Synthesis of novel asymmetrical single-chain phosphoglycol-based bolaamphiphiles

Article abstract of DOI:10.1080/00397911.2013.825806

The synthesis of long-chain 1,ω-diols with orthogonal cleavable protecting groups can be effectively performed with the use of the Grignard coupling reaction, successfully leading to the preparation of novel asymmetrical single-chain phosphoglycol-based bolaamphiphiles-a side-product that always occurred during the synthesis of symmetrical bolalipids.

Full text of DOI:10.1080/00397911.2013.825806

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Synthesis of Novel Asymmetrical
Single-Chain Phosphoglycol-Based
Bolaamphiphiles
Simon Drescher a & Bodo Dobner a
a Institute of Pharmacy, Martin-Luther-Universitaet , Halle ,
Germany
Published online: 27 Dec 2013.
To cite this article: Simon Drescher & Bodo Dobner (2014) Synthesis of Novel Asymmetrical
Single-Chain Phosphoglycol-Based Bolaamphiphiles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:4, 564-573, DOI:
10.1080/00397911.2013.825806
To link to this article: http://dx.doi.org/10.1080/00397911.2013.825806
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Synthetic Communications1, 44: 564–573, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.825806
SYNTHESIS OF NOVEL ASYMMETRICAL
SINGLE-CHAIN PHOSPHOGLYCOL-BASED
BOLAAMPHIPHILES
Simon Drescher and Bodo Dobner
Institute of Pharmacy, Martin-Luther-Universitaet, Halle, Germany
GRAPHICAL ABSTRACT
Abstract The synthesis of long-chain 1,x-diols with orthogonal cleavable protecting groups
can be effectively performed with the use of the Grignard coupling reaction, successfully
leading to the preparation of novel asymmetrical single-chain phosphoglycol-based
bolaamphiphiles—a side-product that always occurred during the synthesis of symmetrical
bolalipids.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Bipolar lipids; bolaamphiphiles; Grignard reaction; synthetic methods
INTRODUCTION
Bipolar tetraether lipids (bolalipids or bolaamphiphiles[1]) are naturally found
in the membranes of certain species of Archaea,[2,3] where they are responsible for the
outstanding stability of these bacteria against extreme living conditions, such as high
Received July 13, 2013.
Address correspondence to Simon Drescher, Institute of Pharmacy, Martin-Luther-Universitaet,
Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany. E-mail: simon.drescher@pharmazie.uni-halle.de
564

ASYMMETRICAL BOLAAMPHIPHILES
565
salt concentrations, high temperatures, and=or low pH values. The structural
imitation of Archaea membrane lipids gave rise to the synthesis of bipolar archaebac-
terial model lipids.[4,5] These model lipids are of great interest because their thermal
and chemical stability as well as their capability to form closed vesicles make them
applicable in fields of biotechnology, material science, and pharmacy.[6–11] For
instance, thermally and chemically stable liposomes made from archaebacterial bola-
lipids (archaeosomes) are an alternative to conventional liposomes in applications as
drug delivery systems.[12] Beside the use of symmetrical archaebacterial model lipids,
asymmetrical bolalipids also attract attention.[13] The present work describes an
novel approach to asymmetrical single-chain bolaamphiphiles.
RESULTS AND DISCUSSION
The crucial factors in the preparation of bipolar archaebacterial model phos-
pholipids are on the one hand an effective, high-yielding synthesis of 1,x-diols and
on the other hand an efficient insertion of the phosphate moiety. In our group, we
use the Sonogashira cross-coupling reaction[14] and the Grignard reaction for the
synthesis of long-chain 1,x-diols. This dilithium tetrachlorocuprate(II)[15] –catalyzed
Grignard reaction can be designed as a homo-coupling[16–19] or a bis-coupling
reaction.[18,20–22] For the insertion of the phosphate headgroup we use the well-
established 2-bromoethylphosphoric acid dichloride as phosphorylation reagent.
According to other studies on bolaphospholipid synthesis,[23,24] this classic reagent
was more efficient than other methods, such as the use of 2-chloro-2-oxo-1,3,
2-dioxaphospholane.
