Synthesis of stereoisomerically pure monoether lipids

Article abstract of DOI:10.1071/CH99001

Four stereoisomerically pure lipids have been synthesized which contain chirally pure phytanol (obtained through resolution of a chiral amide) and chiral glycerol moieties. The lipids were obtained in 7-13% overall yield in eight steps from commercially available materials.

Full text of DOI:10.1071/CH99001

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 52, 1999
© CSIRO Australia 1999
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Aust. J. Chem., 1999, 52, 387–394
.
Synthesis of Stereoisomerically Pure
Monoether Lipids
Christopher J. Burns,A Leslie D. Field,A,B Kikuko Hashimoto,A
Brian J. Petteys,A Damon D. Ridley A and Michael Rose A
A
School of Chemistry and the Cooperative Research Centre for Molecular
Engineering and Technology, University of Sydney, Sydney N.S.W. 2006.
B
Author to whom correspondence should be addressed.
Four stereoisomerically pure lipids have been synthesized which contain chirally pure phytanol (obtained
through resolution of a chiral amide) and chiral glycerol moieties. The lipids were obtained in 7–13%
overall yield in eight steps from commercially available materials.
Introduction
membrane. Lipids of the Archaea consist primarily of
fully saturated, isoprenoid hydrocarbons attached to
glycerol through an ether linkage, thus rendering them
resistant to oxidative and hydrolytic degradation.
For example, the lipids of the archaeabacterium
Halobacterium cutiribrum consist primarily of the chi-
ral diether (1) where the con guration at the glycerol
has been assigned R,6,7 in contrast to conventional
glycerolipids of the prokaryotes and eukaryotes where
the stereochemistry of glycerol is reversed. The com-
plete stereochemistry of the alkyl side chain shown in
(1) has been assigned by degradation and comparison
of the resultant products with materials of known
optical con guration.7 This alkyl chain, found in the
membranes of many other Archaea, is derived from the
C20 residue phytanol (2), found as either C 3 epimer
in Nature.
Life in its simplest of forms, the prokaryotic cell, has
existed on Earth for at least 3 5 billion years. During
the course of evolution the eukaryotic cell became the
basis for the development of the plant and animal
kingdom. A third genotype, the Archaea, has however
recently been classi ed as a new evolutionary lineage.1
Organisms belonging to this family possess similarity
to both prokaryotes in that they have no membrane-
bound nucleus, and eukaryotes through ribosomal RNA
genealogies.
Organisms belonging to the Archaea are widespread
throughout Nature, and are remarkable for the extreme
conditions in which they live. Archaea have recorded
the highest known temperature for an environment
that supports life, 113 C,2 as well as some of the
coldest, 1 8 C, in Antarctic waters.3 They can thrive
in water whose salt content is ve times that of oceanic
waters4 and also where pH values range from below
5 for the acidophiles to above 9 for the alkaliphiles.5
The Archaea are able to exist and thrive in such
extreme conditions through modi cations of their cel-
lular structure. Principally, modi cations of their
cellular membrane components provide them with sta-
bility to these harsh environments. The lipids of both
eukaryotes and prokaryotes are typically comprised
of straight chain partly unsaturated carboxylic acids
linked to glycerol through an ester bond. Hydrolysis
of the ester bond and/or oxidation of the unsaturated
moieties under harsh environmental conditions prob-
ably leads ultimately to the destruction of the cell
There has been considerable interest in recent years
relating to the use of the isoprenoid phytanol (2), and
its phytanylated glycerol derivatives (1) and (3), in
10
studies of membrane formation and function.4,8
The
majority of such publications have employed chirally
impure compounds derived synthetically through the
use of chirally impure phytanol, racemic glycerol, or
both. Only one paper has employed chirally pure
materials; however, in this work only one of the four
possible diastereoisomers of (3) was produced.11 The
e ect that the chirality of both the glycerol and C 3
centres of phytanol has on membrane formation, pack-
ing and function has however never been studied.10 In
this paper we describe the synthesis of two diastereoiso-
mers of phytanol (2) and their subsequent conversion
In this work only changes at the epimeric centres at C 3 of phytanol and C 2 of glycerol are examined, while the stereocentres
at C 7 and C 11 of phytanol remain unaltered (both R, derived from the starting material phytol). Therefore for the purpose of
this paper the possible number of GMPE stereoisomers derived from phytol is considered as four.
Manuscript received 4 January 1999
᭧ CSIRO 1999
0004-9425/99/050387$ 05.00
10.1071/CH99001

388
C. J. Burns et al.
into four diastereomers of glycerol monophytanyl ether
(GMPE) (3).
C 3 in quantitative yield (Scheme 2). The spectro-
scopic data for the mixture (2) were in full accord
with literature data.11 Moss and Fujita have reported
that these diastereomers can be separated by column
chromatography;9 however, we were unable to e ect
any separation using either conventional column chro-
matography or h.p.l.c. The diastereomers could not
be di erentiated in the 1H n.m.r. spectrum (at 400
MHz) nor in the 13C n.m.r. spectrum (at 100 MHz).
Oxidation of the diastereomeric mixture of (2) with
chromium trioxide in a 2 : 1 solution of acetone/acetic
acid provided the phytanic acids (9) in 60% yield.13
Again separation of the diastereomers was impossi-
ble by standard chromatographic techniques and the
individual diastereomers could not be discerned in
high- eld n.m.r. spectra.
