Synthesis and absolute configuration of hylodiglyceride isolated from Hylodendron gabunensis

Article abstract of DOI:10.1016/j.tet.2013.11.021

A recently isolated bismonoglyceride of heptadecanedioic acid, which represents a novel type of natural monoglycerides (i.e., with two instead of only one glycerol unit in the molecular architecture), was synthesized in enantiopure forms using a chiral-pool based approach with the 17-carbon chain constructed from undec-10-enoic acid and oct-7-en-1-ol via a cross metathesis and the stereogenic centers derived from (R)-(2,2-dimethyl-1,3-dioxolan-4-yl) methanol. An analogue with a longer alkyl chain was also synthesized. The synthetic samples not only allowed for establishment of the absolute configuration but also helped to reveal some minor yet unignorable errors in the ¹H NMR data for the natural product. Optical rotation and NMR data acquired in DMSO and DMSO-d₆, respectively, are also presented.

Full text of DOI:10.1016/j.tet.2013.11.021

Tetrahedron 70 (2014) 92e96
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and absolute configuration of hylodiglyceride isolated
from Hylodendron gabunensis
,
,
a,
Wen-Ju Wu a b, Hui-Jun Chen b, Yikang Wu b , Bo Liu
*
*
a Key Laboratory of Green Chemical Technology of College of Heilongjiang Province, School of Chemistry and Environmental Engineering, Harbin
University of Science and Technology, Harbin 150040, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A recently isolated bismonoglyceride of heptadecanedioic acid, which represents a novel type of natural
monoglycerides (i.e., with two instead of only one glycerol unit in the molecular architecture), was
synthesized in enantiopure forms using a chiral-pool based approach with the 17-carbon chain con-
structed from undec-10-enoic acid and oct-7-en-1-ol via a cross metathesis and the stereogenic centers
derived from (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol. An analogue with a longer alkyl chain was
also synthesized. The synthetic samples not only allowed for establishment of the absolute configuration
but also helped to reveal some minor yet unignorable errors in the 1H NMR data for the natural product.
Optical rotation and NMR data acquired in DMSO and DMSO-d6, respectively, are also presented.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 18 September 2013
Received in revised form 31 October 2013
Accepted 7 November 2013
Available online 15 November 2013
Keywords:
Ester
Glyceride
Natural product
Stereochemistry
Lipids
1. Introduction
OH
3'
O
1'
1'
M.p. 64-66 °C
O
Natural
1 (or 3)-acyl-sn-glycerols comprise an important
22
O
OH
[α]D20 +6.2 (c 0.25, CH2Cl2)
family of lipids.1,2 They are also essential precursors to the related
di- and triglycerides. The glycerol residue in 1 (or 3)-acyl-sn-
glycerols is structurally asymmetric and thus may be of either (R)
or (S) configuration. Although such species are unpretentious
compared with most other natural products, the tough (though
hidden to most investigators who are not familiar with this area)
problems unavoidable in their synthesis and handling as well as
analysis caused by the unbelievably facile acyl group migra-
tions,2a,3 along with their biological significance, make these
seemingly rather simple molecules worthy/challenging targets of
study.
1
OH
O
OH
3'
1
O
O
M.p. 87 °C
[α]D20 +10.2 (c 0.20, CH2Cl2)
OH
OH
11
2
Fig. 1. The planar structures given in the literature for the natural hyloglyceride (1)
and hylodiglyceride (2).
2. Results and discussion
Recently, in their investigations of medical plants from Africa,
Nyongha et al.4 isolated and characterized two previously un-
known glycerides (1 and 2, Fig. 1), one of which (1) represents the
longest alkyl chain in the natural monoglycerides so far known,
while the other (2) illustrates a novel (or at least rare)5 subtype of
natural monoglycerides that contain two (rather than only one)
glycerol residue.6 Herein we wish to report on the synthesis and
configuration of 2.
We reasoned that because compound 2 is optically active, it
must have a C2 axis rather than a
s plane (a plane of symmetry).
Consequently, the two stereogenic centers must have the same
absolute configuration. Considering that the 1 and 2 have the same
biogenic origin, we presumed that the glycerol residues in 1 and 2
share the same absolute configuration, which has been proven3 to
be (S) for 1. On the basis of these assumptions, we decided to target
our synthesis at (S,S)-2.
The required bifunctional 17-carbon linear chain was assembled
(Scheme 1) from oct-7-en-1-ol (3) and methyl undec-10-enoicate
* Corresponding authors. E-mail address: yikangwu@sioc.ac.cn (Y. Wu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.021

W.-J. Wu et al. / Tetrahedron 70 (2014) 92e96
93
minimizing any possible acyl group migrations). Thus, the bis-
acetonide 11 was treated with AcOHeH2O (4:1) at 50 ꢀC for
25 min, when TLC showed disappearance of 11 with substantial
amounts of the intermediate monoacetonide 20 still present, the
mixture was quenched and worked up. After column chromatog-
raphy, rather pure (S,S)-2 was obtained, which showed an optical
rotation in good consistence with that for the natural 2, confirming
that the latter must be of (S,S) configuration. The 1H and 13C NMR
for the synthetic 2 were also in excellent consistence with those
reported for the natural 2, except that the exocyclic alkoxy CH2 in
MeO2C
HO
(E)&(Z)
MesN
NMes
Ru
5
3
5/CH2Cl2
Cl
Cl
MeO2C
rt/24 h
51%
Ph
PCy3
5
HO
4
7
6
(R)
O
HO
9
(E)&(Z)
CO2H
O
MeO2C
PDC/DMF 78%
rt/5 h
the glycerol residues appears at
d
4.15 and 4.20 ppm in 1H NMR
4
instead of 4.37 and 4.40 ppm as reported4 for the natural 2.
