Synthesis of defective phospholipids

Article abstract of DOI:10.1021/jo9605455

Phospholipids have been synthesized that possess a normal 16-carbon chain plus a "defective" chain only 8 or 12 carbons long and terminated with methoxyl, hydroxyl, or carboxyl groups. In addition, dimeric phospholipids have been prepared in which two phospholipid units are joined at position-1 with chains of 22 or 32 carbons while unconnected chains at position-2 are, once again, short and functionalized. These phospholipids are potentially useful for constructing membranes that contain cavities or irregularities and, therefore, are capable of serving as self-assembled host systems in which drugs and other guest molecules are retained and, perhaps, eventually released.

Full text of DOI:10.1021/jo9605455

7382
J . Org. Chem. 1996, 61, 7382-7390
Syn th esis of Defective P h osp h olip id s
Fredric M. Menger* and Yue-Ling Wong
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received March 21, 1996X
Phospholipids have been synthesized that possess a normal 16-carbon chain plus a “defective” chain
only 8 or 12 carbons long and terminated with methoxyl, hydroxyl, or carboxyl groups. In addition,
dimeric phospholipids have been prepared in which two phospholipid units are joined at position-1
with chains of 22 or 32 carbons while unconnected chains at position-2 are, once again, short and
functionalized. These phospholipids are potentially useful for constructing membranes that contain
cavities or irregularities and, therefore, are capable of serving as self-assembled host systems in
which drugs and other guest molecules are retained and, perhaps, eventually released.
The premise for this membrane study is straightfor-
true for the ones terminated with OH and COOH groups
where “looping” to the aqueous surface3 could badly
disrupt normal lipid packing. Uncertainties notwith-
standing, it seemed that an examination of the phospho-
lipids, and their ability to incorporate guests via “defec-
tive” membranes, were a worthwhile undertaking. In
this paper, the syntheses of all eight phospholipids in
Figure 1 are described. Biophysical properties of the
lipids will be recounted at a later date.
Much of what is known about phospholipids with two
short chains originates from one particular group.4-8 The
following cites some of their key observations (in which,
for example, C6-C7-PC represents 1-hexanoyl-2-
heptanoyl-sn-3-phosphocholine): (a) Phospholipids with
6-8 carbons in each fatty acyl chain form micelles, not
bilayers. In this sense they resemble phospholipids
having only a single long chain (although the latter have
much lower critical micelle concentrations for an equal
number of carbons). (b) Micelles of the di-C7 or di-C8
lipids grow dramatically with concentration into capsule-
shaped structures. Growth occurs by insertion of the
lipid into the shaft of the capsul to create, ultimately,
long rigid rods. (c) C16-C16-PC (20 mM) mixed with C7-
C7-PC (5 mM) forms a disk with a rounded periphery
(radius ) 86 Å; diameter ) 45 Å). The disk consists of a
circular bilayer of long-chained lipids whose edge is
“capped” by hemicircular short-chained lipids. These
observations apply rather peripherally to our own sys-
tems in which one chain is long (16 carbons) whereas the
other is short to medium (8 or 12 carbons) and terminated
with a heteroatom.
ward: It should be possible, with specially designed
phospholipids, to create bilayer membranes that contain
defects or water-filled cavities. Cavity-bearing mem-
branes could function as self-assembled “host” systems
within which guest molecules are retained. In this
manner, water-soluble drugs and other compounds could
be stored and perhaps eventually released. The chal-
lenge, therefore, was to design and synthesize appropri-
ate phospholipids and, ultimately, to examine their
membranes for the presence of transient or permanent
voids.
Addition of channel compounds to membrane bilayers
has been widely investigated in recent years.1 We
ourselves discovered a simple synthetic compound that
exceeds gramicidin in its ability to guide ions through
bilayers.2 The goals of the present program are, however,
quite different. We are not seeking membrane-spanning
channels so much as enclosed cavities into which ions
and polar molecules can reside for reasonably long time
periods. This is best achieved, in our view, by manipu-
lating the phospholipid structure rather than by inserting
external host compounds into the membrane.
Eight phospholipids were selected for study (Figure 1).
All but the three dimeric lipids possess a “normal” 16-
carbon chain plus a shorter chain of 8 or 12 carbons
terminated by a functional group (OCH3, OTBS, OH, or
COOH). Owing to the asymmetry of the chains, voids
in the membrane are possible depending on exactly how
the molecules arrange themselves in the bilayer. One
could imagine, for example, a set of short chains alligned
on the periphery of a cylinder to encompass, with their
terminal methoxyls, a crown ether-like cavity (Figure 2).
Of course, cavity formation is a dynamic process. Voids
of different sizes could close and reopen rapidly as the
lipid molecules interdigitate or otherwise diffuse through
the bilayer. Alternatively, space-filling but metastable
lipid configurations might seize the opportunity to rear-
range themselves in order to accommodate the spatial
needs of a guest molecule. In other words, upon entering
a partially disordered membrane, a guest might induce
a cavity that, in the absence of the guest, forms only
transiently or not at all.
Phospholipids with one hydrocarbon chain shorter than
the other have also been intensively studied, and we now
summarize some of their important properties: (a) For
modest differences in chain asymmetry, the main transi-
tion temperature (Tm) and the transition enthalpy (∆H)
both decrease with increasing asymmetry.9 For example,
C14-C14-PC, C15-C13-PC, and C16-C12-PC have Tm
values of 24.1, 18.8, and 11.3 °C, respectively. The trends
(3) Menger, F. M.; Wrenn, S. J . Phys. Chem. 1974, 78, 1387-1390.
(4) Lin, T.-L.; Chen, S.-H.; Gabriel, N. E.; Roberts, M. F. J . Phys.
Chem. 1987, 91, 406-413.
(5) Lin, T.-L.; Chen, S.-H.; Roberts, M. F. J . Am. Chem. Soc. 1987,
109, 2321-2328.
Note that there was no certainty that our new phos-
pholipids could even form bilayers. This was especially
(6) Lin, T.-L.; Liu, C.-C.; Roberts, M. F.; Chen, S.-H. J . Phys. Chem.
1991, 95, 6020-6027.
X Abstract published in Advance ACS Abstracts, September 15, 1996.
(1) Fyles, T. M.; J ames, T. D.; Kaye, K. C. J . Am. Chem. Soc. 1993,
115, 12315-12321.
(2) Menger, F. M.; Davis, D. S.; Persichetti, R. A.; Lee, J .-J . J . Am.
Chem. Soc. 1990, 112, 2451-2452.
(7) Bian, J .; Roberts, M. F. J . Phys. Chem. 1991, 95, 2572-2577.
(8) Bian, J .; Roberts, M. F. J . Colloid Interface Sci. 1992, 153, 420-
428.
(9) Lin, H.; Wang, Z.; Huang, C. Biochem. Biophys. Acta 1991, 1067,
17-28.
S0022-3263(96)00545-2 CCC: $12.00 © 1996 American Chemical Society

Phospholipid Membranes as Host-Guest Systems
J . Org. Chem., Vol. 61, No. 21, 1996 7383
O
CH3(CH2)14CO
X(CH2)nCO
O
O
+
N
O
P
O
O–
1
O
O
OC
(CH2)30
CO
O
O
OC(CH2)nX
X(CH2)nCO
O
+
+
N
N
O
P
O
O
P
O
O
O–
O–
2
O
O
OC
(CH2)20
CO
O
O
OC(CH2)3
O
OCH3
CH3O
(CH2)3CO
O
+
+
N
N
O
P
O
O
P
O
O–
O–
3
compd
n
X
1a
1b
1c
7
OCH3
OCH3
OTBS
OH
11
11
11
10
1d
1e
CO2H
2a
2b
7
OCH3
OCH3
11
F igu r e 1. Phospholipids synthesized in this work.
Such an arrangement, as occurs with C18-C10-PC, is
consistent with X-ray data showing a membrane thick-
ness approximating the length of a single long chain. In
the liquid crystalline state (T > Tm), membrane thickness
becomes “normal” (i.e., C18-C10-PC ≈ C14-C14-PC). The
mixed interdigitated mode explains the reversal in the
thermotropic properties mentioned above. (d) Experi-
ments with a spin label (16-doxylstearate) seem to show
restricted motion in C18-C10-PC, but enhanced motional
freedom in C18-C14-PC, relative to the symmetrical
F igu r e 2. Schematic representation of a guest molecule
entering a defect within a membrane host.
1
forms of the lipid in the gel state.13 (e) Both H and 13C
spin-lattice relaxation times at T > Tm indicate inhibited
segmental motion at megahertz frequencies for C18-C10-
PC compared to those for a symmetrical lipid.14 (f)
Mixtures of symmetrical and asymmetrical lipids can
become immiscible at T < Tm. (g) Finally, we should
caution that the study of asymmetrical lipids is not a
simple business. Their degree of hydration,11 liposomal
size,15 and even the bilayer’s thermal history16 are all
known to affect the membrane properties.
are reversed (as will be explained momentarily) with
highly asymmetric lipids, e.g., C18-C10-PC has a Tm
)
18.7 °C and a ∆H ) 9.0 kcal/mol. (b) A structural model,
applicable to modestly asymmetric lipids in the gel state
(T < Tm), incorporates two lipid molecules with their long
and short chains opposing each other:10
It has recently been written: “There have been few
studies related to the solubilization of organic solutes by
vesicles and the removal of these solutes from water”.17
This, plus the complexity of our lipid structures, made
predictions difficult. In any event, the first task at hand
was to synthesize the necessary materials, and this is
the subject of the current paper.
Such chain “interdigitation” becomes more pronounced11
as the asymmetry increases from, say, C18-C16-PC to
C18-C14-PC to C18-C12-PC. (c) When one chain is
roughly half the length of the other, a so-called “mixed
interdigitated” arrangement is believed to exist in the
gel state with excess water.12
(13) Boggs, J . M.; Mason, J . T. Biochem. Biophys. Acta 1986, 863,
231-242.
