Optically active monoacylglycerols: Synthesis and assessment of purity

Article abstract of DOI:10.1002/ejoc.201300247

Despite their simple structures, synthesis of 1(or 3)-acyl-sn-glycerols remains a challenge that cannot be ignored because of facile acyl migrations, which not only complicate the synthesis but also make direct GC or HPLC analysis unfeasible. Assessment of the optical purity of monoacylglycerols has, to date, relied almost exclusively on specific rotation data, which are small in value and thus insensitive to impurities. Now, a simple means to "magnify" the small specific rotations has been found, along with practical methods for the measurement of both 1,2-and 1,3-acyl migrations, which offer a convenient and straightforward alternative to Mori's NMR analysis of Mosher esters. With the aid of these methods, a range of conditions for deacetonide removal were examined en route to the synthesis of two natural monoacylglycerols. Refined hydrolysis conditions, along with useful knowledge about the solubility and reactivity of substrates with an ultra long alkyl chain are also presented. Copyright

Full text of DOI:10.1002/ejoc.201300247

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FULL PAPER
Glycerolipids
C.-Y. Chen, W.-B. Han, H.-J. Chen,
Y. Wu,* P. Gao* ............................... 1–9
Optically Active Monoacylglycerols: Syn-
thesis and Assessment of Purity
Because of facile acyl migrations, the syn-
thesis of enantiopure 1(or 3)-acyl-sn-glycer-
ols is much more difficult than their seem-
ingly very simple structures may imply.
Even assessment of their optical purity is a
difficult task because of the lack of a
feasible means of analysis. Now, new find-
ings have changed everything.
Keywords: Lipids / Rearrangement / Pro-
tecting groups / Glycerolipids / Esters /
Analytical methods
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C.-Y. Chen, W.-B. Han, H.-J. Chen, Y. Wu, P. Gao
FULL PAPER
DOI: 10.1002/ejoc.201300247
Optically Active Monoacylglycerols: Synthesis and Assessment of Purity
Chao-Yuan Chen,[a,b] Wei-Bo Han, Hui-Jun Chen, Yikang Wu,* and Po Gao*
[a]
[a]
[a]
[b]
Keywords: Lipids / Rearrangement / Protecting groups / Glycerolipids / Esters / Analytical methods
Despite their simple structures, synthesis of 1(or 3)-acyl-sn-
glycerols remains a challenge that cannot be ignored be-
cause of facile acyl migrations, which not only complicate the
synthesis but also make direct GC or HPLC analysis unfeas-
ible. Assessment of the optical purity of monoacylglycerols
has, to date, relied almost exclusively on specific rotation
data, which are small in value and thus insensitive to impuri-
ties. Now, a simple means to “magnify” the small specific
rotations has been found, along with practical methods for
the measurement of both 1,2- and 1,3-acyl migrations, which
offer a convenient and straightforward alternative to Mori’s
NMR analysis of Mosher esters. With the aid of these meth-
ods, a range of conditions for deacetonide removal were ex-
amined en route to the synthesis of two natural monoacyl-
glycerols. Refined hydrolysis conditions, along with useful
knowledge about the solubility and reactivity of substrates
with an ultra long alkyl chain are also presented.
Introduction
Naturally occurring monoacylglycerols, an important
family of lipids, normally contain a long alkyl group in the
acyl subunit, with or without additional functionalities on
the chain and/or branching at the chain terminus (Fig-
ure 1). Although it is not clear whether all such natural
monoacylglycerols are optically active, at least in those
cases where optical rotation[1] was measured, the isolated
products were indeed optically active. 1(or 3)-Acyl-sn-glyc-
erols are also essential precursors for asymmetric di- or tri-
acylglycerols. It is thus understandable that there has been
an increasing interest over the years in gaining access to
1
tion.
(or 3)-acyl-sn-glycerols of a predefined absolute configura-
[
2]
We became interested in 1(or 3)-acyl-sn-glycerols because
of a recently identified[ natural product (3, hyloglycerol;
Figure 1) isolated from Hylodendron gabunensis Taub.
3a]
(Fabaceae). This molecule carries the longest (to the best
of our knowledge) alkyl chain among all known natural
monoacylglycerols, and thus represents an extreme example
for this family of lipids.
The hentriacontanoyl chain in 3 is much longer than the
chain in any synthetically confirmed 1(or 3)-acyl-sn-glycerol
(for which the longest is stearoyl). Therefore, it does not
seem wise to assign 3’s configuration by simple comparison
of the optical rotation with a known analogue Ϫ the ultra
Figure 1. Examples of naturally occurring 1(or 3)-acyl-sn-glycerols,
with the definitions for 1- and 3-acyl-sn-glycerols in lipid chemistry
shown in the box. sn = stereospecific numbering.
[
a] State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences,
3
45 Lingling Road, Shanghai 200032, China
E-mail: yikangwu@sioc.ac.cn
[b] School of Chemistry and Materials, Heilongjiang University,
Harbin 150080, China
long alkyl chain in 3 might behave differently from the
shorter ones due to unpredictable chain coiling, folding,
and/or aggregation. An enantioselective synthesis thus ap-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300247.
2
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Optically Active Monoacylglycerols
peared to be necessary; this would not only allow the unam-
biguous assignment of the absolute configuration of natural
3, but also offer an optical rotation reference for other 1(or
3)-acyl-sn-glycerols containing fatty acyl chains of compar-
able lengths that has been missing so far.
As this apparently rather simple synthetic endeavor pro-
ceeded, the intrinsic difficulties [which are greatly belied by
the unpretentious molecular architectures of 1(or 3)-acyl-
sn-glycerols] encapsulated in the assembly of glycerol and
acyl fragments gradually surfaced, and this prompted us
to extend the original simple synthesis into a more general
investigation of optically active monoacylglycerols. Much
useful knowledge was thus gained, and the results are pre-
sented in this paper.
Results and Discussion
Our initial approach is outlined in Scheme 1. To mini-
mize the potential interference from an extra long linear
alkyl chain (vide infra), we planned to access 3 using a 8, 94% for (R)-8; b) 13 (cat.), 9, CH Cl , reflux, 3 h, 64%; c) H
4
Scheme 2. Reagents and conditions: a) Et NBr, 100 °C, 95% for (S)-
2
2
2
cross-metathesis (CM) reaction.
(1 atm), Pd/C, EtOH, room temp., 4 h, 91%; d) H
2
(50 atm), Pd
black, EtOAc, 80 °C, 48 h, 98% for 14, see Supporting Infor-
mation; e) see Supporting Information.