In Sita’s work on the asymmetric hydrogenation of
phytol,13 the purity of the chiral products (chirally
pure phytanol) was determined by conversion into
chiral naphthylethylamide derivatives which exhibited
subtle di erences in chromatographic behaviour and
spectroscopic data.13 The absolute stereochemistry of
the products was deduced from the mechanism of the
chiral hydrogenation catalyst employed.15
The acid chloride was formed in situ from the acid
(9), by using oxalyl chloride and catalytic dimethylfor-
mamide, and reaction with the commercially available
chiral naphthylethylamine (10) furnished the 3R and
3S naphthylethylamide diastereomers (11) and (12) of
phytanic acid in a 6 : 4 ratio† (respectively) in 71%
overall yield (Scheme 2). This mixture could be par-
tially separated by ash column chromatography (6 : 1
hexane/diethyl ether); however, material with >99%
d.e. was obtained following h.p.l.c. The spectroscopic
and physical data for (11) and (12) were in accord
with those reported. Furthermore, the two compounds
exhibited di erences in their 13C n.m.r. spectra and
polarity on t.l.c. and h.p.l.c., thus allowing the absolute
stereochemistry to be assigned by direct comparison
with the data reported by Sita.13
All subsequent reactions were performed on the sep-
arated pure diastereomers, and all subsequent materials
are assumed to be enantiomerically pure. Hydrolysis
of the amides (11) and (12) to obtain the phytanic
acids (13) and (14) proved di cult under standard
conditions (Scheme 3). Treatment of the amide with
concentrated sulfuric acid in tetrahydrofuran at re ux
led over many days to cleavage at the N–alkyl bond of
the chiral auxiliary, generating the primary amides (15)
and (16) (in c. 70% yield) with little or no formation
of the desired acids (13) and (14). Such cleavage in the
hydrolysis of amides is rare, though has been reported
previously.16 The structures of the amides (15) and
(16) were deduced from their spectroscopic data, in
particular the infrared spectra where each exhibits
Results and Discussion
Our route to the four diastereomers of (3) involved
the synthesis of chirally pure phytanols and subse-
quent etheri cation of the known protected, chiral
glycerols (4) and (5) (Scheme 1). Stereochemically
pure phytanol has been obtained in small quantities
from natural sources such as Halobacterium cutiribrum
through a procedure involving a series of extractions
and hydrolyses that break down the lipids to their
corresponding subunits.7 Chirally pure phytanol (e.e.
>99%) has also been obtained synthetically by asym-
metric hydrogenation of the commercially available
allylic alcohol phytol (6).13 The rst method requires
the extensive procedure of culturing the appropriate
Archaea, extraction of the membranous material and
then carrying out the necessary isolation and puri -
cation processes. The second method utilizes a chiral
catalyst that requires independent multistep synthesis.
For these reasons we opted for a more classical route
to enantiomerically pure phytanol involving separation
of appropriate diastereomeric derivatives.
It was our intention to oxidize the C 3 epimeric
phytanols to the corresponding phytanic acids and then
to prepare a diastereomeric mixture of secondary amide
derivatives. Chromatographic separation followed by
removal of the chiral auxiliary would then allow the
chirally pure phytanols (7) and (8) to be obtained.
Etheri cation of glycerol could then be e ected by
suitable derivatization of the chiral phytanols and
reaction with the protected glycerols (4) and (5).
Hydrogenation of the allylic alcohol phytol (6)
under an atmosphere of hydrogen with Raney nickel
as catalyst14 a orded the phytanols (2) epimeric at
* Of the two protected glycerols employed in this work, R isopropylideneglycerol (4) is commercially available, whereas S
isopropylideneglycerol (5) was formed following the procedures of Jung and Shaw,12 and Jackson.12
† Commercially available phytol is supplied as an approximately 65 : 35 mixture of E and Z stereoisomers.

Stereoisomerically Pure Monoether Lipids
389
stretches at 3529, 3410 and 1677 cm 1, consistent with
Hydrolysis of the primary amides (15) and (16) was
achieved with 10 M sulfuric acid in tetrahydrofuran at
re ux; however, yields for this reaction, and time for
completion of the reaction, were variable ranging from
30–70% and 6–14 days.
Hydrolysis of (11) and (12) under milder acidic
conditions (6 M HCl, EtOH), and with ‘anhydrous
t-butoxide’,17 both failed to generate the desired pro-
a primary amide, as well as peaks at
175 5 in
the 13C n.m.r. spectra, again indicative of an amide
carbonyl. Independent synthesis of the amides from
3RS phytanic acid (9) (by treatment of the derived acid
chloride with 33% aqueous ammonia) gave material
indistinguishable (by t.l.c. and 1H n.m.r.) from that
derived from the attempted amide hydrolysis.
Scheme 1. Proposed route to the four diastereomers of GMPE from resolved phytanol.
Scheme 2. (a) Raney nickel/H2, EtOH. (b) CrO3, H2O, 2 : 1 acetone/acetic acid. (c) Oxalyl chloride, catalytic dimethylformamide,
diethyl ether. (d) (R)-(+)-1-(1-Naphthyl)ethylamine (10), triethylamine, CH2Cl2.

390
C. J. Burns et al.
18
ducts, while attempted reductive removal with DIBAL
Bromination of the phytanols (7) and (8) using
aqueous 48% HBr generated the phytanyl bromides
(17) and (18) (81 and 76% respectively) required for
the coupling reactions with the protected glycerols (4)
and (5)12 (Scheme 5). Etheri cation of the protected
glycerols (4) and (5) was e ected by using KOH in
re uxing toluene under Dean–Stark conditions, to fur-
nish the ethers (19)–(22) in approximately 55% yield.
