Verification study for an empirical rule in diverse helical conformational behaviors of asymmetric 1,2-diacyl-sn-glycerols in the solution state

Article abstract of DOI:10.1016/j.tetasy.2017.09.021

Cell-membrane glycerophospholipids and glycolipids have a common asymmetric skeleton of 1,2-diacyl-sn-glycerols. The 1,2-diacyl moiety in solutions permits a rapid equilibrium among three helical conformers, namely gt(+), gg(?), and tg, to display diverse conformational properties. The conformational property changes variably not only by head groups at the sn-3 position, but also by the solvent conditions applied. Recently, we came across an empirical rule in the conformational diversity in the solution state when we assumed the term of ‘helical disparity’ for the equilibrium between gt(+) and gg(?) conformers with reversed helical signs for each other. The sign and magnitude of the helical disparity (%) governs the (+)- or (?)-chirality around the lipid tail and corresponds to the magnitude of the exciton couplet CD (circular dichroism) bands. The empirical rule expresses that the disparity (%) changes linearly by the function of gt(+) population (%). Herein, the rule was verified by ¹H NMR spectroscopy using different types of 1,2-diacyl-sn-glycerols as model compounds. The present paper describes that the rule is formulated with a general equation (Eq-1): ‘helical disparity (%)’ = [gt(+)?gg(?)] (%) = A[gt(+)?B], in which A and B are constants taking values around 1.3 and 38, respectively. This rule is maintained regardless of the 1,2-diacyl and sn-3 substituent groups as far as examined here, while affording several exceptions. With Eq-1 (A = 1.3, B = 38), a conformational diagram can be obtained. This allows us to overview the diverse helical conformational properties of the asymmetric 1,2-diacyl-sn-glycerols in the solutions state.

Full text of DOI:10.1016/j.tetasy.2017.09.021

Tetrahedron: Asymmetry 28 (2017) 1435–1443
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Verification study for an empirical rule in diverse helical
conformational behaviors of asymmetric 1,2-diacyl-sn-glycerols in
the solution state
a,
⇑
a
a
a
a
Yoshihiro Nishida , Yuan Mengfei , Kaito Fujisawa , Sakura Kitagawa , Hirofumi Dohi ,
Hirotaka Uzawa
a
b
Molecular Chirality Research Center, Graduate School of Advanced Integration Science, Chiba University, Matsudo 271-8510, Chiba, Japan
Nanomaterials Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba 305-8565, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2017
Revised 23 September 2017
Accepted 28 September 2017
Available online 23 October 2017
Cell-membrane glycerophospholipids and glycolipids have a common asymmetric skeleton of 1,2-diacyl-
sn-glycerols. The 1,2-diacyl moiety in solutions permits a rapid equilibrium among three helical conform-
ers, namely gt(+), gg(ꢀ), and tg, to display diverse conformational properties. The conformational prop-
erty changes variably not only by head groups at the sn-3 position, but also by the solvent conditions
applied. Recently, we came across an empirical rule in the conformational diversity in the solution state
when we assumed the term of ‘helical disparity’ for the equilibrium between gt(+) and gg(ꢀ) conformers
with reversed helical signs for each other. The sign and magnitude of the helical disparity (%) governs the
Dedicated to the memory of Dr. Howard
Flack
(
+)- or (ꢀ)-chirality around the lipid tail and corresponds to the magnitude of the exciton couplet CD (cir-
cular dichroism) bands. The empirical rule expresses that the disparity (%) changes linearly by the func-
tion of gt(+) population (%). Herein, the rule was verified by H NMR spectroscopy using different types of
1
1,2-diacyl-sn-glycerols as model compounds. The present paper describes that the rule is formulated with
a general equation (Eq-1): ‘helical disparity (%)’ = [gt(+)ꢀgg(ꢀ)] (%) = A[gt(+)ꢀB], in which A and B are
constants taking values around 1.3 and 38, respectively. This rule is maintained regardless of the 1,2-dia-
cyl and sn-3 substituent groups as far as examined here, while affording several exceptions. With Eq-1
(
A = 1.3, B = 38), a conformational diagram can be obtained. This allows us to overview the diverse helical
conformational properties of the asymmetric 1,2-diacyl-sn-glycerols in the solutions state.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
and tg (Fig. 1). The gt(+) and gg(ꢀ) are gauche conformers with
reversed helicities around vicinal oxygens, while the tg is another
rotamer aligning the two oxygens in an antiperiplanar relationship.
Thanks to extensive stereochemical studies on glycerophospho-
The glycerol-types of phospholipids and glycolipids serve as the
major elements of cytoplasm membranes. They have a common
asymmetric skeleton of 1,2-diacyl-sn-glycerol bearing polar head
groups at the sn-3 position. They self-assemble under physiologi-
cal conditions to construct fluid bilayer membranes together with
cholesterol. The chirality2 in the asymmetric sn-glycerol skeleton
should play an important role in their biological functions essential
in our cell lives.
4
–8
lipids,
(ꢀ) conformers in both solution and in the liquid crystalline state.
This trend is also observed among -glycosyl glycerophospholipids
GGPLs) in Mycoplasma cytoplasmic membranes. According to
we know that the 1,2-diacyl moiety favors gt(+) and gg
1
a
9
(
a
1
our results based on H NMR and circular dichroism (CD) spec-
troscopy,
1
0–12
the 1,2-diacyl moiety maintains a regular rule; the
The asymmetric sn-glycerol skeleton is also of interest in terms
of its stereochemistry; it furnishes several conformers by free rota-
tion along each of the sn-1,2 and sn-2,3 C–C single bonds. For
three conformers are distributed in the relative order as gt(+) ꢁ
gg(ꢀ) > tg (%) in the solution state. In particular, sn-3 phosphates
3
and a-glycosyl linkages display notable effects; they increase the
example, the 1,2-diacyl moiety in the solution state permits a rapid
equilibration among three helical conformers, namely gt(+), gg(ꢀ),
population of the gt(+) conformer and amplify the (+)-chirality
1
3
around the 1,2-diacyl moiety. We also encountered another rule,
which may be worthy of discussion and verification. Herein the
1
new rule is verified in our H NMR spectroscopic analyses for those
⇑
Corresponding author.