However, during the syntheses of symmetrical, single-chain bolalipids with
modified chain and headgroup structures,[25] we could isolate an asymmetrical
bolaamphiphile as side-product (in 5–15% yield) at nearly all times while using the
2-bromoethylphosporic acid dichloride. Low-resolution mass spectrometry (MS)
indicated the existence of one hydroxy(2-hydroxyethoxy)phosphoryl (POH)
headgroup—which also can be termed as phosphoglycol group—beside the other
phosphocholine (PC) moiety within one bolalipid molecule. The chemical structures
of these novel asymmetrical bolaamphiphiles could be initially verified by high-
resolution mass spectrometry (HRMS), 1H NMR, and correlation spectrometry
(H,H-COSY NMR) measurements (see the Supplementary Information). The occur-
rence of this side-product is explained as follows: The phosphorylation reaction,
which is performed in dry CHCl3, is followed by a hydrolysis in a tetrahydrofuran
(THF) = water mixture to replace the remaining chlorine atom. During this hydroly-
sis, a substitution of the bromine atom with a hydroxy moiety could occur, which led
to the formation of the POH headgroup (see dashed arrows in Scheme 1). The exist-
ence of this POH group and, hence, the formation of asymmetrical bolalipids, could
be shown for various syntheses, namely the synthesis of 3-dimethylaminopropyl-PC
(DMAPPC), 2-dimethylaminoethyl-PC (DMAEPC), propynyl-PC (PPC), and allyl-
PC (APC) modified bolaamphiphiles[25] (2a–d, Scheme 1, and Supplementary
Information). However, the formation of a bolalipid with two POH headgroups
could not be detected.
To verify the chemical structure of this side-product, a synthetic strategy for
the preparation of asymmetrical single-chain bolaamphiphiles was developed, which

566
S. DRESCHER AND B. DOBNER
Scheme 1. Proposed mechanism for the formation of the asymmetrical side-product including a phospho-
glycol headgroup (dashed arrows) during the preparation of bolaamphiphiles.[25]
is shown for the synthesis of compound 2a. As starting point we chose the
copper(II)-catalyzed Grignard homo-coupling of tetrahydropyranyl (THP)–
protected 16-bromohexadecan-1-ol (THPO-C16-Br, 3), published previously.[18] To
introduce orthogonally cleavable protection groups, the THP moiety was replaced
by the benzyl (Bn) group, which is stable under most acidic and basic conditions
and can be easily cleaved by hydrogenation. Therefore, the sodium salt of benzyl
alcohol was alkylated with THPO-C16-Br (3), in toluene and in the presence of n-
tetrabutylammonium iodide (TBAI). The use of toluene and higher temperatures
(reflux) is recommended in this step because the use of other solvents (e.g., THF)
resulted in lower yields. The THP group of the resulting 2-[(16-benzyloxyhexadec-
1-yl)oxy]tetrahydro-2H-pyran (THPO-C16-OBn, 4) was nearly quantitatively trans-
formed into the corresponding bromide (Br-C16-OBn, 5) while using the procedure
described by Schwarz et al.[26]
In the next step, the same THPO-C16-Br (3) was converted into the Grignard
reagent[18] and subsequently coupled with Br-C16-OBn (5) under catalysis with
dilithium tetrachlorocuprate(II),[15] yielding the 2-[(32-benzyloxydotriacont-1-
yl)oxy]tetrahydro-2H-pyran (THPO-C32-OBn, 6), a long-chain 1,x-diol with ortho-
gonally cleavable protection moieties. For the purification of compound 6 it is useful
to recrystallize the raw product prior to the column chromatography from acetone to
remove the short-chain side-products. The THP group was subsequently removed by
heating compound 6 in methanol with catalytic amounts of pyridinium p-toluenesul-
fonate (PPTS), finally resulting in the formation of 32-benzyloxydotriacontan-1-ol
(HO-C32-OBn, 7; see Scheme 2).