Then we recalled that very similar discrepancies were also ob-
served between the natural and synthetic 1 in our previous work,3
where the confusion was eventually cleared by the data for a closely
related natural analogue as well as its synthetic counterpart.
Therefore, we decided to synthesize 12, a readily accessible ana-
logue of 2 (with three additional CH2 units in the long chain) to see
if the exocyclic alkoxy CH2 show similar chemical shifts in 1H NMR.
Following the route shown in Scheme 2, the known 133 was
treated with Grubbs II catalyst (5) to afford the self-coupling
product 14 as a mixture of (E) and (Z) isomers. The CeC double
bond was then saturated by hydrogenation. The resulting 15, a close
analogue of 11, was then subjected to the mild hydrolysis condi-
tions (AcOHeH2O/50 ꢀC/25 min) to give 12 along with the in-
termediate monoacetonide 120.
6
7
CO2H
9/EDCI/DMAP
CH2Cl2
rt/5 h
LiOH/THF
rt/35 h
85%
90%
3
CO2H
8
7
O
O
O
O
O
(E)&(Z)
O
(S)
(S)
(S)
O
O
O
O
O
(E)&(Z)
H2/Pd-C
EtOAc
O
10
rt/3 h
4
6
O
O
100%
11
(S)
O
OH
O
11
(S)
(S,S)-2'
57%
(S)
O
O
5/CH2Cl2
O
O
HO
O
(S)
55%
13
OH
rt/24 h
AcOH-H2O
O
O
O
13
O
(S)
HO
HO
O
50 °C/25 min
(S)
O
O
HO
O
O
O
O
13
(S)
(S,S)-2
38%
O
O
M.p. 86-87 °C
O
O
O
O
(S)
H2/Pd-C
EtOAc
(S)
[α]D20 +11.2 (c 0.20, CH2Cl2)
O
O
O
O
(E)&(Z)
rt/3 h
Scheme 1.
O
90%
14
7
6
O
O
14
(4) using a cross metathesis catalyzed by Grubbs II catalyst (5). The
cross coupling product could be readily separated from the two
self-coupling products because of the (carefully chosen) distinct
differences in the functional groups.7 It is noteworthy that treat-
ment8 of the reaction mixture with 30% H2O2 made it easier to
remove the last traces of colored (Ru containing) impurities from
the product 6, but the oxidative workup also generated new com-
ponents; chromatography became more tedious than otherwise.
The newly-formed CeC double bond was a mixture of (E) and (Z)
isomers as expected. Although it was somewhat annoying to see
the ‘extra’ signals 13C NMR caused by the co-existence of two iso-
mers, we decided to keep the double bond for a few more steps to
avoid any possible sluggish reactions (caused by a long alkyl chain),
which might occur according to our experience on similar lipid
related compounds.
The alcohol 6 was then oxidized with PDC (pyridium di-
chromate), giving the corresponding acid 7 in 78% yield. The methyl
ester at the other terminal of the long chain was hydrolyzed to
deliver diacid 8, which was condensed with the commercially
available 9 to afford bis-ester 10 with the aid of EDCI (N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide) and DMAP (4-
(dimethylamino)-pyridine).
(S)
OH
O
12'
15
(S)
(S)
O
O
53%
O
O
HO
16
O
O
OH
AcOH-H2O
(S)
HO
HO
50 °C/25 min
(S)
O
O
HO
12
16
O
O
28%
Scheme 2.
As expected from our previous experience with 1, the 1H NMR
for 12 indeed looked almost the same as that for the synthetic 2,
except the six additional protons for the extra non-functionalized
CH2’s in the 1.38e1.16 ppm region; the exocyclic alkoxy CH2 un-
der concern appeared at
d 4.15 and 4.21 ppm, unambiguously
confirming that the data for the synthetic 2 indeed objectively re-
flected the depicted structure, whereas those in the literature did
not (some errors must have occurred therein).
The CeC double bond in 10 was then saturated by atmospheric
hydrogenation over 10% PdeC, affording 11 as a single species in
essentially quantitative yield.
