demonstrate the
stereochemical importance of the cyclopentane on the self-
organizing properties of these bipolar lipids. The presence of
the five-membered ring with either a cis or a trans
stereochemistry, even placed in the middle of a long bipolar
lipid, would therefore influence in a different way (1) its
conformation, leading to a different nature of nano-objects, and
(2) the orientation of the lactosyl polar headgroups attached to
the tetraether backbone, thus favoring or inhibiting the
formation of hydrogen bonds.
2-(4-(5-(Tetrahydro-2H-pyran-2-yloxy)pentadecyl)trans-cy-
clopent-2-enyl)acetic Acid 6. To a solution of CuBr-Me2S (2.0 g,
1.2 equiv, 9.67 mmol) in Me2S (20 mL) and THF (40 mL) at 0 °C
was added Grignard solution 4 (33 mL titrated at 0.29 mol/L, 1.2
equiv, 9.67 mmol). After the mixture was stirred 1 h at room
temperature and cooled at −50 °C, a cold solution of lactone 5 (1 g in
THF (32 mL), 1 equiv, 8.06 mmol) was added dropwise via a syringe.
The resulting mixture was stirred and slowly warmed up to room
temperature (3 h) and then quenched with 1 N HCl. After extraction
with ether, the organic phase was washed with brine and water, dried
over MgSO4, and concentrated under reduced pressure. The crude
product solubilized in chloroform was filtered, and the filtrate was
concentrated under reduced pressure. Purification by column
chromatography (cyclohexane/AcOEt 85:15) gave acid 6 (1.76 g,
4.03 mmol, 50%) as a white solid: Rf = 0.27 (AcOEt/PE 10:90); mp =
CONCLUSIONS
■
The multistep synthesis of two diastereomers containing a
central cyclopentyl ring was achieved in 13 steps. It permits
reaching sufficient amounts of material to start a physicochem-
ical comparative study (i.e., >100 mg). The comparison of the
micrographs obtained by cryoTEM analysis demonstrates the
remarkable influence of the stereochemistry of a tetraether-type
lipid structure (archaeal lipid analogues). The sole change of
the relative stereochemistry of a cyclopentane ring placed in the
middle of a 32 carbon atom chain already induces dramatic
changes in the behavior of such bipolar lipids in aqueous
solutions. Indeed, the cis-isomer would provide a more flexible
conformation to the lipid and led to a lower number of
interactions (hydrogen bonds) between lipids within a
membrane. The trans-isomer seems to reach a higher
conformational rigidity that can be compared to the natural
lipids bearing the same stereochemistry. These conclusions
required several other studies such as small angle X-ray
scattering (SAXS) and pressure isotherm monolayers that
would provide additional evidence of the relationships between
stereochemistry and self-assembling properties. Thanks to the
synthetic scheme described in this article, these studies will be
reported in a near future.
1
58 °C; H NMR (CDCl3, 400 MHz) δ (ppm) 1.24−1.73 (m, 36H,
18CH2), 2.31 (dd, J = 15.4, 8.1 Hz, 1H, CH2CO), 2.40 (dd, J =
15.4, 6.9 Hz, 1H, CH2CO), 2.69 (m, 1H, CyP), 3.11 (m, 1H, CyP),
3.38 (dt, J = 9.6, 6.7 Hz, 1H, CH2CH2O), 3.51 (m, 1H, THP), 3.73
(dt, J = 9.6, 6.9 Hz, 1H, CH2CH2O), 3.88 (m, 1H, THP), 4.59 (m, 1H,
THP), 5.66 (dt, J = 5.6, 2.0 Hz, 1H, CyP), 5.73 (dt, J = 5.5, 1.9 Hz,
1H, CyP); 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.7 (CH2, THP),
25.5, 26.2, 27.9, 29.5 (4CH2), 29.6 (4CH2), 29.7, 29.8, 30.8, 35.8, 36.4
(5CH2), 41.2 (CH2CO), 42.5 (CH, CyP), 44.6 (CH, CyP), 62.3
(CH2, THP), 67.7 (CH2O), 98.8 (CH, THP), 132.7 (CH, CyP),
136.4 (CH, CyP), 176.1 (CO); Accurate mass calcd for C27 H48 O4
Na (M + Na)+ 459.34503, found 459.3450; Accurate mass calcd for
C27 H47 O4 Na2 (M − H + 2Na)+ 481.32697, found 481.3260.
2-(4-(15-(Tetrahydro-2H-pyran-2-yloxy)pentadecyl)trans-cy-
clopent-2-enyl)acetaldehyde 7. To a suspension of LiAlH4 (107
mg, 3 equiv, 2.66 mmol) in diethyl ether (40 mL) at 0 °C was added
dropwise a solution of acid 6 (0.41 g, 1 equiv, 0.89 mmol) in diethyl
ether (20 mL). The mixture was stirred at 0 °C for 1 h, followed by
dropwise addition of water and 1 M aqueous NaOH solution, until gas
evolution had ceased. The suspension was filtered, and the white
residue was washed with diethyl ether. The filtrate was dried over
MgSO4, and the solvent was removed under reduced pressure to give
the intermediary alcohol (375 mg, 0.89 mmol, quant.) as a white solid:
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere with dry, freshly distilled solvents under
anhydrous conditions. Tetrahydrofuran (THF) and diethyl ether
(Et2O) were dried by passage over a column of activated alumina;
dichloromethane (CH2Cl2) was distilled over calcium hydride. All
other reagents were used directly from the supplier without further
purification unless noted. Analytical thin layer chromatography (TLC)
was performed on 60 F254 silica gel nonactivated plates. A solution of
5% H2SO4 in EtOH or ultraviolet fluorescence was used to develop
the plates. Column chromatography was performed on silica gel 60 H
(5−40 μm). Nuclear magnetic resonance spectra were recorded at 400
MHz (1H) and 100 MHz (13C). For CDCl3, CD3OD, and pyridine-d5
solutions, the chemical shifts (δ) are reported as parts per million
1
Rf = 0.39 (AcOEt/PE 20:80); mp = 35 °C; H NMR (CDCl3, 400
MHz) δ (ppm) 1.24−1.87 (m, 38H, 19CH2), 2.66 (m, 1H, CyP), 2.79
(m, 1H, CyP), 3.38 (dt, J = 9.6, 6.7 Hz, 1H, CH2CH2O), 3.59 (m, 1H,
THP), 3.70 (m, 3H, CH2CH2O and CH2−OH), 3.87 (m, 1H, THP),
4.57 (m, 1H, THP), 5.67 (dt, J = 5.7, 1.9 Hz, 1H, CyP), 5.69 (dt, J =
5.7, 1.7 Hz, 1H, CyP); 13C NMR (CDCl3, 100 MHz) δ (ppm) 19.7
(CH2, THP), 22.3, 25.5, 26.2, 28.0, 29.5, 29.59, 29.61, 29.66, 29.74,
29.9, 30.8, 38.9 (18CH2), 41.3 (CH, CyP), 44.8 (CH; CyP), 61.9
(CH2−OH), 62.3 (CH2, THP), 67.7 (CH2O), 98.8 (CH, THP), 133.8
(CH, CyP), 135.4 (CH, CyP). Dess−Martin periodinane (DMP) in
DCM (1.1 mL, 1.1 equiv, 0.98 mmol) was added to a solution of the
previous alcohol (375 mg, 1 equiv, 0.89 mmol) in dichloromethane
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(14 mL). The mixture was stirred for 1 h at room temperature and
then quenched by the addition of saturated aq NaHCO3/saturated aq
Na2S2O3 1:1 (30 mL). The reaction mixture was extracted with Et2O,
and the combined organic layers were washed with saturated aq
NaHCO3, dried (MgSO4), and concentrated under reduced pressure.