The insertion of the first headgroup was carried out using the phosphorylation
reaction with 2-bromoethylphosphoric acid dichloride and the subsequent

ASYMMETRICAL BOLAAMPHIPHILES
567
Scheme 2. Synthetic pathway for the preparation of asymmetrical bolaamphiphiles.
quarternisation with tetramethylpropylenediamine (TMPDA) as described previously.[25]
Because the size of the amine used has a great impact on the yields—leading to
very marginal, detectable amounts of product only in mass spectrometry in the
synthesis of the symmetrical DMAPPC-C32-DMAPPC[25]—poor yields of DMAPPC-
C32-OBn (8) are unfortunately unavoidable. The synthesis of 32-benzylhydroxydo-
triacontane-1-yl-f2-[N-(3-dimethylaminopropyl)-N,N-di-methylammonio]ethylphosphateg
(DMAPPC-C32-OH, 9) was completed after the cleavage of the benzyl protection
group using hydrogenation (5 atm) in ethanol and palladium on carbon as catalyst
(see Scheme 2).
For the conversion of the free hydroxy moiety of compound 9 into the POH
headgroup, various synthetic methods are feasible: Eibl[27] and de Jongh and de
Kruijff[28] have used POCl3 as phosphorylating agent combined with a subsequently
performed reaction with ethylene glycol = TEA and an acidic dioxaphospholane ring

568
S. DRESCHER AND B. DOBNER
opening. On the other hand, Dijkman et al.[29] and Campins et al.[30] have used the
2-chloro-2-oxo-1,3,2-dioxaphospholane methodology. In contrast to these proce-
dures described, we performed this conversion using a comparable phosphorylation
reaction as shown previously. Instead of the final quarternization with tertiary
amines, the bromine atom was exchanged for the hydroxy group in a mixture of
THF=water, alkaline conditions (K2CO3), prolonged reaction time, and slightly
increased temperature. Mass spectrometric analyses of the 32-f[hydroxy(2-
hydroxyethoxy)phosphoryl]oxygdotriacontane-1-yl-f2-[N-(3-dimethylaminopropyl)-
N,N-dimethylammonio]ethylphosphateg (DMAPPC-C32-POH, 2a) achieved from
this asymmetrical synthetic pathway (Scheme 2) are in accordance with those obtained
from the side-product of the symmetrical way (Scheme 1) described previously.
In summary, the synthesis of long-chain 1,x-diols with orthogonally cleavable
protection moieties we have developed in this work offers the possibility for the prep-
aration of a huge variety of asymmetrical single-chain bolaamphiphiles. In addition,
the synthesis of phosphocholines while using the 2-bromoethylphosporic acid
dichloride is connected with the formation of side-products, namely a hydroxy(2-
hydroxyethoxy)phosphoryl (POH) or phosphoglycol headgroup. But how to explain
the importance of these side-products? Because the self-assembly properties of sym-
metrical, single-chain bolaamphiphiles also depends on the protonation state and,
hence, electrostatic interactions of the headgroup,[22,31–34] the combination of both an
amine-modified and, hence, protonable PC headgroup (e.g., DMAPPC) and an acidic
phosphor ester headgroup (POH) in one bolalipid molecule should force new aggregate
structures, such as lamellar sheets, rods, vesicles, or nanotubes. A detailed comparative
physicochemical study of different asymmetrical bolaamphiphiles, such as
DMAPPC-C32-POH (2a) and DMAPPC-C32-OH (9), has been published elsewhere.[13]
EXPERIMENTAL
All chemicals were purchased from Sigma Aldrich Co. and were used without
further purification. All solvents for synthetic purpose were dried and distilled before
use. The purity of all compounds was checked by thin-layer chromatography (TLC)
using silica gel 60 F254 plates. Silica gel (0.063–0.200 mm) was used for column
chromatography of the products. Melting points were determined with a Boetius
1
apparatus. H, 13C, and 31P NMR spectra were recorded on a VNMRS 400-MHz
spectrometer or an Inova 500-MHz spectrometer with the use of CDCl3 or CD3OD
as internal standard. Mass spectrometric data were obtained with a Finnigan MAT
SSQ 710 C (ESI-MS) or were recorded on an AMD 402 (70 eV) spectrometer
(EI-MS). High-resolution mass spectra (HRMS) were recorded on a Thermo Fisher
Scientific LTQ-Orbitrap mass spectrometer with static nano-electrospray ionization.
Elemental analyses were conducted using a Leco CHNS-932.
General Procedure for the Phosphorylation and Quarternization
Reaction
2-Bromoethylphosphoric acid dichloride (0.48 g, 2 mmol) was poured into dry
CHCl3 (10 mL) under cooling with ice water. A solution of 0.5 mL TEA in 10 mL
CHCl3 was added slowly, and the resulting mixture was stirred for 30 min at 0 ꢀC.