As the main purpose of this work was to establish the absolute
configuration of the natural 2, we opted to stop the reaction at an
early stage to secure the optical purity of the hydrolysis product (by
It is also worth of mentioning that the solubility for 2 is rather
poor in CH2Cl2 and somewhat better in DMSO (dimethyl-sulfoxide),
so that it is impossible to acquire a solution of 2 in either solvent
with the concentration higher than c¼0.2 (g/100 mL). The solubility
for 12 is even worse.9 However, DMSO remained to be a much more
suitable solvent for measuring the optical rotations than CH2Cl2 or

94
W.-J. Wu et al. / Tetrahedron 70 (2014) 92e96
CHCl3 as previously observed3 with other monoglycerides, because
of the smaller data errors (more stable readings) and substantially
larger absolute values for the optical rotations.
(m, 4H), 1.42e1.18 (m, 16H) ppm. 13C NMR (100 MHz, CDCl3):
d¼174.4, 130.5e130.0 (several not so well resolved lines), 62.8, 51.4,
34.0, 32.6, 32.51, 32.47, 32.4, 32.2, 32.1, 29.6e28.6 (several not so
well resolved lines), 27.1, 25.63, 25.58, 25.5, 25.2, 24.8 ppm. FT-IR
3. Conclusion
(film):
n
¼3466 (br), 2926, 2854, 1741, 1460, 1437, 1199, 1172,
968 cmꢂ1. ESI-MS m/z 299.4 ([MþH]þ). ESI-HRMS calcd for
The recently isolated hylodiglyceride (2), a unique natural
monoglyceride that contains two (instead of only one as in all
previously known cases) glycerol subunits in the molecular struc-
ture, was synthesized in an enantiopure form through a chiral-pool
based route. The presence of an extra glycerol subunit made the
acyl migrations (a serious, though hidden, problem common to
monoglycerides) even more facile than observed with simple
monoacylglycerols. By careful control of the reaction time (before
acyl migrations occurred to any discernible extents) for the hy-
drolysis of the acetonide protecting groups under the previously
established optimal conditions, the desired bis-monoglycerides
was eventually obtained. The data acquired on the synthetic sam-
ples not only allowed for reliable assignment of the absolute con-
figuration, but also helped to reveal some minor yet unignorable
errors in the 1H NMR data previously reported for the natural
product. Optical rotation and NMR data for 2 in DMSO and DMSO-
d6, respectively, were also recorded, which may serve as more
convenient/reliable references compared with their counterparts
measured in CH2Cl2 (for optical rotation) or CDCl3 (for NMR).
C
18H34O3Na ([MþNa]þ): 321.2400, found 321.2395.
4.3. Oxidation of alcohol 6 to afford acid 7
PDC (472 mg, 1.25 mmol) was added slowly to a solution of al-
cohol 6 (249 mg, 0.84 mmol) in dry DMF (1.0 mL) stirred in an ice-
water bath. After completion of the addition, the mixture was
stirred at the same temperature for 10 min. The cooling bath was
removed. Stirring was continued at ambient temperature for 5 h.
When TLC showed disappearance of 6, Et2O was added, followed by
H2O. The phases were separated. The aq layer was extracted with
Et2O (50 mLꢁ4). The combined organic layers were washed with
H2O (several times, to remove DMF as much as possible) and brine
before concentrated on a rotary evaporator. The residue was passed
through a short pad of silica gel eluting with Et2O. The effluent was
concentrated to left a residue, which was chromatographed (5:1
PE/EtOAc) on silica gel to give acid 7 as a yellowish oil (204 mg,
0.65 mmol, 78% from 6). 1H NMR (400 MHz, CDCl3):
(m, 2H), 3.65 (s, 3H), 2.33 (t, J¼7.5 Hz, 2H), 2.29 (t, J¼7.5 Hz, 2H),
2.10e1.84 (m, 4H), 1.70e1.50 (m, 4H), 1.42e1.18 (m, 14H) ppm. 13
NMR (100 MHz, CDCl3): 179.8, 174.4, 130.9e129.5 (several not so
well resolved lines), 51.4, 34.1, 33.9, 33.8, 33.2, 32.5, 32.4, 32.3, 32.1,
31.7, 29.6e28.5 (several not so well resoled lines), 24.9, 24.53,
d¼5.44e5.28
C
4. Experimental
4.1. General
d
24.49, 24.4, 24.1 ppm. FT-IR (film):
n
¼3650e2400 (a huge lump),
The 1H and 13C NMR spectra were recorded on an Agilent 500/54
NMR spectrometer (operating at 500 MHz for 1H) or a Bruker
AvanceIII 400 (operating at 400 MHz for 1H) as specified in each
individual case below. For spectra recorded in CDCl3, the solvent
residue was set to 7.26 ppm in 1H NMR, while the middle line of
CDCl3 was set to 77.00 ppm in 13C NMR, respectively, as the internal
reference unless otherwise stated. The IR spectra were measured on
a Nicolet 380 Infrared spectrophotometer. ESI-MS data were ac-
quired on a Shimadzu LCMS-2010EV mass spectrometer. HRMS
data were obtained with a Bruker APEXIII 7.0 Tesla FT-MS spec-
trometer. Optical rotations were measured on a Jasco P-1030 po-
larimeter. Melting points were uncorrected (measured on a hot
stage melting point apparatus equipped with a microscope). CH2Cl2
2925, 2854, 1741, 1711, 1459, 1437, 1172 cmꢂ1. ESI-MS m/z 311.8
(Me). ESI-HRMS calcd for C18H31O4 (Me): 311.2228, found 311.2233.
