Synthesis of N-oxyamide-linked neoglycolipids

Article abstract of DOI:10.1021/jo502128h

N-Oxyamide-containing compounds have shown improved metabolic stability and interesting secondary structures due to the good hydrogen bond-donating property of N-oxyamide. β-Glucolipids linked by the N-oxyamide bond have been successfully synthesized as novel mimics of glycoglycerolipids and glycosphingolipids.

Full text of DOI:10.1021/jo502128h

Note
pubs.acs.org/joc
Synthesis of N‑Oxyamide-Linked Neoglycolipids
Na Chen and Juan Xie*
PPSM, ENS Cachan, CNRS UMR 8531, 61 av President Wilson, F-94230 Cachan, France
S
* Supporting Information
ABSTRACT: N-Oxyamide-containing compounds have shown improved metabolic stability and interesting secondary
structures due to the good hydrogen bond-donating property of N-oxyamide. β-Glucolipids linked by the N-oxyamide bond have
been successfully synthesized as novel mimics of glycoglycerolipids and glycosphingolipids.
s part of the glycoconjugate family, glycolipids are
implicated in a variety of important biological phenomena
easily organize into turns and helices through intramolecular
hydrogen bond formation. This unique property makes N-
oxyamide linkage attractive for the modification of biomole-
cules. Furthermore, N-oxypeptides are resistant to chemical and
enzymatic hydrolysis.12 With a continuing interest in N-
oxyamide-containing biomolecules,13 we designed the N-
oxyamide-linked glycolipids, by replacing the ester function in
GGLs by a N-oxyamide (Figure 1). These kinds of glycolipids,
A
such as cell−cell interactions, viral and bacterial infections,
immune response, signal transduction, cell proliferation, etc.
Glycolipids are composed of one or several monosaccharide
residues bound by a glycosidic linkage to a hydrophobic moiety
like an acylglycerol (termed glycoglycerolipids, GGLs) or a
ceramide (glycosphingolipids, GSLs). GGLs and mammalians
GSLs begin with either glucose or galactose attached in α- or β-
linkage to the 1-hydroxyl of mono/diacylglycerol or ceramide.
Ceramides consist of fatty-amide-linked sphingosine (a long-
chain amino alcohol). GGLs mainly exist in plants, algae, and
bacteria. They have shown interesting anti-tumor-promoting
activities.1 Inhibitory effects on DNA polymerase, human Myt1-
kinase, human lanosterol synthase, and antitumor activities have
also been reported.2 Bacterial glycoglycerolipid BbGL2 has
been shown to induce natural killer T cell (NKT cell)
proliferation and cytokine production,3 an important property
known for GSL agelashins.4 As a most abundant and diverse
class of glycolipids in animals, GSLs are found in the plasma
membrane of cells and play key roles in cell−cell interactions
and protein activities.5 As immunostimulating agents,6 these
glycolipids have attracted intensive research interest, in
particular, since the discovery of a potent NKT immune cell
activation effect of synthetic α-galactosyl ceramide (α-GalCer
or KRN7000).7 The design of glycolipid mimics has become a
useful strategy in drug discovery. Modifications have been made
on the sugar part, on the configuration and nature of the
anomeric bond (C-, S-glycoside), on the polar moiety of the
ceramide or glycerol, or on the lipid chains.7 Triazole-
containing glycolipids have also been reported, showing a
comparable stimulatory effect on cytokine production as α-
GalCer.8 The ability to undergo extensive interlipid hydrogen
bonding has been considered to be fundamental for the
functions of glycolipids in membranes, through imparting
structural integrity to the membranes of the organisms.9 N-
Oxyamide bonds in peptide10 and sugar derivatives11 have been
found to be good hydrogen-bond-donating groups due to lone
pair repulsion between adjacent nitrogen and oxygen. They can
Figure 1. Structure of GGLs, GSLs, and N-oxyamide-linked
glycolipids.
never reported in the literature, could be considered as
analogues of both GGL and GSL (Figure 1). Only one
N(OMe)-glycoceramide has very recently been reported
showing potent inhibitory activity against recombinant
endoglycoceramidase II.14 Because the β-linked glucose unit
widely exists in natural glycolipids, we investigated first the
synthesis of O-amino β-glucoglycerol and its application to N-
oxyamide-containing glucolipids.