(14) Halladay, H. N.; Stark, R. E.; Ali, S.; Bittman, R. Biophys. J .
1990, 58, 1449-1461.
(10) Huang, C.; Mason, J . T.; Levin, I. W. Biochemistry 1983, 22,
2775-2780.
(15) Mason, J . T.; Huang, C.; Biltonen, R. L. Biochemistry 1983, 22,
2013-2018.
(11) Mattai, J .; Sripada, P. K.; Shipley, G. G. Biochemistry 1987,
26, 3287-3297.
(16) Lewis, R. N. A. H.; McElhaney, R. N.; O¨ sterberg, F.; Gruner,
S. M. Biophys. J . 1994, 66, 207-216.
(17) Kondo, Y.; Abe, M.; Ogino, K.; Uchiyama, H.; Scamehorn, J .
F.; Tucker, E. E.; Christian, S. D. Langmuir 1993, 9, 899-902.
(12) McIntosh, T. J .; Simon, S. A.; Ellington, J . C.; Porter, N. A.
Biochemistry 1984, 23, 4038-4044.

7384 J . Org. Chem., Vol. 61, No. 21, 1996
Menger and Wong
F igu r e 3. Schemes for the synthesis of the phospholipids.
Resu lts a n d Discu ssion
mine of an ω-bromo acid was displaced with methoxide
or, alternatively, an ω-hydroxy acid was derivatized with
methyl iodide or TBSCl. Scheme II shows how a lyso-
phospholipid was acylated with one of the carboxylic acids
using dicyclohexylcarbodiimide (DCC) and (dimethylami-
no)pyridine (DMAP) in CH2Cl2. These standard proce-
Figure 3, subdivided into three schemes, describes the
synthetic routes to our eight new phospholipids. Scheme
I shows the two ways in which “short” fatty acids were
terminated with either an OCH3 or OTBS group (where
OTBS signifies tert-butyldimethylsiloxy). Thus, the bro-

Phospholipid Membranes as Host-Guest Systems
J . Org. Chem., Vol. 61, No. 21, 1996 7385
2.31 (t, 2 H, J ) 7.5 Hz, CH2CO2H), 1.50-1.63 (comp, 4 H,
(CH2)2), 1.28-1.40 (comp, 6 H, (CH2)3); 13C NMR (75 MHz,
CDCl3) δ 179.6 (CdO), 72.8 (OCH2), 58.3 (OCH3), 34.0, 29.4,
29.0, 28.9, 25.8, 24.5 ((CH2)6CO2H); mass spectrum (FAB) m/ z
175.1330 (C9H18O3 + H requires 175.1334).
dures, detailed in the Experimental Section, gave lipids
1a -e that were identified, usually after column chro-
matography, by NMR, mass spectrometry, and elemental
analysis.
It should be pointed out that our synthetic procedures
are all written in “recipe format” as described in a recent
publication.18 This new format provides all the necessary
information, saves considerable space, and avoids overuse
of the passive voice.
CO2H
CH3O
7
5
12-Meth oxyd od eca n oic Acid (7). Add a solution of 12-
hydroxydodecanoic acid (1.70 g, 7.86 mmol) in THF/DMF (5
mL/2 mL) to a suspension of NaH (1.81 g, 75.42 mmol). Stir
at rt overnight. Add CH3I (9 mL). Heat to reflux overnight.
Cool the reaction mixture to rt. Add H2O (15 mL) and NaOH
(0.4 g). Heat to reflux for 3 h. Add 2 N HCl (25 mL) and
extract with ether (2 × 25 mL). Wash with brine (30 mL).
Dry over Na2SO4, filter, and rotoevaporate. Purify by flash
chromatography (1:1 hexanes/EtOAc) to give 1.20 g (66%) of
7 as a white solid: 1H NMR (75 MHz, CDCl3) δ 3.36 (t, 2 H, J
) 6.7 Hz, CH3OCH2), 3.33 (s, 3 H, CH3OCH2), 2.33 (t, 2 H, J
) 7.5 Hz, CH2CO2H), 1.51-1.67 (comp, 4 H, (CH2)2CH2CO2H),
1.26 (s, 14 H, CH3(CH2)7); 13C NMR (300 MHz, CDCl3) δ 179.7
(CdO), 72.9 (CH2OCH3), 58.4 (CH3OCH2), 34.0 (CH2CO2H),
29.55, 29.49, 29.4, 29.3, 29.2, 29.0, 26.1, 24.7 (fatty CH2); mass
spectrum (FAB) m/ z 231.1951 (C13H26O3 + H requires
231.1960).
Scheme III outlines the steps used to prepared the
dimeric phospholipids 2 and 3. The strategy involved
inserting the phosphatidylcholine group at the very end
of the sequence when the dimeric skeleton was already
in place (i.e., 19-21 to 2 and 3). This aided in the
purification of intermediates which were uncharged
throughout. A high-temperature Glaser coupling, devel-
oped previously by us for constructing macrocyclic lip-
ids,19,20 was key to the synthesis. Thus, ω-acetylenes 13-
15 were joined to form diacetylenes 16-18 via the
following general procedure (recipe format): Bubble O2
into a suspension of CuCl (1.5 equiv) and TMEDA (1.6
equiv) in xylene (3-6 mL) at 140 °C for 15 min. Add a
solution of the mixed-chain diacyl-3-benzyl-sn-glycerol
(0.2-0.7 mmol) in xylene (1-3 mL). Stir at 140-150 °C
for 30 min, cool to rt, dilute with EtOAc (30-60 mL), and
wash with brine (30-60 mL). Dry organic layer over Na2-
SO4, filter, and rotoevaporate. Purify by flash chroma-
tography, eluting with hexanes/EtOAc (2:1) to give the
bis(diacyl-3-benzylglycerol). Note that subsequent hy-
drogenation (10% Pd/C), in which 16-18 were converted
into 19-21, served two purposes: removal of the benzyl
protecting group and saturation of the diacetylenic unit.
Only one other synthetic detail needs mentioning.
Mixed-chain intermediates 13-15 were prepared by first
acylating position-1 of (R)-3-(benzyloxy)-1,2-propanediol
with slightly less than an equivalent of fatty acid (DCC
and DMAP in CH2Cl2 at 20 °C). The second fatty acid
was then placed at position-2 using much the same
conditions. Success of the procedure rests solely upon
the greater reactivity of the primary hydroxyl over the
secondary hydroxyl.
CO2H
CH3O
11
7
12-((ter t-Bu tyld im eth ylsilyl)oxy)d od eca n oic Acid (8).
Add TBSCl (2.87 g, 19.04 mmol) to a solution of 12-hydroxy-
dodecanoic acid (1.51 g, 6.98 mmol) and imidazole (1.23 g,
18.07 mmol) in DMF (10 mL). Stir at rt overnight. Add brine
(50 mL). Extract with ether (2 × 50 mL). Wash with
saturated NaHCO3 (50 mL) and then brine (50 mL). Dry the
ether solution over Na2SO4, filter, and rotoevaporate. Dry in
vacuo overnight to give tert-butyldimethylsilyl 12-((tert-
butyldimethylsilyl)oxy)dodecanoate as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 3.57 (t, 2 H, J ) 6.6 Hz, CH2OSi), 2.27 (t,
2 H, J ) 7.4 Hz, CH2CO2Si), 1.46-1.59 (comp, 4 H, (CH2)2-
CH2OSi), 1.25 (s, 14 H, (CH2)7CH2CO2H), 0.90 (s, 9 H, (CH3)3-
CSiOC(O)), 0.87 (s, 9 H, (CH3)3CSiOCH2), 0.23 (s, 6 H,
(CH3)2SiOCH2), 0.02 (s, 6 H, (CH3)2SiOC(O)); 13C NMR (75
MHz, CDCl3) δ 174.1 (CO2Si), 63.2 (CH2OSi), 36.0, 32.9, 29.6,
29.5, 29.44, 29.40, 29.3, 29.1, 25.8, 25.1 (fatty CH2), 25.9
((CH3)3SiOCH2), 25.5 ((CH3)3CSiOC(O)), 18.3 ((CH3)3CSiOCH2),
17.5 ((CH3)3CHSiOC(O)), -4.8 ((CH3)2Si), -5.3 ((CH3)2Si); mass
spectrum (LSIMS) m/ z 445.3529 (C24H52O3Si2 + H requires
445.3533), 387.
Exp er im en ta l Section
15-Hexadecynoic acid was synthesized from 7-hexadecyn-
1-ol (Lancaster) according to the known procedure.21 10-
Undecynoic acid was pruchased from Lancaster, (R)-3-
(benzyloxy)-1,2-propanediol from Fluka, and (4-methoxy-
phenyl)butyric acid from Aldrich. 1-Palmitoyl-2-hydroxy-sn-
glycero-3-phosphocholine was obtained from Avanti Polar
Lipids. This L-R-lysophosphatidylcholine was reported to be
99% pure; acylation of the alcohol should not affect its
enantiomeric purity. Chloroform, methanol, ethyl acetate,
hexane, and acetone were either reagent or HPLC grade.
8-Meth oxyocta n oic Acid (5). Add 8-bromooctanoic acid
(1.24 g, 5.57 mmol) to a suspension of CH3ONa (3.43 g, 63.42
mmol) in CH3OH (25 mL). Heat to reflux overnight. Add 2
M of HCl(aq) (ca. 5 mL) to neutralize the reaction mixture.
Rotoevaporate the solution. Add 1 M HCl(aq) (50 mL).
Extract with EtOAc (2 × 25 mL). Wash the combined extracts
with brine (50 mL). Dry over Na2SO4, filter, and rotoevapo-
rate. Purify by flash chromatography (1:1 hexanes/EtOAc) to
give 0.76 g (78%) of 5 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 3.35 (t, 2 H, J ) 6.6 Hz, OCH2), 3.31 (s, 3 H, CH3O),
CO2H
TBSO
11
8
Dissolve in CH3OH (125 mL) and a solution of K2CO3 (1.82
g, 18.36 mmol) in H2O (25 mL). Stir for 30 min. Add pH 2.0
buffer (50 mL) and then 2 N HCl (ca. 10 mL) until pH 7-8.