The compounds exhibited spectroscopic data in full
accord with their proposed structures.
Acid hydrolysis of the ketals using a catalytic amount
of acid in 10 : 1 dioxan/water a orded the four isomers
of glycerol monophytanyl ether (23)–(26) in excellent
yield (90% average yield). Spectroscopic data for each
compound were in full accord with their proposed
structures, with compound (23) having spectroscopic
data in agreement with those reported previously for
this material.11 The optical rotation of material in this
work ([ ]D = +0 49) was di erent to that reported
returned only starting material. The method of
Evans and coworkers19 for the hydrolysis of secondary
amides, involving the in situ formation of the active
N -nitrosamide followed by hydrolysis with lithium
hydroperoxide, gave the best and most reproducible
method (50% overall yield) for the preparation of the
acids (13) and (14) (Scheme 4).
The material obtained from this reaction was di cult
to purify by conventional methods, and analytically
pure material was obtained only after h.p.l.c. These
materials were identical in all respects (excepting opti-
cal rotation) to the mixture of diastereomeric acids (9)
obtained by oxidation of phytanol (2) discussed above.
3R and 3S Phytanic acids (13) and (14), respectively,
were reduced to the corresponding phytanols (7) and
(8) with LiAlH4. The reduction proceeded in excellent
yield, with spectroscopic data and optical rotations in
agreement with those reported for materials synthesized
by asymmetric hydrogenation of phytol.13
([ ]D
=
0 94).
Scheme 3. (a) Conc. H2SO4, tetrahydrofuran, re ux 14 days. Preferentially form (15) and (16) instead of (13) and (14).
Scheme 4. (a) Sodium nitrite, 2 : 1 acetic anhydride/acetic acid, 0 C to room temperature.
tetrahydrofuran/H2O, 0 C to room temperature. (c) LiAlH4, tetrahydrofuran.
(b) LiOH/H2O2, 3 : 1
Many thanks to Dr Percy H. Carter for additional information relating to this reaction.

Stereoisomerically Pure Monoether Lipids
391
samples dissolved in CDCl3 containing tetramethylsilane as
internal reference. Electron ionization (e.i.) mass spectra were
recorded on a modi ed Kratos mass spectrometer calibrated
with per uorokerosene (PFK). Chemical ionization (c.i.) mass
spectra were recorded on an AEI Ms30 spectrometer with
methane as the ionizing gas. Microanalyses were performed
by the Campbell Microanalytical Laboratory, Department of
Chemistry, University of Otago, Dunedin, New Zealand. DEPT
experiments were conducted to assist with the assignment of
13C n.m.r. spectra. Puri cations were achieved by ash chro-
matography on silica gel (0 040–0 063 mm) unless otherwise
stated. Retention factors (RF) of compounds were determined
by thin-layer chromatography on Merck 60 F254 plates. Optical
rotations were recorded on an Optical Activity Polaar 2001
spectrometer at ambient temperature.
Conclusion
The total synthesis of the four diastereomers of glyc-
erol monophytanyl ether (3) in chirally pure form has
been achieved in eight steps from commercially avail-
able phytol (6) in 7–13% overall yield. Identi cation
of a reproducible route to both diastereomers of phy-
tanol also allows the preparation of other phytanylated
membrane-forming materials, such as 1,2-diphytanyl-
sn-glycerol20 and its phosphatidylcholine derivative,21
in chirally pure form. Studies on the formation
and properties of membranes from these and related
materials are currently under way.22
All reactions were performed under an atmosphere of dry
nitrogen. Anhydrous tetrahydrofuran was obtained by distil-
lation from sodium benzophenone ketyl immediately prior to
use. All other solvents were distilled and all reagents were
commercial grade.
Experimental
1H and 13C n.m.r. spectra were recorded on Bruker AC-
200 (200 MHz) and AMX-400 (400 MHz) spectrometers with
Scheme 5. (a) 48% HBr, conc. H2SO4. (b) R or S Isopropylideneglycerol (4) or (5), KOH, toluene. (c) Catalytic HCl, 10 : 1
dioxan/H2O.

392
C. J. Burns et al.
(3 RS,7 R,11R)-3,7,11,15-Tetramethylhexadecan-1-ol (2)
Partisil 10 column, 13 5 ml/min ow rate) gave rstly the 3R
isomer (11): RF 0 32 (2 : 1 hexane/diethyl ether) (Found: C,
82 4; H, 10 9; N, 2 8. Calc. for C32H51NO: C, 82 5; H,
11 0; N, 3 0%). [ ]D +28 7 (c, 2 6 in CHCl3) (lit.13 [ ]D27
+40 75 ). 1H n.m.r., 13C n.m.r. identical to those of the 3RS
amide. Further elution provided the 3S isomer (12): RF 0 27
(2 : 1 hexane/diethyl ether) (Found: C, 82 5; H, 11 1; N, 2 8.
Calc. for C32H51NO: C, 82 5; H, 11 0; N, 3 0%). [ ]D +28 4
(c, 2 3 in CHCl3) (lit.13 [ ]D27 +43 39 ). 1H n.m.r., 13C n.m.r.
identical to those of the 3RS amide.