ASYMMETRICAL BOLAAMPHIPHILES
569
Subsequently, 0.5 mmol of dotriacontane-1,32-diol (for the synthesis of 2a–d),
1 mmol of HO-C32-OBn (7; for the synthesis of 8), and 1 mmol of DMAPPC-C32-
OH (9; for the synthesis of 2a), respectively, were added in one portion, and the
mixture was gently heated until the alcohol had completely dissolved. The stirring
was continued for 24 h at 25 ꢀC. Afterward, crushed ice was added to the solution,
and the mixture was stirred vigorously for another 2 h. The organic layer was sepa-
rated and the aqueous phase was extracted with CHCl3 (3 ꢁ 15 mL). The combined
organic layers were evaporated, and the crude bromoethyl ester was dissolved in
10 mL THF=H2O (9=1, v=v) and stirred for a further 1.5 h.
For the subsequently performed quarternization reaction (products 2a–d, 8),
the solvent was evaporated and the oily residue was transferred into a mixture of
CHCl3 (15 mL), acetonitrile (15 mL), and ethanol (5 mL). The pure amine (20 mmol)
was added slowly, and the mixture was kept in a close tube at 45 ꢀC for 48 h. For the
alternative alkaline substitution of the bromine atom (synthesis of 2a via 9), equimo-
lar amounts of K2CO3 were added to the THF=H2O mixture, which was stirred for
10 h at room temperature.
For workup, the complete mixture was concentrated by evaporation of the sol-
vent, and the residue was purified by column chromatography using CHCl3=MeOH=
H2O as eluent and gradient technique to give products as white substances.
General Procedure for the Grignard Coupling Reaction
A solution of 12.7 g 2-[(16-bromohexadec-1-yl)oxy]tetrahydro-2H-pyran[18]
(THPO-C16-Br, 3, 31.2 mmol) in dry THF (75 mL) was added dropwise with stirring
to magnesium turnings (1.22 g, 50 mmol) under an argon atmosphere. After the exo-
thermic reaction had subsided, the mixture was stirred at 45 ꢀC for 3 h. The excess
magnesium was removed under argon and the Grignard solution was cooled to
ꢂ5 ꢀC. A freshly prepared solution of Li2CuCl4 (0.1 M in THF, 3.0 mL) was added
with stirring. After a solution of 9.94 g Br-C16-OBn (5, 24.2 mmol) in dry THF
(70 mL) was added in one portion, stirring was continued for further 3 h at about
0 ꢀC. For workup Et2O (150 mL) was added and the resulting mixture was poured
into a cold saturated solution of NH4Cl (150 mL). The organic layer was separated
and the aqueous phase was extracted with Et2O (2 ꢁ 50 mL). The combined organic
phases were washed with H2O and brine, dried over Na2SO4, and concentrated to
dryness under reduced pressure. The crude product was recrystallized from acetone
to remove the short-chain by-products. The final purification was carried out by
chromatography using a heptane=CHCl3 gradient (þ0.5% TEA) as eluent to obtain
8.7 g (55%) of THPO-C32-OBn (6).
Spectral Data for Selected Compounds
32-f[Hydroxy(2-hydroxyethoxy)phosphoryl]oxygdotriacontane-1-yl-f2-
[N-(3-dimethylaminopropyl)-N,N-dimethylammonio]ethylphosphateg (DMAPPC-
C32-POH, 2a). White, waxy solid; 1H NMR (500 MHz, CDCl3=CD3OD): d ¼
1.15–1.28 [m, 56H, (CH2)28], 1.48–1.54 [m, 4H, OCH2CH2(CH2)28CH2CH2O],
2.09–2.16 (m, 2H, NCH2CH2CH2N), 2.62 [s, 6H, (H3C)2NCH2], 2.83–2.91 [m, 2H,
(H3C)2NCH2], 3.08 [s, 6H, CH2N(CH3)2CH2], 3.29–3.43 [m, 2H, (H3C)2NCH2-
CH2CH2N], 3.49–3.51 (m, 2H, NCH2CH2O), 3.60–3.62 (m, 2H, OCH2CH2OH),

570
S. DRESCHER AND B. DOBNER
3.72–3.77 [m, 4H, OCH2(CH2)30CH2O], 3.80–3.85 (m, 2H, OCH2CH2OH), 4.08–
4.12 ppm (m, 2H, NCH2CH2O); 31P NMR (161.9 MHz, CDCl3=CD3OD):
d ¼ 1.455, 0.012 ppm; ESI-MS: m=z ¼ 842.1 [M ꢂ H]ꢂ, 844.8 [M þ H]þ, 866.1
[Mþ Na]þ. Anal. calcd. (%) for C43H92N2O9P2 ꢃ 2H2O: C, 58.74; H, 11.00; N, 3.19.