Rotoevaporate. Cool in the ice bath and add 2 N HCl dropwise
while stirring until pH 6-7. Saturate the solution with NaCl.
Extract with ether (3 × 75 mL). Wash the combined extracts
with brine (50 mL). Dry over Na2SO4, filter, and rotoevapo-
rate. Purify by flash chromatography (2:1 hexanes/EtOAc) to
give 1.85 g (80%) of 8 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 11.1 (s, br, 1 H, CO2H), 3.59 (t, 2 H, J ) 6.6 Hz,
CH2OSi), 2.33 (t, 2 H, J ) 7.4 Hz, CH2CO2H), 1.46-1.64 (comp,
4 H, (CH2)2CH2CO2H), 1.26 (s, br, 14 H, (CH2)7CH2CO2H), 0.88
(s, 9 H, (CH3)3CSi), 0.39 (s, 6 H, (CH3)2Si); 13C NMR (75 MHz,
CDCl3) δ 180.2 (CO2H), 63.3 (CH2OSi), 34.1, 32.8, 29.6, 29.5,
29.4, 29.2, 29.0, 25.8, 24.7 (fatty CH2), 26.0 ((CH3)3CSi), 18.3
((CH3)3CSi), -5.1 ((CH3)2Si); mass spectrum (LSIMS) m/ z
331.2662 (C18H38O3Si + H requires 331.2668).
(18) Menger, F. M. Chem. Br. 1996, 29.
(19) Menger, F. M.; Brocchini, S.; Chen, X. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1492-1493.
1-P a lm itoyl-2-(8-m eth oxyocta n oyl)-sn-glycer o-3-p h os-
p h och olin e (1a ). Dissolve 1-palmitoyl-2-hydroxy-sn-glycero-
3-phosphocholine (100 mg, 0.20 mmol), carboxylic acid 5 (77
mg, 0.44 mmol), and DMAP (60 mg, 0.49 mmol) in CH2Cl2 (2
(20) Menger, F. M.; Chen, X. Y. Tetrahedron Lett. 1996, 37, 323-
326.
(21) Menger, F. M.; Chen, X. Y.; Brocchini, S.; Hopkins, H. P.;
Hamilton, D. J . Am. Chem. Soc. 1993, 115, 6600-6608.

7386 J . Org. Chem., Vol. 61, No. 21, 1996
Menger and Wong
mL). Add 1,3-dicyclohexylcarbodiimide (100 mg, 0.48 mmol).
Stir at rt for 2 days. Remove the white solid by filtration
through a small cotton wool plug in a 6 in. pipet. Rotoevapo-
rate the filtrate. Purify twice by column chromatography (65:
35:4 CHCl3/CH3OH/H2O; 1 in. diameter × 2 in. height flash
silica gel; elution rate ca. 4 mL/min) to give 46 mg (35%) of
1a . Lyophilize to give white solid: 1H NMR (300 MHz, CDCl3)
δ 5.15 (m, 1 H, C2H), 4.35 (dd, 1 H, J ) 12.0, 2.6 Hz, C1H),
4.26 (m, 2 H, POCH2CH2N), 4.08 (dd, 1 H, J ) 12.0, 7.2 Hz,
C1H), 3.82-3.95 (comp, 2 H, C3H2), 3.77 (m, 2 H, CH2N), 3.28-
3.33 (comp, 14 H, CH2OCH3 and N(CH3)3), 2.26 (t, 2 H, J )
6.9 Hz, CH2CO2), 2.23 (t, 2 H, J ) 6.9 Hz, CH2CO2), 1.45-
1.56 (comp, 6 H, fatty CH2), 1.16-1.32 (comp, 30 H, fatty CH2),
0.84 (t, 3 H, J ) 6.6 Hz, CH3CH2); 13C NMR (75 MHz, CDCl3)
δ 173.4, 173.0 (CdO), 72.7 (CH2OCH3), 70.5 (d, J ) 7.3 Hz,
C2), 66.2 (d, J ) 5.9 Hz, CH2N), 63.2 (d, J ) 5.4 Hz, C3), 62.9
(C1), 59.2 (d, J ) 5.3 Hz, POCH2CH2N), 58.4 (CH3OCH2), 54.2
(N(CH3)3), 34.2, 34.0, 31.8, 29.6, 29.52, 29.47, 29.3, 29.11, 29.06,
28.9, 25.9, 24.82, 24.78, 22.6 (fatty CH2), 14.0 (CH3CH2); mass
spectrum (FAB) m/ z 652.4540 (C33H66NO9P + H requires
652.4553).
Rotoevaporate the filtrate. Purify twice by column chroma-
tography (65:35:4 CHCl3/CH3OH/H2O; 1 in. diameter × 2 in.
height flash silica gel; elution rate ca. 4 mL/min) to give 225
mg (81%) of 1c. Lyophilize to give a white solid: 1H NMR
(300 MHz, CDCl3) δ 5.18 (m, 1 H, C2H), 4.38 (dd, 1 H, J )
12.0, 2.6 Hz, C1H), 4.30 (m, 2 H, POCH2CH2N), 4.11 (dd, 1 H,
J ) 12.0, 7.3 Hz, C1H), 3.85-3.97 (comp, 2 H, C3H2), 3.80 (m,
2 H, CH2N), 3.58 (t, 2 H, J ) 6.6 Hz, CH2OSi), 3.36 (s, 9H,
N(CH3)3), 2.28 (t, 2 H, J ) 7.3 Hz, CH2CO2), 2.236 (t, 2 H, J )
7.3 Hz, CH2CO2), 1.45-1.58 (comp, 6 H, fatty CH2), 1.24 (comp,
38 H, fatty CH2), 0.88 (s, 9H, (CH3)3CSi), 0.87 (t, 3 H, J ) 6.6
Hz, CH3CH2), 0.33 (s, 6H, (CH3)2Si); 13C NMR (75 MHz, CDCl3)
δ 173.5, 173.1 (CdO), 70.5 (d, J ) 7.6 Hz, C2), 66.3 (d, J ) 6.2
Hz, CH2N), 63.4 (d, J ) 5.40 Hz, C3), 63.3 (CH2OSi), 62.9 (C1),
59.3 (d, J ) 4.6 Hz, POCH2CH2N), 54.4 (N(CH3)3), 34.3, 34.1,
32.9, 31.9, 29.7, 29.6, 29.52, 29.46, 29.3, 29.2, 25.8, 25.0, 24.9,
22.6 (fatty CH2), 26.0 ((CH3)3CSi), 18.3 ((CH3)3CSi), 14.1 (CH3-
CH2), -5.3 ((CH3)2Si); mass spectrum (LSIMS) m/ z 808.5888
(C42H86NO9PSi + H requires 808.5888).
O
CH3(CH2)14CO
O
O
TBSO(CH2)11CO
O
+
CH3(CH2)14CO
N
O
P
O
O
CH3O(CH2)7CO
O
+
O–
N
O
P
O
1c
O–
1-P a lm it oyl-2-(12-h yd r oxyd od eca n oyl)-sn-glycer o-3-
p h osp h och olin e (1d ). Add a solution of 2 mL of HOAc/H2O/
THF (3:1:1) to 1c (22 mg, 0.027 mmol). Stir at rt for 1 h. Dry
in vacuo. Purify twice by column chromatography (65:35:4
CHCl3/CH3OH/H2O; 1 in. diameter × 2 in. height flash silica
gel; elution rate ca. 4 mL/min) to give 13 mg (70%) of 1d .
Lyophilize to give a white solid: 1H NMR (300 MHz, CDCl3) δ
5.15 (m, 1 H, C2H), 4.35 (dd, 1 H, J ) 11.9, 2.4 Hz, C1H), 4.24
(m, 2 H, POCH2CH2N), 4.09 (dd, 1 H, J ) 11.9, 7.3 Hz, C1H),
3.82-3.97 (comp, 2 H, C3H2), 3.73 (m, 2 H, CH2N), 3.53 (t, 2H,
J ) 6.6 Hz, CH2OH), 3.30 (s, 9 H, N(CH3)3), 2.26 (t, 2 H, J )
7.4 Hz, CH2CO2), 2.24 (t, 2 H, J ) 7.6 Hz, CH2CO2), 1.45-
1.55 (comp, 6 H, fatty CH2), 1.22 (comp, 38 H, fatty CH2), 0.84
(t, 3 H, J ) 6.6 Hz, CH3CH2); 13C NMR (75 MHz, CDCl3) δ
173.4, 173.1 (CdO), 70.5 (d, J ) 7.4 Hz, C2), 66.2 (d, J ) 5.5
Hz, CH2N), 63.3 (d, J ) 4.7 Hz, C3), 62.9 (C1), 62.4 (CH2OH),
59.2 (d, J ) 4.6 Hz, POCH2CH2N), 54.2 (N(CH3)3), 34.2, 34.1,
32.7, 31.8, 29.6, 29.5, 29.31, 29.26, 29.2, 29.1, 28.9, 28.8, 25.7,
24.8, 24.7, 22.6 (fatty CH2), 14.0 (CH3CH2); mass spectrum
(LSIMS) m/ z 694.5031 (C36H72O9NP + H requires 694.5023).
Anal. Calcd for C36H72NO9P: C, 62.31; H, 10.46; N, 2.02.
Found: C, 62.24; H, 10.49; N, 2.01.