The synthetic strategy toward N-oxyamide-containing
glucolipids would be the stereoselective synthesis of O-amino
β-glucoglycerol 10 through Mitsunobu reaction on glycosyl-
glycerol 7, which can be obtained via glycosylation with
Received: September 16, 2014
© XXXX American Chemical Society
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dx.doi.org/10.1021/jo502128h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Next, esterification of the O-phthaloylamino β-glucoglycerol
10 with palmitic acid using 1-ethyl-3-(3-(dimethylamino)-
propyl)carbodiimide (EDC) furnished the glucolipid 11 in
excellent yield (98%) (Scheme 4). Hydrazinolysis under mild
conditions (1.1 equiv, 20 min at 0 °C) deprotected selectively
the phthaloyl group. Coupling of the resulting oxyamine 12
with different fatty acids led successfully to the neoglycolipids
13−17 in 64−87% yield. The NH of the N-oxyamide bond
Scheme 1. Retrosynthesis of N-Oxyamide-Linked
Glycolipids
1
appeared between 8.81 and 8.87 ppm on the H NMR in
CDCl3. Final deacetylation was realized with hydrazine at 50 °C
in EtOH to give the target compounds 18−22. Due to their
amphiphilic nature, some glycolipids are lost during the
workup, leading to low yields (34−61%).
In conclusion, we have achieved the first synthesis of N-
oxyamide-linked β-glucolipids from readily available D-glucose
penta-acetate and D-mannitol via the O-amino β-glucoglycerol
10 as a versatile intermediate. Different lipid chains could be
easily introduced on hydroxyl and oxyamine functions to access
a variety of glycolipid structures. Synthesis of 1,2-di-O-benzyl-
sn-glycerol 5 has also been optimized.
Scheme 2. Preparation of 1,2-Di-O-benzyl-sn-glycerol 5
EXPERIMENTAL SECTION
■
3,4-O-Isopropylidene-D-mannitol (2). To a stirred solution of
30% aq AcOH (200 mL) was added D-mannitol triacetonide 1 (10 g,
33.1 mmol). The mixture was stirred at 40 °C. After 1 h, the solution
was evaporated and residual AcOH removed by repeated coevapora-
tion with toluene. Dry acetone was added, and the mixture was
thoroughly stirred with excess anhyd K2CO3 and then filtered. The
insoluble material (remaining mannitol) was washed with acetone, and
the combined filtrates were evaporated. The residue was then
dissolved in a small volume of EtOAc and allowed to crystallize at rt
to give pure product (5.89 g, 80.1%): Rf = 0.43 (CH2Cl2/MeOH 10/
dibenzylated glycerol 5, followed by introduction of lipid chains
and final deprotection (Scheme 1).
The required glycerol 515 was prepared in 64% overall yield
from D-(+)-mannitol, as outlined in Scheme 2. It is important
to control the reaction conditions to convert triacetonide 116 to
3,4-isopropylidene-D-mannitol 2.15 Deprotection with 70%
AcOH at 40 °C15 gave 50% yield of 2. The best result (80%)
was obtained using 30% AcOH17 at 40 °C during 1 h.
Glycosylation of glycerol 5 was realized with per-O-acetyl-α-
D-glucopyranosyl bromide generated from D-glucose penta-
acetate (Scheme 3). Dropwise addition of glycosyl bromide in
dry acetonitrile into the solution containing compound 5,
HgBr2, and Hg(CN)2 is crucial to prepare β-glucoglycerol 615
in good yield (75% for two steps). After debenzylation,
regioselective silylation of 718 required the presence of N-
methylimidazole and iodine19 as promoter to ensure good
reactivity and regioselectivity. The oxyamine function was then
introduced via Mitsunobu reaction with PhthNOH to afford
compound 9 with inversion of configuration.20 Removal of the
TBS group was achieved with catalytic AcCl in MeOH in 72%
yield, instead of TBAF which deprotected acetyl groups, leading
to a mixture of products.
1
1); H NMR (400 MHz, acetone-d6) δ 4.73 (s, 2H, 2 × OH), 3.96−
3.90 (m, 2H, 2 × CH), 3.77−3.54 (m, 8H, 2 × CH, 2 × CH2, 2 ×
OH), 1.32 (s, 6H, 2 × CH3); 13C NMR (100 MHz, acetone-d6) δ
109.8 (Cq), 80.8, 74.2 (CH); 64.6 (CH2), 27.3 (CH3).