Scheme 1. A retrosynthetic analysis for 3.
The synthesis (Scheme 2) was executed all the way to 12
without complications. However, debenzylation turned out
to be entirely impossible (see Supporting Information), in
sharp contrast to the situation with the stearoyl[ counter-
part or (R)-8.
4]
Cleaving the benzyl group with DDQ[5] before the CM
reaction was possible (Scheme 3). However, the product
Scheme 3. Reagents and conditions: a) DDQ, 100 °C, see text;
(i.e., 16) contained an extra doublet at δ = 3.81 ppm(arising
2
b) TMSOTf, Ac O, –40 °C, 82%; c) see text. DDQ = 2,3-dichloro-
from the -CH - units in the 1,2-acyl migration product ac- 5,6-dicyano-1,4-benzoquinone. TMSOTf = trimethylsilyl triflate.
2
[6,7]
1
cording to Haraldsson ) in its H NMR spectrum, while
the alternative route[ via diacetate 19 suffered from diffi-
culties in the removal of the acetyl groups (see Supporting
Information).
8]
meric excess) values of the 1(or 3)-sn-glycerols were
Using the cleavage of an acetonide group as the final step measured in addition to optical rotations to indicate their
to access 1(or 3)-sn-glycerols is very common. However, optical purities. However, the preparation of a Mosher ester
acyl migration still is a major and largely unsolved prob- was required for each sample. Analysis of the NMR spectra
[
2a–2c,2f,2k]
lem,
although in most cases the complications is also cumbersome. Therefore, a more straightforward
were not described in detail (e.g., without mentioning the means for measuring the ee values of 1(or 3)-acyl-sn-glycer-
doublet at δ ≈ 3.8 ppm). The optical purity of the final 1(or ols is still desirable. For this reason, in connection with the
3
)-sn-glycerol products has almost exclusively been assessed removal of the acetonide group from a model system (22,
[9]
using their specific rotations, which are normally rather readily accessible from commercially available 20 and 21),
small in value (around or less than, say, 5.0) and thus are we first developed a four-step sequence (Scheme 4, lower
not sensitive indicators for the presence of impurities.
half) for converting 1(or 3)-acyl-sn-glycerols (in this case,
Recently, a distinct advance[ was made by Mori. For 23) into the corresponding monobenzylated glycerols (here,
2a]
the first time (to the best of our knowledge) the ee (enantio- 24) for chiral HPLC analysis.
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C.-Y. Chen, W.-B. Han, H.-J. Chen, Y. Wu, P. Gao
FULL PAPER
CH Cl , H BO /HO(CH ) OMe/reflux,[2c,2f,2k]Zn(NO3)2/
[
10]
2
2
[
3
3
2 2
11]
[2a]
MeCN, and HOAc/H O (4:1). The results are summa-
2
rized in Table 1.
The results with CF CO H (aq.)/CH Cl , which has been
3
2
2
2
widely used in total synthesis with general satisfaction, were
discouraging in our system. Before all of the starting mate-
rial (i.e., 22) was hydrolyzed, the isolated product (i.e., 23)
already contained significant amounts of the 2-acyl isomer
(which is very likely to be “invisible” in the ee measuring
methods of Mosher ester analysis or chiral HPLC analysis)
1
as revealed by the doublet at δ = 3.81 ppm in the H NMR
spectrum. Also, chiral HPLC analysis gave an ee value of
5
3% (Table 1, entry 1).
Boric acid in HO(CH ) OMe
[
2c,2f,2k]
(Table 1, entry 2)
2
2
appears to be very mild. However, after 2 h at reflux, when
only part of the starting material (i.e., 22) was consumed,
significant amounts of the 2-acyl isomer were already de-
tected in the isolated product (i.e., 23), with the ee value
being 46%.
Scheme 4. Reagents and conditions: a) EDCI, DMAP, CH
°C, 3 h, 92%; b) different conditions in the literature, see text; for
measuring the ee value of (S)-23: c) acetone, pTsOH, room temp.,
h; d) LiOH, THF/H O (10:1, v/v), room temp., 12 h; e) BnBr,
NaH, DMF, room temp., 2 h; f) AcOH/H
1% overall from 23 (4 steps). EDCI
aminopropyl)-NЈ-ethylcarbodiimide]; DMAP
2
Cl
2
,
Mori reported[2a] that the Zn(NO ) /MeCN conditions
3
2
0
gave 1-palmitoyl-sn-glycerol with 90% ee (measured by the
Mosher method). However, in our case with the 1-hexanoyl
O (4:1, v/v), 50 °C, 2 h, group (which is much smaller in size than the palmitoyl
6
2
2
9
=
[N-(3-dimethyl-
4-(dimethyl-
group), these conditions led to the formation of significant
amounts of the 2-acyl-isomer [inseparable from the 1(or 3)-
acyl-sn-glycerols], as shown by the doublet at δ = 3.81 ppm
=
amino)pyridine; pTsOH = p-toluenesulfonic acid; DMF = N,NЈ-
dimethylformamide.
1
in the H NMR spectrum. The ee value for the isolated 23
(
measured from the corresponding 24) was only 14%
In the event, the diol that resulted from hydrolysis of the (Table 1, entry 3).
acetonide was first reprotected as an acetonide. The acyl
In 4:1 AcOH/H O, excessive acyl migration occurred at
2
group was then hydrolyzed, and the primary hydroxy group 130 °C within 30 min (Table 1, entry 4). At 50 °C, the best
was benzylated. Finally, the acetonide was hydrolyzed again temperature found by Mori, a minimum formation of the
to give stable diol 24 (91% overall yield from 23). Because 2-acyl isomer was observed in our case with the 1-hexanoyl
of the ease of its detection by UV light and its suitable group, with the ee value for the isolated 23 being 98%
polarity, diol 24 can be readily analyzed by chiral HPLC. (Table 1, entry 5) when the hydrolysis was run for only
The ee value for 23 (or its counterparts in different cases) 30 min. When the reaction time was prolonged to 2 h as in
[
2a]
can thus be indirectly estimated from the ee value of the the literature, acyl migration occurred to a more signifi-
corresponding 24.
cant extent (77% ee, Table 1, entry 6); the longer the reac-
Having established the means for the rapid detection of tion time, the poorer the optical purity that was observed
,2-acyl migration and a feasible and reliable method for (Table 1, entries 7–9).