1a
1-P a lm it oyl-2-(12-m et h oxyd od eca n oyl)-sn-glycer o-3-
p h osp h och olin e (1b). Dissolve 1-palmitoyl-2-hydroxy-sn-
glycero-3-phosphocholine (156 mg, 0.315 mmol) and acid 7 (227
mg, 0.98 mmol) in CH2Cl2 (5 mL) (warming in a water bath
at ca. 40 °C may be needed). Add DMAP (37 mg, 0.30 mmol)
and a solution of 1,3-dicyclohexylcarbodiimide (204 mg, 0.99
mmol) in CH2Cl2 (2 mL). Stir at rt for 2 days. Remove the
white solid by filtration through a small cotton wool plug in a
6 in. pipet. Rotoevaporate the filtrate. Purify twice by column
chromatography (65:35:4 CHCl3/CH3OH/H2O; 1 in. diameter
× 2 in. height flash silica gel; elution rate ca. 4 mL/min) to
give 165 mg (74%) of 1b. Lyophilize to give white solid: 1H
NMR (300 MHz, CDCl3) δ 5.13 (m, 1 H, C2H), 4.34 (dd, 1 H, J
) 12.0, 2.7 Hz, C1H), 4.25 (m, 2 H, POCH2CH2N), 4.06 (dd, 1
H, J ) 12.0, 7.3 Hz, C1H), 3.88 (m, 2 H, C3H2), 3.78 (m, 2 H,
CH2N), 3.34 (s, 9 H, N(CH3)3), 3.30 (t, 2H, J ) 6.7 Hz, CH2-
OCH3), 3.27 (s, 3H, CH2OCH3), 2.23 (t, 2 H, J ) 7.5 Hz, CH2-
CO2), 2.21 (t, 2 H, J ) 7.4 Hz, CH2CO2), 1.44-1.57 (comp, 6
H, fatty CH2), 1.20 (s, 38 H, fatty CH2), 0.82 (t, 3 H, J ) 6.6
Hz, CH3CH2); 13C NMR (75 MHz, CDCl3) δ 173.4, 173.0 (CdO),
72.8 (CH2OCH3), 70.5 (d, J ) 7.6 Hz, C2), 66.2 (CH2N), 63.2
(d, J ) 4.5 Hz, C3), 62.9 (C1), 59.2 (POCH2CH2N), 58.4 (CH3-
OCH2), 54.2 (N(CH3)3), 34.2, 34.0, 31.8, 29.6, 29.5, 29.46, 29.38,
29.3, 29.22, 29.20, 29.05, 29.02, 26.0, 24.85, 24.78, 22.5 (fatty
CH2), 14.0 (CH3CH2); mass spectrum (FAB) m/ z 708.5184
(C37H74NO9P + H requires 708.5179). Anal. Calcd for
C37H74NO9P‚1.5H2O: C, 60.46; H, 10.56; N, 1.91. Found: C,
60.41; H, 10.52; N, 1.91.
O
CH3(CH2)14CO
O
HO(CH2)11CO
O
+
N
O
P
O
O–
1d
O
1-P a lm it oyl-2-(11-ca r b oxyu n d eca n oyl)-sn-glycer o-3-
p h osp h och olin e (1e). Warm a mixture of 1-palmitoyl-2-
hydroxy-sn-glycero-3-phosphocholine (104 mg, 0.210 mmol)
and 1,10-decanedicarboxylic acid (0.47 g, 2.31 mmol) in CH2-
Cl2 (10 mL) at ca. 40 °C in a water bath until most of the diacid
dissolved. Add DMAP (22 mg, 0.18 mmol) and then a solution
of 1,3-dicyclohexylcarbodiimide (114 mg, 0.55 mmol) in CH2-
Cl2 (1 mL). Stir for 3 days. Filter through a small cotton wool
plug in a 6 in. pipet. Rotoevaporate the filtrate. Purify twice
by column chromatography (65:35:4 CHCl3/CH3OH/H2O; 1 in.
diameter × 2 in. height flash silica gel; elution rate ca. 4 mL/
min) to give 31 mg (21%) of 1e. Lyophilize to give white
solid: 1H NMR (300 MHz, CDCl3) δ 5.18 (m, 1 H, C2H), 4.26-
4.40 (comp, 3 H, C1H and POCH2CH2N), 4.11 (dd, 1 H, J )
11.5, 7.0 Hz, C1H), 3.93 (m, 2 H, C3H2), 3.77 (m, 2 H, CH2N),
3.31 (s, 9 H, N(CH3)3), 2.17-2.35 (comp, 6 H, CH2CO2), 1.50-
CH3(CH2)14CO
O
CH3O(CH2)11CO
O
+
N
O
P
O
O–
1b
1-P a lm itoyl-2-[(12-((ter t-bu tyld im eth ylsilyl)oxy)d od e-
can oyl]-sn-glycer o-3-ph osph och olin e (1c). Dissolve 1-palm-
itoyl-2-hydroxy-sn-glycero-3-phosphocholine (170 mg, 0.343
mmol) and 8 (0.58 g, 1.76 mmol) in CH2Cl2 (5 mL) (warming
in a water bath at ca. 40 °C was needed). Add DMAP (41 mg,
0.336 mmol) and then a solution of 1,3-dicyclohexylcarbodi-
imide (0.49 g, 2.40 mmol) in CH2Cl2 (2 mL). Stir for 2 days.
Filter through a small cotton wool plug in a 6 in. pipet.

Phospholipid Membranes as Host-Guest Systems
J . Org. Chem., Vol. 61, No. 21, 1996 7387
1.65 (comp, 6 H, J ) 6.9 Hz, CH2CH2CO2), 1.45-1.56 (comp,
6 H, fatty CH2), 1.23 (comp, 36 H, fatty CH2), 0.86 (t, 3 H, J )
6.6 Hz, CH3CH2); 13C NMR (75 MHz, CDCl3) δ 176.5 (CO2H),
173.4, 173.1 (CdO), 70.5 (d, J ) 7.3 Hz, C2), 66.3 (d, J ) 5.0
Hz, CH2N), 63.5 (d, J ) 3.6 Hz, C3), 62.8 (C1), 59.3 (d, J ) 3.6
Hz, POCH2CH2N), 54.3 (N(CH3)3), 34.8, 34.1, 31.9, 29.7, 29.5,
29.3, 29.1, 28.9, 28.8, 28.6, 25.0, 24.8, 24.6, 22.6 (fatty CH2),
and DMAP (20 mg, 0.16 mmol) in CH2Cl2 (4 mL). Stir at rt
overnight. Filter through a small cotton wool plug in a 6 in.
pipet. Purify by flash chromatography eluting with hexanes/
EtOAc (3:1) to afford 0.79 g (78%) of 13 as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.21-7.33 (comp, 5 H, Ar-H), 5.21
(m, 1 H, C2H), 4.52 (d, 1 H, J ) 12.2 Hz, CHPh), 4.47 (d, 1 H,
J ) 12.2 Hz, CHPh), 4.31 (dd, 1 H, J ) 11.8, 3.7 Hz, C1H),
4.15 (dd, 1 H, J ) 11.8, 6.3 Hz, C1H), 3.55 (d, 2 H, J ) 5.2 Hz,
C3H2), 3.31 (t, 2 H, J ) 6.6 Hz, CH3OCH2), 3.28 (s, 3 H, OCH3),
2.28 (t, 2 H, J ) 7.5 Hz, CH2CO2), 2.24 (t, 2 H, J ) 7.5 Hz,
CH2CO2), 2.13 (td, 2 H, J ) 7.0, 2.6 Hz, CH2CtC), 1.90 (t, 1
H, J ) 2.6 Hz, CtCH), 1.44-1.58 (comp, 8 H, fatty CH2), 1.04-
1.40 (comp, 24 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ
173.1, 172.8 (CdO), 137.5, 128.2, 127.6, 127.4 (ArC), 84.5
(CtCH), 73.1 (CH2Ph), 72.6 (CH2OCH3), 69.8 (C2), 68.1, 68.0
(C3, CtCH), 62.4 (C1), 58.3 (CH3O), 34.1, 33.9, 29.4, 29.32,
29.29, 29.1, 28.9, 28.8, 28.6, 28.3, 25.8, 24.7 (fatty CH2), 18.2
(CH2CtCH); mass spectrum (LSIMS) m/ z 573.4153 (C35H56O6
+ H requires 573.4155).
14.1 (CH3CH2); mass spectrum (LSIMS) m/ z 708.4825 (C36H70
NO10P + H requires 708.4816).
-
O
CH3(CH2)14CO
O
HO2C(CH2)10CO
O
+
N
O
P
O
O–
1e
1-(15-Hexa d ecyn oyl)-3-ben zyl-sn-glycer ol (11). Add a
solution of 1,3-dicyclohexylcarbodiimide (0.61 g, 2.98 mmol)
in CH2Cl2 (1 mL) dropwise to a solution of (R)-3-(benzyloxy)-
1,2-propanediol (0.52 g, 2.85 mmol), 15-hexadecynoic acid2
(0.68 g, 2.68 mmol), and DMAP (30 mg, 0.25 mmol) in CH2Cl2
(4 mL) at 20 °C. Stir overnight. Filter through a small cotton
wool plug in a 6 in. pipet. Rotoevaporate the filtrate. Purify
by flash chromatography (first eluting with hexanes/EtOAc (3:
1) to get rid of the diacylation product and then 1:1 hexanes/
EtOAc to collect the desired monoacylated product) to afford
0.74 g (66%) of 11 as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 7.24-7.36 (comp, 5 H, Ar-H), 4.53 (s, 2 H, CH2Ph), 4.10-
4.19 (comp, 2 H, C1H2), 4.01 (m, 1 H, C2H2), 3.53 (dd, 1 H, J )
9.6, 4.4 Hz, C3H), 3.47 (dd, 1 H, J ) 9.6, 6.0 Hz, C3H), 2.80 (d,
1 H, OH), 2.30 (t, 2 H, J ) 7.5 Hz, CH2CO2), 2.16 (td, 2 H, J
) 7.0, 2.6 Hz, CH2CtC), 1.93 (t, 1 H, J ) 2.6 Hz, CtCH),
1.46-1.61 (comp, 4 H, fatty CH2), 1.07-1.42 (comp, 18 H, fatty
CH2); mass spectrum (LSIMS) m/ z 417.3003 (C26H40O4 + H
requires 417.3005).