4.4. Hydrolysis of 7 to give diacid 8
A solution of 7 (204 mg, 0.65 mmol) and LiOH (monohydrate,
58 mg, 1.38 mmol) in THF (4 mL) and H2O (0.5 mL) was stirred at
ambient temperature for 36 h, when TLC showed completion of the
reaction. The reaction mixture was acidified with 1 N HCl to ca. pH 5
before being extracted with EtOAc, washed with H2O and brine, and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (2:1 PE/EtOAc) on silica
gel afforded diacid 8 as a white solid (160 mg, 0.54 mmol, 85%). Mp
83e84 ꢀC. 1H NMR (500 MHz, CDCl3):
J¼7.5 Hz, 4H), 2.06e1.88 (m, 4H), 1.63 (br quint, J¼6.8 Hz, 4H),
1.44e1.14 (m, 14H) ppm. 13C NMR (125 MHz, CDCl3):
131.0e129.5 (several not so well resolved lines), 34.10, 34.06, 33.96,
32.53, 32.51, 32.46, 32.28, 32.25, 32.1, 29.6e28.4 (several not so well
resolved lines), 27.2, 26.9, 24.6, 24.5, 24.1 ppm. FT-IR (film of a so-
d¼5.42e5.32 (m, 2H), 2.34 (t,
ꢀ
was dried with activated 4 A MS (molecular sieves). All chemicals
were reagent grade and used as purchased. Column chromatogra-
phy was performed on silica gel (300e400 mesh) under slightly
positive pressure. PE¼petroleum ether (chromatography solvent,
bp 60e90 ꢀC).
d
¼180.5,
4.2. Cross metathesis reaction of 3 and 4 leading to 6
lution in CH2Cl2):
n
¼3630e2200 (a huge lump), 2926, 2853, 1708,
1410, 1287, 1234, 967, 929 cmꢂ1. ESI-MS m/z 297.4 (Me). ESI-HRMS
A suspension of 3 (200 mg, 1.56 mmol), 4 (890 mg, 4.49 mmol),
and Grubbs II catalyst 5 (89 mg, 0.11 mmol) in dry CH2Cl2 (4 mL)
was stirred at ambient temperature under argon for 24 h (initially
purple and gradually turned to dark brown with time). When TLC
showed complete disappearance of 3, aq H2O2 (30%, 3 mL) was
added slowly to the mixture (gas bubbles evolved) with cooling in
an ice-water bath. After stirring at ambient temperature for 2 h, the
almost black mixture was partition between H2O (10 mL) and
EtOAc (50 mL). The aq layer was extracted with EtOAc (50 mLꢁ3).
The combined organic layers were washed with brine (10 mL) and
dried over anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (10:1 PE/EtOAc) on silica
calcd for C17H29O4 (Me): 297.2071, found 297.2070.
4.5. Condensation of diacid 8 with alcohol 9 to give bis-ester 10
To a solution of diacid 8 (35 mg, 0.12 mmol) in dry CH2Cl2 (1 mL)
stirred in an ice-water bath were added in turn alcohol 9 (31 mg,
0.24 mmol), DMAP (2 mg, 0.016 mmol), and EDCI (60 mg,
0.31 mmol). After completion of the addition, the mixture was
stirred at the same temperature for 30 min. The cooling bath was
removed. Stirring was continued at ambient temperature for 5 h.
When TLC showed completion of the reaction, the mixture was
concentrated on a rotary evaporator. The residue was chromato-
gel gave 6 as a colorless oil (235 mg, 0.79 mmol, 51% from 3). 1
NMR (400 MHz, CDCl3):
¼5.42e5.29 (m, 2H), 3.65 (s, 3H), 3.61 (t,
J¼6.9 Hz, 2H), 2.28 (t, J¼7.5 Hz, 2H), 2.06e1.84 (m, 5H), 1.66e1.48
H
graphed (10:1 PE/EtOAc) on silica gel to give bis-ester 10 as a col-
orless oil (55 mg, 0.10 mmol, 90%). [
NMR (500 MHz, CDCl3):
30
d
a
]
D
þ1.3 (c 1.00, CHCl3). 1H
d
¼5.43e5.27 (m, 2H), 4.29 (br quint,

W.-J. Wu et al. / Tetrahedron 70 (2014) 92e96
95
J¼5.8 Hz, 2H), 4.14 (dd, J¼11.7, 4.8 Hz, 2H), 4.07 (dd, J¼17.1, 5.6 Hz,
2H), 4.06 (dd, J¼7.5, 2.8 Hz, 2H), 3.72 (dd, J¼8.3, 6.4 Hz, 2H), 2.32 (t,
J¼7.3 Hz, 4H), 2.10e1.86 (m, 4H), 1.75e1.50 (m, 4H), 1.41 (s, 6H), 1.35
(s, 6H), 1.34e1.20 (m, 14H) ppm. 13C NMR (125 MHz, CDCl3):
(film of a solution in CH2Cl2):
n
¼3253 (br), 2916, 2849, 1733, 1178,
1108, 1052 cmꢂ1. ESI-MS m/z 471.6 ([MþNa]þ). ESI-HRMS calcd for
C
23H44O8Na ([MþNa]þ): 471.29284, found 471.2927.