1
measuring the ee values of 1(or 3)-acyl-sn-glycerols, we went
It should be noted that acyl migration also occurred
on to examine several sets of promising mild conditions for readily under basic conditions. For instance, when 23
cleaving acetonides, including CF CO H (50% aq.)/ (15 mg, obtained under the optimal conditions for aceton-
3
2
Table 1. Hydrolysis of the acetonide in 22 under different conditions.
Entry
Conditions
CF CO H/CH
BO /2-ME /reflux/2 h
3 2
Zn(NO ) /MeCN/50 °C/1 h
Area for δ = 3.81 ppm[a]
ee for 23 [%][b]
1
2
3
4
5
6
7
8
9
3
2
2
c]
Cl
2
/r.t./1 h
0.37
0.24
0.34
0.41
0.06
0.13
0.20
0.26
0.40
53
46
14
15
98
77
61
37
20
[
H
3
3
[
d]
[
e]
AcOH/H
AcOH/H
AcOH/H
AcOH/H
AcOH/H
AcOH/H
2
2
2
2
2
2
O/130 °C/30 min
[e]
O/50 °C/30 min
O/50 °C/2 h[
O/50 °C/4 h
O/50 °C/8 h[
e]
[e]
e]
O/50 °C/16 h[
e]
1
[
a] The integral for the doublet at δ = 3.81 ppm (the methylene groups in the 2-acyl isomer) in the H NMR spectrum measured on the
crude product mixture, with the multiplet at δ = 3.92 ppm (the methine group in 23) set to unity for comparison. [b] Measured by chiral
3 2 2 2
HPLC analysis of the 24 derived from 23. [c] 2-ME = 2-methoxyethanol. [d] Zn(NO ) ·6H O was used. [e] 4:1 (v/v) AcOH/H O was used,
with 50 °C being the bath temperature.
4
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Optically Active Monoacylglycerols
ide removal) was treated with Et N (0.4 mL) and DMAP
3
(
2 mg) in CH Cl (0.5 mL) at ambient temperature, the rela-
2 2
tive integral (initially 0.06) for the doublet at δ = 3.81 ppm
1
in the H NMR spectrum was measured to be 0.11, 0.19,
0.21, 0.29, and 0.46 at 15 min, 30 min, 1 h, 2 h, and 4 h,
respectively.
Efforts were also made to find a better solvent, in which
the usually rather small optical rotations for 1(or 3)-acyl-
sn-glycerols may be substantially “magnified”. A few sol-
vents that had not been tested for 1(or 3)-acyl-sn-glycerols
by previous investigators, including 2,6-lutidine, DMF, and
DMSO (dimethyl sulfoxide), were then examined for 23.
The results are summarized in Table 2.
2 2
Scheme 5. Reagents and conditions: a) EDCI, DMAP, CH Cl ,
Table 2. Specific rotation for 23 measured in different solvents.
0
2
°C, 5 h, 96%; b) AcOH/H O (4:1, v/v), 50 °C, 30 min, 96%.
2
8
Entry
Solvent (c = 1.0)
CHCl
CH Cl
[α]
D
1
2
3
4
5
6
7
3
–1.3
+0.2
+0.8
Table 3. The results of hydrolysis of the acetonide in 26.
2
2
Entry
Time
Area for δ = 3.84 ppm[a]
[α]
D
25[b]
ee for 27 [%][c]
toluene
acetone
2,6-lutidine
DMF
+5.5
1
2
3
4
5
6
30 min
1 h
1.5 h
2 h
4 h
12 h
0
0
0
0.03
0.12
0.29
–10.4
–10.1
–9.5
–8.6
–6.8
–5.4
Ͼ99
Ͼ99
99.6
91
50
35
+10.7
+10.7
+11.9
DMSO
Under otherwise identical conditions, the smallest values
were found with CHCl , CH Cl , and toluene (Table 2, en-
tries 1–3). In a more polar solvent (acetone), the rotation
3
2
2
[
a] The integral for the doublet at δ = 3.84 ppm (the methylene
groups in the 2-acyl isomer) in the H NMR spectrum measured
1
value was substantially larger (Table 2, entry 4). In 2,6-luti- on the crude product mixture after work-up, with the integral for
the multiplet at δ = 3.93 ppm (the methine group in 27) set to unity
dine or DMF, the rotation for 23 almost doubled. The
largest rotation (+11.9) was observed in DMSO. As larger
specific rotations lead to smaller errors and thus higher pre-
for comparison. [b] Measured in DMSO at c = 1.0. [c] Measured
by chiral HPLC analysis of the 24 derived from 27.
cision in data comparison, DMSO seems to be the solvent
of choice for measuring specific rotations for 1(or 3)-acyl-
sn-glycerols.
The knowledge gained from studying model compound
23 was then examined carefully with 27 (3-stearoyl-sn-glyc-
erol), which could be generally applicable in the synthesis
of biologically relevant 1(or 3)-acyl-sn-glycerols. As shown
in Scheme 5, condensation of (S)-20 (to make full use of
the reagent in hand) and stearic acid gave 26 in 96% yield.
The hydrolysis of the acetonide with AcOH/H O to deliver
2
2
7 was then monitored closely. Aliquot samples were taken
1
out of the reaction flask at selected time points, and the H
NMR spectra of the crude mixtures were recorded to see
the intensity of the doublet at δ = 3.81 ppm. The optical
rotations for the purified 27 were then measured in DMSO,
and the ee values were determined by chiral HPLC analysis
of the corresponding (R)-24 prepared by the aforemen-
tioned four-step sequence.
The results are shown in Table 3 and Figure 2. After ex-
posure of 26 to AcOH/H O at 50 °C for 15 min, more than
2
80% of the starting acetonide had already reacted. And by
3
0 min, reaction was complete. Up to 1 h, no 1,2-acyl mi-
Figure 2. The effect of reaction time on the 1,2-acyl migration in
gration product could be detected (i.e., no doublet at all at the cleavage of the acetonide in 26 with AcOH/H O at 50 °C, as
2
δ = 3.84 ppm), and no decrease in the optical rotation or shown by the relative intensity of the doublet at δ = 3.84 ppm in
1
the H NMR spectra of the samples taken out of the reaction flask
the ee value occurred (Table 3, entries 1 and 2).
(
(
and worked up immediately) at 30 min (trace A), 2 h (trace B), 4 h
trace C), and 12 h (trace D), respectively. Note that the chemical
However, after a further 30 min, acyl migrations became
detectable (Table 3, entry 3, see also Figure 1). By 2 h, the
shifts for such molecules are slightly dependent on the concentra-
changes were substantial (Table 3, entry 4). Further exten- tion of the NMR sample; see also Table 3.