O
(CH2)13CO
CH3O(CH2)7CO
OBn
O
13
1-(15-H e xa d e cyn oyl)-2-(12-m e t h oxyd od e ca n oyl)-3-
ben zyl-sn-glycer ol (14). Add a solution of 1,3-dicyclohexyl-
carbodiimide (0.22 g, 1.08 mmol) in CH2Cl2 (1 mL) to a solution
of 11 (0.39 g, 0.93 mmol), carboxylic acid 7 (0.22 g, 0.96 mmol),
and DMAP (10 mg, 0.08 mmol) in CH2Cl2 (5 mL). Stir at rt
overnight. Filter through a small cotton wool plug in a 6 in.
pipet. Purify by flash chromatography eluting with hexanes/
EtOAc (4:1) to afford 0.42 g (72%) of 14 as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.17-7.29 (comp, 5 H, Ar-H), 5.18
(m, 1 H, C2H), 4.49 (d, 1 H, J ) 12.1 Hz, CHPh), 4.44 (d, 1 H,
J ) 12.1 Hz, CHPh), 4.29 (dd, 1 H, J ) 11.8, 3.7 Hz, C1H),
4.12 (dd, 1 H, J ) 11.8, 6.4 Hz, C1H), 3.52 (d, 2 H, J ) 5.2 Hz,
C3H2), 3.28 (t, 2 H, J ) 6.5 Hz, CH3OCH2), 3.24 (s, 3 H, OCH3),
2.25 (t, 2 H, J ) 7.4 Hz, CH2CO2), 2.21 (t, 2 H, J ) 7.5 Hz,
CH2CO2), 2.09 (td, 2 H, J ) 7.0, 2.6 Hz, CH2CtC), 1.88 (t, 1
H, J ) 2.6 Hz, CtCH), 1.40-1.57 (comp, 8 H, fatty CH2), 1.21
(s, 32 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ 172.7, 172.5
(CdO), 137.4, 128.0, 127.4, 127.2 (ArC), 84.2 (CtCH), 72.9
(CH2Ph), 72.5 (CH2OCH3), 69.7 (C2), 67.9 (C3, CtCH), 62.3
(C1), 58.1 (CH3O), 33.9, 33.7, 29.4, 29.3, 29.2, 29.1, 29.0, 28.8,
28.7, 28.4, 28.2, 25.9, 24.6, 24.5 (fatty CH2), 18.0 (CH2CtCH);
mass spectrum (FAB) m/ z 629.4758 (C39H64O6 + H requires
629.4781).
O
(CH2)13CO
HO
OBn
11
1-(10-Un d ecyn oyl)-3-ben zyl-sn-glycer ol (12). Add a so-
lution of 1,3-dicyclohexylcarbodiimide (111 mg, 0.54 mmol) in
CH2Cl2 (1 mL) dropwise to a solution of (R)-3-(benzyloxy)-1,2-
propanediol (105 mg, 0.57 mmol), 10-undecynoic acid (92 mg,
0.50 mmol), and DMAP (8 mg, 0.06 mmol) in CH2Cl2 (2 mL)
at rt. Stir overnight. Filter through a small cotton wool in a
6 in. pipet. Rotoevaporate the filtrate. Purify by flash
chromatography eluting with hexanes/EtOAc (3:1) to afford
110 mg (65%) of 12 as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.27-7.37 (comp, 5 H, Ar-H), 4.55 (s, 2 H, CH2Ph),
4.09-4.21 (comp, 2 H, C1H2), 4.02 (m, 1 H, C2H2), 3.54 (dd, 1
H, J ) 9.6, 4.4 Hz, C3H), 3.48 (dd, 1 H, J ) 9.6, 5.9 Hz, C3H),
2.65 (d, 1 H, OH), 2.31 (t, 2 H, J ) 7.5 Hz, CH2CO2), 2.17 (td,
2 H, J ) 7.0, 2.6 Hz, CH2CtC), 1.93 (t, 1 H, J ) 2.6 Hz,
CtCH), 1.46-1.62 (comp, 4 H, fatty CH2), 1.29-1.42 (comp,
18 H, fatty CH2); mass spectrum (LSIMS) m/ z 347.2222
(C21H30O4 + H requires 347.2222).
O
(CH2)13CO
CH3O(CH2)11CO
OBn
O
14
1-(10-Un d ecyn oyl)-2-[4-(4′-m eth oxyp h en yl)bu tyr oyl]-
3-ben zyl-sn-glycer ol (15). Add a solution of 1,3-dicyclohexyl-
carbodiimide (72 mg, 0.349 mmol) in CH2Cl2 (1 mL) to a
solution of 12 (110 mg, 0.317 mmol), (4-methoxyphenyl)butyric
acid acid (64 mg, 0.329 mmol), and DMAP (4 mg, 0.033 mmol)
in CH2Cl2 (4 mL). Stir at rt overnight. Filter through a small
cotton wool plug in a 6 in. pipet. Purify by flash chromatog-
raphy eluting with hexanes/EtOAc (4:1) to afford 127 mg (76%)
of 15 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.27-
7.34 (comp, 5 H, OCH2Ar-H), 7.09 (d, 2 H, J ) 8.5 Hz, CH3O-
Ar-H), 6.83 (d, 2 H, J ) 8.5 Hz, CH3O-Ar-H), 5.28 (m, 1 H,
C2H), 4.57 (d, 1 H, J ) 12.2 Hz, OCHPh), 4.52 (d, 1 H, J )
12.2 Hz, OCHPh), 4.38 (dd, 1 H, J ) 11.9, 3.8 Hz, C1H), 4.21
(dd, 1 H, J ) 11.9, 6.4 Hz, C1H), 3.78 (s, 3 H, OCH3), 3.61 (d,
2 H, J ) 5.1 Hz, C3H2), 2.61 (t, 2 H, J ) 7.5 Hz, CH2CH2Ar),
2.35 (t, 2 H, J ) 7.4 Hz, CH2CO2), 2.29 (t, 2 H, J ) 7.5 Hz,
CH2CO2), 2.18 (td, 2 H, J ) 7.0, 2.5 Hz, CH2CtC), 1.88-1.98
O
(CH2)8CO
HO
OBn
12
1-(15-Hexa d ecyn oyl)-2-(8-m eth oxyocta n oyl)-3-ben zyl-
sn-glycer ol (13). Add a solution of 1,3-dicyclohexylcarbodi-
imide (0.42 g, 2.04 mmol) in CH2Cl2 (1.5 mL) to a solution of
11 (0.74 g, 1.77 mmol), carboxylic acid 5 (0.31 g, 1.78 mmol),

7388 J . Org. Chem., Vol. 61, No. 21, 1996
Menger and Wong
(comp, 3 H, CtCH and CH2CH2Ar), 1.48-1.62 (comp, 4 H,
fatty CH2), 1.24-1.48 (comp, 8 H, fatty CH2); 13C NMR (75
MHz, CDCl3) δ 173.1, 172.6 (CdO), 157.7, 137.5, 133.2, 129.2,
128.2, 127.6, 127.4, 113.6 (ArC), 84.5 (CtCH), 73.1 (CH2Ph),
70.0 (C2), 68.1 (C3, CtCH), 62.5, (C1), 55.0 (CH3OAr), 33.93,
33.88, 33.4, 28.9, 28.8, 28.7, 28.5, 28.3, 26.6, 24.6 (fatty CH2),
18.2 (CH2CtCH); mass spectrum (FAB) m/ z 522.2978 (C32H42O6
requires 522.2981).
O
(CH2)13CO
CH3O(CH2)11CO
OBn
O
2
17
(25 mL) and wash with brine (25 mL). Dry over Na2SO4, filter,
and rotoevaporate. Purify by flash chromatography eluting
with hexanes/EtOAc (2:1) to afford 107 mg (84%) of 18 as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.28-7.36 (comp,
10 H, OCH2Ar-H), 7.09 (d, 4 H, J ) 8.4 Hz, CH3O-Ar-H), 6.83
(d, 4 H, J ) 8.4 Hz, CH3O-Ar-H), 5.27 (m, 2 H, C2H), 4.57 (d,
2 H, J ) 12.1 Hz, OCHPh), 4.52 (d, 2 H, J ) 12.1 Hz, OCHPh),
4.37 (dd, 2 H, J ) 11.9, 3.7 Hz, C1H), 4.20 (dd, 2 H, J ) 11.9,
6.4 Hz, C1H), 3.78 (s, 6 H, OCH3), 3.60 (d, 4 H, J ) 5.1 Hz,
C3H2), 2.60 (t, 4 H, J ) 7.4 Hz, CH2CH2Ar), 2.35 (t, 4 H, J )
7.4 Hz, CH2CO2), 2.21-2.30 (comp, 8 H, CH2CO2 and CH2CtC),
1.92 (p, 4 H, CH2CH2Ar), 1.46-1.61 (comp, 8 H, fatty CH2),
1.28-1.45 (comp, 16 H, fatty CH2); 13C NMR (75 MHz, CDCl3)
δ 173.1, 172.6 (CdO), 157.7, 137.5, 133.2, 129.2, 128.2, 127.6,
127.5, 113.6 (ArC), 73.1 (CH2Ph), 70.0 (C2), 68.1 (C3), 65.2
(CtC), 62.5 (C1), 55.0 (CH3OAr), 33.94, 33.89, 33.4, 28.91,
28.86, 28.7, 28.6, 28.1, 26.6, 24.6 (fatty CH2), 19.0 (CH2CdC);
mass spectrum (FAB) m/ z 1042.5817 (C64H82O12 requires
1042.5806).