1,2,5,6-Tetra-O-benzyl-3,4-O-isopropylidene-D-mannitol (3).
NaH (60%, 6.36 g, 159 mmol) was added to a stirred solution of 2
(5.88 g, 26.49 mmol) in dry DMF (200 mL). The suspension was
stirred for 0.5 h at 0 °C in an ice bath. BnBr (15.11 mL, 127 mmol)
was then added, and the stirring continued at rt overnight. Ice was
added to destroy the excess NaH, and the solution was then
concentrated, diluted with saturated aq NH4Cl, and the product
extracted with EtOAc (200 mL). The extract was washed with water
and brine, dried over MgSO4, and evaporated. Purification by column
chromatography (petroleum ether/EtOAc 15/1) afforded compound
3 as a colorless syrup (15.10 g, 98%): Rf = 0.31 (petroleum ether/
EtOAc 10/1); 1H NMR (400 MHz, CDCl3) δ 7.41−7.17 (m, 20H, H-
Ph), 4.73 (d, J = 11.8 Hz, 2H, 2 × CH), 4.57 (d, J = 11.7 Hz, 2H, 2 ×
CH), 4.48−4.46 (m, 4H, 2 × CH2), 4.24−4.15 (m, 2H, 2 × CH),
3.81−3.55 (m, 6H, 2 × CH2, 2 × CH), 1.35 (s, 6H, 2 × CH3); 13C
Scheme 3. Synthesis of O-Amino β-Glucoglycerol 10
B
dx.doi.org/10.1021/jo502128h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Synthesis of N-Oxyamide-Linked Neoglycolipids
NMR (100 MHz, CDCl3) δ 138.6, 138.5 (Cq); 128.5, 128.4, 128.0,
127.7, 127.6 (CH-Ph); 109.9 (Cq); 79.4, 78.6 (CH); 73.4, 72.9, 70.7
(CH2); 27.3 (CH3).
(m, 2H, H-6′), 3.99−3.69 (m, 3H, H-2,3), 3.65 (ddd, J = 10.0, 4.5, 2.3
Hz, 1H, H-5′), 3.59−3.57 (m, 2H, H-1), 2.07, 2.04, 2.03, 2.01 (4 × s,
12H, 4 × OAc); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.5, 169.6,
169.5 (CO); 138.5, 138.3 (Cq); 128.6, 128.5 (CH-Ph); 101.2 (C-
1′), 76.8 (CH), 73.6 (CH2), 72.9 (C-3′), 72.3 (CH2), 71.9 (C-5′),
71.4 (C-2′), 69.8, 69.4 (CH2); 68.5 (C-4′), 62.0 (C-6′), 20.9, 20.8
(OAc).
1,2,5,6-Tetra-O-benzyl-D-mannitol (4). Compound 3 (15.10 g,
25.96 mmol) was treated with 1 M aq HCl/MeOH (1:9, v/v, 250 mL)
under reflux for 4 h, when TLC showed a new single spot. Excess solid
NaHCO3 was added, and the solution evaporated to give an oil which
was dissolved in EtOAc (300 mL), dried over MgSO4, and evaporated.
Purification by column chromatography (petroleum ether/EtOAc 5/
1) afforded compound 4 (13.08 g, 93%) as a colorless syrup: Rf = 0.12
(petroleum ether/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ 7.34−
7.26 (m, 20H, H-Ph), 4.72 (d, J = 11.5 Hz, 2H, 2 × CH), 4.59 (d, J =
11.5 Hz, 2H, 2 × CH), 4.54 (s, 4H, 2 × CH2), 3.96 (m, 2H, 2 × CH),
3.80−3.65 (m, 6H, 2 × CH2, 2 × CH), 3.04 (s, 1H, OH), 3.02 (s, 1H,
OH); 13C NMR (100 MHz, CDCl3) δ 138.3, 138.1 (Cq); 128.5, 128.1,
127.9, 127.8 (CH-Ph); 79.3 (CH); 73.6, 73.2, 70.3 (CH2); 70.1 (CH).