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C.-Y. Chen, W.-B. Han, H.-J. Chen, Y. Wu, P. Gao
FULL PAPER
[
3a]
sion of the reaction time led to very serious isomerization 4.40 (dd, J = 11.2, 3.5 Hz, 1 H) ppm, respectively. In the
13
(Table 3, entries 5 and 6).
C NMR spectra, a difference of 0.9 ppm was also ob-
The optical rotation of 26 in DMSO was also substan- served for a carbon at δ ≈ 32 ppm between the two sets of
[
1h]
tially larger than the values measured in e.g., MeOH,
data (δ = 31.9 ppm for synthetic 3 and δ = 32.8 ppm for
[
2a]
[12]
pyridine,
DMSO may be the generally preferred solvent for measur- tained some minor errors. To confirm this, we looked into
ing the optical rotations of 1(or 3)-acyl-sn-glycerols. the NMR spectroscopic data for other known 1(or 3)-fatty
or THF,
which unambiguously shows that natural 3). It thus seemed that the data for natural 3 con-
Next, we proceeded with the synthesis of 3. As shown in acyl-sn-glycerols, including 27, for supporting evidence.
Scheme 6, condensation of (R)-20 with undec-10-enoic acid And indeed, all the corresponding data are consistent with
10 gave 28 in 97% yield. Introduction of the additional 21 the data for the synthetic but not the natural 3.
carbon atoms was effected in a cross-metathesis reaction
mediated by the Grubbs II catalyst (13). The resulting C=C ral product
To be on the safe side, we also synthesized (S)-2, a natu-
[
1a]
closely related to 3, by the sequence shown
double bond was saturated by hydrogenation over Pd black in Scheme 7.
under atmospheric H at ambient temperature to deliver 30
2
in 98% yield.
Scheme 7. Reagents and conditions: a) EDCI, DMAP, CH
2 2
Cl ,
0
°C, 10 h, 95%; b) AcOH/H O (4:1, v/v), 65 °C, 10 min, 91%.
2
All the data for the synthetic and natural 2 were in good
agreement with each other, which thus proved that natural
has an (S) configuration. Neither the synthetic nor the
natural 2 has any signals in the δ = 4.30–4.40 ppm region
2
1
13
of their H NMR spectra. And in the C NMR spectrum,
the signal in question appeared at δ = 31.8 ppm. As the
structural difference between 2 and 3 is almost negligible,
Scheme 6. Reagents and conditions: a) EDCI, DMAP, CH
2
Cl
2
,
0
c) H
H
°C, 2 h, 97%; b) Grubbs II (cat. 13), 9, CH Cl , reflux, 6 h, 45%;
2
2 2
(1 atm), Pd black, EtOAc, room temp., 48 h, 98%; d) AcOH/ the data for 2, along with those for other closely related
2
O (4:1, v/v), 65 °C, 8 min, 91%.
1(or 3)-acyl-sn-glycerols including 27, clearly show that
either the reported data for natural 3 contain minor errors
Cleavage of the acetonide with AcOH/H O deserves fur-
2
(
as mentioned above) or, which is less likely, the structure
ther remarks. At 50 °C, the substrate (i.e., 30) did not dis-
solve at all, which made it impossible to run the reaction.
Reducing the water content in the solvent mixture to almost
pure acetic acid did not lead to any improvement. Fortu-
nately, the problem was solved by raising the bath tempera-
ture to 65 °C. At this temperature, complete hydrolysis
[3b]
of the natural hyloglycerol was incorrectly assigned.
Conclusions
Two natural monoacylglycerols both containing an ultra
could be achieved in 8 min without any discernible forma- long alkyl chain (hentriacontanoyl and heptacosanoyl) were
tion of the 2-acyl isomer. This required pre-warming the synthesized using enantiopure (R)-(2,2-dimethyl-1,3-diox-
solvent mixture in a 65 °C bath to allow precise control of olan-4-yl)methanol as a chiral building block. Comparison
the reaction time at 65 °C. The ee value of the 24 derived of the physical and spectroscopic data confirmed the pre-
from (S)-3 was determined to be 93%.
The spectroscopic data for the synthetic (S)-3 generally absolute configuration to be (S). Data comparison also
viously assigned structure for natural 2 and established the
1
13
agreed well with the data reported for natural 3. However, showed that the H and C NMR spectroscopic data re-
1
in the H NMR spectrum, the protons of the CH O group ported for the natural hyloglycerol (i.e., 3) might contain
2
bonded to the acyl group appeared in the synthetic sample some minor errors (see also Tables S1 and S2, Supporting
at δ = 4.15 (dd, J = 11.5, 6.0 Hz, 1 H) and 4.22 (dd, J Information). In connection with the syntheses of 2 and 3,
=
11.8, 4.8 Hz, 1 H) ppm, whereas those for the natural the general problems in accessing optically active
compound were at δ = 4.37 (dd, J = 11.2, 5.5 Hz, 1 H) and monoacylglycerols, namely control and detection of acyl
6
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Optically Active Monoacylglycerols
migrations and assessment of optical purity of the final H), 1.38–1.19 (m, 4 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. FT-IR (film):
–
1
ν˜ = 3316, 2960, 2925, 2854, 1730, 1417, 1260, 1099, 799 cm . ESI-
MS: m/z = 213.0 [M + Na] .
products, were also addressed. A simple means to “mag-
nify” the normally rather small specific rotations for the
monoacylglycerols was found (i.e., recording the optical ro-
tations in DMSO). Methods for the quantitative measure-
ment of the 1,2- and 1,3-acyl migrations were also intro-
duced. With the aid of these measures, several sets of mild
conditions for the removal of acetonides developed by pre-
vious investigators were re-examined. Some of them led to
significant acyl migration. The conditions reported by Mori
+
Condensation of (S)-20 with Stearic Acid (25) To Give 26: A mixture
of (S)-20 [d-(+)-1,2-isopropylideneglycerol; 1.03 g, 7.58 mmol],
stearic acid (2.22 g, 7.58 mmol), EDCI (1.62 g, 8.34 mmol), and
DMAP (46 mg, 0.38 mmol) in dry CH Cl (60 mL) was stirred at
2 2
ambient temperature for 5 h. The mixture was concentrated on a
rotary evaporator. Water (15 mL) and was added. The mixture was
extracted with Et
2
O (3ϫ 15 mL). The combined organic extracts
SO . Re-
were washed with brine, and dried with anhydrous Na
2
4
were shown to be the mildest, and these conditions were moval of the solvent on a rotary evaporator left an oily residue,
further refined in this work for the individual substrates, which was purified by chromatography (30:1, PE/EtOAc) on silica
especially those bearing an ultra long alkyl chain and thus gel to give known[ ester 26 (2.91 g, 7.31 mmol, 96%) as a white
2a]
[
2a]
26
solid, m.p. 41–43 °C (ref. m.p. 40–41 °C). [α]
D
= –2.4 (c = 0.40,
): δ = 4.35–4.28 (m, 1 H), 4.17
dd, J = 11.3, 4.5 Hz, 1 H), 4.12–4.05 (m, 2 H), 3.79–3.66 (m, 1
H), 2.34 (t, J = 7.5 Hz, 2 H), 1.68–1.56 (m, 2 H), 1.44 (s, 3 H), 1.37
s, 3 H), 1.40–1.20 (m, 28 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm. ESI-
having a poor solubility. The methods developed and the
knowledge gained may facilitate studies of similar com-
pounds in general.