E-mail address: tdn_nishida@msn.com (Y. Nishida).
https://doi.org/10.1016/j.tetasy.2017.09.021
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0

1
436
Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
Fig. 1. Structures of asymmetric 1,2-diacyl-sn-glycerols and their helical conformational properties around 1,2-diacyl moiety.
sorts of asymmetric 1,2-diacyl-sn-glycerols, which include 1,2-
dibenzoyl-sn-glycerols 1–12 (Chart 1).
In the 1H NMR analysis of 1,2-dipalmitoyl-sn-glycerols,13 we
plotted the helical disparities (%) against the populations of gt(+)
conformer to afford a linear correlation. The following equation
(
Eq-1) expresses the linear relationship;
2
2
. Results and discussion
Eq-1 : ‘the helical disparity’ ð%Þ ¼ ½gtðþÞ ꢀ ggðꢀÞꢂ ð%Þ ¼ A½gtðþÞ ꢀ Bꢂ;
in which gt(+) and gg(ꢀ) are fractional distributions (%) and deter-
.1. Definition of the helical conformational property of 1,2-
diacyl-sn-glycerols with the ‘helical disparity’ and ‘helical
volume’
1
mined in our H NMR Karplus analysis. A and B are constants with
values of 1.34 and 37.9, respectively, estimated from the linear
relationship.
The 1,2-diacyl moiety gives two gauche conformers, namely gt
(
+) and gg(ꢀ), which have (+)- and (ꢀ)-helicity, respectively
We assume that the two constants (A and B) may vary due to
several factors such as the acyl groups in the 1,2-moiety and the
solvents applied. It is also possible that the linear relationship
may be valid in only limited cases. Since we believe that the
defined helical conformational property is of high significance for
understanding the stereochemistry of cell-membrane 1,2-diacyl-
sn-glycerols, we tried to evaluate the empirical rule using different
types of 1,2-diacyl-sn-glycerols, which include the series of 1,2-
dibenzoyl-sn-glycerols 1–12.
around the 1,2-diol esters. This gives another conformer, namely
tg, which aligns the vicinal oxygens in an antiperiplanar relation-
ship (Fig. 1). The helical conformational property is determined
by the equilibrium position of the three helical conformers. In
1
2
our preceding study , we introduced the terms of ‘helical disparity
%)’ and ‘helical volume (%)’. The helical disparity (%) is defined as
(
the difference in populations between gt(+) and gg(ꢀ) conformers,
and the helical volume (%) as the sum of their populations. The
helical disparity (%) informs us the sign and magnitude of chirality
around the 1,2-diacyl moiety. The helical volume (%) informs us
how far extents the two helical conformers occupy the conforma-
tional equilibrium around the 1,2-diacyl moiety. These parameters
2.2. Evaluation of Eq-1 using C2-symmetric triacylglycerols in
CDCl solutions
3
1
can be estimated precisely by using our H NMR Karplus relation-
First, we evaluated Eq-1 using three types of C2-symmetric tri-
acylglycerols bearing different acyl groups (Chart 2).
ship, and the results are in good agreement with the exciton cou-
plet CD bands of Nakanishi et al. and Harada et al.1
4,15
Chart 1. Structures of asymmetric 1,2-dibenzoyl-sn-glycerols 1–12.

Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
1437
Chart 2. C2-Symmetric triacyl sn-glycerols with different acyl groups.
1
The fundamental H NMR data of their H1proR and H1proS sig-
the present analysis, the population (%) of each rotamer may
involve experimental deviations within ± 3%. Eq-1 is able to repro-
duce the helical conformational properties of the three tpes of C2-
2
nals are assigned definitively with our chirally H-labeled sn-glyc-
erols.1
0,16
Using our H NMR Karplus relationship, the fractional
1
12
distributions (%) of the three helical conformers were estimated
and used for estimating the helical disparity (%) and the helical vol-
ume (%) as summarized in Table 1. Due to the C2-symmetry in
these triacylglycerols, the helical conformational property around
the 1,2-diacyl moiety is adaptable to the property around the sn-
symmetric triacylglycerols in CDCl
mental deviations.
3
solutions within the experi-
2.3. Evaluation of Eq-1 using asymmetric 1,2-dibenzoyl-sn-
glycerols 2–7 with ester or ether linkages at the sn-3 position
2
,3 position by changing the (+)/(ꢀ)-sign in the gt(+) and gg(ꢀ)
conformers as well as in the helicity index defined as the disparity
Next, asymmetric triacyl sn-glycerols 2 and 3 were examined
(entries 1 and 2, Table 3). Their conformational properties are sim-
ilar to those of the preceding symmetric triacyl sn-glycerols,
though the solvents used are different from each other. Entries
3–5 indicate that the helical disparity (%) increases with the
replacement of the sn-3 ester linkages in 2 and 3 with the ether
(
%) of the two gauche conformers (%).
Entries 1–3 indicate that these triacylglycerols exhibit a similar
conformational properties to each other; the three rotamers are
distributed in the order gt(+) ꢁ gg(ꢀ) > tg (%), while the helical dis-
parity (%) varies in a low range between 0% and 6%. The helical dis-
parity of 1 takes a value around 0%, meaning that the populations
of gt(+) and gg(ꢀ) conformers compete opposed to each other. The
helical volumes (%) vary in a narrow range around 75%, permitting
the antiperiplanar tg conformer around 25% in the equilibrium. The
three rotamers are populated in a random fashion taking values
between 25% and 38%, while they keep the popular relationship
of gt(+) ꢁ gg(ꢀ) > tg. As judged from the common conformational
property in these triacylglycerols, differences in lengths and sizes
in acyl groups may be of little importance. Their ester moiety plays
a greater role in determining the conformational property as far as
examined in the solution state.
4
ones in 4 and 5. The increase is pronounced in methanol-d solu-
11,12
tions and in good accordance with our preceding CD studies.
With Eq-1 (A = 1.34, B = 37.9) and the population of the gt(+)
conformer, we calculated the magnitudes (%) of both the helical
disparity and helical volume. The results are given in parenthesis
in Table 3. The calculated values are in good agreement with the
experimental ones. This means that Eq-1 covers the notable sol-
vent effects on the 3-O-alkylated compounds 5 and 6.