O
(CH2)8CO
CH3O
(CH2)3CO
OBn
O
15
1,1′-(15,17-Dotr ia con ta d iyn e-1,32-d ioyl)bis[2-(8-m eth -
oxyocta n oyl)-3-ben zyl-sn-glycer ol] (16). Bubble O2 into a
suspension of CuCl (70 mg, 0.70 mmol) and TMEDA (110 µL,
0.73 mmol) in xylenes (3 mL) at 140 °C for 15 min. Add a
solution of 14 (0.31 g, 0.54 mmol) in xylenes (2 mL). Stir at
140-150 °C for 15 min. Cool to rt. Dilute with EtOAc (9 mL)
and wash with water (2 × 5 mL). Dry over Na2SO4, filter,
and rotoevaporate. Purify by flash chromatography eluting
with hexanes/EtOAc (2:1) to afford 0.277 g (89%) of 16 as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.27-7.36 (comp,
10 H, Ar-H), 5.23 (m, 2 H, C2H), 4.55 (d, 2 H, J ) 12.1 Hz,
CHPh), 4.50 (d, 2 H, J ) 12.1 Hz, CHPh), 4.33 (dd, 2 H, J )
11.8, 3.7 Hz, C1H), 4.17 (dd, 2 H, J ) 11.8, 6.5 Hz, C1H), 3.58
(d, 4 H, J ) 5.1 Hz, C3H2), 3.34 (t, 4 H, J ) 6.6 Hz, CH3OCH2),
3.31 (s, 6 H, OCH3), 2.20-2.33 (comp, 12 H, CH2CO2 and
CH2CtC), 1.45-1.61 (comp, 16 H, fatty CH2), 1.24-1.40
(comp, 48 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ 173.3,
172.9 (CdO), 137.6, 128.3, 127.7, 127.5 (ArC), 73.2 (CH2Ph),
72.7 (CH2OCH3), 70.0 (C2), 68.2 (C3), 65.2 (CtC), 62.5 (C1),
58.5 (CH3O), 34.2, 34.0, 29.5, 29.4, 29.2, 29.0, 28.9, 28.8, 28.3,
25.9, 24.8 (fatty CH2), 19.1 (CH2CtCH); mass spectrum
(LSIMS) m/ z 1143.8078 (C70H110O12 + H requires 1143.8076).
O
(CH2)8CO
CH3O
(CH2)3CO
O
OBn
2
18
1,1′-(D o t r ia c o n t a n e -1,32-d io y l)b is [2-(8-m e t h o x y -
octa n oyl)-sn-glycer ol] (19). Stir a solution of 16 (0.25 g, 0.22
mmol) in absolute EtOH (4 mL) and glacial AcOH (1.5 mL)
under H2 in the presence of 10% Pd/C (26 mg) at rt overnight.
Dilute with CHCl3 (5 mL) and filter through Celite (the product
is not soluble in EtOH/AcOH). Wash the catalyst with CHCl3.
Rotoevaporate the filtrate to give 0.20 g (92%) of 19 as a white
solid: 1H NMR (300 MHz, CDCl3) δ 4.99 (m, 2 H, C2H), 4.24
(dd, 2 H, J ) 11.9, 3.8 Hz, C1H), 4.10 (dd, 2 H, J ) 11.9, 6.2
Hz, C1H), 3.60 (d, 4 H, J ) 5.5 Hz, C3H2), 3.26 (t, 4 H, J ) 6.6
Hz, CH3OCH2), 3.22 (s, 6 H, OCH3), 3.08 (t, 2 H, J ) 5.5 Hz,
C3H2OH), 2.24 (t, 4 H, J ) 7.4 Hz, CH2CO2), 2.19 (t, 4 H, J )
7.4 Hz, CH2CO2), 1.44-1.60 (comp, 12 H, fatty CH2), 1.12-
1.29 (comp, 64 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ
173.4, 173.1 (CdO), 72.6 (CH2OCH3), 71.8 (C2), 62.1 (C1), 60.9
(C3), 58.2 (CH3O), 34.0, 33.8, 29.5, 29.2, 29.0, 28.9, 28.8, 28.7,
25.7, 24.63, 24.57 (fatty CH2).
O
(CH2)13CO
CH3O(CH2)7CO
OBn
O
2
16
1,1′-(15,17-Dotr ia con ta d iyn e-1,32-d ioyl)bis[2-(12-m eth -
oxyd od eca n oyl)-3-ben zyl-sn-glycer ol] (17). Bubble O2 into
a suspension of CuCl (104 mg, 1.05 mmol) and TMEDA (160
µL, 1.06 mmol) in xylenes (6 mL) at 140 °C for 15 min. Add
a solution of 14 (0.42 g, 0.66 mmol) in xylenes (3 mL). Stir at
140-150 °C for 30 min. Cool to rt. Dilute with EtOAc (60
mL) and wash with brine (50 mL). Dry over Na2SO4, filter,
and rotoevaporate. Purify by flash chromatography eluting
with hexanes/EtOAc (2:1) to afford 0.40 g (95%) of 17 as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.19-7.26 (comp,
10 H, Ar-H), 5.18 (m, 2 H, C2H), 4.49 (d, 2 H, J ) 12.1 Hz,
CHPh), 4.44 (d, 2 H, J ) 12.1 Hz, CHPh), 4.29 (dd, 2 H, J )
11.9, 3.7 Hz, C1H), 4.12 (dd, 2 H, J ) 11.9, 6.3 Hz, C1H), 3.52
(d, 4 H, J ) 5.1 Hz, C3H2), 3.28 (t, 4 H, J ) 6.5 Hz, CH3OCH2),
3.24 (s, 6 H, OCH3), 2.13-2.27 (comp, 12 H, CH2CO2 and
CH2CtC), 1.39-1.55 (comp, 16 H, fatty CH2), 1.20 (s, 64 H,
fatty CH2); 13C NMR (75 MHz, CDCl3) δ 172.8, 172.5 (CdO),
137.5, 128.1, 127.4, 127.2 (ArC), 72.9 (CH2Ph), 72.6 (CH2-
OCH3), 69.7 (C2), 68.0 (C3), 65.2 (CtC), 62.3 (C1), 58.1 (CH3O),
34.0, 33.7, 29.4, 29.32, 29.26, 29.21, 29.17, 29.0, 28.82, 28.77,
28.6, 28.1, 25.9, 24.65, 24.58 (fatty CH2), 18.9 (CH2CtC); mass
spectrum (LSIMS) m/ z 1255.9319 (C78H126O12 + H requires
1255.9328), 1257 (M + H).
O
(CH2)15CO
CH3O(CH2)7CO
OH
O
2
19
1,1′-(Dotr ia con ta n e-1,32-d ioyl)bis[2-(12-m eth oxyd od e-
ca n oyl)-sn-glycer ol] (20). Stir a solution of 17 (103 mg,
0.082 mmol) in absolute EtOH (4 mL) and glacial AcOH (2
mL) under H2 in the presence of 10% Pd/C (11 mg) at rt
overnight. Dilute with CHCl3 (5 mL) and filter through Celite
(the product is not soluble in EtOH/AcOH). Wash the catalyst
with CHCl3. Rotoevaporate the filtrate to give 85 mg (95%)
of 20 as a white solid: 1H NMR (300 MHz, CDCl3) δ 5.05 (m,
2 H, C2H), 4.29 (dd, 2 H, J ) 11.9, 4.3 Hz, C1H), 4.18 (dd, 2 H,
J ) 11.9, 5.9 Hz, C1H), 3.68 (d, 4 H, J ) 5.0 Hz, C3H2), 3.32 (t,
4 H, J ) 6.7 Hz, CH3OCH2), 3.29 (s, 6 H, OCH3), 2.30 (t, 4 H,
J ) 7.2 Hz, CH2CO2), 2.28 (t, 4 H, J ) 7.2 Hz, CH2CO2), 1.44-
1.65 (comp, 12 H, fatty CH2), 1.08-1.35 (comp, 80 H, fatty
CH2); 13C NMR (75 MHz, CDCl3) δ 173.6, 173.3 (CdO), 72.9
1,1′-(10,12-Docosa d iyn e-1,22-d ioyl)b is[2-(4-(4′-m et h -
oxyp h en yl)bu tyr oyl)-3-ben zyl-sn-glycer ol] (18). Bubble
O2 into a suspension of CuCl (37 mg, 0.374 mmol) and TMEDA
(60 µL, 0.397 mmol) in xylenes (5 mL) at 140 °C for 15 min.
Add a solution of 15 (127 mg, 0.243 mmol) in xylenes (2 mL).
Stir at 140-150 °C for 30 min. Cool to rt. Dilute with EtOAc

Phospholipid Membranes as Host-Guest Systems
J . Org. Chem., Vol. 61, No. 21, 1996 7389
(CH2OCH3), 72.0 (C2), 62.1 (C1), 61.2 (C3), 58.4 (CH3O), 34.2,
34.0, 29.6, 29.54, 29.51, 29.45, 29.38, 29.3, 29.2, 29.1, 29.03,
28.97, 26.0, 24.82, 24.79 (fatty CH2); mass spectrum (FAB) m/ z
1083.9034 (C64H122O12 + H requires 1083.9015), 1090 (M +
Li+).
O
(CH2)15CO
O
P
CH3O(CH2)7CO
O
Br
O
O
OCH2CH2CN
O
(CH2)15CO
2
22
CH3O(CH2)11CO
p h a te)] (23). Add a solution of 2-bromoethanol (165 mg, 1.32
mmol) in dry THF (0.5 mL) dropwise to a solution of N,N-
diisopropylamino chlorophosphite (0.31 mL, 1.41 mmol) and
Et3N (202 µL, 1.45 mmol) in THF (3 mL) at rt under Ar. Stir
for 1 h. Filter through a small cotton wool plug in a 6 in. pipet.
Add 1H-tetrazole (70 mg, 1.00 mmol) and then diol 20 (85 mg,
0.078 mmol) to the filtrate. Stir at rt for another 30 min. Add
30% aqueous H2O2 (0.2 mL). Stir for 15 min. Rotoevaporate.