A solution of phytol (49 3 g, 167 mmol) in ethanol (250 ml)
was stirred under an atmosphere of hydrogen over Raney
nickel (10 3 g, 50% slurry in water) for 60 h. The catalyst
was removed by ltration through CeliteR and the ltrate
concentrated under reduced pressure to give (2) (49 3 g, 100%)
as a colourless oil: 1H n.m.r. (200 MHz) (CDCl3) 0 83–0 91,
m, 15H; 1 03–1 59, m, 24H; 3 64–3 72, m, 2H, H 1. 13C
n.m.r. (50 MHz) (CDCl3) 19 59–19 74, overlapping signals,
non-terminal CH3 groups; 22 6, CH3; 22 7, CH3; 24 4, CH2;
24 5, CH2; 24 8, CH2; 28 0, CH; 29 5, CH; 32 8, CH;
37 3–37 5, overlapping signals, CH2 groups; 39 4, CH2; 39 9,
CH2; 40 0, CH2; 61 2, CH2OH. Mass spectrum (c.i.) m/z 298
(M+, 100%), 281 (41), 226 (15), 211 (22), 196 (26), 183 (28),
168 (30), 155 (31).
(3 R,7 R,11R)-3,7,11,15-Tetramethylhexadecanamide (15)
Concentrated H2SO4 (5 ml) was added to a solution of (11)
(0 98 g, 2 10 mmol) in tetrahydrofuran (25 ml) and the solution
heated at re ux for 14 days under nitrogen. After cooling to
room temperature the solvent was removed under reduced pres-
sure, water (100 ml) was added and the solution extracted with
dichloromethane (3 75 ml). The combined organic extracts
were washed with brine (175 ml), dried (Na2SO4) and ltered
through a pad of silica. After removal of the solvent in vacuum
the resultant dark brown oil was puri ed by using 3 : 1 to
1 : 1 hexane/ethyl acetate as eluent to provide (15) (273 mg,
41 7%) as a rust-coloured wax. Analytically pure material
was obtained by h.p.l.c. puri cation with 1 : 1 hexane/ethyl
acetate as eluent (Whatman Partisil 10 column, 13 5 ml/min
ow rate): RF 0 15 (1 : 1 hexane/ethyl acetate) (Found: C,
76 9; H, 13 2; N, 4 4. C20H41NO requires C, 77 1; H, 13 3;
(3 RS,7 R,11 R)-3,7,11,15-Tetramethylhexadecanoic Acid (9)
Chromium trioxide (0 80 g, 8 0 mmol) in water (1 ml) was
added dropwise to a solution of (2) (1 g, 3 3 mmol) in acetone
(40 ml) and acetic acid (20 ml) at room temperature. Stirring
was continued for 1 h and water (50 ml) was added, followed
by enough solid sodium metabisul te to destroy the excess
oxidant. The majority of the solvent was removed in vacuum,
the residue taken up in water (60 ml) and extracted with
diethyl ether (3 20 ml). The combined organic extracts were
washed with water (50 ml), dried (Na2SO4) and the solvent
was removed under reduced pressure to give the crude material
as a pale yellow oil. Puri cation with 2 : 1 hexane/diethyl
N, 4 5%). [ ]D +2 4 (c, 3 3 in CHCl3).
1677 cm
3529, 3410,
max
.
1H n.m.r. (200 MHz) (CDCl3) 0 83–0 87, m,
1
ether as eluent gave (9) (625 mg, 61% yield) as a colourless
1
12H; 0 95, d, J 6 2 Hz, 3H; 1 06–1 40, m, 22H; 1 52, sept, J
6 6 Hz, 1H, H 3; 1 90–2 28, m, 1H; 5 70, br s, 2H, NH. 13C
n.m.r. (50 MHz) (CDCl3) 19 58, CH3; 19 65, CH3; 19 73,
CH3; 22 61, CH3; 22 70, CH3; 24 39, CH2; 24 45, CH2;
24 78, CH2; 27 96, CH; 30 74, CH; 32 76, CH; 37 14, CH2;
37 21, CH2; 37 28, CH2; 37 39, CH2; 37 44, CH2; 39 36,
CH2; 43 61, CH2; 175 53, amide CO. Mass spectrum (c.i.)
m/z 312 (M+H+, 100%).
oil: RF 0 70 (1 : 1 hexane/diethyl ether).
1709 cm
.
max
1H n.m.r. (200 MHz) (CDCl3) 0 83–0 88, m, 12H; 0 97, d,
J 6 6 Hz, 3H; 1 03–1 40, m, 20H; 1 49, sept, J 6 5 Hz, 1H,
H 3; 1 90–2 05, m, 1H; 2 08–2 20, m, 1H; 2 31–2 41, m, 1H.
Mass spectrum (c.i.) m/z 312 (M+, 3%), 157 (21), 139 (18),
111 (25), 97 (46), 87 (87), 71 (69), 57 (93), 43 (100).
(3 RS,7 R,11 R)-3,7,11,15-Tetramethyl-N-[(1 0R)-1 0-(1-
naphthyl)ethyl]hexadecanamide
(3 S,7 R,11 R)-3,7,11,15-Tetramethylhexadecanamide (16)
N,N -Dimethylformamide (1 drop) followed by oxalyl chlo-
ride (482 mg, 3 80 mmol) was added to a solution of (9) (1 08
g, 3 46 mmol) in diethyl ether (20 ml). The reaction mixture
was stirred for 1 h under nitrogen at room temperature,
the solvent removed under reduced pressure and the residue
dissolved in dichloromethane (15 ml). A solution of (R)-(+)-1-
(1-naphthyl)ethylamine (0 65 g, 3 8 mmol) in dichloromethane
(5 ml) and triethylamine (1 01 g, 10 mmol) was added and
the stirring continued under nitrogen for an additional 2 h.
The solvent was removed under reduced pressure, the residue
dissolved in hexane and ltered through a short pad of CeliteR.