Purification by column chromatography (PE/AcOEt 95:5) gave
aldehyde 7 (288 mg, 0.68 mmol, 77%) as a white solid: Rf = 0.33
(PE/AcOEt 95:5); mp = 29 °C; 1H NMR(CDCl3, 400 MHz) δ (ppm)
1.24−1.36 (m, 24H, 12CH2), 1.49−1.84 (m, 12H, (2CH2, THP),
(CH2, CyP), 3CH2), 2.40 (ddd, J = 16.5, 7.8, 2.1 Hz, 1H, CH2CHO),
2.49 (ddd, J = 16.6, 6.4, 1.9 Hz, 1H, CH2CHO), 2.67 (m, 1H, CyP),
3.16 (m, 1H, CyP), 3.38 (dt, J = 9.6, 6.7 Hz, 1H, CH2O), 3.49 (m, 1H,
THP), 3.73 (dt, J = 9.6, 6.9 Hz, 1H, CH2O), 3.86 (m, 1H, THP), 4.57
(m, 1H, THP), 5.64 (dt, J = 5.6, 2.1 Hz, 1H, CyP), 5.73 (dt, J = 5.6,
2.0 Hz, 1H, CyP), 9.77 (t, J = 2.0 Hz, 1H, CHO); 13C NMR (CDCl3,
100 MHz) δ (ppm) 19.7 (CH2, THP), 25.5, 26.2, 27.9, 29.5, 29.59,
29.60 (9CH2), 29.63 (2CH2), 29.64 (CH2), 29.66 (3CH2), 30.8, 35.8,
36.4 (3CH2), 39.0 (CH, CyP), 44.7 (CH, CyP), 49.9 (CH2CHO),
62.3 (CH2, THP), 67.7 (CH2O), 98.8 (CH, THP), 132.5 (CH, CyP),
136.5 (CH, CyP), 202.5 (CHO); Accurate mass calcd for C27 H48 O3
Na (M + Na)+ 443.35012, found 443.3512. Anal. for C27 H48 O3 calcd
C, 77.09; H, 11.50. Found C, 76.96; H, 11.70.
(CH, CyP), 45.0 (CH, CyP), 62.3 (CH2, THP), 67.7 (CH2O), 70.5
(CH2OBn), 72.8 (CH2Ph), 98.8 (CH, THP), 127.4 (CH, Ph), 127.6
(2CH, Ph), 128.2 (CH=), 128.3 (2CH, Ph), 130.7 (CH=), 134.2
(CH, CyP), 135.2 (CH, CyP), 138.7 (C, Ph); Accurate mass calcd for
C47 H80 O3 Na (M + Na)+ 715.60052, found 715.6016. Anal. for C47
H80 O3 calcd C, 81.44; H, 11.63. Found C, 81.60; H, 11.63.
2-(15-((3-(15-(Benzyloxy)pentadecyl)-trans-cyclopentyl)-
pentadecyloxy)tetrahydro-2H-pyran 11. A solution of 9 (1.0 g,
1.0 equiv, 1.44 mmol) in THF/EtOH 1:1 (100 mL) was stirred in the
presence of PtO2 (100 mg, 10% wt) under a 10 bar pressure of
hydrogen gas at room temperature for 1 h. The solvent was removed
by evaporation, and the residue was purified by silica gel column
chromatography (cyclohexane/CH2Cl2 60:40) to afford compound 11
(0.99 g, 1.42 mmol, 84%) as a white solid: Rf = 0.32 (cyclohexane/
1
CH2Cl2 60:40); mp = 41 °C; H NMR (CDCl3, 400 MHz) δ (ppm)
1.00−1.14 (m, 2H, CyP), 1.25−1.34 (m, 52H, 26CH2), 1.47−1.65 (m,
10H, (CH2, THP), 4CH2), 1.68−1.87 (m, 6H, (4CH, CyP), (CH2,
THP)), 3.38 (td, J = 6.7, 9.6 Hz, 1H, CH2O), 3.46 (t, J = 6.6 Hz, 2H,
CH2OBn), 3.49 (m, 1H, THP), 3.73 (td, J = 6.9, 9.6 Hz, 1H, CH2O),
3.87 (ddd, J = 11.2, 7.4, 3.6 Hz, 1H, THP), 4.50 (s, 2H, CH2Ph), 4.57
(m, 1H, THP), 7.27−7.34 (m, 5H, Ph); 13C NMR (CDCl3, 100 MHz)
δ (ppm) 19.7 (CH2, THP), 25.5, 26.19, 26.24 (4CH2), 28.7 (2CH2),
29.6 (4CH2), 29.66 (3CH2), 29.69 (9CH2), 29.73 (3CH2), 29.76
(2CH2), 29.9 (2CH2), 30.8 (CH2, THP), 33.0 (2CH2), 36.8 (2CH2),
38.8 (3C, CyP), 62.3 (CH2, THP), 67.7 (CH2O), 70.5 (CH2OBn),
72.8 (CH2Ph), 98.8 (CH, THP), 127.4 (CH, Ph), 127.6 (2CH, Ph),
128.3 (2CH, Ph), 138.7 (C, Ph); Accurate mass calcd for C47 H84 O3
Na (M + Na)+ 719.63182, found 719.6318. Anal. for C47 H84 O3 calcd
C, 80.97; H, 12.14. Found C, 80.98; H, 12.16.
(13-(Benzyloxy)tridecyl)triphenylphosphonium Bromide 8.
To a solution of bromide derivative (0.62 g, 1.0 equiv, 1.67 mmol) in
AcOEt (10 mL) was added triphenylphosphine (0.88 g, 2.0 equiv, 3.33
mmol), and the resulting mixture was refluxed for 4 days. After the
mixture was cooled to room temperature, the crystallized triphenyl-
phosphine oxide was filtered and washed with cold toluene. Column
chromatography over silica gel (CH2Cl2/MeOH 100:0 then 95:5)
gave the phosphonium salt 8 (0.40 g, 0.63 mmol, 38%) as a yellow oil:
15,15′-((trans-Cyclopentane-1,3-diyl)dipentadecan-1-ol 2b.