1,2-Di-O-benzyl-sn-glycerol (5). To a solution of 4 (14.10 g, 26
mmol) in MeOH (250 mL) was added an aq solution of NaIO4 (8.56
g, 40 mmol in 150 mL of water). The reaction mixture was stirred for
3 h at rt, after which time TLC analysis revealed the oxidation to be
complete (Rf = 0.52, petroleum ether/EtOAc 3/1). The reaction
mixture was diluted with MeOH (200 mL) and cooled. The
precipitate was filtered off, and to the filtrate was added NaBH4
(9.84 g, 260 mmol). After 1 h, the reaction mixture was treated with
AcOH, and the solution evaporated to a small volume which was
diluted in CH2Cl2 (300 mL), dried over MgSO4, and concentrated.
Purification by column chromatography (petroleum ether/EtOAc 3/
1) afforded compound 5 (13.87 g, 98%) as a colorless syrup: Rf = 0.24
(petroleum ether/EtOAc 3/1); 1H NMR (400 MHz, CDCl3) δ 7.38−
7.26 (m, 10H, H-Ph), 4.74−4.53 (m, 4H, 2 × CH2), 3.79−3.57 (m,
5H, 2 × CH2, CH), 2.05 (s, 1H, OH); 13C NMR (100 MHz, CDCl3)
δ 138.4, 138.1 (Cq); 128.6, 128.6, 128.0, 127.9, 127.8 (CH-Ph); 78.1
(CH); 73.7, 72.3, 70.3, 63.0 (CH2).
(2R)-1-O-(2′,3′,4′,6′-Tetra-O-acetyl-β-D-glucopyranosyl)-
glycerol (7). A mixture of 6 (12 g, 20 mmol) and 10% Pd/C (1.8 g)
in EtOAc (100 mL) containing 5 mL each of EtOH and AcOH was
vigorously shaken under H2 at rt overnight. The catalyst was filtered
off, and the filtrate evaporated. Purification by column chromatog-
raphy (CH2Cl2/MeOH 25/1) afforded compound 7 (6 g, 71%) as a
1
white solid: Rf = 0.12 (CH2Cl2/MeOH 25/1); H NMR (400 MHz,
CDCl3) δ 5.22 (t, J = 9.6 Hz, 1H, H-3′), 5.11−5.04 (m, 1H, H-4′),
5.04−4.97 (m, 1H, H-2′), 4.55 (d, J = 7.8 Hz, 1H, H-1′), 4.25−4.16
(m, 2H, H-6′), 3.89−3.79 (m, 3H, H-2,3), 3.77−3.57 (m, 3H, H-1,5′),
2.32 (s, 2H, 2 × OH), 2.11, 2.07, 2.04, 2.01 (4 × s, 12H, 4 × OAc);
13C NMR (100 MHz, CDCl3) δ 170.8, 170.3, 169.7, 169.5 (CO);
101.4 (C-1′), 72.6 (C-3′), 72.0 (C-5′), 71.3 (C-2′), 70.5 (CH), 68.4
(C-4′), 63.4, 61.9 (CH2); 20.8, 20.7 (OAc).
1-O-tert-Butyldimethylsilyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-
D-glucopyranosyl)-sn-glycerol (8). To a solution of 7 (2 g, 4.74
mmol), N-methylimidazole (1.14 mL, 14.22 mmol), and iodine (3.61
g, 14.22 mmol) in anhyd THF (20 mL) under Ar at 0 °C was added
TBSCl (0.86 g, 5.69 mmol). The reaction mixture was stirred for 20
min at 0 °C and then quenched with saturated aq Na2S2O3 and diluted
with EtOAc (50 mL). The aqueous layers were extracted with EtOAc
(2 × 50 mL). The combined organic layers were dried over MgSO4,
filtered, concentrated, and purified by column chromatography over
silica gel (CH2Cl2/MeOH 100/1) to afford 8 (2.43 g, 95.7%) as a
yellowish paste: Rf = 0.74 (CH2Cl2/MeOH 100/3); [α]D −9.7 (c 0.1,
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.20 (dd, J = 12.0, 6.9 Hz,
1H, H-3′), 5.05 (t, J = 9.7 Hz, 1H, H-4′), 4.98 (dd, J = 9.6, 8.1 Hz, 1H,
H-2′), 4.54 (d, J = 7.9 Hz, 1H, H-1′), 4.25−4.11 (m, 2H, H-6′), 3.82−
3.68 (m, 4H, H-2,3,5′), 3.62−3.58 (m, 2H, H-1), 2.08, 2.04, 2.01, 1.99
(2R)-1,2-Di-O-benzyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-
glucopyranosyl)glycerol (6). To a solution of α-D-glucose penta-
acetate (2 g, 5.12 mmol) in CH2Cl2 (15 mL) was added HBr (33% in
AcOH, 7 mL, 41 mmol) at 0 °C. The mixture was stirred at rt under
Ar for 6 h, and then the solution was neutralized with aq NaHCO3.