After removal of the solvent in vacuum, the crude product
was puri ed by using 2 : 1 hexane/diethyl ether as eluent to
provide the title 3RS amide (1 41 g, 87 8%) as a pale yellow
gum: RF 0 36 (2 : 1 hexane/diethyl ether). 1H n.m.r. (200
MHz) (CDCl3) 0 82–0 88, m, 15H; 1 00–1 40, m, 20H; 1 51,
sept, J 6 5 Hz, 1H, H 3; 1 68, d, J 6 8 Hz, 3H; 1 90–2 05,
m, 2H; 2 14–2 24, m, 1H; 5 63, d, J 8 1 Hz, 1H; 5 95, m,
1H; 7 38–7 55, m, 4H; 7 80, d, J 8 0 Hz, 1H; 7 87, d, J
8 0 Hz, 1H; 8 14, d, J 8 1 Hz, 1H. 13C n.m.r. (50 MHz)
(CDCl3) 19 56, 19 66, 20 46, 22 53, 22 62, 24 25, 24 37,
24 71, 27 89, 30 85, 32 70, 37 07, 37 22, 37 33, 37 38, 39 29,
44 35, 44 61, 122 47, 123 53, 125 03, 125 82, 126 47, 128 33,
128 63, 131 13, 133 87, 138 17, 171 37. Mass spectrum (c.i.)
m/z 466 (M+, 100%), 312 (10), 155 (21).
The amide (16) was prepared in an identical fashion to
that used for the preparation of (15), with (12) as the starting
material to a ord (16) (Found: C, 77 1; H, 13 2; N, 4 4.
C
20H41NO requires C, 77 1; H, 13 3; N, 4 5%). [ ]D 2 2
(c, 2 2 in CHCl3). RF, i.r. 1H n.m.r., and 13C n.m.r. data
were identical to those of (15).
(3 R,7 R,11 R)-3,7,11,15-Tetramethylhexadecanoic Acid
(13)
A solution of (11) (595 mg, 1 28 mmol) in a 2 : 1 mixture
of acetic anhydride/acetic acid (20 ml) was chilled to 0 C
and sodium nitrite (881 mg, 12 8 mmol) was added. The
reaction mixture was allowed to warm to room temperature
and stirred under nitrogen for 4 h after which time t.l.c. (1 : 1
hexane/diethyl ether) showed the starting material had been
consumed. After adding diethyl ether (25 ml) and chilling the
solution to 0 C, saturated NaHCO3 (50 ml) was added and
the mixture stirred for 10 min. Diethyl ether (50 ml) and
saturated NaHCO3 (25 ml) were added and the organic layer
was separated, washed with saturated NaHCO3 (3 50 ml),
brine (50 ml), dried (Na2SO4) and the solvent removed in
vacuum. The crude material was used immediately in the next
reaction. The dark yellow liquid was dissolved in tetrahydro-
furan (15 ml) and water (5 ml), chilled to 0 C and lithium
hydroxide (306 mg, 12 8 mmol) added followed by 30% hydro-
gen peroxide (2 6 ml). The reaction was allowed to warm
to room temperature and stirring continued under nitrogen
for 24 h after which time sodium metabisul te (2 7g, 10%
excess) was added to the recooled solution. Water (25 ml) was
added and the reaction mixture stirred for 5 min at 0 C after
(3 R,7 R,11 R)-3,7,11,15-Tetramethyl-N-[(1 0R)-1 0-(1-
naphthyl)ethyl]hexadecanamide (11) and its (3 S,7 R,11 R)
Isomer (12)
H.p.l.c. of the 3RS amide (described in the previous para-
graph) with 8 8 : 1 2 hexane/ethyl acetate as eluent (Whatman

Stereoisomerically Pure Monoether Lipids
393
which time the tetrahydrofuran was removed under reduced
pressure and water (20 ml) added. The aqueous phase was
extracted with ethyl acetate (3 30 ml), the combined organic
extracts were washed with brine (50 ml), dried (Na2SO4) and
the solvent was removed in vacuum to give a yellow liquid. The
residue was partially puri ed with 2 : 1 hexane/diethyl ether
as eluent to give a mixed polar fraction containing the acid
along with an unknown impurity (373 mg, 93%). Analytically
pure material was obtained by h.p.l.c. puri cation (Whatman
Partisil 10 column, 13 5 ml/min ow rate) with a mixture of
0 2% acetic acid and 3% ethyl acetate in hexane to give (13)
(335 mg, 42 1%) as a pale yellow oil: [ ]D +4 6 (c, 6 7 in
CHCl3) (lit.13 [ ]D27 +4 50 ). RF, i.r. and 1H n.m.r. data
were identical to those of (9).
(3 S,7 R,11 R)-1-Bromo-3,7,11,15-tetramethylhexadecane
(18)
The bromide (18) was prepared in an identical fashion to
that used for the preparation of (17), with (8) as the starting
material to a ord (18) (385 mg, 76%) (Found: C, 66 4; H,
11 6.
C20H41Br requires C, 66 5; H, 11 4%). [ ]D +3 1
(c, 7 7 in CHCl3). RF, 1H n.m.r. and 13C n.m.r. data were
identical to those for (17).