2.4. Evaluation of Eq-1 using asymmetric 1,2-dibenzoyl-sn-
glycerols 8–12 with various sn-3 substituent groups
By applying the population (%) of the gt(+) conformer in Table 1
to Eq-1 (A = 1.34, B = 37.9), we calculated the populations (%) of gg
Here, we evaluate Eq-1 using a pair of b-D- and b-L-glycosyl
compounds 8 and 9 (entries 1–4, Table 4). Entries 1 and 2 show
that the conformational property of 8 is similar to those of 5 and
6 with the sn-3 ether linkages. The 1,2-diacyl moiety in 8 displays
a notable increase in the gt(+) conformer and (+)-chirality in the
(
ꢀ) and tg conformers, the helical disparity (%), and the helical vol-
ume (%) as summarized in Table 2. The results in entries 1–3 are in
good agreement with the experimental values derived from the H
1
NMR Karplus analysis. By a digital resolution (J values ± 0.12 Hz) in
Table 1
1
3
H NMR analysis of helical conformational properties of C2-symmetric triacyl sn-glycerols in CDCl solutions.
1H NMR dataa d ppm ( J Hz)
3
Rotamers (%)b around
Helicity index around sn-1,2 position
Entry
Compounds (acyl groups)
Solv
sn-1,2 position
H1proR
H1proS
gt(+)
gg(–)
tg
Sign
Disparity [gtꢀgg] %
Volume [gt+gg] %
1
2
3
tri-Bz 1 (benzoyl)
tri-Ac (acetyl)
tri-Pal (palmitoyl)
CDCl
CDCl
CDCl
3
3
3
4.69 (5.8)
4.16 (5.9)
4.15 (6.0)
4.76 (4.4)
4.30 (4.4)
4.29 (4.4)
38
39
41
37
36
35
25
25
24
+
+
+
1
3
6
75
75
76
a
10
H1proR and H1proS signals are discriminated between each other according to our previously reported study on chirally deuterated sn-glycerols.
b
12
17
Calculated with the following simultaneous equations which are introduced from a general Karplus formula of Haasnoot et al. The values (%) may involve deviations
1
within ±3% by digital resolution (<0.12 Hz) of 500 MHz H NMR spectroscopy.
3JH1proS;H2ðHzÞ ¼ 2:5gtðþÞ þ 2:3ggðꢀÞ þ 10:6tg
3JH1proR;H2ðHzÞ ¼ 10:2gtðþÞ þ 1:3ggðꢀÞ þ 5:8tg
gtðþÞ þ ggðꢀÞ þ tg ¼ 100
ð1Þ
ð2Þ
ð3Þ

1
438
Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
Table 2
Recalculation of helical conformational properties by Eq-1 (A = 1.34, B = 37.9) applying the population (%) of gt(+) estimated in 1H NMR analysis.
Entry
Comp.
Solv.
Calcd with Eq-1 and the population (%) of gt(+)
gt(+) % (obs)
gg(ꢀ) % (obs)
tg % (obs)
Sign
Disparity % (obs)
Volume % (obs)
1
2
3
tri-Bz 1
tri-Ac
tri-Pal
CDCl
CDCl
CDCl
3
3
3
38 (38)
39 (39)
41 (41)
37.9 (37)
37.6 (36)
36.9 (35)
24.1 (25)
23.4 (25)
22.1 (24)
+
+
+
0.1 (1)
1.4 (3)
4.1 (6)
75.9 (75)
76.6 (75)
77.9 (76)
Table 3
Helical conformational properties of asymmetric triacyl sn-glycerols 2 and 3 and 3-O-alkyl or 3-O-silyl 1,2-dibenzoyl-sn-glycerols 4–7 in the solution states.
Solva
1
H NMR data dppm
b
Rotamers (%)c around
Helicity index around sn-1,2
Entry
Compounds
3
(
J Hz)
sn-1,2
(X at sn-3)
No
H1proR
H1proS
gt(+)
gg(ꢀ)
tg
Sign
Disparityd [gtꢀgg]%
Volumed [gt+gg]%
1
2
3
4
5
6
7
8
CH
CH
CH
CH
3
3
3
3
COO-
2
3
4
5
M
M
M
CDCl
M
CDCl
M
M
4.60 (6.1)
4.60 (5.8)
4.56 (6.8)
4.61 (6.2)
4.59 (6.6)
4.63 (6.2)
4.62 (6.6)
4.61 (6.6)
4.70 (4.2)
4.70 (4.2)
4.68 (3.7)
4.68 (3.9)
4.70 (3.7)
4.70 (4.0)
4.74 (3.9)
4.71 (3.7)
43
39
54
46
52
45
50
52
35
39
31
36
33
35
32
33
22
22
15
18
15
20
18
15
+
±
+
+
+
+
+
+
8 (6.8)
0 (1.4)
78 (79.2)
78 (76.6)
85 (86.5)
82 (81.1)
85 (85.2)
80 (80.6)
82 (83.9)
85 (85.2)
(CH
O-
2
)
14COO-
14CH O-
23 (21.5)
10 (10.7)
19 (18.8)
10 (9.5)
18 (16.2)
19 (18.8)
(CH
2
)
2
3
PhCH
2
O-
6
7
3
t
Bu(CH
)
3 2
SiO-
a
b
c
M = methanol-d
4
.
10
H1proR and H1proS signals are discriminated according to our previously reported method.
Calculated with the same Karplus equation as already cited in Table 1. The values (%) may involve deviations within ±3% by digital resolution (<0.12 Hz) of 500 MHz 1
12
H
NMR spectroscopy.
d
Values in parenthesis are obtained with Eq-1 (A = 1.34, B = 37.9) and the population (%) of gt(+) given in the left column.
Table 4
Helical conformational properties of asymmetric 1,2-dibenzoyl-sn-glycerols 8–12 bearing various substituting groups at the sn-3 position.