A solution of 11 (1.0 g, 1.0 equiv, 1.43 mmol) in THF/EtOH 1:1 (100
mL) was stirred in the presence of 10% palladium on activated
charcoal (300 mg, 0.2 equiv, 0.28 mmol) under an atmosphere of
hydrogen gas at room temperature for 1 h. The catalyst was removed
by filtration after heating to 40 °C and washed with a hot EtOH/THF
mixture, and the filtrate was concentrated to dryness under reduced
pressure. The residue was purified by flash silica gel column
chromatography (cyclohexane/AcOEt 80:20) to give the THP ether
compound (0.81 g, 1.33 mmol, 94%) as a white solid: Rf = 0.43
1
Rf = 0.36 (CH2Cl2/MeOH 95:5); H NMR (CDCl3, 400 MHz) δ
(ppm) 1.18 (m, 16H, 8CH2), 1.63 (m, 6H, 3CH2), 3.45 (t, J = 6.7 Hz,
2H, CH2OBn), 3.70 (m, 2H, CH2P), 4.49 (s, 2H, CH2Ph), 7.31 (m,
5H, PhCH2), 7.70 (m, 6H, (Hmeta, Ph3P)), 7.81 (m, 9H, Hortho/para
,
Ph3P); 13C NMR (CDCl3, 100 MHz) δ (ppm) 22.64 (d, J = 4 Hz,
CH2−CH2−CH2−P), 22.69 (d, J = 49 Hz, CH2P), 26.15, 29.15, 29.23,
29.43, 29.47 (5CH2), 29.50 (2CH2), 29.61, 29.74 (2CH2), 30.37 (d, J
= 16 Hz, CH2−CH2−P), 70.52 (CH2OBn), 72.82 (CH2Ph), 118.49
(d, J = 85 Hz, 3Cquat (PPh3)), 127.42 (CH(OBn)), 127.59
(2CH(OBn)), 128.30 (2CHOBn), 130.42 (d, J = 12 Hz, 3CHortho-
(Ph3)), 133.70 (d, J = 10 Hz, 3CHmeta(Ph3)), 134.89 (d, J = 3 Hz,
3CHpara(Ph3)), 138.68 (Cquat(OBn)); 31P NMR (CDCl3, 100
MHz) δ (ppm) 24.5; Accurate mass calcd for C38 H48 O P (M)+
551.34428, found 551.3446.
1
(cyclohexane/AcOEt 90:10); mp = 59 °C; H NMR (CDCl3, 400
MHz) δ (ppm) 1.02−1.14 (m, 2H, CyP), 1.25−1.36 (m, 52H,
26CH2), 1.49−1.61 (m, 11H, (CH2, THP), 4CH2, OH), 1.68−1.87
(m, 6H, (CH, CyP), (CH2, THP)), 3.38 (td, J = 6.7, 9.6 Hz, 1H,
CH2O), 3.50 (m, 1H, THP), 3.64 (m, 2H, CH2OH), 3.72 (td, J = 6.9,
9.6 Hz, 1H, CH2O), 3.87 (m, 1H, THP), 4.57 (m, 1H, THP); 13C
NMR (CDCl3, 100 MHz) δ (ppm) 19.7 (CH2, THP), 25.5, 25.7, 26.2
(3CH2), 28.7 (2CH2), 29.4, 29.5 (2CH2), 29.60 (2CH2), 29.61
(2CH2), 29.65 (2CH2), 29.68 (2CH2), 29.72 (2CH2), 29.75 (1CH2),
29.9 (2CH2), 30.8 (CH2, THP), 32.8 (CH2), 33.0 (2CH, CyP), 36.8
(2CH2), 38.8 (3C, CyP), 62.3 (CH2, THP), 63.1 (CH2OH), 67.7
(CH2O), 98.8 (CH, THP); Accurate mass calcd for C40 H78 O3 Na (M
+ Na)+ 629.58487, found 629.5833. Anal. for C40 H78 O3 calcd C,
79.14; H, 12.95. Found C, 79.05; H, 12.90. A solution of the previous
THP ether (1.3 g, 1.0 equiv, 2.14 mmol) and PTSA (100 mg, 0.1
equiv, 0.21 mmol) in CHCl3/MeOH 1:1 (100 mL) was stirred at 55
°C for 2 h. The reaction mixture was quenched with saturated aq
NaHCO3 and extracted three times with chloroform. The combined
extracts were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Purification by column chromatography
(cyclohexane/AcOEt 80:20) gave the diol 2b (0.76 g, 1.45 mmol,
89%) as a white solid: Rf = 0.3 (cyclohexane/AcOEt 80:20); mp = 89
2-(15-(4-(15-(Benzyloxy)pentadec-2-enyl)trans-cyclopent-2-
enyl)pentadecyloxy)tetrahydro-2H-pyran 9. To a suspension of
dried phosphonium bromide 8 (1.5 g, 1.5 equiv, 2.36 mmol) in dry
THF (14 mL), n-butyllithium (1.35 mol/L in hexane, 1.76 mL, 1.5
equiv, 2.36 mmol) was added at 0 °C. The reaction mixture was stirred
for 30 min at 0 °C, and aldehyde 7 (666 mg, 1.0 equiv, 1.58 mmol)
dissolved in dry THF (2 mL) was added at −20 °C. After stirring for
12 h at room temperature and cooling at 0 °C, the reaction was
quenched with water and diluted with ether. The organic layer was
separated, and the aqueous layer was extracted with ether. The
combined organic extracts were washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The crude material was
purified by silica gel chromatography (cyclohexane/CH2Cl2 60:40) to
yield 9 (780 mg, 1.12 mmol, 71%) as a colorless oil: Rf = 0.62 (PE/
1
AcOEt 95:5); H NMR (CDCl3, 400 MHz) δ (ppm) 1.34 (m, 40H,
20CH2), 1.60 (m, 15H, (2CH2, THP), (CH2, CyP), 5CH2), 1.82 (m,
1H, (CH2, THP)), 2.01 (m, 4H, 2CH2), 2.72 (m, 2H, CyP), 3.38 (dt, J
= 9.6, 6.7 Hz, 1H, CH2O), 3.46 (t, J = 6.7 Hz, 2H, CH2OBn), 3.49 (m,
1H, THP), 3.73 (dt, J = 9.6, 6.9 Hz, 1H, CH2O), 3.87 (ddd, J = 11.1,
7.6, 3.6 Hz, 1H, THP), 4.50 (s, 2H, CH2Ph), 4.58 (m, 1H, THP), 5.38
(m, 2H, CHCH), 5.65 (dt, J = 5.7, 1.8 Hz, 1H, CyP), 5.67 (dt, J =
5.7, 1.8 Hz, 1H, CyP), 7.33 (m, 5H, Ph); 13C NMR (CDCl3, 100
MHz) δ (ppm) 19.7 (CH2, THP), 25.5, 29.19, 29.24 (3CH2), 27.3
(CH2), 28.0, 29.3 (2CH2), 29.49 (2CH2), 29.55 (CH2), 29.60
(5CH2), 29.66 (CH2), 29.68 (6CH2), 29.73, 29.75, 29.76, 29.90
(4CH2), 30.8 (CH2, THP), 33.4 (CH2), 36.12, 36.17 (2CH2), 44.8
1
°C; H NMR (CDCl3, 400 MHz) δ (ppm) 1.02−1.14 (m, 2H, CyP),
1.25−1.36 (m, 54H, 27CH2), 1.53−1.60 (m, 6H, 2CH2, 2OH), 1.75−
1.83 (m, 4H, CyP), 3.64 (t, J = 6.6 Hz, 4H, 2CH2OH); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 25.7 (3CH2), 28.7 (2CH2), 29.4 (3CH2),
29.59 (2CH2), 29.61 (2CH2), 29.65 (2CH2), 29.68 (8CH2), 29.72
(CH2), 29.9 (2CH2), 32.9 (2CH2), 33.0 (CH, CyP), 36.8 (CH2), 38.8
(3C, CyP), 63.1 (2CH2OH); Accurate mass calcd for C35 H70 O2 Na
(M + Na)+ 545.52735, found 545.5267; Accurate mass calcd for C35
9744
dx.doi.org/10.1021/jo201827h|J. Org. Chem. 2011, 76, 9738−9747

The Journal of Organic Chemistry
Article
H71 O2 (M + H)+ 523.54541, found 523.5462. Anal. for C35 H70 O2
calcd C, 80.39; H, 13.49. Found C, 80.71; H, 13.32.