1
3 3
CHCl ). H NMR (400 MHz, CDCl
(
(
+
MS: m/z = 421.5 [M + Na] .
Experimental Section
Removal of the Acetonide in 26 To Give 27: A solution of acetonide
2
6 (103 mg, 0.26 mmol) in AcOH/H
stirred at 50 °C (bath) for 30 min. The heating bath was removed,
and NaHCO (saturated aq.; 5 mL) was added. The mixture was
extracted with EtOAc (3ϫ 10 mL). The combined organic extracts
were washed with brine and dried with anhydrous Na SO . Re-
moval of the solvent on a rotary evaporator and chromatography
2
O (4:1, v/v; 2.5 mL) was
General: NMR spectra were recorded with a Bruker Avance NMR
spectrometer operating at 400 MHz ( H). IR spectra were
1
3
measured with a Nicolet 380 Infrared spectrophotometer. ESI-MS
data were acquired with a Shimadzu LCMS-2010EV mass spec-
trometer. HRMS data were obtained with a Bruker APEXIII 7.0
Tesla FT-MS spectrometer. Optical rotations were measured with
a Jasco P-1030 polarimeter. Melting points were measured with
a hot-stage melting point apparatus equipped with a microscope.
2
4
2a]
(
2:1, PE/EtOAc) on silica gel gave known[
diol 27 (90 mg,
[2a]
0.25 mmol, 96%) as a white solid, m.p. 74–76 °C (ref. m.p. 73–
2
5
29
74 °C). [α]
D
= +1.4 (c = 20.00, CHCl
3
); [α]
D
= –7.4 (c = 0.65,
2 2
CH Cl was dried with activated 4 Å MS (molecular sieves). All
2
9
[2a]
23
DMSO); [α]
D D
= –4.2 (c = 2.55, pyridine) {ref. [α] = –3.83 (c =
chemicals were reagent grade and used as purchased. Column
chromatography was performed on silica gel (300–400 mesh) under
slightly positive pressure. PE = petroleum ether (b.p. 60–90 °C).
2.63, pyridine)}. ee Ͼ99%, as shown by chiral HPLC analysis of
the compound 24 derived from 27 using the four-step sequence
1
3
developed in this work. H NMR (400 MHz, CDCl ): δ = 4.21 (dd,
Condensation of (R)-20 with 21 To Give 22: A mixture of (R)-20 [l- J = 11.7, 4.7 Hz, 1 H), 4.15 (dd, J = 11.7, 6.2 Hz, 1 H), 3.98–3.89
(
–)-1,2-isopropylideneglycerol; 400 mg, 3.03 mmol], n-hexanoic
acid (351 mg, 3.03 mmol), EDCI (640 mg, 3.33 mmol), and DMAP
2
19 mg, 0.15 mmol) in dry CH Cl (25 mL) was stirred at ambient s, 1 H), 1.68–1.53 (m, 2 H), 1.45–1.20 (m, 28 H), 0.88 (t, J = 6.8 Hz,
(m, 1 H), 3.70 (dd, J = 11.2, 3.7 Hz, 1 H), 3.60 (dd, J = 11.5,
5.7 Hz, 1 H), 2.54 (br. s, 1 H), 2.35 (t, J = 7.6 Hz, 2 H), 2.10 (br.
(
2
temperature for 3 h. The mixture was concentrated on a rotary
evaporator. The residue was purified by chromatography (30:1, PE/
EtOAc) on silica gel to give known ester 22 (636 mg, 2.78 mmol,
3 H) ppm. ESI-MS: m/z = 381.4.
Condensation of Alcohol (R)-20 with Undec-10-enoic Acid (10) To
Give Ester 28: A mixture of (R)-20 [l-(+)-1,2-Isopropylidenegly-
cerol, 103 mg, 0.76 mmol], undec-10-enoic acid (10; 140 mg,
27
[13]
9
2%) as a colorless oil. [α]
D
= –12.1 (c = 1.25, hexane) {ref.
25
1
[α]
D
3
= –12.2 (c = 1.20, hexane)}. H NMR (400 MHz, CDCl ): δ
0
0
.76 mmol), EDCI (162 mg, 0.84 mmol), and DMAP (5 mg,
.04 mmol) in dry CH Cl (8 mL) was stirred at ambient tempera-
=
4.29 (quint, J = 5.3 Hz, 1 H), 4.14 (dd, J = 11.5, 4.6 Hz, 1 H),
2
2
4
7
.10–4.03 (m, 2 H), 3.72 (dd, J = 8.3, 6.4 Hz, 1 H), 2.32 (t, J =
.7 Hz, 2 H), 1.61 (quint, J = 7.2 Hz, 2 H), 1.41 (s, 3 H), 1.35 (s, 3
ture for 2 h. The mixture was concentrated on a rotary evaporator.