Solva
1
H NMR data dppm
b
Rotamers (%)c around
Helicity index around sn-1,2
Entry
Compounds
3
(
J Hz)
sn-1,2
(X at sn-3)
No
H1proR
H1proS
gt(+)
gg(ꢀ)
tg
Sign
Disparityd [gtꢀgg]%
Volumed [gt+gg]%
1
2
3
4
5
6
7
8
9
b-D-Glc(Ac)
4
-O-
8
CDCl
M
CDCl
M
CDCl
M
CDCl
M
3
4.50 (5.9)
4.60 (6.6)
4.54 (6.2)
4.53 (6.2)
4.44 (5.6)
4.54 (6.0)
4.68 (5.4)
4.66 (6.1)
4.49 (6.1)
4.49 (7.0)
4.65 (3.9)
4.70 (3.6)
4.64 (3.9)
4.70 (3.9)
4.56 (5.0)
4.63 (4.5)
4.72 (4.6)
4.78 (3.9)
4.53 (4.2)
4.60 (3.3)
42
52
46
46
32
40
32
45
43
59
39
33
36
36
36
35
41
37
35
31
19
15
18
18
32
25
27
18
22
10
+
+
+
+
-
+
ꢀ
+
+
+
3 (5.4)
81 (78.6)
85 (85.2)
82 (81.2)
82 (81.2)
68 (72.0)
75 (77.3)
73 (72.0)
82 (80.6)
78 (79.2)
90 (89.8)
19 (18.8)
10 (10.8)
10 (10.8)
ꢀ4 (ꢀ8.0)
5 (2.8)
b-L-Glc(Ac)
4
-O-
9
3
3
3
3
4-CH
Br-
H
3
Ph-SO
3
-
10
11
12
ꢀ9 (ꢀ8.0)
8 (9.5)
CDCl
M
8 (6.6)
28 (28.2)
1
0
a
b
c
M = methanol-d
4
.
10,16
H1proR and H1proS signals are discriminated according to our previously reported method.
Calculated with the Karplus equation cited in Table 1. The values (%) may involve deviations within ±3% by digital resolution (<0.12 Hz) of 500 MHz H NMR spectroscopy.
Values in parenthesis are obtained with Eq-1 (A = 1.34, B = 37.9) applying the gt(+) population (%) given in the left column.
1
d
polar solvent (entry 2). On the other hand, the b-L-glucopyranoside
shows a marginal change by the two solvents applied (entries 3
and 4). Although we recognized the difference between 8 and 9
substantial deviation from the values calculated with Eq-1. The
tosyl group may have an alternative interaction with 1,2-dibenzoyl
groups to cause the deviation from the empirical equation.
Entry 10 in Table 4 indicates that the simplest 3-deoxy com-
pound 12 (X = H) has the highest helical disparity (+28%) and vol-
ume (90%) among the 1,2-dibenzoyl-sn-glycerols examined here.
In addition, this compound permits a strong solvent effect to
increase the (+)-helicity in the methanol solution. The empirical
equation well reproduces the notable conformational property of
the simple 1,2-dibenzoate 12 in the solution states.
9
also in our preceding CD study,1
1,12
we have no clear rationaliza-
tion for the solvent effect largely different between the glycoside
isomers. The equation Eq-1 is applicable to the two isomers,
though the helical disparity of 8 (+5.4%) calculated by Eq-1 seemed
to have a substantial deviation from the experimental value (+3%).
Entries 5–8 in Table 4 indicate that the sn-3 substituents in 10
(
tosyl) and 11 (Br) display a remarkable effect for decreasing the
population of gt(+) and increasing that of the antiperiplanar tg con-
former. The resulted relationship in the order as gg(ꢀ) > gt(+) is
very unusual. In our experiments, this unusual relationship occurs
when 1,2-dipalmitin (1,2-dipalmitoyl-sn-glycerol) is dissolved in
2.5. A general trend in the conformational equilibrium in all the
asymmetric 1,2-dibenzoyl-sn-glycerols 1–12 in the solution
states
13
CDCl
3
in the absence of methanol-d
4
.
Eq-1 satisfies the unusual
conformational property of 10 and 11 which is located in the equi-
librium between S1 and S2 in Figure 2. On the other hand, the heli-
cal disparity and volume (%) of 10 in CDCl (entry 5) display a
3
As shown in Figure 2, a linear relationship is obtained between
the helical disparity (%) and the population (%) of gt(+), when we
use the results of 1–12 in Tables 1–4.

Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
1439
Fig. 2. A linear relationship between the helical disparity (%) and the population (%) of gt(+) as observed in the helical conformational properties of 1–12 in solution states
solvents: C = CDCl , M = methanol-d ).
(
3
4
From the linear line, the A and B constants in Eq-1 were deter-
mined be 1.32 and 37.6, respectively. These values are close to
conformational behavior, in which the relative order of gt(+) > gg
(ꢀ) > tg (%) is maintained. The solvent effects as discussed above
appear either between S1 and S3 or between S2 and S4. There, a
significant shift is induced in the equilibrium between gt(+) and
tg conformers by the solvents used. The changes in the population
(%) of the gg(ꢀ) conformer are rather limited in ranges between S1
(40%) and S3 (35%) and between S2 (38%) and S4 (30%).
those obtained from the analysis of 1,2-dipalmitoyl-sn-glycerols
(
A = 1.34, B = 37.9 in Eq-1).13 This result supports the idea that
the formula Eq-1 (A = 1.3, B = 38) can be applied to a wide range
of 1,2-diacyl-sn-glycerols in the solution state and is independent
of the acyl lengths and sizes. On the other hand, we have to pay
attention to the result that the sn-3 tosyl compound 10 displayed
a substantial deviation from Eq-1. The empirical equation may
cause substantial deviations to a certain type of 1,2-diacyl-sn-
glycerols.
Eq-1 (A = 1.32, B = 37.6) is converted into a conformational dia-
gram as shown in Figure 3. This diagram represents the overall
helical conformational properties that we have observed for the
In the region between S1 and S2, the relative order of gt(+) and
9
–12
gg(ꢀ) is reversed from the rule of gt(+) > gg(ꢀ).
three conformers equilibrate in a random fashion. The conforma-
tional properties of 10 (tosyl) and 11 (bromide) in CDCl are
involved in this region. They shift to the region between S2 and
S3 in methanol-d
and maintain the popular rule of gt(+) > gg(ꢀ) > tg.
In all of the 1,2-dibenzoyl-sn-glycerols examined here, the sim-
ple 3-deoxy compound 12 in methanol-d exhibits the highest gt
(+) population (59%) and represents a property around the S4
Moreover, the
3
4
1
,2-dibenzoyl-sn-glycerols 1–12 in the solution state.