1.25−1.34 (54H, m, 27CH2), 1.21−1.58 (4H, m, 2CH2), 1.67−1.81
(4H, m, (4CH, CyP), 2.48 (2H, d, J = 4.2 Hz, 2OH), 3.42−3.58 (12H,
m, 6CH2O), 3.99 (2H, m, 2CHO), 4.56 (4H, s, 2CH2Ph), 7.26−7.38
(10H, m, 2Ph); 13C NMR (CDCl3, 100 MHz) δ (ppm) 26.1 (2CH2),
28.7 (2CH2), 29.5 (2CH2), 29.60 (2CH2), 29.61 (2CH2), 29.67
(2CH2), 29.70 (10CH2), 29.73 (2CH2), 30.0 (2CH2), 33.0 (2CH,
CyP), 36.8 (2CH2), 38.76 (3C, CyP), 69.5 (2CHO), 71.4 (2CH2O),
71.7 (2CH2O), 71.8 (2CH2O), 73.5 (2CH2Ph), 127.7 (6CH, Ph),
128.4 (4CH, Ph), 130.0 (2C, Ph); Accurate mass calcd for C55 H94 O6
Na (M + Na)+ 873.69426, found 873.6946. Anal. for C55 H94 O6 calcd
C, 77.59; H, 11.13. Found C, 76.99; H, 11.07.
1,1′-O-((16,19-Methylidene)tetratriacontane)bis-(R)-glycidol
12a,b. To a solution of diol 2 (1.0 g, 1.0 equiv, 1.91 mmol) in hot
cyclohexane (5 mL), a NaOH aqueous solution (50% wt, 1.83 g, 12
equiv, 22.9 mmol) and TBAB (370 mg, 0.6 equiv, 1.15 mmol) were
added. After the mixture was stirred for 15 min at room temperature,
epichlorhydrine (1.79 mL, 1.0 equiv, 1.9 mmol) was added. The
resulting mixture was stirred at 70 °C for 12 h, cooled to room
temperature, and then diluted with water. The viscous precipitate was
filtered out and washed with AcOEt. The organic layer was separated,
and the aqueous layer was extracted with AcOEt and then with
CH2Cl2. The combined organic extracts were washed with brine, dried
over MgSO4, and concentrated. The crude material was purified by
silica gel chromatography (cyclohexane/AcOEt 90:10) to yield
diepoxyde 12 (0.54 g, 0.85 mmol) as white solid (monoepoxyde
alcohol (0.40 g, 0.69 mmol) was also isolated): Rf = 0.56
(cyclohexane/AcOEt 80:20). cis (12a): yield = 51%; mp = 60 °C;
1,1′-Di-O-benzyle-2,2′-di-O-(3,7,11(R)-3,7,11,15-tetrameth-
yl-hexadecyl)-3,3′-O-((16,19-methylidene)tetratriacontane)-di-
sn-glycerol 14a,b. Sodium hydride (60% in oil, 246 mg, 5.0 equiv,
6.16 mmol) dispersed in dry THF (20 mL) and diol 13 (1.05 g, 1.0
equiv, 1.23 mmol) was added in solution in THF (20 mL). The
reaction mixture was stirred for 1.5 h at room temperature, and then
PhytBr (1.07 g, 2.4 equiv, 2.96 mmol) was added in solution in THF
(4 mL). The solvent was distilled out during heating, and the reaction
mixture was kept at 130 °C for 12 h. After cooling, water was added,
and the reaction mixture was diluted with ether. The organic layer was
washed with water and brine and dried over MgSO4. The solvent was
removed under reduced pressure, and the resulting crude mixture was
purified by silica gel chromatography (cyclohexane/CH2Cl2 1:1) to
afford 14 as a colorless oil: Rf = 0.23 (cyclohexane/CH2Cl2 1:1). cis
1
[α]D20 = −4.0 (c 1, CH2Cl2); H NMR (CDCl3, 400 MHz) δ (ppm)
0.62 (1H, dt, J = 11.8, 9.9 Hz, CyP), 1.02−1.13 (2H, m, CyP), 1.25−
1.34 (52H, m, 26CH2), 1.54−1.62 (4H, m, 2CH2), 1.74−1.82 (4H, m,
CyP), 1.90 (1H, m, CyP), 2.61 (2H, dd, J = 5.0, 2.7 Hz, (CH2,
epoxide)), 2.80 (2H, dd, J = 5.0, 4.1 Hz, (CH2, epoxide)), 3.14 (2H,
m, (CH, epoxide)), 3.38 (2H, dd, J = 11.5, 5.6 Hz, CH2O), 3.47 (2H,
td, J = 6.7, 9.3 Hz, CH2O), 3.49 (2H, td, J = 6.7, 9.3 Hz, CH2O), 3.69
(2H, dd, J = 11.5, 3.1 Hz, CH2O); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 26.1 (2CH2), 28.7 (2CH2), 29.5 (2CH2), 29.59 (2CH2), 29.61