d
¼173.5, 131.6e129.5 (several not so well resolved lines), 109.7,
4.8. Self-coupling of 13 to afford 14
73.6, 66.3, 64.5, 34.04, 34.01, 33.90, 33.3, 32.50, 32.47, 32.4, 32.3,
32.1, 29.6e28.5 (several not so well resolved lines), 26.6, 25.3, 24.8,
A (purple) suspension of 13 (315 mg, 1.06 mmol) and catalyst 5
(45 mg, 0.05 mmol) in dry CH2Cl2 (4 mL) was stirred at ambient
temperature under argon for 24 h. Aq H2O2 (30%, 2 mL) was added
slowly to the dark brown mixture (gas bubbles evolved). After
stirring at ambient temperature for 2 h, the further darked mixture
was partition between H2O (10 mL) and EtOAc (50 mL). The aq layer
was extracted with EtOAc (50 mLꢁ3). The combined organic layers
were washed with brine (10 mL) and dried over anhydrous Na2SO4.
Removal of the solvent by rotary evaporation and column chro-
matography (2:1 PE/EtOAc) on silica gel gave a mixture of (E)- and
24.7, 24.3 ppm. FT-IR (film):
n
¼2986, 2926, 2855, 1748, 1456, 1380,
1371, 1215, 1161, 1057, 972, 842 cmꢂ1. ESI-MS m/z 549.6 ([MþNa]þ).
ESI-HRMS calcd for C29H50O8Na ([MþNa]þ): 549.3398, found
549.3411.
4.6. Hydrogenation of 10 to give 11
A mixture of 10 (126 mg, 0.24 mmol) and 10% PdeC (60 mg,
washed with water, EtOH and EtOAc before use) in EtOAc (2.5 mL)
was stirred under H2 (1 atm) at ambient temperature for 3 h, when
TLC showed completion of the reaction (no yellow spot could be
seen on the TLC plate when visualizing with KMnO4). The solids
were filtered off. The filtrate was concentrated by rotary evapora-
tion to afford 11 as a white waxy solid (130 mg, 0.25 mmol, 100%).
(Z) isomers of 14 as a colorless oil (in a fridge it became an off-white
28
wax, which melt at round 28 ꢀC, 165 mg, 0.29 mmol, 55%). [
a]
D
þ1.0 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3)
¼5.40e5.28 (m,
d
2H), 4.28 (br quint, J¼5.8 Hz, 2H), 4.13 (dd, J¼11.7, 4.9 Hz, 2H),
4.09e4.01 (m, 4H), 3.71 (dd, J¼8.3, 6.1 Hz, 2H), 2.31 (t, J¼7.6 Hz, 4H),
2.04e1.82 (m, 4H), 1.59 (br quint, J¼6.9 Hz, 4H), 1.40 (s, 6H), 1.34 (s,
Mp 51e52 ꢀC. [
a
]
D
30 þ1.1 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3):
d¼4.28 (br quint, J¼5.8 Hz, 2H), 4.13 (dd, J¼11.5, 4.7 Hz, 2H), 4.06
6H), 1.32e1.18 (m, 20H) ppm. 13C NMR (100 MHz, CDCl3)
d
¼173.5,
(dd, J¼15.1, 6.6 Hz, 2H), 4.05 (dd, J¼5.8, 4.3 Hz, 2H), 3.71 (dd, J¼8.7,
6.4 Hz, 2H), 2.31 (t, J¼7.5 Hz, 4H), 1.59 (br, quint, J¼7.1 Hz, 4H), 1.40
(s, 6H), 1.34 (s, 6H), 1.31e1.15 (m, 22H) ppm. 13C NMR (125 MHz,
130.3, 130.24, 130.17, 129.8, 109.7, 73.6, 66.3, 64.4, 34.0, 32.5, 29.63,
29.58, 29.50, 29.4, 29.25, 29.20, 29.1, 29.0, 28.97, 28.90, 28.8, 27.1,
26.6, 25.3, 24.8 ppm. FT-IR (film of a concd. solution in CH2Cl2):
CDCl3):
d
¼173.6, 109.7, 73.6, 66.3, 64.4, 34.0, 29.6, 29.54, 29.52,
n
¼2986, 2928, 2854, 1743, 1381, 1372, 1219, 1159, 1087, 1056, 841,
29.49, 29.4, 29.1, 29.0, 26.6, 25.3, 24.8 ppm. FT-IR (film of a solution
772 cmꢂ1. ESI-MS m/z 591.9 ([MþNa]þ). ESI-HRMS calcd for
in CH2Cl2):
n
¼2926, 2854, 1741, 1458, 1371, 1260, 1160, 1089,
C
32H56O8Na ([MþNa]þ): 551.38674, found 591.38773.