4
The diagram is segmented by S1ꢃS5 to several regions. The
5
12,13
region between S1 and S4 covers all of the helical conformational
properties of 1–12 in the solution state examined herein. The con-
formational equilibrium between S2 and S4 represents a typical
boundary. Hauser et al. and our group
have disclosed
that all of the cell-membrane glycerophospholipids display a
conformational property around the S4 boundary similar to the
case of 12. In the case of the phospholipids, however, they keep
the strong (+)-chirality regardless of the solvents applied.
Moreover, they can display an extraordinary rotational mode
close to an S5 boundary, in which the 1,2-diacyl moiety
swings between the gt(+) and gg(ꢀ) conformers excluding the tg
5
,12,13
conformation.
2
1
.6. Rational design of 3-sulfonyl 1,2-dipalmitoyl-sn-glycerols
3 and 14 exhibiting a unique conformational property around
the 1,2-diacyl moiety
The tosyl compound 10 displays the unusual conformational
behavior to give the relationship of gg(ꢀ) > gt(+) around the 1,2-
diacyl moiety. The sn-3 sulfonate group may have a unique stere-
ochemical effect different largely from that of sn-3 phosphates.13
To examine this expectation, 3-mesyl and 3-tosyl 1,2-dipalmi-
toyl-sn-glycerols 13 and 14 (Chart 3) were prepared in a reported
1
8,19
1
way
and analyzed by H NMR spectroscopy in our way. In this
section, we compared the results with the helical conformational
property of 1,2-diplamitoyl-sn-glycero-3-phosphocholine (DPPC).
1
Similarly to other 1,2-diacyl-sn-glycerols, the H NMR spectrum
of 13 gives a pair of double-doublet signals of H1proR (d 4.19 ppm)
and H1proS (d 4.33 ppm) (Fig. 4a). H3proR and H3proS signals
Fig. 3. A conformational diagram derived with Eq-1 (A = 1.32, B = 37.6) by issuing
gt(+) (%) between 20% and 75% at 5% interval.

1
440
Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
Chart 3. Structures of compounds 13 and 14 bearing sulfonyl esters at the sn-3 position.
good accordance with our expectations from the 3-tosylate 10. The
sn-3 sulfonate esters have a notable effect to randomize the three
rotamers. Eq-1 (A = 1.34, B = 37.9) satisfies the helical conforma-
tional property of 13 (entries 1 and 2, Table 5) to indicate that
the 3-mesylate follows the empirical rule. On the other hand, Eq-
1
makes substantial deviations in the 3-tosylate 14 (entry 3) sim-
ilarly to what we observed in the 1,2-dibenzoyl 3-tosylate 10.
These 3-toylates are included in the exceptional cases. Compared
to the properties of the 3-mesylates, the populations of gg(ꢀ) con-
former decrease by several percentages while the populations of tg
conformer are increased. The 3-tosyl group seems to have a nota-
ble effect to stabilize the antiperiplanar conformer at the expense
of both the gt(+) and gg(ꢀ) conformers.
The effect of the sn-3 sulfonate may be similar to those of the
sn-3 acyl groups. As mentioned before in Table 1, the C2-symmetric
triacylglycerols display a helical conformational property close to
the S2 section (Fig. 3). In the circular dichroism study of 2 and
1
2
3,
we have concluded that sn-3 (or sn-1) acyl groups randomize
the conformational property of triacylglycerols. As can be seen
from the results in Table 5, the sn-3 sulfonate esters have a stron-
ger effect to randomize the three conformers around the 1,2-acyl
moiety than the sn-3 acyl groups.
Fig. 4. Partial 1H NMR spectra of (a) 3-mesylate 13 in CDCl
choline (DPPC) in a mixture of methanol-d and CDCl (1:10, v/v).
and (b) phosphatidyl-
3
4
3
Entries 4 and 5 indicate that DPPC displays a strong (+)-chirality
1
3
appear in a narrow region and overlap partly with the signals of
around the 1,2-diacyl moiety. The helical disparity and helical
volume exceeds 30% and 85%, respectively. Though the structures
of sulfonate and phosphate esters look analogous each other, they
induce helical conformational properties largely different from
each other. The strong (+)-chirality is characteristic of the cell-
membrane glycerophospholipids bearing the phosphate group at
the sn-3 position. We assume that their excellent helical properties
1
H1proS. Compared with the H NMR spectrum of DPPC (Fig. 4b),
a notable difference was observed in the 3J coupling constants of
each H1proR and H1proS as well as in their chemical shifts. These
differences come from a notable difference in conformational prop-
erties between 13 and DPPC.
Entries 1 and 2 in Table 5 indicate that the three rotamers in 13
equilibrate in a random fashion. This behavior marginally changes
in the two different solvents examined. The observed property is in
2
1–23
play an important role in their functions
membrane-bound enzymes.
also as activators of
2
4–28
Table 5
The helical conformational properties of 3-sulfonyl 1,2-dipalmitoyl-sn-glycerols 13 and 14 compared with that of phosphatidylcholine (DPPC) in organic solvents.
Solva
1
H NMR data d ppm ( J Hz)
3
Rotamers (%)d around sn-1,2
Helicity indexd around sn-1,2
Entry
Compounds (Y=)
H1proR
H1proS
gt(+)
gg(ꢀ)
tg
Sign
Disparity [gtꢀgg]% Volume [gt+gg]%
1
2
3
4
5
13 (CH
3
SO
2
-)
CDCl
C/M (10/1)
3
4.19 (5.7)
4.19 (5.7)
4.11 (5.7)
4.13 (7.3)
4.33 (4.6)
4.35 (4.5)
4.25 (4.7)
4.40 (2.9)
4.40 (3.5)
36
36
35
64
59
37
38
37
30
27
27
26
28
6
ꢀ
ꢀ
ꢀ
+
ꢀ1 (ꢀ2.6)
ꢀ2 (ꢀ2.6)
ꢀ2 (ꢀ4.0)
34 (34.9)
32 (28.2)
73 (74.6)
74 (74.6)
72 (74.0)
94 (93.1)
86 (89.8)
14 (pCH
DPPC (phosphocholine)
3
PhSO
2
-)
CDCl
CDCl
3
b
b
c
3
C/M (10/1)
4.14 (7.2)c
14
+
f
Values in parenthesis for the disparity and volume are calculated with Eq-1 (A = 1.34, B = 37.9) applying the population (%) of gt(+) given in the left column.
a
Solvents; C = CDCl
3
, M = methanol-d
4
(M). C/M represents v/v rations of mixed solvents.
b1
H NMR data are reported in the database of ‘Spectral Database for Organic Chemistry (SDBS), No. 16108HSP-45-792’ in http://sdbs.db.aist.gojp/sdbs/vgi-bin/direct_
20
frame_top.cgi
c1
13
H NMR data are reported in our preceding study.
d
Calculated with the Karplus equation given in Table 1. The values (%) may involve deviations within ±3% by digital resolution (<0.12 Hz) of 500 MHz 1H NMR
spectroscopy.

Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
1441
3
. Conclusion
expanded in the region between d 4.0 ppm and d 4.5 ppm. The
manual process is of high significance for the current H NMR anal-
1
We have described that the empirical rule as formulated with
ysis since peak tops determined by computer systems do not
always point at a weighted center correctly.
Eq-1 can be applied to both 1,2-dibenzoyl and 1,2-dipalmitoyl-
sn-glycerols in the solution states using CDCl and methanol-d
Discrimination between H1proR and H1proS signals is crucial
3
4
1
0
2
as the solvents. The conformational diagram available from the
empirical equation is useful to study their helical conformational
properties in the solution states. We have reported in our preced-
ing papers that asymmetric 1,2-acyl-sn-glycerols and the related
herein. In our previous study, chirally H-labelled triacylglycerols
were prepared (Chart 4) and applied for the unambiguous discrim-
ination between H1proR and H1proS signals. The results have
shown an empirical relationship between the two H1 signals; the
H1proS signals appear downfield from the H1proR signals (d
H1proS > d H1proR ppm) and have lower smaller coupling con-
chiral 1,2-diols keep the relationship of gt(+) ꢁ gg(ꢀ) > tg regard-
less of sn-3 substituents.9
–12
Herein we have disclosed that this
3
3
rule has some exceptions; the sn-3 bromine and sulfonate com-
pounds induce the unusual relationship of gg(ꢀ) > gt(+) > tg
around the 1,2-diacyl moiety. The conformational diagram
involves also the unusual conformational property in the area
between S1 and S2 sections.
stants ( JH1proR,H2 > JH1proS,H2 Hz). This rule is maintained
among all the 1,2-diacetyl, 1,2-dipalmitoyl and 1,2-dibenzoyl sn-
glycerols regardless of the sn-3 substituting groups. The validity
of this rule is confirmed in a comparative analysis using circular
1
1,12
dichroism (CD) spectroscopy.
We have prepared the sn-3 sulfonate esters 13 and 14 under the
assumption that they may display a unique conformational prop-
erty, which we observed. They are able to increase the antiperipla-
nar tg conformer by randomizing the population of the three
conformers. There are several discussions about the influences of
4.3. Calculation of fractional populations (%) of three staggered
conformers around 1,2-diacyl group with Karplus relationship
1
7
A general Karplus equation of Haasnoot et al. was extended
2
9,30
12
the tg conformer.
Although the tg conformer is excluded in
into the following simultaneous equations,
X-ray crystallographic analyses,4 the antiperiplanar disposition
of the 1,2-diacyl chains may associate with the deformation of
membrane lamellar structures leading to membrane fusion or divi-
sion. The sulfonyl glycerolipids 13 and 14 may be useful in the
study on the dynamics of fluid membranes.
–6
3JH1proS;H2ðHzÞ ¼ 2:5gtðþÞ þ 2:3ggðꢀÞ þ 10:6tg
3JH1proR;H2ðHzÞ ¼ 10:2gtðþÞ þ 1:3ggðꢀÞ þ 5:8tg
gtðþÞ þ ggðꢀÞ þ tg ¼ 100ð%Þ
3
4
4
. Materials and methods
.1. Model compounds
From the vicinal coupling constants ( J Hz) of H1proR and
H1proS signals, the fractional populations (%) of the three stag-
gered conformers are calculated.
All of the 1,2-dibenzoyl-sn-glycerols 1–1211 and triacyl sn-glyc-
4.4. Estimation of the ‘helicity index’, ‘helical disparity (%)’, and
‘helical volume (%)’
erols1 in Table 1 were prepared and identified in our former stud-
0
ies. The 3-mesyl and 3-tosyl derivatives 13 and 14 were prepared
1
8,19
The ‘helicity index’12 comprises three items, namely ‘(+) or (ꢀ)-
sign’, ‘helical disparity (%)’ and ‘helical volume (%)’. The helical dis-
parity (%) is the difference in populations (%) between gt(+) and gg
(ꢀ) conformers. The disparity has either ‘(+) or (ꢀ)-sign’, which
corresponds to the sign of exciton couplet CD bands. When the
gt(+) conformer is preferred to the gg(ꢀ) conformer, the sign is
positive. The absolute value in the helical disparity (%) corresponds
to the magnitude of the exciton couplet CD bands. The helical vol-
ume (%) is the summation of gt(+) and gg(ꢀ) conformers. The vol-
ume expresses to what extent a given glycerolipid can adopt the
two helical conformers [gt(+) and gg(ꢀ)] around the 1,2-diacyl
moiety.
in reported manners.
chemical purity over 95% ( H NMR evaluations).
All the compounds studied here have
1
4
.2. Discrimination between H1proR and H1proS signals in the
1
present H NMR spectroscopic analysis
3
Each of the model compounds is dissolved in either CDCl or
methanol-d
4
(deuterium content >99.5%) at ca. 10 mM concentra-
tions. H NMR spectroscopy is measured on JEOL 400 MHz or
00 MHz instruments at temperatures between 20 and 22 °C.
1
5
3
Chemical shifts (d ppm) and coupling constants ( J Hz) of H1proR
and H1proS signals are obtained manually with 1H NMR spectra
Chart 4. Chirally 2H-labelled tribenzoyl-sn-glycerol (1S)- and (1R)-[1- H]-1 (Ref. 10).