Dissolve the residue in CHCl3 (15 mL). Wash with 0.5 N HCl
(15 mL) and then brine (15 mL). Dry over Na2SO4, filter, and
rotoevaporate to give a white solid. Purify by flash chroma-
tography eluting with EtOAc/hexanes (3:1) (200 mL) and then
EtOAc/hexanes (8:1) to give a white solid. Wash the solid with
pentane. Purify again by column chromatography eluting with
CHCl3/CH3OH (10:1) (1 in. diameter × 7 in. height flash silica
gel column) to give 60 mg (49%) of 23 as a white solid: 1H
NMR (300 MHz, CDCl3) δ 5.23 (m, 2 H, C2H), 4.11-4.38 (comp,
16 H, C1H2 and C3H2 and POCH2CH2Br and POCH2CH2CN),
3.53 (t, 4 H, J ) 5.8 Hz, CH2Br), 3.33 (t, 4 H, J ) 6.6 Hz,
CH3OCH2), 3.29 (s, 6 H, OCH3), 2.76 (t, 4 H, J ) 6.2 Hz, CH2-
CN), 2.31 (t, 4 H, J ) 7.7 Hz, CH2CO2), 2.29 (t, 4 H, J ) 7.8
Hz, CH2CO2), 1.50-1.65 (comp, 12 H, fatty CH2), 1.15-1.35
(comp, 80 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ 173.1,
172.7 (CdO), 116.1 (CtN), 72.8 (CH2OCH3), 69.1 (d, J ) 7.8
Hz, C2), 67.3 (d, J ) 5.7 Hz), 66.0 (d, J ) 5.5 Hz), 62.2 (d, J )
5.0 Hz) (C3, POCH2CH2Br, POCH2CH2CN), 6.13 (C1), 58.4
(CH3O), 34.0, 33.9, 29.6, 29.55, 29.46, 29.43, 29.39, 29.34,
29.27, 29.24, 29.17, 29.02, 28.97, 26.0, 24.7 (CH2Br and fatty
CH2), 19.5 (d, J ) 7.2 Hz, CH2CN); mass spectrum (FAB) m/ z
1561.7726 (C74H136Br2N2O18P2 + H requires 1561.7708).
OH
O
2
20
1,1′-(Docosa n e-1,22-d ioyl)bis[2-(4-(4′-m eth oxyp h en yl)-
bu tyr oyl)-3-ben zyl-sn-glycer ol] (21). Add absolute EtOH
(4 mL) and glacial AcOH (2 mL) to 18 (107 mg, 0.102 mmol).
Add EtOAc (1.5 mL) until 18 was dissolved. Stir the reaction
mixture under H2 in the presence of 10% Pd/C (17 mg) at 20
°C overnight. Dilute with CHCl3 (5 mL) and filter through
Celite (the product is not soluble in EtOH/AcOH). Wash the
catalyst with CHCl3. Rotoevaporate the filtrate to give 87 mg
(98%) of 21 as a white solid: 1H NMR (300 MHz, CDCl3) δ
7.09 (d, 4 H, J ) 8.5 Hz, CH3O-Ar-H), 6.81 (d, 4 H, J ) 8.5
Hz, CH3O-Ar-H), 5.08 (m, 2 H, C2H), 4.32 (dd, 2 H, J ) 12.0,
4.2 Hz, C1H), 4.20 (dd, 2 H, J ) 12.0, 5.8 Hz, C1H), 3.77 (s, 6
H, OCH3), 3.70 (d, 4 H, J ) 5.1 Hz, C3H2), 3.04 (s, br, 2 H,
OH), 2.58 (t, 4 H, J ) 7.5 Hz, CH2CH2Ar), 2.27-2.37 (comp, 8
H, CH2CO2), 1.91 (p, 4 H, J ) 7.5 Hz, CH2CH2Ar), 1.56-1.61
(comp, 4 H, fatty CH2), 1.24 (comp, 32 H, fatty CH2); 13C NMR
(75 MHz, CDCl3) δ 173.7, 173.1 (CdO), 157.8, 133.2, 129.3,
113.6 (ArC), 72.1 (C2), 62.0 (C1), 61.3 (C3), 55.1 (CH3OAr), 34.0,
33.4, 29.6, 29.5, 29.4, 29.2, 29.0, 26.6, 24.8 (fatty CH2); mass
spectrum (FAB) m/ z 871.5593 (C50H78O12 + H requires
871.5571).
O
(CH2)10CO
CH3O
(CH2)3CO
O
O
OH
2
(CH2)15CO
21
O
P
CH3O(CH2)11CO
O
Br
O
O
1,1′-(D o t r ia c o n t a n e -1,32-d io y l)b is [1-(8-m e t h o x y -
octa n oyl)-sn-glycer o-3-(2-br om oeth yl 2-cya n oeth yl p h os-
p h a te)] (22). Add a solution of 2-bromoethanol (51 µL, 0.72
mmol) in dry THF (0.5 mL) dropwise to a solution of N,N-
diisopropylamino chlorophosphite (0.17 mL, 0.76 mmol) and
Et3N (106 µL, 0.76 mmol) in THF (1.5 mL) at rt under Ar.
Stir for 1 h. Filter through a small cotton wool plug in a 6 in.
pipet. Add 1H-tetrazole (52 mg, 0.74 mmol) and then diol 19
(107 mg, 0.11 mmol) to the filtrate. Stir at rt for another 30
min. Add 30% aqueous H2O2 (0.2 mL). Stir for 15 min.
Rotoevaporate. Dissolve the residue in CHCl3 (15 mL). Wash
with 0.5 N HCl (15 mL) and then brine (15 mL). Dry over
Na2SO4, filter, and rotoevaporate to give a colorless oil. Purify
three times by column chromatography eluting with CHCl3/
CH3OH (10:1) (1.5 in. diameter × 6.5 in. height flash silica
gel column) to give 118 mg (74%) of 22 as a viscous oil: 1H
NMR (300 MHz, CDCl3) δ 5.22 (m, 2 H, C2H), 4.09-4.37 (comp,
16 H, C1H2 and C3H2 and POCH2CH2Br and POCH2CH2CN),
3.52 (t, 4 H, J ) 5.6 Hz, CH2Br), 3.31 (t, 4 H, J ) 6.6 Hz,
CH3OCH2), 3.28 (s, 6 H, OCH3), 2.71 (t, 4 H, J ) 6.1 Hz,
CH2CN), 2.30 (t, 4 H, J ) 7.9 Hz, CH2CO2), 2.28 (t, 4 H, J )
8.1 Hz, CH2CO2), 1.49-1.61 (comp, 12 H, fatty CH2), 1.15-
1.34 (comp, 64 H, fatty CH2); 13C NMR (75 MHz, CDCl3) δ
173.1, 172.6 (CdO), 116.1 (CtN), 72.7 (CH2OCH3), 69.1 (d, J
) 7.6 Hz, C2), 67.2 (d, J ) 5.0 Hz), 66.0 (d, J ) 5.5 Hz), 62.2
(d, J ) 5.9 Hz) (C3, POCH2CH2Br, POCH2CH2CN), 61.3 (C1),
58.4 (CH3O), 34.0, 33.9, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0,
28.8, 25.8, 24.7, 24.6 (CH2Br and fatty CH2), 19.5 (d, J ) 7.3
OCH2CH2CN
2
23
1,1′-(Docosa n e-1,22-d ioyl)bis[2-(4-(4′-m eth oxyp h en yl)-
bu tyr oyl)-sn-glycer o-3-(2-br om oeth yl 2-cya n oeth yl p h os-
p h a te)] (24). Add a solution of 2-bromoethanol (53 mg, 0.43
mmol) in dry THF (0.5 mL) dropwise to a solution of N,N-
diisopropylamino chlorophosphite (0.11 mL, 0.76 mmol) and
Et3N (68 µL, 0.49 mmol) in THF (1 mL) at rt under Ar. Stir
for 1 h. Filter through a small cotton wool plug in a 6 in. pipet.
Add 1H-tetrazole (71 mg, 1.01 mmol) and then diol 21 (60 mg,
0.069 mmol) to the filtrate. Stir at rt for another 30 min. Add
30% aqueous H2O2 (0.2 mL). Stir for 15 min. Rotoevaporate.
Dissolve the residue in CHCl3 (15 mL). Dry over Na2SO4,
filter, and rotoevaporate to give a colorless oil. Purify by flash
chromatography eluting with EtOAc to give a white solid.
Wash the solid with pentane (3 × 5 mL). Purify again by
column chromatography eluting with CHCl3/CH3OH (10:1) (1
in. diameter × 7 in. height flash silica gel column; elution rate
2.5 mL/min) to give 67 mg (49%) of 24 as a white solid: 1H
NMR (300 MHz, CDCl3) δ 7.07 (d, 4 H, J ) 8.4 Hz, CH3O-Ar-
H), 6.81 (d, 4 H, J ) 8.4 Hz, CH3O-Ar-H), 5.25 (m, 2 H, C2H),
4.12-4.37 (comp, 16 H, C1H2 and C3H2 and POCH2CH2Br and
POCH2CH2CN), 3.76 (s, 6 H, OCH3), 3.51 (t, 4 H, J ) 5.6 Hz,
CH2Br), 2.73 (t, 4 H, J ) 6.1 Hz, CH2CN), 2.58 (t, 4 H, J ) 7.5
Hz, CH2CH2Ar), 2.29 (t, 4 H, J ) 7.5 Hz, CH2CO2), 2.34 (t, 4
H, J ) 7.5 Hz, CH2CO2), 1.90 (p, 4 H, J ) 7.5 Hz, CH2CH2Ar),
1.53-1.60 (comp, 4 H, fatty CH2), 1.23 (s, 32 H, fatty CH2);
13C NMR (75 MHz, CDCl3) δ 173.1, 172.4 (CdO), 157.8, 133.1,
129.3, 113.7 (Ar-C), 116.1 (CtN), 69.2 (d, J ) 7.6 Hz, C2), 67.3
Hz, CH2CN); mass spectrum (LSIMS) m/ z 1449.6471 (C66H120
Br2N2O18P2 + H requires 1449.6456), 1452 (M + H).