(2CH2), 29.66 (2CH2), 29.69 (10CH2), 29.73 (2CH2), 30.0 (2CH2),
31.6 (2CH, CyP), 36.8 (2CH2), 40.1 (2CH, CyP), 40.7 (CH2, CyP),
44.7 (2CH2O), 50.9 (2CHO), 71.5 (2CH2O), 71.7 (2CH2O);
Accurate mass calcd for C41 H78 O4 Na (M + Na)+ 657.57978,
20
1
(14a): yield = 72%; [α]D = +1.3 (c 1, CH2Cl2); H NMR (CDCl3,
400 MHz) δ (ppm) 0.62 (1H, dt, J = 11.0, 9.9 Hz, CyP), 0.83−0.87
(30H, m, 10CH3), 1.01−1.40 (98H, m, 48CH2, (CH2, CyP)), 1.49−
1.66 (8H, m, 8CHCH3), 1.72−1.83 (4H, m, (2CH, CH2, CyP)),
1.87−1.90 (1H, m, (CH2, CyP)), 3.42 (4H, t, J = 6.7 Hz, 2CH2O),
3.46−3.66 (14H, m, 6CH2O, 2CHO), 4.55 (4H, s, 2CH2Ph), 7.26−
7.34 (10H, m, 10CH, Ph); 13C NMR (CDCl3, 100 MHz) δ (ppm)
19.7 (2CH3), 19.75 (2CH3), 19.78 (2CH3), 22.6 (2CH3), 22.7
(2CH3), 24.4 (2CH2), 24.5 (2CH2), 24.8 (2CH2), 26.1 (2CH2), 28.0
(2CH), 28.7 (2CH2), 29.5 (2CH), 29.7 (16CH2), 29.8 (2CH2), 30.0
(2CH), 31.6 (2CH2, CyP), 33.0 (2CH2), 36.8 (2CH2), 37.1 (4CH2),
37.3 (4CH2), 37.4 (2CH2), 37.46 (2CH2), 37.52 (2CH2), 39.4
(2CH2), 40.1 (2CH, CyP), 40.7 (CH2, CyP), 68.9 (2CH2O), 70.3
(2CH2O), 70.8 (2CH2O), 71.7 (CH2O), 73.4 (2CH2Ph), 77.9
(2CHO), 127.5 (2CH, Ph), 127.6 (4CH, Ph), 128.3 (4CH, Ph),
found 657.5786. Anal. for C41 H78 O4 calcd C, 77.54; H, 12.38. Found
20
C, 77.39; H, 12.42. trans (12b): yield = 45%; mp = 60 °C; [α]D
=
−3.6 (c 1, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.02−1.13
(2H, m, CyP), 1.25−1.34 (54H, m, 27CH2), 1.54−1.62 (4H, m,
2CH2), 1.74−1.82 (4H, m, CyP), 2.61 (2H, dd, J = 5.0, 2.7 Hz, (CH2,
epoxide)), 2.80 (2H, dd, J = 5.0, 4.1 Hz, (CH2, epoxide)), 3.14 (2H,
m, (CH, epoxide)), 3.38 (2H, dd, J = 11.5, 5.6 Hz, CH2O), 3.47 (2H,
td, J = 6.7, 9.3 Hz, CH2O), 3.49 (2H, td, J = 6.7, 9.3 Hz, CH2O), 3.69
(2H, dd, J = 11.5, 3.1 Hz, CH2O); 13C NMR (CDCl3, 100 MHz) δ
(ppm) 26.1 (2CH2), 28.7 (2CH2), 29.5 (2CH2), 29.59 (2CH2), 29.61
(2CH2), 29.66 (2CH2), 29.69 (10CH2), 29.73 (2CH2), 30.0 (2CH2),
33.0 (2CH, CyP), 36.8 (2CH2), 38.8 (3C, CyP), 44.7 (2CH2O), 50.9
(2CHO), 71.5 (2CH2O 1), 71.7 (2CH2O); Accurate mass calcd for
C41 H78 O4 Na (M + Na)+ 657.57978, found 657.5794. Anal. for C41
H78 O4 calcd C, 77.54; H, 12.38. Found C, 77.58; H, 12.51.
20
138.4 (2C, Ph). trans (14b): yield = 60%; [α]D = +1.2 (c 1,
CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.83−0.87 (30H, m,
10CH3), 1.01−1.40 (100H, m, 48CH2, (2CH2, CyP)), 1.49−1.66 (8H,
m, 8CHCH3), 1.72−1.83 (4H, m, 2CH, CH2, CyP), 3.42 (4H, t, J =
6,7 Hz, 2CH2O), 3.46−3.66 (14H, m, 6CH2O, 2CHO), 4.55 (4H, s,
2CH2Ph), 7.26−7.34 (10H, m, 10CH, Ph); 13C NMR (CDCl3, 100
MHz) δ (ppm) 19.7 (2CH3), 19.75 (2CH3), 19.78 (2CH3), 22.6
(2CH3), 22.7 (2CH3), 24.4 (2CH2), 24.5 (2CH2), 24.8 (2CH2), 26.1
(2CH2), 28.0 (2CH), 28.7 (2CH2), 29.5 (2CH), 29.65, 29.71
(16CH2), 29.8 (2CH2), 30.0 (2CH), 32.8 (2CH2, CyP), 33.0
(2CH2), 36.8 (2CH2), 37.1 (4CH2), 37.3 (4CH2), 37.4 (2CH2),
37.46 (2CH2), 37.52 (2CH2), 38.8 (3C, CyP), 39.4 (2CH2), 68.9
(2CH2O), 70.3 (2CH2O), 70.8 (2CH2O), 71.7 (CH2O), 73.4
(2CH2Ph), 77.9 (2CH), 127.5 (2CH, Ph), 127.6 (4CH, Ph), 128.3
(4CH, Ph), 138.4 (2C, Ph); Accurate mass calcd for C95 H174 O6 Na
(M + Na)+ 1434.32081, found 1434.3189. Anal. for C95 H174 O6 calcd
C, 80.79; H, 12.42. Found C, 80.89; H, 12.08.