The resulting 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide was
extracted with CH2Cl2 (100 mL), dried over MgSO4, and evaporated
to give a syrup. To a solution of 1,2-di-O-benzyl-sn-glycerol (5) (1.41
g, 5.2 mmol), HgBr2 (0.94 g, 2.6 mmol), and Hg(CN)2 (0.66 g, 2.6
mmol) in dry MeCN (20 mL) was added dropwise over a period of 1
h a solution of glycosyl bromide in MeCN (10 mL). The reaction
solution was stirred at rt overnight and then concentrated to an oil
which was dissolved in CH2Cl2 (100 mL) and washed with saturated
aq KBr (2 × 30 mL) and water (30 mL). The dried (MgSO4) organic
layer was concentrated. Purification by column chromatography
(petroleum ether/EtOAc 3/1) afforded compound 6 (2.30 g, 75%)
as a colorless paste: Rf = 0.39 (petroleum ether/EtOAc 2/1); 1H NMR
(400 MHz, CDCl3) δ 7.37−7.28 (m, 10H, H-Ph), 5.18 (t, J = 9.4 Hz,
1H, H-3′), 5.09 (t, J = 9.7 Hz, 1H, H-4′), 5.00 (dd, J = 9.5, 8.2 Hz, 1H,
H-2′), 4.65 (s, 2H, CH2), 4.57−4.50 (m, 3H, H-1′, CH2), 4.28−4.09
(4 × s, 12H, 4 × OAc), 0.88 (s, 9H, t-Bu), 0.05 (s, 6H, Si(CH3)2); 13
C
NMR (100 MHz, CDCl3) δ 170.7, 170.3, 169.5, 169.4 (CO); 101.4
(C-1′), 72.8 (C-3′), 71.9 (C-5′), 71.7 (CH2), 71.4 (C-2′), 70.5 (CH),
68.5 (C-4′), 63.7, 62.0 (CH2); 25.9, 20.8, 20.7 (CH3); 18.3 (Cq, t-Bu),
−5.4 (CH3, Si(CH3)2); HRMS (ESI) m/z [M + H]+ calcd for
C23H41O12Si 537.2367; found 537.2362 (all HRMS spectra were
recorded on a Q-TOF MaXis using standard conditions).
(2R)-2-O-Phthalimido-1-O-tert-butyldimethylsilyl-3-O-
(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)glycerol (9). To a
solution of 8 (2.10 g, 3.91 mmol) in toluene (60 mL) were added
Ph3P (3.08 g, 11.7 mmol), PhthNOH (1.91 g, 11.7 mmol), and DIAD
(2.30 mL, 11.7 mmol) at 0 °C. The resulting mixture was stirred at rt
for 2 h under Ar and then extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine (50 mL), dried over
MgSO4, filtered, evaporated, and purified by column chromatography
over silica gel (petroleum ether/EtOAc 3/1) to afford 9 (2.39 g, 90%)
as a paste: Rf = 0.53 (petroleum ether/EtOAc 1/1); [α]D −13.3 (c 0.1,
C
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The Journal of Organic Chemistry
Note
1
CHCl3); H NMR (400 MHz, CDCl3) δ 7.83−7.70 (m, 4H, Phth),
(m, 2H, H-1a,2), 3.79−3.65 (m, 2H, H-1b,5′), 2.32 (t, J = 7.5 Hz, 2H,
CH2), 2.09, 2.07, 2.03, 2.01 (4 × s, 12H, 4 × OAc), 1.68−1.57 (m, 2H,
CH2), 1.39−1.20 (m, 24H, 12 × CH2), 0.88 (t, J = 6.7 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 173.9, 170.8, 170.4, 169.5 (CO);
5.16 (t, J = 9.6 Hz, 1H, H-3′), 5.02 (t, J = 9.8 Hz, 1H, H-4′), 4.92 (dd,
J = 9.4, 8.1 Hz, 1H, H-2′), 4.66 (d, J = 7.8 Hz, 1H, H-1′), 4.39−4.41
(m, 1H, H-2), 4.21 (dd, J = 12.3, 4.8 Hz, 1H, H-6′a), 4.15−4.06 (m,
2H, H-3a,6′b), 3.93 (dd, J = 11.7, 6.2 Hz, 1H, H-3b), 3.89 (d, J = 4.7
Hz, 2H, H-1), 3.69 (ddd, J = 10.0, 4.7, 2.2 Hz, 1H, H-5′), 2.06, 2.01,