(S)-2,2-Dimethyl-1,3-dioxolan-4-methanol (5)
The glycerol derivative (5) was prepared from 1,2:5,6-di-
O-isopropylidene-D-mannitol by established procedures.12 The
material was used, without further puri cation, in subsequent
reactions. 1H n.m.r. (200 MHz) (CDCl3) 1 37, s, 3H, CH3;
1 43, s, 3H, CH3; 2 16, br s, 1H, OH; 3 58, dd, J 11 7, 5 0
Hz, 1H, H 1; 3 73, dd, J 11 7, 3 8 Hz, 1H, H 1; 3 78, dd,
J 8 2, 6 6 Hz, 1H, H 3; 4 03, dd, J 8 2, 6 7 Hz, 1H, H 3;
4 18–4 29, m, 1H (glycerol numbering has been used for the
n.m.r. assignments).
(3 S,7 R,11 R)-3,7,11,15-Tetramethylhexadecanoic Acid (14)
The acid (14) was prepared in an identical manner to that
used for the preparation of (13), with (12) (1 19 g, 2 55 mmol)
as starting material to a ord (14) (405 mg, 50 7%): [ ]D 4 9
(c, 7 8 in CHCl3) (lit.13 [ ]D27 4 45 ). RF, 1H n.m.r., and
i.r. data were identical to those for (9).
(2 S)-1,2-Isopropylidene-3-[(3 0R,7 0R,11 0R)-3 0,7 0,11 0,15 0-
tetramethylhexadecyl]glycerol (19)
(3 R,7 R,11 R)-3,7,11,15-Tetramethylhexadecan-1-ol (7)
A Soxhlet apparatus containing LiAlH4 (1 25 g, 32 9 mmol)
immersed in dry tetrahydrofuran (10 ml) was attached to a
round-bottomed ask charged with (13) (333 mg, 1 07 mmol)
in tetrahydrofuran (30 ml). The solution was heated at re ux
under nitrogen for 3 h after which time the contents were cooled
to room temperature and a mixture of tetrahydrofuran and
water (5 ml, 3 : 1) was added. The solvent was removed under
reduced pressure, 3 M HCl (50 ml) was added and the product
extracted into diethyl ether (3 30 ml). The combined organic
extracts were washed with brine (25 ml), dried (Na2SO4) and
the solvent was removed under reduced pressure to give the
crude material as a clear yellow oil. Puri cation with 95 : 5
hexane/ethyl acetate as eluent provided (7) (312 mg, 98%) as
a clear oil: RF 0 29 (9 : 1 hexane/ethyl acetate). [ ]D +2 9
(c, 6 2 in CHCl3) (lit.13 [ ]D27 +2 70 ). 1H n.m.r. and 13C
n.m.r. spectra were identical to those of (2).
A round-bottomed ask containing a solution of (5) (62 5 mg,
0 47 mmol) and powdered KOH (188 mg, 4 7 mmol) in toluene
(15 ml) was tted with a Dean–Stark apparatus and heated at
re ux under nitrogen for 1 h. After cooling to room tempera-
ture, (17) (217 mg, 0 60 mmol) in toluene (5 ml) was added and
the mixture heated at re ux for 24 h. The cooled solution was
diluted with diethyl ether (35 ml), washed sequentially with
water (25 ml), 0 25 M HCl (25 ml), 2 5% aqueous NaHCO3
(25 ml), water (25 ml), brine (25 ml), dried (Na2SO4) and the
solvent removed to give the crude product as a yellow oil.
Puri cation by using 97 : 3 hexane/ethyl acetate a orded (19)
(120 mg, 61 5%) as a clear oil: RF 0 55 (9 : 1 hexane/ethyl
acetate) (Found: C, 75 9; H, 12 7.
75 7; H, 12 7%). [ ]D +9 5 (c, 9 0 in CHCl3). 1H n.m.r.
(200 MHz) (CDCl
C26H52O3 requires C,
3) 0 82–0 88, m, 15H; 1 02–1 68, m, 24H;
1 36, s, 3H; 1 42, s, 3H; 3 37–3 56, m, 4H, H 3, H 10; 3 72, dd,
J 8 2, 6 4 Hz, 1H, H 1; 4 06, dd, J 8 2, 6 4 Hz, 1H, H 1; 4 26,
dddd (apparent pentuplet), J 6 4 Hz, 1H, H 2. 13C n.m.r.
(50 MHz) (CDCl3) 19 69, CH3; 22 63, CH3; 22 72, CH3;
24 36, CH2; 24 47, CH2; 24 80, CH2; 25 43, CH3; 26 78,
CH3; 27 98, CH; 29 86, CH; 32 78, CH; 36 52, CH2; 36 60,
CH2; 37 40, CH2; 39 37, CH2; 66 96, CH2OC(CH3)2; 70 19,
(3 S,7 R,11 R)-3,7,11,15-Tetramethylhexadecan-1-ol (8)
The alcohol (8) was prepared in an identical manner to that
used for the preparation of (7), with (14) (395 mg, 1 26 mmol)
as the starting material to a ord (8) (368 mg, 97 6%): [ ]D
2 3 (c, 8 3 in CHCl3) (lit.13 [ ]D27 2 72 ). 1H n.m.r. and
13C n.m.r. spectra were identical to those of (2).
CH2OCH2(C19H39); 71 86, CH2OCH2(C19H39); 74 76, CH;
+
109 34, quaternary. Mass spectrum (e.i.) m/z 398 (M CH3
,
51%), 133 (19), 127 (10), 123 (17), 111 (25), 101 (100).