800 cmꢂ1. ESI-MS m/z 551.8 ([MþNa]þ). ESI-HRMS calcd for
C
29H52O8Na ([MþNa]þ): 551.35544, found 551.3566.
4.9. Hydrogenation of 14 to give 15
4.7. Hydrolysis of the acetonide in 11 to afford (S,S)-2 and
(S,S)-20
A mixture of 14 (140 mg, 0.25 mmol) and 10% PdeC (60 mg,
washed with water, EtOH and EtOAc before use) in EtOAc (2.5 mL)
was stirred under H2 (1 atm) at ambient temperature for 3 h, when
TLC showed completion of the reaction (no more yellow spot could
be seen on the TLC plate when visualizing with KMnO4). The solids
were filtered off. The filtrate was concentrated by rotary evapora-
A solution of 11 (130 mg, 0.25 mmol) in HOAceH2O (4:1, v/v,
2.5 mL) was stirred at 50 ꢀC for 25 min (when TLC showed disap-
pearance of 11). The heating bath was removed. H2O (10 mL) was
added to the reaction mixture. Powdered solid NaHCO3 (ca. 3.0 g)
was added very slowly to neutralize the HOAc. The mixture was
extracted with EtOAc (30 mLꢁ3), washed with brine and dried over
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
left a residue, which was chromatographed on silica to give (S,S)-20
(the less polar component, a white solid, eluting with 1:2 PE/EtOAc,
70 mg, 0.14 mmol, 57% from 11) and (S,S)-2 (the more polar com-
ponent, a white solid, eluting with 8:1 CH2Cl2/MeOH, 42 mg,
tion to afford 15 as a white wax (128 mg, 0.22 mmol, 90%). Mp
28
54e55 ꢀC. [
d
a
]
D
þ1.0 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
¼4.30 (br quint, J¼6.1 Hz, 2H), 4.15 (dd, J¼11.3, 4.6 Hz, 2H), 4.08
(dd, J¼17.1, 6.3 Hz, 2H), 4.07 (dd, J¼7.2, 3.1 Hz, 2H), 3.73 (dd, J¼8.4,
6.2 Hz, 2H), 2.33 (t, J¼7.0 Hz, 4H), 1.61 (br quint, J¼7.2 Hz, 4H), 1.43
(s, 6H), 1.36 (s, 6H), 1.34e1.18 (m, 28H) ppm. 13C NMR (125 MHz,
CDCl3)
d
¼173.6, 109.8, 73.6, 66.3, 64.5, 34.1, 29.66, 29.65, 29,62,
29.57, 29.4, 29.2, 29.1, 26.7, 25.4, 24.9 ppm. FT-IR (film of a concd.
0.09 mmol, 38% from 11). Data for (S,S)-20: Mp 47e48 ꢀC. [
a
]
26 þ0.4
solution in CH2Cl2):
n
¼2985, 2961, 2919, 2850, 1735, 1261, 1160,
D
(c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
d
¼4.30 (br quint,
1091, 1051, 1028, 801 cmꢂ1. ESI-MS m/z 593.9 ([MþNa]]þ). ESI-
J¼5.8 Hz, 1H), 4.20e4.10 (m, 3H), 4.10e4.03 (m, 2H), 3.91 (br quint,
J¼5.2 Hz, 1H), 3.72 (dd, J¼8.5, 6.1 Hz, 1H), 3.68 (dd, J¼10.9, 3.4 Hz,
1H), 3.58 (dd, J¼12.1, 5.9 Hz, 1H), 2.32 (br t, J¼7.7 Hz, 4H), 1.60 (br
quint, J¼7.1 Hz, 4H), 1.42 (s, 3H), 1.35 (s, 3H), 1.33e1.16 (m, 22H)
HRMS calcd for
593.4023.
C
32H58O8Na ([MþNa]þ): 593.40239, found
4.10. Hydrolysis of the acetonides in 15 to afford 12 and 120
ppm. 13C NMR (100 MHz, CDCl3):
66.3, 65.1, 64.5, 63.3, 34.09, 34.05, 29.5e29.0 (several not so well
resolved lines), 26.6, 25.3, 24.8 ppm. FT-IR (film of a solution in
d
¼174.3, 173.7, 109.8, 73.6, 70.2,
A solution of 15 (104 mg, 0.18 mmol) in HOAceH2O (4:1, v/v,
2.5 mL, with the stock solution pre-warmed at 50 ꢀC before use)
was stirred at 50 ꢀC for 25 min (when TLC showed disappearance of
15). The heating bath was removed. H2O (10 mL) was added to the
reaction mixture. Powdered NaHCO3 (ca. 3.0 g) was added very
slowly to neutralize the HOAc. The mixture was extracted with
EtOAc (30 mLꢁ3), washed with brine, and dried over anhydrous
Na2SO4. Removal of the solvent by rotary evaporation left a residue,
which was chromatographed on silica to give 120 (the less polar
component, a white waxy solid, eluting with 1:2 PE/EtOAc, 50 mg,
0.09 mmol, 53% from 15) and 12 (the more polar component,
a white powder, eluting with 8:1 CH2Cl2/MeOH, 25 mg, 0.05 mmol,
28% from 11).