1.99, 1.96 (4 × s, 12H, 4 × OAc), 0.77 (s, 9H, t-Bu), −0.02, −0.03 (2
× s, 6H, Si(CH3)2); 13C NMR (100 MHz, CDCl3) δ 170.8, 170.4,
169.6, 169.6 (CO), 163.7 (CO, Phth); 134.5, 129.0 (Cq), 123.6
(Phth), 100.8 (C-1′), 87.0 (C-2), 73.0 (C-3′), 71.8 (C-5′), 71.2 (C-
2′), 68.4 (C-4′), 68.0, 62.0, 61.9 (CH2); 25.8, 20.8, 20.8, 20.7 (CH3);
18.2 (Cq, t-Bu), −5.6 (CH3, Si(CH3)2); HRMS (ESI) m/z [M + H]+
calcd for C31H44NO14Si 682.2531; found 682.2526.
2-O-Phthalimodo-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-gluco-
pyranosyl)-sn-glycerol (10). To a solution of 9 (1.0 g, 1.47 mmol)
in MeOH (30 mL) was added AcCl (16 μL, 0.22 mmol) at 0 °C. The
resulting mixture was stirred at rt for 2 h under Ar and then extracted
with CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with brine, dried over MgSO4, filtered, evaporated, and purified by
column chromatography over silica gel (petroleum ether/EtOAc 1/1)
to give 10 (0.59 g, 72%) as a white powder. mp 72 °C: Rf = 0.23
101.2 (C-1′), 80.1 (CH), 72.8 (C-3′), 72.0 (C-5′), 71.3 (C-2′), 68.5
(C-4′), 68.0, 62.0, 61.9, 34.3, 32.1, 29.8, 29.6, 29.5, 29.4, 29.3, 25.1,
22.8 (CH2); 20.9, 20.8, 20.7, 14.2 (CH3); HRMS (ESI) m/z [M + H]+
calcd for C33H58NO13 676.3908; found 676.3903.
General Procedure A for N-Oxyamide Formation. Synthesis
of (2R)-2-O-Acylamino-1-O-palmitoyl-3-O-(2′,3′,4′,6′-tetra-O-
acetyl-β-D-glucopyranosyl)glycerol (13−17). To a solution of
carboxylic acid (0.25 mmol) in anhyd CH2Cl2 (4 mL) were added
HOBt (0.5 mmol), EDC·HCl (0.5 mmol), and Et3N (0.5 mmol)
under Ar at 0 °C. After being stirred for 20 min, the oxyamine 12 (0.25
mmol) was added. The resulting mixture was stirred at rt overnight.
The solution was diluted with EtOAc (25 mL), washed with aq HCl (1
N, 2 × 10 mL), saturated aq NaHCO3 (2 × 10 mL), and brine (10
mL), dried over MgSO4, filtered, evaporated, and purified by column
chromatography over silica gel (petroleum ether/EtOAc 2/1).
(2R)-2-O-Hexanoylamino-1-O-palmitoyl-3-O-(2′,3′,4′,6′-
tetra-O-acetyl-β-D-glucopyranosyl)glycerol (13). From 12 (153
mg, 0.23 mmol) and hexanoic acid, compound 13 was obtained as a
paste (145 mg, 82%): Rf = 0.60 (petroleum ether/EtOAc 1/1); [α]D
1
(petroleum ether/EtOAc 1/1); [α]D −17.3 (c 0.1, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.87−7.74 (m, 4H, Phth), 5.22−5.15 (m, 1H,
H-3′), 5.03 (t, J = 10.1 Hz, 1H, H-4′), 4.97 (m, 1H, H-2′), 4.64 (d, J =
7.8 Hz, 1H, H-1′), 4.32−4.26 (m, 1H, H-2), 4.22 (dd, J = 12.3, 4.9 Hz,
1H, H-6′a), 4.14−4.06 (m, 2H, H-3a,6′b), 4.01 (dd, J = 11.6, 6.3 Hz,
1H, H-3b), 3.83−3.66 (m, 3H, H-1,5′), 2.07, 2.04, 1.99, 1.97 (4 × s,
12H, 4 × OAc); 13C NMR (100 MHz, CDCl3) δ 170.8, 170.3, 169.6,
169.5 (CO), 164.6 (CO, Phth); 135.0, 128.8 (Cq); 124.0 (Phth),
100.9 (C-1′), 88.1 (CH), 72.8 (C-3′), 71.9 (C-5′), 71.1 (C-2′), 68.5
(C-4′), 67.8, 61.9, 60.4 (CH2); 20.8, 20.7, 20.7 (OAc); HRMS (ESI)
m/z [M + H]+ calcd for C25H30NO14 568.1666; found 568.1661.