(3 R,7 R,11 R)-1-Bromo-3,7,11,15-tetramethylhexadecane
(17)
(2 R)-2,3-Isopropylidene-1-[(3 0R,7 0R,11 0R)-3 0,7 0,11 0,15 0-
tetramethylhexadecyl]glycerol (20)
A mixture of (7) (312 mg, 1 05 mmol), aqueous 48% HBr
(50 ml) and conc. H2SO4 (0 5 ml) were heated at re ux under
nitrogen for 24 h. Upon cooling to room temperature the
mixture was extracted with hexane (3 25 ml). The combined
organic extracts were dried (Na2SO4) and the solvent was
removed in vacuum to give the crude product as a dark brown
oil. Puri cation with hexane as eluent a orded (17) (306 mg,
81 0%) as a colourless oil: RF 0 75 (hexane). [ ]D 3 3 (c,
6 1 in CHCl3) (lit.13 [ ]2D7 2 90 ). 1H n.m.r. (200 MHz)
(CDCl3) 0 82–0 90, m, 15H; 1 0–1 95, m, 24H; 3 34–3 50,
This compound was prepared in an identical fashion to that
used for the preparation of (19), with (R)-2,2-dimethyl-1,3-
dioxolan-4-methanol (67 4 mg, 0 51 mmol) and (17) (211 mg,
0 58 mmol) as starting materials to a ord (20) (120 mg, 57 1%)
(Found: C, 75 9; H, 13 0.
C26H52O3 requires C, 75 7; H,
12 7%). [ ]D 6 4 (c, 8 8 in CHCl3). RF, 1H n.m.r. and
13C n.m.r. data were identical to those for the 2S isomer (19).
m, 2H, H 1. 13C n.m.r. (50 MHz)
(CDCl3) 18 95, CH3;
(2 S)-1,2-Isopropylidene-3-[(3 0S,7 0R,11 0R)-3 0,7 0,11 0,15 0-
tetramethylhexadecyl]glycerol (21)
19 00, CH3; 19 71, CH3; 22 64, CH3; 22 73, CH3; 24 23,
CH2; 24 48, CH2; 24 82, CH2; 27 98, CH; 29 71, CH; 31 68,
CH; 32 12, CH2; 32 78, CH; 36 80 CH2; 36 85, CH2; 37 31,
CH2; 37 40, CH2; 39 39, CH2; 40 06, CH2; 40 13, CH2. Mass
spectrum (c.i.) m/z 361 (M+H+, 29%), 359 (M+, 26), 347
(15), 281 (71), 223 (34), 211 (57), 197 (54), 183 (60), 169 (71),
155 (76), 141 (67), 127 (95), 113 (100).
This compound was prepared in an identical fashion to that
used for the preparation of (19), with (5) (85 0 mg, 0 64 mmol)
and (18) (278 mg, 0 77 mmol) as starting materials to a ord
(21) (140 mg, 52 8%): [ ]D +6 4 (c, 12 7 in CHCl3). RF,
1H n.m.r. and 13C n.m.r. data were identical to those of (19).

394
C. J. Burns et al.
(2 R)-2,3-Isopropylidene-1-[(3 0S,7 0R,11 0R)-3 0,7 0,11 0,15 0-
tetramethylhexadecyl]glycerol (22)
Acknowledgments
We gratefully acknowledge nancial support from
the Australian Government through the Cooperative
Research Centre for Molecular Engineering and Tech-
nology and to Paci c Dunlop Pty Ltd for the award
of a Paci c Dunlop Research Scholarship (B.J.P.).
This compound was prepared in an identical fashion to that
used for the preparation of (19), with (R)-2,2-dimethyl-1,3-
dioxolan-4-methanol (98 0 mg, 0 74 mmol) and (18) (315 mg,
0 87 mmol) as starting materials to a ord (22) (128 mg, 41 8%)
(Found: C, 75 8; H, 12 5.
C26H52O3 requires C, 75 7; H,
12 7%). [ ]D 8 7 (c, 11 2 in CHCl3). RF, 1H n.m.r. and
13C n.m.r. data were identical to those of (19).
References
(2 R)-3-[(3 0R,7 0R,11 0R)-3 0,7 0,11 0,15 0-Tetramethyl-
hexadecyl]glycerol (23)
1
Woese, C. R., Magrum, L. J., and Fox, G. E., J. Mol.
Evol., 1978, 11, 245; Woese, C. R., Sci. Am., 1981, 244, 94.
Blochl, E., Rachel, R., Burggraf, S., Hafenbradl, D., Jan-
2
Water (1 ml) and conc. HCl (0 1 ml) were added to a
solution of (19) (102 mg, 0 25 mmol) in 1,4-dioxan (10 ml).
The mixture was heated at re ux under nitrogen for 4 h after
which time the solvent was removed under reduced pressure.
The residue was diluted with ethyl acetate (25 ml), washed with
water (25 ml), 5% aqueous NaHCO3 (25 ml), brine (25 ml),
dried (Na2SO4) and the solvent removed in vacuum to give
the crude material as a colourless viscous oil. Puri cation with
diethyl ether as eluent gave (23) (88 mg, 96%) as a colourless
viscous oil: RF 0 39 (diethyl ether). [ ]D +0 5 (c, 4 1 in
nasch, H. W., and Stetter, K. O., Extremophiles, 1997, 1,
14.
DeLong, E., Science, 1998, 280, 542.
Yamauchi, K., Doi, K., Kinoshita, M., Kii, F., and Fukuda,
3
4
H., Biochim. Biophys. Acta, 1992, 1110, 171.
Madigan, M. T., and Marrs, B. L., Sci. Am., 1997, 276, 82.
Kates, M., Palameta, B., and Yengoyan, L. S., Biochemistry,
5
6
1965, 4, 1595; Kates, M., Yengoyan, L. S., and Sastry, P.