2

1
442
Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
5
5
. Experimental
5.1.2. 1,2-Dipalmitoyl-sn-glycerol II
The preceding product I (300 mg) was dissolved in a mixture of
n-hexane and 2-propanol (1:5, 60 mL) and hydrogenated for 3 h
.1. General
with Pd(OH)
the completion of the reaction, the mixture was filtrated with a
pad of celite in a mixture of CHCl and methanol (100:1) and evap-
2 2
under H atmosphere at room temperature. After
All reactions are carried out under a dry argon atmosphere.
Yields refer to chromatographically and spectroscopically homoge-
neous material. Anhydrous solvents are purchased from Wako Pure
Chemical Industries Co., Ltd. All other chemicals for the syntheses
are purchased from Wako Pure Chemical Industries Co., Ltd.
3
orated to give 1,2-dipalmitoyl-sn-glycerol 3 (248 mg, 96%) as a col-
orless powder. A part of this product (100 mg) was recrystallized
1
from hot ethanol. The H NMR spectrum of II matched with the
1
(
Osaka, Japan), Sigma–Aldrich Co., or Tokyo Kasei Kogyo (Tokyo,
H NMR spectrum of an authentic sample (Aldrich, CAS: 30334-
Japan). Reagents purchased at the highest commercial quality are
used without further purification. All reactions are monitored by
thin-layer chromatography (TLC) carried out on silica gel 60-F254
precoated plates (Merck) using UV light and cerium sulfate/molyb-
dic acid solution as visualizing agent. Silica gel BW-80S (average
particle size 100 mesh, Fuji Silicia Chemical Co., Ltd.) or BW-300
71-5).
5.1.3. 1,2-Dipalmitoyl-3-methanesulfonyl-sn-glycerol 13
The preceding crude product II (200 mg, 0.35 mmol) was dis-
solved in dry pyridine (10 mL) and reacted with methanesulfonyl
chloride (MsCl) (61 mg, 1.5 ꢄ 0.35 mmol) for 3 h at room temper-
ature. The reaction mixture was poured into a mixture of crashed
ice and water (100 mL), and the mixture was vigorously stirred.
Precipitates were collected by filtration and dried. TLC (silica gel,
toluene/ethyl acetate = 10:1) showed the presence of two com-
pounds in the crude material (major spot at Rf = 0.59 and minor
spot at Rf = 0.65). Purification with column chromatography on
(
average particle size 60 mesh, Fuji Silicia Chemical Co., Ltd.) is
employed for flash column chromatography.
ESI-HRMS spectra are recorded on a ThermoFisher Exactive.
NMR spectra are recorded with a JEOL ECA 500 spectrometer
equipped with Delta 5.02. Unless otherwise stated, 1H NMR (500
MHz) spectra are recorded at 25 °C using internal tetramethylsi-
13
lane (TMS) at 0 ppm, and
C NMR (125 MHz) spectra were
2
SiO in a mixture of n-hexane and ethyl acetate (10:1) afforded
recorded at 125 MHz using internal CDCl
lowing abbreviations are used to explain the multiplicities: s = sin-
glet, d = doublet, t = triplet, m = multiplet, br = broad.
3
at 77.16 ppm. The fol-
13 as a waxy solid (163 mg, 72%). 13: mp = 57.8–59.2 °C (softening
1
temperature = 45.7 °C). H NMR (CDCl
CH
), 1.25–1.35 (48H, m, 2 ꢄ pal-(CH
3
), d
H
0.88 (6H, t, 2 ꢄ pal-
3
2
)
12), 1.62 (4H, m, 2 ꢄ pal-C
CH OR
CH OBn
2
2
i
H
OOCO(CH ) CH3
2 14
H
C
OOCO(CH )14CH
2 3
C
CH OCO(CH ) CH3
CH OCO(CH ) CH3
2
2 14
2
2 14
II : R =
H
I
ii
1
1
3: R = -SO CH
4: R = -SO PhCH
iii
2
3
2
3
(
i) H
rt, 96%, (ii) methanesulfonyl chloride (1.5 mol. equiv) in a mixture
of pyridine and CH Cl (1:5, v/v), 0 °C ? rt, 72%, (iii) p-toluenesul-
fonyl chloride (1.5 mol. equiv) in a mixture of pyridine and CH Cl
1:5, v/v), 0 °C ? rt, 80%
2
, Pd(OH)
2
in a mixture of n-hexane and 2-propanol (1:4, v/v),
b H ,), 2.32ꢃ2.36 (4H, t, 2 ꢄ pal-C H ), 3.06 (3H, s, OSO CH ),
2
a
2
2
3
4.19 (1H, dd, 5.6 and 11.9 Hz, glycerol H1proR), 4.33 (1H, dd, 4.6
and 11.9 Hz, glycerol H1proS), 4.33 (1H, dd, 5.3 and 11.2 Hz, glyc-
erol H3proS or H3proR), 4.39 (1H, dd, 3.9 and 11.2 Hz, glycerol
2
2
2
2
1
3
(
3 C
H3proR or H3proS), 5.28 (1H, m, glycerol H2). C NMR (CDCl ) d
1
3 2 3
4.1 (pal-CH ), 22.7 (pal-CH CH ), 24.79 (pal-C b), 24.84 (pal-C
5
.1.1. 3-Benzyl-1,2-dipalmitoyl-sn-glycerol I
A purified syrup of 3-benzyl-sn-glycerol (250 mg, 1.37 mmol)
was dissolved in dry pyridine (15 mL) containing 4-(dimety-
lamino)pyridine (50 mg). To the stirred solution was added a CH
Cl
b), 29.1ꢃ29.7 (pal-(CH ) ꢄ 2), 31.9 (pal-CH ꢄ 2), 34.0 (pal-C ),
2
10
2
a
34.1 (pal-C ), 37.8 (-OSO CH ), 61.5 (glycerol sn-1), 66. 9 (glycerol
a
2
3
sn-3), 68.6 (glycerol sn-2), 172.9 (–C@O), 173.3 (–C@O). ESI-HRMS
+
4
2
-
(positive mode): 664.5181 (M+NH ). Elementary analysis calcu-
2
solution (5 mL) of palmitoyl chloride (942 mg, 2.5 ꢄ 1.37
lated for C36H74O NS = 664.518.