1,1′-Di-O-benzyle-3,3′-O-((16,19-methylidene)-
tetratriacontan)-di-sn-glycerol 13a,b. Diepoxyde 12 (924 mg, 1.0
equiv, 1.45 mmol), commercially available sodium methanolate (15
mg, 0.1 equiv, 0.15 mmol) and benzyl alcohol (3.0 mL, 20 equiv, 29
mmol) were vigorously stirred at 70 °C for 12 h. At room temperature,
the reaction mixture was extracted with CH2Cl2, and the combined
organic layers were washed with saturated aq NaCl, dried (MgSO4),
concentrated, and freeze-dried. Purification by silica gel column
chromatography (cyclohexane/AcOEt 80:20) gave the compound 13
(1.09 g, 1.28 mmol) as a white solid: Rf = 0.23 (cyclohexane/AcOEt
20
80:20). cis (13a): yield = 83%; mp = 52 °C; [α]D = −5.0 (c 1,
1
CH2Cl2); H NMR (CDCl3, 400 MHz) δ (ppm) 0.62 (1H, dt, J =
2,2′-Di-O-(3,7,11(R)-3,7,11,15-tetramethyl-hexadecyl)-3,3′-
O-((16,19-methylidene)tetratriacontane)-di-sn-glycerol
15a,b. A solution of 11 (797 mg, 1.0 equiv, 0.56 mmol) in THF/
EtOH 1:1 (15 mL) was stirred in the presence of 20% Pd(OH)2/C
(80 mg) under an atmosphere of hydrogen gas at room temperature
for 3 h. The catalyst was removed by filtration after the solvent was
heated to 40 °C and washed with the hot EtOH/THF mixture, and
the filtrate was concentrated to dryness under reduced pressure. The
residue was purified by flash silica gel column chromatography
(cyclohexane/AcOEt 80:20) to give the tetraether 15 as a white solid:
Rf = 0.17 (cyclohexane/AcOEt 90:10). cis (15a): yield = 96%; mp =
11.0, 9.9 Hz, CyP), 1.00−1.14 (2H, m, CyP), 1.25−1.34 (52H, m,
26CH2), 1.21−1.58 (4H, m, 2CH2), 1.67−1.81 (4H, m, CyP), 1.87−
1.91 (1H, m, CyP), 2.48 (2H, d, J = 4.2 Hz, 2OH), 3.42−3.58 (12H,
m, 6CH2O), 3.99 (2H, m, 2CHO), 4.56 (4H, s, 2CH2Ph), 7.26−7.38
(10H, m, 2Ph); 13C NMR (CDCl3, 100 MHz) δ (ppm) 26.1 (2CH2),
28.7 (2CH2), 29.5 (2CH2), 29.60 (2CH2), 29.61 (2CH2), 29.67
(2CH2), 29.70 (10CH2), 29.73 (2CH2), 30.0 (2CH2), 31.6 (2CH,
CyP), 36.8 (2CH2), 40.1 (2CH, CyP), 40.7 (CH2, CyP), 69.5
(2CHO), 71.4 (2CH2O), 71.7 (2CH2O), 71.8 (2CH2O), 73.4
(2CH2Ph), 127.7 (6CH, Ph), 128.4 (4CH, Ph), 130.0 (2C, Ph).
trans (13b): yield = 74%; mp = 52 °C; [α]D20 = −4.8 (c 0.5, CH2Cl2);
1H NMR (CDCl3, 400 MHz) δ (ppm) 1.00−1.14 (2H, m, CyP),
20
1
35 °C; [α]D = +4.6 (c 1, CH2Cl2); H NMR (CDCl3, 400 MHz) δ
(ppm) 0.62 (1H, m, CyP), 0.83−0.89 (30H, m, 10CH3), 1.03−1.40
9745
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Article
(98H, m, 48CH2, (CH2, CyP)), 1.47−1.66 (8H, m, 8CH), 1.73−1.85
(4H, m, (2CH, CH2, CyP), 1.85−1.89 (1H, m, CyP), 2.17 (2H, t, J =
6.7, OH), 3.41−3.75 (18H, m, 8CH2O, 2CHO); 13C NMR (CDCl3,
100 MHz) δ (ppm) 19.68, 19.74, 19.76 (6CH3), 22.6 (2CH3), 22.7
(2CH3), 24.4 (2CH2), 24.5 (2CH2), 24.8 (2CH2), 26.1 (2CH2), 26.9
(2CH2), 28.0 (2CH), 28.7 (2CH2), 29.5 (2CH), 29.61 (2CH2), 29.62
(2CH2), 29.7 (10CH2), 29.8 (2CH2), 30.0 (2CH2), 31.6 (2CH2,
CyP), 32.8 (4CH), 36.8 (2CH2), 37.1 (2CH2), 37.3 (4CH2), 37.35
(4CH2), 37.38 (2CH2), 37.45 (2CH2), 37.49 (2CH2), 39.4 (2CH2),
40.2 (CH, CyP), 40.7 (CH2, CyP), 63.1, 68.6, 71.0, 71.9, 78.3
(8CH2O, 2CHO); Accurate mass calcd for C81 H162 O6 Na (M + Na)+
1254.22691, found 1254.2295. Anal. for C81 H162 O6 calcd C, 78.96; H,
13.25. Found C, 78.68; H, 13.29. trans (15b): yield = 92%; mp = 34
°C; [α]D = +4.9 (c 1.4, CH2Cl2); H NMR (CDCl3, 400 MHz) δ
(ppm) 0.83−0.89 (30H, m, 10CH3), 1.03−1.40 (100H, m, 48CH2,
2CH2, CyP), 1.47−1.66 (8H, m, 8CH), 1.73−1.85 (4H, m, CyP), 2.17
(2H, t, J = 6.7, OH), 3.41−3.75 (18H, m, 8CH2O, 2CHO); 13C NMR
(CDCl3, 100 MHz) δ (ppm) 19.68, 19.74, 19.76 (6CH3), 22.6
(2CH3), 22.7 (2CH3), 24.4 (2CH2), 24.5 (2CH2), 24.8 (2CH2), 26.1
(2CH2), 26.9 (2CH2), 28.0 (2CH), 28.7 (2CH2), 29.5 (2CH), 29.61
(2CH2), 29.62 (2CH2), 29.7 (10CH2), 29.8 (2CH2), 30.0 (2CH2),
32.8 (4CH), 33.0 (CH2, CyP), 36.8 (2CH2), 37.1 (2CH2), 37.3
(4CH2), 37.35 (4CH2), 37.38 (2CH2), 37.45 (2CH2), 37.49 (2CH2),
38.8 (3C, CyP), 39.4 (2CH2), 63.1, 68.6, 71.0, 71.9, 78.3 (8CH2O,
2CHO); Accurate mass calcd for C81 H162 O6 Na (M + Na)+
1254.22691, found 1254.2291. Anal. for C81 H162 O6 calcd C, 78.96;
H, 13.25. Found C, 79.37; H, 13.31.