Found: C, 58.45; H, 10.83; N, 3.01. HRMS: calcd for C43H93N2O9P2 [Mþ H]þ
843.6351; found 843.6356; C43H92N2O9NaP2 [M þ Na]þ 865.6170; found 865.6176.
32-f[Hydroxy(2-hydroxyethoxy)phosphoryl]oxygdotriacontane-1-yl-f2-
[N-(2-dimethyl-aminoethyl)-N,N-dimethylammonio]ethylphosphateg (DMAEPC-
C32-POH, 2b). White, waxy solid; 1H NMR (500 MHz, CDCl3=CD3OD): d ¼
1.14–1.26 [m, 56H, (CH2)28], 1.47–1.53 [m, 4H, OCH2CH2(CH2)28CH2CH2O], 2.47
[s, 6H, (H3C)2NCH2], 3.04–3.12 [bm, 2H, (H3C)2NCH2], 3.13 [s, 6H,
CH2N(CH3)2CH2], 3.50–3.52 (m, 2H, NCH2CH2O), 3.58–3.63 [m, 4H, OCH2-
CH2OH, (H3C)2NCH2CH2N], 3.71–3.76 [m, 4H, OCH2(CH2)30CH2O], 3.79–3.82
(m, 2H, OCH2CH2OH), 4.09–4.13 ppm (m, 2H, NCH2CH2O); 31P NMR
(161.9 MHz, CDCl3=CD3OD): d ¼ ꢂ0.315, ꢂ0.562 ppm; ESI-MS: m=z ¼ 828.0 [M
– H]ꢂ, 830.0 [M þ H]þ, 852.0 [M þ Na]þ. Anal. calcd (%) for C42H90N2O9P2 ꢃ 2H2O:
C, 58.31: H, 10.95; N, 3.24, Found: C, 58.37; H, 10.56; N, 3.41. HRMS: calcd. for
C42H91N2O9P2 [M þ H]þ 829.6194; found 829.6208.
32-f[Hydroxy(2-hydroxyethoxy)phosphoryl]oxygdotriacontane-1-yl-[2-
(N,N-dimethyl-N-prop-2-yn-1-ylammonio)ethylphosphate] (PPC-C32-POH,
2c). White, waxy solid; 1H NMR (500 MHz, CDCl3=CD3OD): d ¼ 1.08–1.17
[m, 56H, (CH2)28], 1.40–1.47 [m, 4H, OCH2CH2(CH2)28CH2CH2O], 2.92 (t,
4J ¼ 2.5 Hz, 1H, HCꢄCCH2N), 3.09 (s, 6H, 2 ꢁ CH3), 3.49–3.54 (m, 4H,
NCH2CH2O, OCH2CH2OH), 3.64–3.70 [m, 4H, OCH2(CH2)30CH2O], 3.72–3.76
4
(m, 2H, OCH2CH2OH), 4.04–4.08 (m, 2H, NCH2CH2O), 4.21 ppm (d, J ¼ 2.5 Hz,
2H, HCꢄCCH2N); 13C NMR (100 MHz, CDCl3=CD3OD): d ¼ 25.0, 25.2, 28.7,
28.8, 29.0 (2 signals), 29.1 (3 signals), 29.8 (d, POCH2CH2CH2), 30.2 (d,
POCH2CH2CH2), 50.6 (CH3), 54.80 (b, HCꢄCCH2), 58.2 (d, NCH2CH2O), 60.9
(d, OCH2CH2OH), 63.7 (d, OCH2CH2OH), 65.5 [d, POCH2(CH2)31O], 66.4 [d,
POCH2(CH2)31O], 67.4 (d, NCH2CH2O), 70.4 (HCꢄC), 81.4 ppm (HCꢄC); 31P
NMR (161.9 MHz, CDCl3=CD3OD): d ¼ 0.127, ꢂ0.156 ppm; ESI-MS: m=z ¼ 794.5
[M ꢂ H]ꢂ, 818.6 [M þ Na]þ. Anal. calcd. (%) for C41H83NO9P2 ꢃ 2H2O: C, 59.18;
H, 10.58; N, 1.68. Found: C, 59.35; H, 10.71; N, 1.87. HRMS: calcd for
C41H84NO9P2Na [M þ H þ Na]2þ 409.7754; found 409.7754; C41H84NO9P2
[M þ H]þ 796.5616; found 796.5619.