CH2Cl2):
n
¼3391 (br), 2918, 2850, 1738, 1467, 1386, 1373, 1246, 1198,
1172, 1082, 1052, 847, 772 cmꢂ1. ESI-MS m/z 511.8 ([MþNa]þ). ESI-
HRMS calcd for
C
26H48O8Na ([MþNa]þ): 511.32414, found
511.3238. Data for (S,S)-2: Mp 86e87 ꢀC. [
a
]
28 þ11.3 (c 0.20, CH2Cl2)
D
(lit.4
NMR (500 MHz, CDCl3):
[
a
]
þ10.2 (c 0.20, CH2Cl2)), [
a]
þ17.6 (c 0.20, DMSO). 1H
20
28
D
D
d
¼4.20 (dd, J¼12.0, 4.5 Hz, 2H), 4.15 (dd,
J¼11.5, 6.3 Hz, 2H), 3.93 (br quint, J¼5.1 Hz, 2H), 3.70 (dd, J¼12.1,
4.0 Hz, 2H), 3.60 (dd, J¼10.8, 5.9 Hz, 2H), 2.35 (t, J¼7.6 Hz, 4H),
2.25e1.90 (a lump, 4H), 1.63 (br quint, J¼7.3 Hz, 4H), 1.38e1.16 (m,
22H) ppm. 13C NMR (125 MHz, CDCl3):
d¼174.4, 70.3, 65.2, 63.3,
34.1, 29.7e29.0 (several not so well resolved lines), 24.9 ppm. FT-IR

96
W.-J. Wu et al. / Tetrahedron 70 (2014) 92e96
27
Data for 120: Mp 55e56 ꢀC. [
(500 MHz, CDCl3)
a
]
þ0.3 (c 1.00, CHCl3). 1H NMR
References and notes
D
d
¼4.29 (br quint, J¼5.9 Hz, 1H), 4.19e4.09 (m,
1. (a) Qi, S.-H.; Zhang, S.; Huang, J.-S.; Xiao, Z.-H.; Wu, J.; Long, L.-J. Chem. Pharm.
Bull. 2004, 52, 986e988; (b) Omura, S.; Nakagawa, A.; Fukamachi, N.; Otaguro,
K.; Kobayashi, B. J. Antibiot. 1986, 39, 1180e1181; (c) Kitahara, T.; Aono, S.; Mori,
K. Biosci. Biotechnol. Biochem. 1995, 59, 78e82; (d) Zeng, X.; Xiang, L.; Li, C.-Y.;
Wang, Y.; Qiu, G.; Zhang, Z.-X.; He, X. Fitoterapia 2012, 83, 609e616; (e) Akeda,
Y.; Shibata, K.; Ping, X.; Tanaka, T.; Taniguchi, M. J. Antibiot. 1995, 48, 363e368; (f)
Wang, J.-F.; Dai, H.-Q.; Wei, Y.-L.; Zhu, H.-J.; Yan, Y.-M.; Wang, Y.-H.; Long, C.-L.;
Zhong, H.-M.; Zhang, L.-X.; Cheng, Y.-X. Chem. Biodiversity 2012, 7, 2046e2053;
(g) Hirao, S.; Tara, K.; Kuwano, K.; Tanaka, J.; Ishibashi, F. Biosci. Biotechnol. Bio-
chem. 2012, 76, 372e374; (h) Okuyama, E.; Hasegawa, T.; Matsushita, T.; Fuji-
moto, H.; Ishibashi, M.; Yamazaki, M. Chem. Pharm. Bull. 2001, 49, 154e160.
2. (a) Mori, K. Tetrahedron 2012, 68, 8441e8449; (b) Stamatov, S. D.; Stawinski, J.
Org. Biomol. Chem. 2007, 5, 3787e3800; (c) Neef, A. B.; Schultz, C. Angew. Chem.,
Int. Ed. 2009, 48, 1498e1500; (d) ter Horst, B.; Seshadri, C.; Sweet, L.; Young, D.
C.; Feringa, B. L.; Moody, D. B.; Minnaard, A. J. J. Lipid Res. 2010, 51, 1017e1022; (e)
Batovska, D. I.; Tsubota, S.; Kato, Y.; Asano, Y.; Ubukata, M. Tetrahedron: Asym-
metry 2004, 15, 3551e3559; (f) Rejzek, M.; Vacek, M.; Wimmer, Z. Helv. Chim.
Acta 2000, 83, 2756e2760; (g) Li, A.; Baker, D. L.; Tigyi, G.; Bittman, R. J. Org.
Chem. 2006, 71, 629e635; (h) Kubiak, R. J.; Bruzik, K. S. J. Org. Chem. 2003, 68,
960e968; (i) Alcaraz, M.-L.; Peng, L.; Klotz, P.; Goeldner, M. J. Org. Chem. 1996, 61,
192e201; (j) Vaique, E.; Guy, A.; Couedelo, L.; Gosse, I.; Durand, T.; Cansell, M.;
Pinet, S. Tetrahedron 2010, 66, 8872e8879; (k) Redden, P. R.; Lin, X.; Horrobin, D.