7
mmol), and the reaction mixture was stirred at room temperature
until the reaction was completed (2–6 h). The mixture was treated
5.1.4. 1,2-Dipalmitoyl-3-tosyl-sn-glycerol 14
with sat. NaHCO
3
aq. solution (1 mL), stirred at room temperature
The preceding crude product II (100 mg, 0.18 mmol) was dis-
solved in dry pyridine (1 mL) and reacted with p-toluenesulfonyl
chloride (71 mg, 1.5 ꢄ 0.37 mmol) for 22 h at room temperature.
Water was poured into the reaction mixture, and chloroform was
added. The mixture was washed with water and saturated brine.
for 3 h, and evaporated. The residue was diluted with a 10:1 (v/v)
mixture of toluene and ethyl acetate (60 mL), and the organic layer
washed with aqueous solutions of sat. NaCl, sat. NaHCO
3
, and again
sat. NaCl. After dried over MgSO , the organic layer was evaporated
4
to afford a solid (912 mg). Part of the crude solid (500 mg) was
recrystallized from hot ethanol and hexane, and the purified pro-
duct (378 mg) was identified as 3-benzyl-1,2-dipalmitoyl-sn-glyc-
erol I with the H NMR spectrum of an authentic sample (Aldrich,
CAS: 30403-51-1).
The organic phase was dried over MgSO , and concentrated. TLC
(silica gel, toluene/ethyl acetate = 10:1) showed the presence of
two compounds in the crude material (a major spot at Rf = 0.65
and a minor spot at Rf = 0.68). Purification with column chro-
matography on SiO2 in a mixture of toluene and ethyl acetate
4
1

Y. Nishida et al. / Tetrahedron: Asymmetry 28 (2017) 1435–1443
1443
(
50:1) afforded 14 as a way solid (81 mg, 61%). 14: mp = 64.4–65.1
7. Hong, M.; Schmidt-Rohr, K.; Zimmermann, H. Biochemistry 1996, 35. 8355-
1
8341.
°
C (softening temperature = 60.0 °C). H NMR (CDCl
t, 2 ꢄ pal-CH ), 1,22ꢃ1.27 (48H, m, 2 ꢄ pal-(CH 12), 1.54 (4H, m, 2
,), 2.23 (4H, t, 2 ꢄ pal-C ), 2.46 (3H, s, PhCH ), 4.11
1H, dd, 5.7 and 11.9Hz, glycerol H1proR), 4.14 (1H, dd, 5.0 and
3 H
); d 0.88 (6H,
8.
Krishnamurty, S.; Stefanov, M.; Mineva, T.; Begu, S.; Devoissell, J. M.; Goursot,
3
2
)
A.; Zhu, R.; Salahub, D. R. J. Phys. Chem. B 2008, 112, 13433–13442.
9. Nishida, Y.; Shingu, Y.; Mengfei, Y.; Fukuda, K.; Dohi, H.; Matsuda, S.; Matsuda,
ꢄ pal-C b H
2
a
H
2
3
K. Beilstein J. Org. Chem. 2012, 8, 629–639.
(
1
0. Nishida, Y.; Uzawa, H.; Hanada, S.; Ohrui, H.; Meguro, H. Agric. Biol. Chem. 1989,
3, 2319–2323.
11. Uzawa, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1990, 55, 116–122.
1
0.9 Hz, glycerol H3proR or H3proS), 4.18 (1H, dd, 4.3 and 10.8
5
Hz, glycerol H3proS or H3proR), 4.25 (1H, dd, 4.4 and 11.9 Hz, glyc-
erol H1proS), 5.22 (1H, m, glycerol H2), 7.36 (2H, m, Ph-H3 and H5),
1
1
1
1
2. Yuan, M.; Dohi, H.; Uzawa, H.; Nishida, Y. Tetrahedron: Asymmetry 2015, 26,
138–1144.
3. Nishida, Y.; Yuan, M.; Fukuda, K.; Fujisawa, K.; Dohi, H.; Uzawa, H. Beilstein J.
Org. Chem. 2017, 13, 1999–2009.
4. Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy Exciton Coupling in
Organic Stereochemistry; University Science Books: California, 1983.
5. Wiesler, W.; Nakanishi, K. J. Am. Chem. Soc. 1989, 111, 3446.
1
7
2
(
.79 (2H, m, Ph-H2 and H6). 13C NMR (CDCl
3
); d
10 ꢄ 2), 33.8 (pal-C
), 61. 3 (glycerol sn-3), 67.1 (glycerol sn-1), 68.2 (glycerol
sn-2), 127.9 (Ph-C1), 129.8 (Ph-C3 and C5), 132.5 (Ph-C4), 172.6
C
14.0 (pal-CH
3
),
2.6 (Ph-CH
pal-C
a
3
), 29.1ꢃ29.8 (pal-(CH
2
)
a
), 33.9
(
+
–C@O), 173.0 (–C@O). ESI-HRMS (negative mode):757.4858 (M
16. Uzawa, H.; Nishida, Y.; Hanada, S.; Ohrui, H.; Meguro, H. Chem. Commun. 1989,
62–863.
7. Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783–
790.
18. Golding, B. T.; Ioannou, P. V. Synthesis 1977, 423–424.
ꢀ
8
Cl ) Elementary analysis calculated for C43
H
74
O
7
SCl = 757.4838.
1
2
Acknowledgements
19. Guanti, G.; Banfi, L.; Basso, A.; Bevilacqua, E.; Bondanza, L.; Riva, R. Tetrahedron:
Asymmetry 2004, 15, 2889–2892.
This work was supported by Grant in Aid from the Japan Society
of the Promotion of Science (KAKENHI 25450146, KAKENHI
20. ‘‘Spectral Database for Organic Chemistry (SDBS), No. 16108HSP-45-792” in
http://sdbs.db.aist.gojp/sdbs/vgi-bin/direct_frame_top.cgi.
1
6K07711). We thank all staffs at Center for Analytical Instrumen-
21. Christie, W. ‘‘Phosphatidylcholine” in the AOCS Lipid Library (http://lipidlibrary.
aocs.org/lipids/pc/index.htm).
tation of Chiba University for their technical supports for NMR and
other spectroscopic measurements.
2
2
2. Farooqui, A. A. in ‘‘Glycerophospholipids” (http://www.els.net/WileyCDA/
ElsArticle/refId-a0000726.html).
3. ‘‘Cell
membrane”
in
Nature
Education
(http://www.nature.com/
scitable/topicpage/cell-membranes-14052567).
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