Water (15 mL) and was added. The mixture was extracted with
H), 1.32–1.23 (m, 4 H), 0.87 (t, J = 7.1 Hz, 3 H) ppm. ESI-MS:
Et
2
O (3ϫ 15 mL). The combined organic extracts were washed
SO . Removal of the sol-
+
m/z = 253.3 [M + Na] .
with brine and dried with anhydrous Na
2
4
vent on a rotary evaporator left an oily residue, which was purified
Removal of the Acetonide in 22 To Give 23: A solution of acetonide
by chromatography (30:1, PE/EtOAc) on silica gel to give ester 28
2
2 (50 mg, 0.22 mmol) in AcOH/H
at 50 °C (bath) for 30 min. The heating bath was removed, and
NaHCO (saturated aq.; 5 mL) was added. The mixture was ex-
tracted with EtOAc (3ϫ 10 mL). The combined organic extracts
were washed with brine and dried with anhydrous Na SO . Re-
moval of the solvent on a rotary evaporator and chromatography
2
O (4:1, v/v; 2.5 mL) was stirred
2
8
(
220 mg, 0.74 mmol, 97%) as a colorless oil. [α]
D
= –1.40 (c = 3.50,
): δ = 5.88–5.71 (m, 1 H),
.06–4.86 (m, 2 H), 4.36–4.26 (m, 1 H), 4.16 (dd, J = 11.6, 4.8 Hz,
H), 4.12–4.02 (m, 2 H), 3.73 (dd, J = 8.3, 6.4 Hz, 1 H), 2.34 (t,
1
3 3
CHCl ). H NMR (400 MHz, CDCl
5
1
3
2
4
J = 7.6 Hz, 2 H), 2.03 (q, J = 6.9 Hz, 2 H), 1.65–1.59 (m, 2 H),
1
3
[14]
1.43 (s, 3 H), 1.37 (s, 3 H), 1.35–1.24 (m, 10 H) ppm. C NMR
(2:1, PE/EtOAc) on silica gel gave known
diol 23 (39 mg,
= –1.3 (c = 1.00, CHCl );
= +11.9 (c = 1.00, DMSO). ee = 98%, as shown by chiral
2
8
(100 MHz, CDCl ): δ = 173.6, 139.2, 114.1, 109.8, 73.7, 66.3, 64.5,
0.21 mmol, 93%) as a colorless oil. [α]
D
3
3
2
8
34.1, 33.7, 29.24, 29.15, 29.1, 29.0, 28.9, 26.7, 25.4, 24.9 ppm. FT-
[α]
D
IR (film): ν˜ = 2986, 2928, 2856, 1742, 1640, 1456, 1371, 1161, 1057,
HPLC analysis of the compound 24 derived from 23 by the four-
–
1
+
1
910, 843 cm . ESI-MS: m/z = 321.3 [M + Na] . ESI-HRMS: calcd.
for C17
step sequence developed in this work. H NMR (400 MHz,
Na [M + Na]+ 321.20363; found 321.20371.
30 4
H O
CDCl
3
): δ = 4.23–4.07 (m, 2 H), 3.92 (quint, J = 5.6 Hz, 1 H), 3.68
dd, J = 11.5, 3.8 Hz, 1 H), 3.58 (dd, J = 11.6, 5.8 Hz, 1 H), 2.72
br. s, 2 H), 2.34 (t, J = 7.5 Hz, 2 H), 1.62 (quint, J = 7.6 Hz, 2
(
(
Coupling of 28 with Docos-1-ene (9) To Give 29: A mixture of 28
(70 mg, 0.23 mmol), docos-1-ene (9; 434 mg, 1.41 mmol), and
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30247
/KAP1
Date: 18-05-13 12:27:29
Pages: 9
C.-Y. Chen, W.-B. Han, H.-J. Chen, Y. Wu, P. Gao
(3 mL) was 0.12 mmol) in dry CH Cl (5 mL) was stirred at ambient tempera-
FULL PAPER
Grubbs II catalyst 13 (9 mg, 0.01 mmol) in dry CH
2
Cl
2
2
2
stirred at reflux under argon for 6 h. The solids were filtered off.
The filtrate was concentrated on a rotary evaporator. The residue
was purified by chromatography (40:1, PE/EtOAc) on silica gel to
give 29 (60 mg, 0.10 mmol, 45%; a mixture of the cis/trans isomers)
ture for 10 h. The mixture was concentrated on a rotary evaporator.
Water (15 mL) and was added. The mixture was extracted with
Et
with brine (20 mL), and dried with anhydrous Na
of the solvent on a rotary evaporator left an oily residue, which
): δ = 5.44–5.31 (m, 2 H), 4.31 (quint, J was purified by chromatography (25:1, PE/EtOAc) on silica gel to
5.0 Hz, 1 H), 4.16 (dd, J = 11.6, 4.8 Hz, 1 H), 4.12–4.03 (m, 2 give ester 32 (120 mg, 0.23 mmol, 95%) as a white solid, m.p. 66–
H), 3.73 (dd, J = 8.3, 6.1 Hz, 1 H), 2.33 (t, J = 7.5 Hz, 2 H), 2.03–
2
O (3ϫ 15 mL). The combined organic extracts were washed
2
SO . Removal
4
as a white solid, m.p. 76–79 °C. [α]2
NMR (400 MHz, CDCl
8
1
D
3
= –0.9 (c = 1.33, CHCl ). H
3
=
2
8
1
67 °C. [α]
D 3 3
= –2.5 (c = 0.20, CHCl ). H NMR (400 MHz, CDCl ):
1
1
.91 (m, 4 H), 1.66–1.58 (m, 2 H), 1.43 (s, 3 H), 1.37 (s, 3 H), 1.40– δ = 4.29 (quint, J = 6.0 Hz, 1 H), 4.14 (dd, J = 11.4, 4.7 Hz, 1 H),
.20 (m, 46 H), 0.87 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz,
): δ = 173.6, 130.5, 130.4, 130.23, 130.16, 109.8, 73.7, 66.3,
4.11–4.02 (m, 2 H), 3.72 (dd, J = 8.5, 6.1 Hz, 1 H), 2.32 (t, J =
CDCl
3
7.5 Hz, 2 H), 1.65–1.55 (m, 2 H), 1.41 (s, 3 H), 1.34 (s, 3 H), 1.40–
1
3
6
4.5, 34.1, 32.59, 32.55, 32.53, 31.9, 29.8–29.1 (many unresolved 1.20 (m, 46 H), 0.86 (t, J = 6.7 Hz, 3 H) ppm. C NMR (100 MHz,
C’s), 26.7, 25.4, 24.9, 22.7, 14.1 ppm. FT-IR (film of a concentrated CDCl ): δ = 173.5, 109.7, 73.6, 66.3, 64.4, 34.0, 31.9, 29.7–29.1
solution in CH Cl ): ν˜ = 2924, 2853, 1745, 1465, 1371, 1260, 1087, (many unresolved C’s), 26.6, 25.3, 24.8, 22.6, 14.0 ppm. FT-IR
01 cm . All attempts to acquire mass spectra for this compound (film of a concentrated solution in CH Cl ): ν˜ = 2916, 2848, 1741,
1473, 1261, 1089, 799 cm . ESI-MS: m/z = 547.6 [M + Na] . ESI-
HRMS: calcd. for C33
Na [M + Na]+ 547.46968; found
47.47035.