-
1,1′-(Dotr ia con ta n e-1,32-d ioyl)bis[1-(12-m eth oxyd od e-
ca n oyl)-sn-glycer o-3-(2-br om oeth yl 2-cya n oeth yl p h os-

7390 J . Org. Chem., Vol. 61, No. 21, 1996
Menger and Wong
(d, J ) 5.3 Hz), 66.0 (d, J ) 5.6 Hz), 62.2 (d, J ) 5.7 Hz) (C3,
POCH2CH2Br, POCH2CH2CN), 61.3 (C1), 55.1 (CH3O), 33.95,
33.87, 29.6, 29.5, 29.4, 29.31, 29.28, 29.15, 29.0, 26.5, 24.7 (CH2-
Br & fatty CH2), 19.5 (d, J ) 7.1 Hz, CH2CN).
bolaform phospholipid 2b (41 mg, 76%). Lyophilize to give a
white solid: 1H NMR (300 MHz, CDCl3/CD3OD (1:1)) δ 5.17
(m, 2 H, C2H), 4.33-4.38 (m, 2 H, C1H), 4.18 (m, 4 H, POCH2-
CH2N), 4.09 (dd, 2 H, J ) 12.0, 7.0 Hz, C1H), 3.93 (t, 4 H, J )
6.2 Hz, C3H2), 3.55 (t, 4 H, J ) 4.5 Hz, CH2N), 3.33 (t, 4 H, J
) 6.7 Hz, CH2OCH3), 3.28 (s, 6 H, J ) 6.6 Hz, OCH3), 3.16 (s,
18 H, N(CH3)3), 2.22-2.29 (comp, 8 H, CH2CO2), 1.49-1.53
(comp, 12 H, fatty CH2), 1.05-1.34 (comp, 80 H, fatty CH2);
13C NMR (75 MHz, CDCl3/CD3OD (1:1)) δ 173.9, 173.5 (CdO),
72.9 (CH2OCH3), 70.3 (d, J ) 8.3 Hz, C2), 66.3 (d, J ) 2.8 Hz,
CH2N), 63.5 (d, J ) 5.5 Hz, C3), 62.6 (C1), 58.9 (d, J ) 5.2 Hz,
POCH2CH2N), 58.1 (CH3OCH2), 53.9 (N(CH3)3), 34.1, 33.9,
29.70, 29.67, 29.57, 29.4, 29.3, 29.2, 29.0, 25.9, 24.8, 24.7 (fatty
CH2); mass spectrum (FAB) m/ z 1414.0106 (C74H146N2O18P2
+ H requires 1414.0124).
O
(CH2)10CO
O
P
CH3O
(CH2)3CO
O
Br
O
O
OCH2CH2CN
2
24
1,1′-(D o t r ia c o n t a n e -1,32-d io y l)b is [1-(8-m e t h o x y -
octa n oyl)-sn-glycer o-3-p h osp h och olin e] (2a ). Condense
anhydrous trimethylamine gas (ca. 3 mL of liquid trimethyl-
amine at -78 °C) in a solution of 22 (67 mg, 0.046 mmol) in
anhydrous acetonitrile (3.5 mL) at -78 °C in a heavy-walled
vessel. Seal the vessel tightly and warm slowly to rt. Stir at
50-60 °C for 2 days. Cool the reaction mixture to <-20 °C
before opening. Evaporate excess trimethylamine slowly
under a stream of N2 in a hood. Dilute the residue with CHCl3/
CH3OH (1:1) (5 mL) and transfer to a round-bottomed flask.
Rotoevaporate. Purify twice by column chromatography (0.5
in. diameter × 2 in. height flash silica gel column; elution rate
ca. 4 mL/min) eluting first with CHCl3/CH3OH/H2O (65:35:4)
to get rid of the higher Rf side product and then with CHCl3/
CH3OH/acetone/H2O (3:3:2:1) to elute off the desired bolaform
phospholipid 2a (44 mg, 73%). Lyophilize to give a white
solid: 1H NMR (300 MHz, CDCl3/CD3OD (1:1)) δ 5.18 (m, 2
H, C2H), 4.38 (dd, 2 H, J ) 12.0, 3.2 Hz, C1H), 4.21 (m, 4 H,
POCH2CH2N), 4.11 (dd, 2 H, J ) 12.0, 6.8 Hz, C1H), 3.95 (t, 4
H, J ) 6.1 Hz, C3H2), 3.57 (t, 4 H, J ) 4.6 Hz, CH2N), 3.35 (t,
4 H, J ) 6.6 Hz, CH2OCH3), 3.29 (s, 6 H, OCH3), 3.18 (s, 18 H,
N(CH3)3), 2.29 (t, 4 H, J ) 7.3 Hz, CH2CO2), 2.27 (t, 4 H, J )
7.3 Hz, CH2CO2), 1.50-1.57 (comp, 12 H, fatty CH2), 1.19-
1.34 (comp, 64 H, fatty CH2); 13C NMR (75 MHz, CDCl3/CD3-
OD (1:1)) δ 173.8, 173.3 (CdO), 72.7 (CH2OCH3), 70.3 (d, J )
7.8 Hz, C2), 66.2 (CH2N), 63.5 (d, J ) 5.4 Hz, C3), 62.4 (C1),
58.9 (d, J ) 5.0 Hz, POCH2CH2N), 57.9 (CH3OCH2), 53.7
(N(CH3)3), 33.93, 33.98, 33.84, 29.5, 29.3, 29.2, 29.1, 28.9, 28.8,
25.7, 24.7, 24.6 (fatty CH2); mass spectrum (FAB) m/ z
1031.8850 (C66H130N2O18P2 + H requires 1301.8872).
O
(CH2)15CO
O
CH3O(CH2)11CO
O
+
N
O
P
O
O–
2
2b
1,1′-(Docosa n e-1,22-d ioyl)bis[2-(4-(4′-m eth oxyp h en yl)-
bu t yr oyl)-sn-glycer o-3-p h osp h och olin e] (3). Condense
anhydrous trimethylamine gas (ca. 2 mL of liquid trimethyl-
amine at -78 °C) in a solution of 24 (67 mg, 0.050 mmol) in
toluene (3 mL) at -78 °C in a heavy-walled vessel. Seal the
vessel tightly and warm slowly to rt. Stir at 60-65 °C for 2
days. Cool the reaction mixture to <-20 °C before opening.
Evaporate excess trimethylamine slowly under a stream of N2
in a hood. Dilute the residue with CHCl3/CH3OH (1:1) (5 mL)
and transfer to a round-bottomed flask. Rotoevaporate. Purify
twice by column chromatography (0.5 in. diameter × 2 in.
height flash silica gel column; elution rate ca. 4 mL/min)
eluting first with CHCl3/CH3OH/H2O (65:35:4) to get rid of the
higher Rf side product and then with CHCl3/CH3OH/acetone/
H2O (3:3:2:1) to elute off the desired bolaform phospholipid 3
(45 mg, 76%). Lyophilize to give a white solid: 1H NMR (300
MHz, CDCl3/CD3OD (1:1)) δ 7.04 (d, 4 H, J ) 8.6 Hz, CH3O-
Ar-H), 6.78 (d, 4 H, J ) 8.4 Hz, CH3O-Ar-H), 5.19 (m, 2 H,
C2H), 4.37 (dd, 2 H, J ) 12.0, 3.2 Hz, C1H), 4.18 (m, 4 H,
POCH2CH2N), 4.12 (dd, 2 H, J ) 12.0, 6.9 Hz, C1H), 3.95 (t, 4
H, J ) 6.1 Hz, C3H2), 3.73 (s, 6 H, OCH3), 3.53 (t, 4 H, J ) 4.3
Hz, CH2N), 3.15 (s, 18 H, N(CH3)3), 2.54 (t, 4 H, J ) 7.5 Hz,
CH2CH2Ar), 2.22-2.32 (comp, 8 H, CH2CO2), 1.85 (p, 4 H, J
) 7.5 Hz, CH2CH2Ar), 1.50-1.55 (comp, 4 H, fatty CH2), 1.20
(s, 32 H, fatty CH2); 13C NMR (75 MHz, CDCl3/CD3OD (1:1)) δ
175.9, 175.2 (CdO), 159.9, 135.4, 131.3, 115.8 (Ar-C), 72.5 (d,
J ) 8.1 Hz, C2), 68.4 (CH2N), 65.6 (d, J ) 5.2 Hz, C3), 64.6
(C1), 61.0 (d, J ) 4.9 Hz, POCH2CH2N), 57.0 (CH3O), 55.9
(N(CH3)3), 35.9, 35.4, 31.6, 31.4, 31.2, 31.0, 28.7, 26.8 (fatty
CH2); mass spectrum (FAB) m/ z 1201.6707 (C60H102N2O18P2
+ H requires 1201.6681).
O
(CH2)15CO
O
CH3O(CH2)7CO
+
N
O
P
O
O
O–
2
2a
1,1′-(Dotr ia con ta n e-1,32-d ioyl)bis[1-(12-m eth oxyd od e-
ca n oyl)-sn-glycer o-3-p h osp h och olin e] (2b). Condense an-
hydrous trimethylamine gas (ca. 3 mL of liquid trimethylamine
at -78 °C) in a solution of 23 (60 mg, 0.038 mmol) in toluene
(3 mL) and anhydrous acetonitrile (0.5 mL) at -78 °C in a
heavy-walled vessel. Seal the vessel tightly and warm slowly
to rt. Stir at 50-60 °C for 2 days. Cool the reaction mixture
to <-20 °C before opening. Evaporate excess trimethylamine
slowly under a stream of N2 in a hood. Dilute the residue with
CHCl3/CH3OH (1:1) (5 mL) and transfer to a round-bottomed
flask. Rotoevaporate. Purify twice by column chromatography
(0.5 in. diameter × 2 in. height flash silica gel column; elution
rate ca. 4 mL/min) eluting first with CHCl3/CH3OH/H2O (65:
35:4) to get rid of the higher Rf side product and then with
CHCl3/CH3OH/acetone/H2O (3:3:2:1) to elute off the desired
O
(CH2)10CO
O
(CH2)3CO
O
CH3O
+
N
O
P
O
O–
2
3
Ack n ow led gm en t. This work was supported by the
National Institutes of Health.
J O9605455