5.73 (4H, m, H-2b, (CHO, Lact)), 5.79 (2H, t, J = 9.5 Hz, (CHO,
Lact)), 7.11−8.02 (70H, m, (14H, Bz)); 13C NMR (CDCl3, 100
MHz) δ (ppm) 18.4, 19.3, 19.7, 22.6 (5CH3), 24.2, 24.5, 24.8, 26.0,
28.0 (CH2), 28.7 (CH), 29.47, 29.52, 29.61, 29.63, 29.65, 29.69, 29.73,
29.74, 30.0, 32.79, 32.80, 33.0 (CH2, CyP), 33.8, 36.9, 37.3, 37.37,
37.40, 37.5, 38.8 (3C, CyP), 39.4, 58.5, 61.0, 62.4, 67.5 (CHO), 68.1,
69.9 (CHO), 70.4, 70.6, 71.4, 71.5, 71.6 (CHO), 71.7, 71.8 (CHO),
72.85, 72.91, 72.94 (CHO), 76.0 (CHO), 77.6, 101.0 (OCHO), 101.4
(OCHO), 128.20, 128.23, 128.3, 128.50, 128.53, 128.56, 128.62,
128.66, 128.8, 129.35, 129.41, 129.5, 129.59, 129.63, 129.73, 129.76,
130.0 (35CH, Bz), 133.1, 133.2, 133.3, 133.4, 133.5 (7C, Bz), 164.8,
165.1, 165.2, 165.4, 165.5, 165.8. A solution of sodium methanolate in
MeOH (0.1 mol/L, 16 mL, 5.0 equiv, 1.62 mmol) was added to a
solution of glycosylated tetraether protected-1 (1.0 g, 1.0 equiv, 0.32
mmol) in MeOH (25 mL) and CH2Cl2 (20 mL). The resulting
mixture was stirred at room temperature for 12 h and neutralized by
adding Amberlite IR 120 resin. After filtration and concentration, the
residue was purified by silica gel column chromatography (CHCl3/
MeOH 80:20) and recrystallization (Et2O) to yield final compound 1
(313 mg, 0.17 mmol) as white solid. cis (1a): yield = 66%; mp > 250
°C; [α]D20 = −5.7 (c 1, CHCl3/MeOH 80:20); 1H NMR (pyridine-d5,
400 MHz) δ (ppm) 0.71−0.77 (m, 1H, CyP), 0.88−0.94 (30H, m,
10CH3), 1.10−1.53 (98H, m, 48CH2, (CH2, CyP), 1.59−1.72 (8H, m,
8CH), 1.83−1.90 (4H, m, 2CH, CH2, CyP), 2.09−2.13 (m, 1H, CyP),
3.46−3.52 (4H, m, 2CH2O), 3.71 (2H, dd, J = 9.8, 6.1 Hz, CH2O),
3.77−3.84 (6H, m, 3CH2O), 3.87−3.90 (2H, m, (2CH, Lact)), 3.95−
4.02 (4H, m, (4CH, Lact)), 4.04−4.09 (2H, m, 2CH, Lact), 4.14−4.18
(4H, m, 4CH, Lact), 4.26−4.35 (6H, m, (6CH, Lact)), 4.37−4.43
(2H, m, CH2O), 4.45−4.57 (10H, m, CH2O, (6CH, Lact), 2CHO),
4.90 (2H, d, J = 7.9 Hz, OCHO), 5.12 (2H, d, J = 7.9 Hz, OCHO),
6.10−7.30(m, OH); 13C NMR (pyridine-d5, 100 MHz) δ (ppm)
20.26, 20.31, 23.1, 23.2 (CH3), 25.1, 25.2, 25.5, 26.9 (CH2), 28.6
(CH), 29.5, 30.2, 30.35, 30.41 (CH2), 30.5 (CH), 30.56, 30.7, 31.8
(2CH2, CyP), 32.3 (CH2), 33.4, 33.5 (CH), 37.4, 37.9, 38.04, 38.07,
38.10, 38.2, 39.9 (CH2), 40.8 (CH, CyP), 41.3 (CH2, CyP), 62.4, 62.5,
68.2, 72.0 (CH2), 72.8, 75.0, 75.6, 76.8, 77.0, 77.6, 78.9, 82.4 (CH,
Lact), 105.2 (OCHO), 106.1 (OCHO); Accurate mass calcd for C105
H202 O26 Na (M + Na)+ 1902.43821, found 1902.4375. trans (1b):
yield = 48%; mp > 250 °C; [α]D20 = −5.3 (c 1, CHCl3/MeOH 80:20);
1H NMR (pyridine-d5, 400 MHz) δ (ppm) 0.88−0.94 (30H, m,
10CH3), 1.10−1.53 (100H, m, 48CH2, (2CH2, CyP)), 1.59−1.72 (8H,
m, 8CH), 1.83−1.90 (4H, m, (2CH, CH2, CyP)), 3.46−3.52 (4H, m,
2CH2O), 3.71 (2H, dd, J = 9.8, 6.1 Hz, CH2O), 3.77−3.84 (6H, m,
3CH2O), 3.87−3.90 (2H, m, (2CH, Lact)), 3.95−4.02 (4H, m, (4CH,
Lact)), 4.04−4.09 (2H, m, (2CH, Lact)), 4.14−4.18 (4H, m, (4CH,
Lact)), 4.26−4.35 (6H, m, (6CH, Lact)), 4.37−4.43 (2H, m, CH2O),
4.45−4.57 (10H, m, CH2O, (5CH, Lact), 2CHO), 4.90 (2H, d, J = 7.9
Hz, OCHO), 5.12 (2H, d, J = 7.9 Hz, OCHO), 6.10−7.30 (m, OH);
13C NMR (pyridine-d5, 100 MHz) δ (ppm) 20.26, 20.31, 23.1, 23.2
(CH3), 25.1, 25.2, 25.5, 26.9 (CH2), 28.6 (CH), 29.5, 30.2, 30.3, 30.4
(CH2), 30.5 (CH), 30.6, 30.66, 32.3 (CH2), 33.4, 33.46 (CH), 33.51
(2CH2, CyP), 37.4, 37.9, 38.04, 38.07, 38.10, 38.2, 39.9 (CH2), 40.8
(3C, CyP), 62.4, 62.5, 68.2, 72.0 (CH2), 72.8, 75.0, 75.6, 76.8, 77.0,
77.6, 78.9, 82.4 (CH, Lact), 105.2 (OCHO), 106.1 (OCHO);
Accurate mass calcd for C105 H202 O26 Na (M + Na)+ 1902.43821,
found 1902.4379.