F. Chem. Phys. Lipids 1996, 79, 9e19.
3H), 4.09e4.01 (m, 2H), 3.90 (br quint, J¼5.2 Hz, 1H), 3.72 (dd,
J¼8.3, 6.3 Hz, 1H), 3.67 (dd, J¼10.8, 3.3 Hz, 1H), 3.57 (dd, J¼11.6,
5.8 Hz, 1H), 2.32 (t, J¼7.1 Hz, 4H), 1.60 (br quint, J¼7.3 Hz, 4H), 1.41
(s, 3H), 1.35 (s, 3H), 1.32e1.16 (m, 28H) ppm. 13C NMR (125 MHz,
CDCl3) ¼174.3, 173.6, 109.8, 73.6, 70.2, 66.3, 65.1, 64.4, 63.3, 34.09,
34.05, 29.60, 29.58, 29.56, 29.51, 29.34, 29.2, 29.0, 26.6, 25.3, 24.83,
24.82 ppm. FT-IR (film of a solution in CH2Cl2):
d
n
¼3412 (br), 2986,
2918, 2849, 1733, 1473, 1386, 1374, 1263, 1228, 1191, 1095, 1051, 847,
802 cmꢂ1. ESI-MS m/z 553.9 ([MþNa]þ). ESI-HRMS calcd for
C
29H54O8Na ([MþNa]þ): 553.37109, found 553.3701.
26
Data for 12: Mp 91e92 ꢀC. [
a
]
þ15.8 (c 0.20, DMSO). 1H NMR
D
(500 MHz, CDCl3):
d
¼4.21 (dd, J¼11.6, 5.1 Hz, 1.8H), 4.15 (dd, J¼11.5,
6.4 Hz, 1.8H), 3.96e3.90 (m, 1.8H), 3.72e3.58 (m, 4.6H), 2.35 (t,
J¼7.4 Hz, 4H), 1.63 (br quint, J¼7.3 Hz, 4H), 1.40e1.20 (m, 28H) ppm.
13C NMR (125 MHz, DMSO-d6, with the central line for the solvent
signal set to 39.52 ppm as the internal reference)
65.5, 62.6, 33.5, 29.04 (ca. twice as intense as other lines in the
29e28 ppm region), 28.99, 28.89, 28.7, 28.5, 24.5 ppm. FT-IR (film of
d¼173.0, 69.3,
3. Chen, C.-Y.; Han, W.-B.; Chen, H.-J.; Wu, Y.-K.; Gao, P. Eur. J. Org. Chem. 2013,
4311e4318.
4. Nyongha, A. T.; Hussain, H.; Dongo, E.; Ahmed, I.; Kronhn, K. Nat. Prod. Commun.
2010, 5, 1939e1940.
5. For the only similar compounds (biseasters of glycerol) recorded in the litera-
ture, see: (a) Karam, A.; Gu, Y.; Jerome, F.; Douliez, J.-P.; Barrault, J. Chem.
a solution in CH2Cl2):
n
¼3257 (br), 2916, 2848, 1733, 1462, 1194,
1176, 1051 cmꢂ1. ESI-MS m/z 513.7 ([MþNa]þ). ESI-HRMS calcd for
C
26H50O8Na ([MþNa]þ): 513.33979, found 513.3399.
ꢁ ^
Commun. 2007, 2222e2224; (b) Grac¸ a, J.; Santos, S. Chem. Phys. Lipids 2006, 144,
96e107.
Acknowledgements
6. Normally, diglycerides refer to those species that have two acyl groups on two
out of three hydroxyl groups in a glycerol molecule. Therefore, the name hylo-
diglycerol may be not so appropriate.
7. The cross coupling product from oct-7-en-1-ol (3) and undec-10-enoic acid was
of the same polarity and thus inseparable from the self-coupling product of the
acid.
This work was supported by the National Basic Research Pro-
gram of China (the 973 Program, 2010CB833200), the National
Natural Science Foundation of China (21172247, 21032002,
20921091) and Chinese Academy of Sciences.
8. Knight, D. W.; Morgan, I. R.; Proctor, A. J. Tetrahedron Lett. 2010, 51, 638e640.
9. The extremely low solubility of 12 in CH2Cl2 made it impossible to record the
optical rotation in CH2Cl2. The [a] reading in DMSO was quite stable, though
D
Supplementary data
the highest concentration was only c¼0.20 (g/100 mL). The solubility of 12 in
CDCl3 (in which 12 was rather unstable, with significant acyl group migra-
tions occurred easily at ambient temperature over several hours) was slightly
better than that in CH2Cl2; a more or less acceptable 1H NMR could be thus
obtained. Recording of the 13C NMR for 12 was satisfactorily achieved only in
DMSO-d6, in which the 1H NMR suffered serious line broadening and hence
senseless.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.021.
These data include MOL files and InChiKeys of the most important
compounds described in this article.