32-f[Hydroxy(2-hydroxyethoxy)phosphoryl]oxygdotriacontane-1-yl-[2-
(N-allyl-N,N-di-methylammonio)ethylphosphate] (APC-C32-POH, 2d). White,
waxy solid; 1H NMR (500 MHz, CDCl3=CD3OD): d ¼ 1.15–1.27 [m, 56H, (CH2)28],
1.48–1.58 [m, 4H, OCH2CH2(CH2)28CH2CH2O], 3.03 (s, 6H, 2 ꢁ CH3), 3.45–3.46
(m, 2H, OCH2CH2OH), 3.62–3.65 (m, 2H, NCH2CH2O), 3.75–3.80 and 3.83–3.88
2
=
[2 m, 4H, OCH2(CH2)30CH2O], 3.91 (d, J ¼ 7.3 Hz, 2H, NCH2CH CH2), 3.92–
3.94 (m, 2H, OCH2CH2OH), 4.13–4.19 (m, 2H, NCH2CH2O), 5.60–5.67 (m, 2H,
=
NCH2CH CH2), 5.89 ppm (ddt, 3J[E] ¼ 17.3 Hz, 3J[Z] ¼ 10.3 Hz, 3J ¼ 7.3 Hz,
1H, NCH2CH¼CH2); 13C NMR (100 MHz, CDCl3=CD3OD): d ¼ 25.0, 25.2,
28.7, 28.9, 29.0, 29.1 (4 signals), 29.2, 29.9 (d, POCH2CH2CH2), 30.2

ASYMMETRICAL BOLAAMPHIPHILES
571
(d, POCH2CH2CH2), 50.3 (CH3), 58.2 (d, NCH2CH2O), 60.9 (d, OCH2CH2OH),
63.5 (b, OCH2CH2OH), 65.6 [d, POCH2(CH2)31O], 66.7 [d, POCH2(CH2)31O],
=
=
67.4 (b, NCH2CH CH2), 67.6 (d, NCH2CH2O), 123.9 (CH CH2), 129.1 ppm
(CH¼CH2); 31P NMR (161.9 MHz, CDCl3=CD3OD): d ¼ ꢂ 0.181, ꢂ0.199 ppm;
ESI-MS: m=z ¼ 796.9 [M – H]-, 799.6 [M þ H]þ, 821.2 [M þ Na]þ. Anal. calcd. (%)
for C41H85NO9P2 ꢃ 2H2O: C, 59.04; H, 10.76; N, 1.68. Found: C, 59.40, H, 10.90;
N, 1.96. HRMS: calcd. for C41H86NO9P2Na [M þ H þ Na]2þ 410.7832; found
410.7831, C41H86NO9P2 [M þ H]þ 798.5772; found 798.5773.