3
2
2
–1
8
2
2
–
1
+
failed.
64 4
H O
Hydrogenation of 29 To Give 30: A mixture of 29 (26 mg,
5
0.04 mmol) and Pd black (5 mg) in EtOAc (2 mL) was stirred at
Removal of the Acetonide in 32 To Give (S)-2: The same procedure
for the conversion of 30 to (S)-3 given above was used, and gave
ambient temperature under H (1 atm) for 2 d. The solids were fil-
2
tered off. The filtrate was concentrated on a rotary evaporator. The
residue was purified by chromatography (10:1, PE/EtOAc) on silica
gel to give 30 (27 mg, 0.05 mmol, 98%) as a white solid, m.p. 69–
(
S)-2 (17 mg, 0.03 mmol, 91%) after chromatography (2:1, PE/
[1a]
23
EtOAc) on silica gel, m.p. 65–66 °C (ref. 64–65 °C). [α]
(c = 0.20, pyridine) {ref.
[α] = +11.4 (c = 0.20, DMSO). ee = 96% as determined by chiral
D
D
= +7.8
[1a]
26
1 °C. [α]2
7
1
[α] = +7.5 (c = 0.20, pyridine)};
7
D
= –0.7 (c = 2.00, CHCl
3
). H NMR (400 MHz, CDCl
3
):
D
2
9
δ = 4.31 (quint, J = 5.9 Hz, 1 H), 4.16 (dd, J = 11.6, 4.6 Hz, 1 H),
HPLC analysis of the compound 24 derived from (S)-2 by the four-
4
7
1
.12–4.03 (m, 2 H), 3.73 (dd, J = 8.3, 6.4 Hz, 1 H), 2.34 (t, J =
1
step sequence described in the text. H NMR (400 MHz, CDCl
3
):
.6 Hz, 2 H), 1.65–1.58 (m, 2 H), 1.43 (s, 3 H), 1.37 (s, 3 H), 1.40–
.20 (m, 54 H), 0.88 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
δ = 4.24–4.11 (m, 2 H), 3.98–3.89 (m, 1 H), 3.70 (dd, J = 11.3,
.6 Hz, 1 H), 3.60 (dd, J = 11.7, 5.8 Hz, 1 H), 2.36 (t, J = 7.1 Hz,
H), 1.70–1.59 (m, 2 H), 1.40–1.20 (m, 46 H), 0.87 (t, J = 6.2 Hz,
3
H) ppm. C NMR (100 MHz, CDCl ): δ = 174.4, 70.3, 65.1,
3
2
3
CDCl
3
): δ = 173.6, 109.8, 73.7, 66.4, 64.5, 34.1, 31.9, 29.7–29.1
many unresolved C’s), 26.7, 25.4, 24.9, 22.7, 14.1 ppm. FT-IR
film of a concentrated solution in CH Cl ): ν˜ = 2917, 2849, 1740,
463, 1261, 1095, 760 cm . All attempts to acquire mass spectra
(
(
1
1
3
2
2
–1
63.3, 34.1, 31.9, 29.7–29.1 (many unresolved C’s), 24.9, 22.6,
1
1
4.1 ppm. FT-IR (film): ν˜ = 3332, 2917, 2848, 1735, 1461, 1257,
for this compound failed.
–
1
+
052, 799 cm . ESI-MS: m/z = 507.7 [M + Na] . ESI-HRMS
Removal of the Acetonide in 30 To Give (S)-3: Acetonide 30 (20 mg,
Na [M + Na]+ 507.43838; found 507.43759.
60 4
calcd. for C30H O
2
0.03 mmol) was dissolved in AcOH/H O (4:1, v/v; 2.5 mL). The
Conversion of the 1(3)-Acyl-sn-Glycerol Into 24 (Representative Pro-
cedure, with 23 as the Substrate) and Chiral HPLC Analysis for
the ee Values: A solution of 23 (30 mg, 0.16 mmol) and pTsOH
solvent was taken from a stock solution that had been pre-warmed
to 65 °C in another bath for Ͼ30 min to more precisely control the
hydrolysis time at 65 °C. The mixture was stirred at 65 °C (bath)
(
monohydrate, 0.5 mg) in acetone (2 mL) was stirred at ambient
for 8 min. The heating bath was removed, and NaHCO
aq.; 5 mL) was added. The mixture was extracted with EtOAc (3ϫ
0 mL). The combined organic extracts were washed with brine,
and dried with anhydrous Na SO . Removal of the solvent on a
3
(saturated
temperature for 6 h. Na HCO (saturated aq.; 5 mL) was added.
2
3
The mixture was extracted with EtOAc (3ϫ 10 mL). The combined
1
organic extracts were washed with brine (10 mL), and dried with
2
4
anhydrous Na
2
SO
4
. The solvent was removed on a rotary evapora-
O (10:1,
rotary evaporator and chromatography (2:1, PE/EtOAc) on silica
gel gave diol 3 (17 mg, 0.03 mmol, 91%) as a white solid, m.p. 65–
tor. The residue (a colorless oil) was dissolved in THF/H
2
[
3a]
28
[3a]
v/v; 2.2 mL) containing LiOH (10 mg, 0.25 mmol). The mixture
was stirred at ambient temperature for 12 h. Water (5 mL) was
added. The mixture was extracted with EtOAc (3ϫ 10 mL). The
combined organic extracts were washed with brine (10 mL), and
6
6 °C (ref. 64–66 °C). [α]
D
= +6.3 (c = 0.25, CH
2
Cl
= +13.4 (c = 0.25, DMSO). ee
93%, as determined by chiral HPLC analysis of the compound
2
) {ref. [α]
2
0
29
D
2 2 D
= +6.2 (c = 0.25, CH Cl )}; [α]
=
24 prepared from (S)-3 by the four-step sequence described in this
1
dried with anhydrous Na
dissolved in dry DMF (2 mL). NaH (60% in mineral oil; 10 mg,
.4 mmol) was then added. The yellowish mixture was stirred in
2 4
SO . The residue (a colorless oil) was
work. H NMR (400 MHz, CDCl
1
3
): δ = 4.22 (dd, J = 11.8, 4.8 Hz,
H), 4.15 (dd, J = 11.5, 6.0 Hz, 1 H), 3.97–3.90 (m, 1 H), 3.70
0
(
(
dd, J = 11.5, 4.0 Hz, 1 H), 3.60 (dd, J = 11.6, 5.7 Hz, 1 H), 2.45
br. s, 1 H), 2.35 (t, J = 7.6 Hz, 2 H), 1.70–1.52 (m, 2 H), 1.40–
an ice-water bath for 40 min. BnBr (20 μL, 0.18 mmol) was added
.20 (m, 54 H), 0.87 (t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
dropwise. The mixture was stirred at ambient temperature for 2 h.