S., Biochim. Biophys. Acta, 1965, 98, 252.
Kates, M., Joo, C. N., Palameta, B., and Shier, T.,
Biochemistry, 1967, 6, 3329.
7
CHCl3) (lit.11 [ ]D 0 94 ).
1463, 1377, 1119, 1047 cm
3384, 2953, 2925, 2868,
max
.
1H n.m.r. (200 MHz) (CDCl3)
1
8
Lazrak, T., Milon, A., Wol , G., Albrecht, A.-M., Miehe,
0 81–0 88, m, 15H; 0 98–1 65, m, 24H; 2 66, br s, 2H, OH;
3 45–3 88, m, 7H. 13C n.m.r. (50 MHz)
(CDCl3) 19 61,
M., Ourisson, G., and Nakatani, Y., Biochim. Biophys.
Acta, 1987, 903, 132.
Moss, R. A., and Fujita, T., Tetrahedron Lett., 1990, 31,
7559.
Yamauchi, K., and Kinoshita, M., Prog. Polym. Sci., 1993,
18, 763.
Joo, C. N., Shier, T., and Kates, M., J. Lipid Res., 1968,
9, 782.
CH3; 19 67, CH3; 19 73, CH3; 22 61, CH3; 22 70, CH3;
24 34, CH2; 24 45, CH2; 24 78, CH2; 27 95, CH; 29 87,
CH; 32 75, CH; 36 50, CH2; 36 58, CH2; 37 36, CH2; 37 42,
CH2; 39 33, CH2; 64 20, CH2OCH2(C19H39); 70 13, CH2OH;
70 48, CHOH; 72 42, CH2OCH2(C19H39). Mass spectrum
(c.i.) m/z 373 (M+H+, 100%).
9
10
11
12
Jung, M. E., and Shaw, T. J., J. Am. Chem. Soc., 1980,
(2 S)-1-[(3 0R,7 0R,11 0R)-3 0,7 0,11 0,15 0-Tetramethyl-
hexadecyl]glycerol (24)
102, 6304; Jackson, D. Y., Synth. Commun., 1988, 18, 337.
Sita, L. R., J. Org. Chem., 1993, 58, 5285.
Jellum, E., Eldjarn, L., and Try, K., Acta Chem. Scand.,
1966, 20, 2535.
13
14
This compound was prepared in an identical fashion to that
used for the preparation of (23), with (20) (97 mg, 0 24 mmol)
as starting material to a ord (24) (78 mg, 89%) (Found: C,
73 5; H, 13 0. C23H48O3. 61 H2O requires C, 73 5; H, 13 0%).
[ ]D +4 5 (c, 3 9 in CHCl3). RF, 1H n.m.r. and 13C n.m.r.
data were identical to those of (23).
15
Takaya, H., Ohta, T., Sayo, N., Kumobayashi, H., Akuta-
gawa, S., Inoue, S., Kasahara, I., and Noyori, R., J. Am.
Chem. Soc., 1987, 109, 1596.
Lacey, R. N., J. Chem. Soc., 1960, 1633; Stodola, F. H., J.
Org. Chem., 1972, 37, 178.
Gassman, P. G., Hodgson, P. K. G., and Balchunis, R. J.,
J. Am. Chem. Soc., 1976, 98, 1275.
Davisson, V. J., and Poulter, C. D., J. Am. Chem. Soc.,
1993, 115, 1245.
16
17
(2 R)-3-[(3 0S,7 0R,11 0R)-3 0,7 0,110,15 0-Tetramethyl-
hexadecyl]glycerol (25)
18
This compound was prepared in an identical fashion to that
used for the preparation of (23), with (21) (125 mg, 0 30 mmol)
as starting material to a ord (25) (109 mg, 96%) (Found: C,
74 1; H, 13 2. C23H48O3 requires C, 74 1; H, 13 0%). [ ]D
2 0 (c, 10 2 in CHCl3). RF, 1H n.m.r. and 13C n.m.r. data
were identical to those of (23).
19
Evans, D. A., Carter, P. H., Dinsmore, C. J., Barrow, J.
C., Katz, J. L., and Kung, D. W., Tetrahedron Lett., 1997,
38, 4535.
Stewart, L. C., and Kates, M., Chem. Phys. Lipids, 1989,
50, 23.
20
21
Redwood, W. R., Pfei er, F. R., Weisbach, J. A., and
(2 S)-1-[(3 0S,7 0R,11 0R)-3 0,7 0,11 0,15 0-Tetramethyl-
hexadecyl]glycerol (26)
Thompson, T. E., Biochim. Biophys. Acta, 1971, 233, 1;
Gutknecht, J., J. Membr. Biol., 1988, 106, 83.
Cornell, B. A., Braach-Maksvytis, V. L. B., King, L. G.,
22
This compound was prepared in an identical fashion to that
used for the preparation of (23), with (22) (112 mg, 0 27 mmol)
as starting material to a ord (26) (87 mg, 86%) (Found: C,
73 9; H, 13 1. C23H48O3 requires C, 74 1; H, 13 0%). [ ]D
1 3 (c, 8 2 in CHCl3). RF, 1H n.m.r. and 13C n.m.r. data
were identical to those of (23).
Osman, P. D. J., Raguse, B., Wieczorek, L., and Pace, R.
J., Nature (London), 1997, 387, 580; Raguse, B., Braach-
Maksvytis, V., Cornell, B. A., King, L. G., Osman, P. D.
J., Pace, R. J., and Wieczorek, L., Langmuir, 1998, 14,
648.