2-[(32-Benzyloxydotriacont-1-yl)oxy]tetrahydro-2H-pyran. (THPO-C32-
1
OBn, 6). White solid, mp 62–64 ꢀC; H NMR (400 MHz, CDCl3): d ¼ 1.24–1.37
[m, 56H, (CH2)28], 1.47–1.63 (m, 8H, 4 ꢁ CH2CH2O), 1.66–1.73 [m, 1H,
CHOCH2CH2(CH2)30O], 1.77–1.85 [m, 1H, CHOCH2CH2(CH2)30O], 3.36 [dt,
2J ¼ 9.6 Hz, 3J ¼ 6.7 Hz, 1H, CHOCH2(CH2)31O], 3.44 [t, 3J ¼ 6.7 Hz, 2H,
CHO(CH2)31CH2O], 3.45–3.51 [m, 1H, OCH2(CH2)3CH], 3.71 (dt, 2J ¼ 9.6 Hz,
3J ¼ 6.8 Hz, 1H, CHOCH2(CH2)31O), 3.83–3.88 [m, 1H, OCH2(CH2)3CH], 4.48 (s,
2H, CH2C6H5), 4.55–4.57 (m, 1H, OCHO), 7.23–7.33 ppm (m, 5H, C6H5);
13C NMR (100 MHz, CDCl3): d ¼ 19.7, 25.5, 26.2, 26.3, 29.5, 29.6 (2 signals), 29.7
(2 signals), 29.8 (2 signals), 30.8 (CH2CH), 62.3 [OCH2(CH2)3CH], 67.7 [CHOCH2
(CH2)15], 70.6 (OCH2C6H5), 72.9 (CH2OCH2C6H5), 98.8 (CH), 127.4, 127.6,
128.3, 138.8 ppm; EI-MS (70 eV): m=z (%) ¼ 657 (12) [M]þ. Anal. calcd (%) for
C44H80O3 (657.10): C, 80.42; H, 12.27. Found: C, 80.81; H, 12.15.
32-Hydroxydotriacontane-1-yl-f2-[N-(3-dimethylaminopropyl)-N,N-dime-
thylammonio]ethyl-phosphateg (DMAPPC-C32-OH, 9). White solid, mp 115–
118 ꢀC; 1H NMR (400 MHz, CDCl3=CD3OD): d ¼ 1.23–1.35 [m, 56H, (CH2)28],
1.47–1.54 (m, 2H, CH2CH2CH2O), 1.56–1.64 (m, 2H, CH2CH2CH2O), 2.13–2.21
(m, 2H, NCH2CH2CH2N), 2.70 [s, 6H, (H3C)2N], 2.93 [t, J ¼ 7.4 Hz, 2H,
(H3C)2NCH2], 3.17 [s, 6H, CH2N(CH3)2CH2], 3.46–3.51 [m, 2H, (H3C)2NCH2-
CH2CH2N], 3.52 (t, J ¼ 6.8 Hz, 2H, CH2OH), 3.59–3.62 (m, 2H, NCH2CH2O),
3.83 [‘‘quar,’’ J ¼ 6.6 Hz, 2H, OCH2(CH2)31OH], 4.17–4.22 ppm (m, 2H,
NCH2CH2O); 13C NMR (100 MHz, CDCl3=CD3OD): d ¼ 18.9, 25.3 (d, POCH2-
CH2CH2), 28.9, 29.0, 29.1 (2 signals), 29.2 (6 signals), 30.3 [d, POCH2-
CH2(CH2]30OH], 32.0 (CH2CH2OH), 36.6, 42.9 [(H3C)2NCH2CH2CH2], 51.7
[t, CH2N(CH3)2CH2], 53.9 [b, (H3C)2NCH2CH2CH2], 58.4 (d, NCH2CH2O), 61.4
(b, NCH2CH2O), 61.8 [(H3C)2NCH2CH2CH2], 62.8 (b, CH2OH), 65.6 ppm [d,
POCH2(CH2)31OH]; 31P NMR (161.9 MHz, CDCl3=CD3OD): d ¼ ꢂ0.233 ppm;
ESI-MS: m=z ¼ 719.53 [M þ H]þ, 742.57 [M þ Na]þ, 1438.07 [2 M þ H]þ. Anal.
calcd, (%) for C41H87N2O5P ꢃ 2H2O: C, 65.21; H, 12.15; N, 3.71. Found: C, 65.46;
H, 12.31; N, 3.85. HRMS: calcd. for C41H88N2O5P [M þ H]þ 719.6425; found
719.6411.
SUPPORTING INFORMATION
1
Full experimental detail; H, 13C, and 31P NMR; MS; and HRMS spectra can
be found via the Supplementary Content section of this article’s Web page.

572
S. DRESCHER AND B. DOBNER
ACKNOWLEDGMENTS
We thank Andrea Sinz and Christian Ihling (Department of Pharmaceutical
Chemistry and Bioanalytics, Martin-Luther-University, Halle-Wittenberg) for the
high-resolution mass spectrometry analysis.
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