NH Cl (saturated aq.; 5 mL) was added, followed by water (5 mL).
4
The mixture was extracted with EtOAc (3ϫ 10 mL). The combined
1
CDCl
unresolved C’s), 24.9, 22.7, 14.1 ppm. FT-IR (film of a concen-
trated solution in CH Cl ): ν˜ = 3307, 2918, 2849, 1736, 1463, 1256,
108, 799 cm . ESI-MS: m/z = 563.9 [M + Na] . ESI-HRMS:
3
): δ = 174.4, 70.3, 65.1, 63.3, 34.1, 31.9, 29.7–29.1 (many
organic extracts were washed with brine (10 mL), and dried with
2
2
–1
+
anhydrous Na
tor. The yellowish oily residue was dissolved in AcOH/H
v/v; 2.5 mL) and the mixture was stirred at 50 °C for 2 h. Water
Condensation of Alcohol (R)-20 with Heptacosanoic Acid (31) To (5 mL) was added, followed by NaHCO (saturated aq.; 5 mL). The
2
SO
4
. The solvent was removed on a rotary evapora-
1
+
2
O (4:1,
68 4
calcd. for C34H O Na [M + Na] 563.50098; found 563.49871.
3
Give Ester 32: A mixture of (R)-20 [l-(+)-1,2-Isopropylidenegly-
cerol; 32 mg, 0.24 mmol], heptacosanoic acid (31; 100 mg,
mixture was extracted with EtOAc (3ϫ 10 mL). The combined or-
ganic extracts were washed with brine (10 mL) and dried with an-
2 4
0.24 mmol), EDCI (50 mg, 0.26 mmol), and DMAP (20 mg, hydrous Na SO . Removal of the solvent on a rotary evaporator
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30247
/KAP1
Date: 18-05-13 12:27:29
Pages: 9
Optically Active Monoacylglycerols
and column chromatography (2:1, PE/EtOAc) on silica gel gave 24
Chem. 2006, 71, 629–635; h) R. J. Kubiak, K. S. Bruzik, J. Org.
1
Chem. 2003, 68, 960–968; i) M.-L. Alcaraz, L. Peng, P. Klotz,
M. Goeldner, J. Org. Chem. 1996, 61, 192–201; j) E. Vaique, A.
Guy, L. Couedelo, I. Gosse, T. Durand, M. Cansell, S. Pinet,
Tetrahedron 2010, 66, 8872; k) P. R. Redden, X. Lin, D. F. Hor-
robin, Chem. Phys. Lipids 1996, 79, 9–19.
(26 mg, 0.15 mmol, 91% overall from 23) as a colorless oil.
H
NMR (400 MHz, CDCl ): δ = 7.39–7.27 (m, 5 H), 4.54 (s, 2 H),
3
3.93–3.84 (m, 1 H), 3.68 (dd, J = 11.4, 3.6 Hz, 1 H), 3.60 (dd, J =
1
1.4, 5.6 Hz, 1 H), 3.57–3.49 (m, 2 H), 2.78 (br. s, 2 H) ppm. ESI-
+
MS m/z = 205.1 [M + Na] . The optical rotation and ee values
depended on the source of the starting 1(3)-acyl-sn-glycerol.
[
3] a) A. T. Nyongha, H. Hussain, E. Dongo, I. Ahmed, K.
Krohn, Nat. Prod. Commun. 2010, 5, 1939–1940; b) our re-
peated efforts, either direct or via the journal editor/colleagues
in their institution, to contact the authors of ref 3a were unsuc-
cessful.
4] O.-Y. Jeon, E. M. Carreira, Org. Lett. 2010, 12, 1772–1775.
5] a) N. Ikemoto, S. L. Schreiber, J. Am. Chem. Soc. 1992, 114,
The ee values of the samples of 24 prepared using the above pro-
cedure were measured by chiral HPLC on a CHIRALPAK AD-H
column (0.46 ϫ 25 cm, particle size 5 μm) eluting with 95:5 n-hex-
ane/iPrOH at a flow rate of 0.7 mL/min with the detector set to
[
[
214 nm.
2
524–2536; b) D. Crich, O. Vinogradova, J. Org. Chem. 2007,
72, 3581–3584.
Supporting Information (see footnote on the first page of this arti-
1
13
[6] That the doublet at δ ≈ 3.8 ppm stems from the -CH
2
- units in
cle): Copies of the H and C NMR spectra, chiral HPLC traces
for 24, tabular data comparison for natural and synthetic 2 and 3,
detailed information about the unsuccessful routes to 3 and related
experimental procedures.
2
-acyl-sn-glycerol was first shown by Haraldsson et al.: G. G.
˝
˝
Haraldsson, B. O. Gudmundsson, O. Almarsson, Tetrahedron
995, 51, 941–952.
1
[
7] It is interesting to note that although the acyl migration prob-
lem has been discussed, in: many papers on the synthesis of
monoacylglycerols, ref.[ was never cited. Also, the doublet at δ
6]
Acknowledgments
1
≈
3.8 ppm was neither mentioned nor included in the H NMR
spectroscopic data listings, although in the scanned spectra in
the Supporting Information of a few recent publications, this
doublet was apparently present. See, for example: a) R. J. Kub-
iak, K. S. Bruzik, J. Org. Chem. 2003, 68, 960–968; b) H. Naka-
mura, N. Ueda, H. S. Ban, M. Ueno, S. Tachikawa, Org. Bi-
omol. Chem. 2012, 10, 1374–1380; c) Z. Li, D. L. Baker, G.
Tigyi, R. Bittman, J. Org. Chem. 2006, 71, 629–635. The mul-
tiplet at δ ≈ 3.9 ppm (the C-2 methine group of 2-acyl-sn-glyc-
erols) may be partially overlapping with the olefinic protons for
C=C double-bond(s)-containing 1(or 3)-acyl-sn-glycerols, and
hence not so useful/sensitive as the doublet at δ ≈ 3.8 ppm in
the detection of 2-acyl-sn-glycerols.
This work was supported by the National Basic Research Program
of China (973 Program, grant number 2010CB833200), the
National Natural Science Foundation of China (NSFC) (grant
numbers 21172247, 21032002, 20921091, 20621062) and the Chi-
nese Academy of Sciences.
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Received: February 16, 2013
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Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
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