20
1
1,1′-Di-O-(β-D-galactopyranosyl)-β-D-glucopyranose)-2,2′-
di-O-(3,7,11(R)-3,7,11,15-tetramethyl-hexadecyl)-3,3′-O-
((16,19-methylidene)tetratriacontane)-di-sn-glycerol 1a,b. Hy-
droxylated tetraether 15 (525 mg, 1.0 equiv, 0.43 mmol) and 2,3,6-tri-
O-benzoyl-4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-α-D-
glucopyranose trichloroacetimidate 16 (2.59 g, 5.0 equiv, 2.13 mmol)
were dissolved in CH2Cl2 (45 mL). TMSOTf (5% in CH2Cl2, 154 μL,
0.1 equiv, 0.04 mmol) was added. After being stirred for 2 h at room
temperature, the reaction was quenched with saturated aq NaHCO3,
and the precipitate was filtered out and washed with CH2Cl2. The
filtrate was concentrated under reduced pressure and purified by silica
gel column chromatography (cyclohexane/AcOEt 80:20) to give
glycosylated tetraether protected-1 (1.08 g, 0.32 mmol) as a white
solid: Rf = 0.5 (cyclohexane/AcOEt 70:30), cis (protected-1a): yield =
20
1
92%; mp = 71 °C; [α]D = +27.5 (c 1, CH2Cl2); H NMR (CDCl3,
400 MHz) δ (ppm) 0.58−0.66 (m, 1H, CyP), 0.70 (6H, d, J = 6.5 Hz,
2CH3), 0.81−0.87 (26H, m, CH3), 0.99−1.40 (104H, m, 48CH2,
6CH, (CH2, CyP), 1.47−1.54 (2H, m, 2CH), 1.74−1.85 (4H, m,
(2CH, CH2, CyP)), 1.86−1.93 (m, 1H, CyP), 3.19−3.91 (26H, m,
6CH2O, 2CHO), 4.25 (2H, t, J = 9.5 Hz, (CHO, Lact)), 4.46−4.60
(4H, m, 2CH2O), 4.76 (2H, d, J = 7.9 Hz, CHO, Lact), 4.85 (2H, d, J
= 7.9 Hz, (CHO, Lact)), 5.35 (2H, dd, J = 10.3, 3.5 Hz, (CHO, Lact)),
5.47 (2H, dd, J = 9.9, 7.9 Hz, (CHO, Lact)), 5.69−5.73 (4H, m,
(CHO, Lact)), 5.79 (2H, t, J = 9.5 Hz, (CHO, Lact)), 7.11−8.02
(70H, m, (14H, Bz)); 13C NMR (CDCl3, 100 MHz) δ (ppm) 18.4,
19.3, 19.7, 22.6 (5CH3), 24.3, 24.5, 24.8, 26.0, 28.0 (CH2), 28.7 (CH),
29.47, 29.52, 29.61, 29.63, 29.65, 29.69, 29.73, 29.74, 30.0, 31.6 (CH2,
CyP), 32.79, 32.80, 33.8, 36.9, 37.3, 37.37, 37.40, 37.5, 40.2 (2CH,
CyP), 40.7 (CH2, CyP), 58.5, 61.0, 62.4, 67.5 (CHO), 68.1, 69.9
(CHO), 70.4, 70.6, 71.4, 71.5, 71.6 (CHO), 71.7, 71.8 (CHO), 72.85,
72.91, 72.94 (CHO), 76.0 (CHO), 77.6, 101.0 (OCHO), 101.4
(OCHO), 128.20, 128.23, 128.3, 128.50, 128.53, 128.56, 128.62,
128.66, 128.8, 129.35, 129.41, 129.5, 129.59, 129.63, 129.73, 129.76,
130.0 (35CH, Bz), 133.1, 133.2, 133.3, 133.4, 133.5 (7C, Bz), 164.8,
165.1, 165.2, 165.4, 165.5, 165.8. trans (protected-1b): yield = 76%;
CryoTEM Studies. Samples used in the CryoTEM studies were
prepared from a lipid film obtained by evaporation of a CHCl3/MeOH
2:1 solution (1.0 mg in 1.0 mL) of the lipids (N2 flow). The films were
dried under reduced pressure overnight and hydrated by 1.0 mL of
pure water at 45 °C. After one night, the samples were sonicated (2 ×
5 min) at 45 °C (thermocontrolled sonic bath). Each sample (5 μL)
was deposited on a grid covered with a carbon film having 2 μm
diameter holes previously exposed to treatment with UV-ozone. The
excess of water was removed by absorption with filter paper to form a
thin layer of water suspended inside the holes. This grid was then
plunged quickly in liquid ethane (−178 °C). Grids were then placed in
a suitable object carrier for observing the samples at −170 °C.
Observation under a microscope was carried out in the mode Low
Dose, limiting the effects of beam irradiation on the lipid material.
20
1
mp = 69 °C; [α]D = +30.1 (c 1, CH2Cl2); H NMR (CDCl3, 400
MHz) δ (ppm) 0.70 (6H, d, J = 6.5 Hz, 2CH3), 0.81−0.87 (26H, m,
CH3), 0.99−1.40 (106H, m, 48CH2, 6CH(Phyt), (CH2, CyP)), 1.47−
1.54 (2H, m, 2CH), 1.74−1.85 (4H, m, (CH, CH2, CyP), 3.19−3.91
(26H, m, 6CH2O, 2CHO), 4.25 (2H, t, J = 9.5 Hz, (CHO, Lact)),
4.46−4.60 (4H, m, 2CH2O), 4.76 (2H, d, J = 7.9 Hz, (OCHO, Lact)),
4.85 (2H, d, J = 7.9 Hz, (OCHO, Lact)), 5.35 (2H, dd, J = 10.3, 3.5
Hz, (CHO, Lact)), 5.47 (2H, dd, J = 9.9, 7.9 Hz, (CHO, Lact)), 5.69−
9746
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Article
Images were recorded using an ultrasensitive camera 2K × 2K with a
pixel size of 14 μm. The electron dose used was 10−20 electrons/Å2.
The image resolution under these conditions was about 2 nm.
(11) Markowski, T.; Drescher, S.; Meister, A.; Hause, G.; Blume, A.;
Dobner, B. Eur. J. Org. Chem. 2011, 5894−5904. Miyawaki, K.;
Harada, A.; Takagi, T.; Shibakami, M. Synlett 2003, 349−352. Auzely-
Velty, R.; Benvegnu, T.; Plusquellec, D.; Mackenzie, G.; Haley, J. A.;
Goodby, J. W. Angew. Chem., Int. Ed. 1998, 37, 2511−2515.
(12) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994. Cui, W.; Li, F.; Allinger, N. L. J. Am. Chem.
Soc. 1993, 115, 2943−2951.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds. This
information is available free of charge via the Internet at http://
pubs.acs.org/.
(13) Ruiz de Ballesteros, O.; Cavallo, L.; Auriemma, F.; Guerra, G.
Macromolecules 1995, 28, 7355−7362.
(14) Corti, M.; Cantu, L.; Brocca, P.; Del Favero, E. Curr. Opin.
Colloid Interface Sci. 2007, 12, 148−154.
AUTHOR INFORMATION
■
(15) Brard, M.; Laine,
́ ́ ́
C.; Rethore, G.; Laurent, I.; Neveu, C.;
Corresponding Author
Lemieg
̀
re, L.; Benvegnu, T. J. Org. Chem. 2007, 72, 8267−8279.
*E-mail: loic.lemiegre@ensc-rennes.fr (L.L.); thierry.
benvegnu@ensc-rennes.fr (T.B.).
(16) Curran, D. P.; Chen, M. H.; Leszczweski, D.; Elliott, R. L.;
Rakiewicz, D. M. J. Org. Chem. 1986, 51, 1612−1614.
(17) Drescher, S.; Meister, A.; Blume, A.; Karlsson, G.; Almgren, M.;
Dobner, B. Chem.Eur. J. 2007, 13, 5300−5307.
ACKNOWLEDGMENTS
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(18) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989,
111, 2735−2737.
The Agence Nationale de la Recherche (ANR-09-JCJC-0034)
and the Reg
́
ion Bretagne are gratefully acknowledged,
(19) Sita, L. R. J. Org. Chem. 1993, 58, 5285−5287. Takaya, H.;
Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.;
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(20) Yamauchi, K.; Kinoshita, M. Prog. Polym. Sci. 1993, 18, 763−
804.
respectively, for financial support and a Ph.D. grant to A.J.
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