(2R)-1-O-Palmitoyl-2-O-phthalimido-3-O-(2′,3′,4′,6′-tetra-O-
acetyl-β-D-glucopyranosyl)glycerol (11). To a solution of palmitic
acid (0.26 g, 1.02 mmol) in anhyd CH2Cl2 (10 mL) were added
DMAP (0.25 g, 2.04 mmol), EDC·HCl (0.39 g, 2.04 mmol), and Et3N
(0.28 mL, 2.04 mmol) under Ar at 0 °C. After the mixture was stirred
for 20 min, compound 10 (0.58 g, 1.02 mmol) was added. The
resulting mixture was stirred at rt overnight. The solution was diluted
with EtOAc (30 mL), washed with aq HCl (1 N, 2 × 15 mL),
saturated aq NaHCO3 (2 × 15 mL), and brine (15 mL), dried over
MgSO4, filtered, evaporated, and purified by column chromatography
over silica gel (petroleum ether/EtOAc 2/1) to afford 11 (1.05 g,
98.6%) as a white solid: mp 65 °C; Rf = 0.54 (petroleum ether/EtOAc
1
−35.7 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H,
NH), 5.24 (t, J = 9.5 Hz, 1H, H-3′), 5.09 (t, J = 9.7 Hz, 1H, H-4′),
5.02 (dd, J = 9.6, 7.8 Hz, 1H, H-2′), 4.57 (d, J = 8.0 Hz, 1H, H-1′),
4.42 (dd, J = 12.2, 3.2 Hz, 1H, H-3a), 4.32−4.09 (m, 4H, H-2,3b,6′),
4.03−3.96 (m, 1H, H-1a), 3.81−3.68 (m, 2H, H-1b,5′), 2.39−2.33 (m,
2H, CH2), 2.17−2.01 (m, 14H, 4 × OAc, CH2), 1.73−1.57 (m, 4H, 2
× CH2), 1.39−1.21 (m, 28H, 14 × CH2), 0.96−0.86 (m, 6H, 2 ×
CH3); 13C NMR (100 MHz, CDCl3) δ 174.4, 170.8, 170.3, 169.6
(CO); 100.7 (C-1′), 82.2 (CH), 72.5 (C-3′), 72.1 (C-5′), 71.5 (C-
2′), 68.4 (C-4′), 67.9, 61.8, 61.4, 34.2, 33.2, 32.1, 31.5, 29.8, 29.8, 29.6,
29.5, 29.4, 29.2, 25.2, 25.0, 22.8, 22.5 (CH2); 20.9, 20.7, 14.3, 14.1
(CH3); HRMS (ESI) m/z [M + H]+ calcd for C39H68NO14 774.4640;
found 774.4634.
(2R)-2-O-Octanoylamino-1-O-palmitoyl-3-O-(2′,3′,4′,6′-
tetra-O-acetyl-β-D-glucopyranosyl)glycerol (14). From 12 (151
mg, 0.22 mmol) and octanoic acid, compound 14 was obtained as a
paste (147 mg, 82%): Rf = 0.62 (petroleum ether/EtOAc 1/1); [α]D
1
−49.3 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H,
NH), 5.24 (t, J = 9.4 Hz, 1H, H-3′), 5.09 (t, J = 9.6 Hz, 1H, H-4′),
5.02 (t, J = 8.8 Hz, 1H, H-2′), 4.57 (d, J = 7.8 Hz, 1H, H-1′), 4.42 (d, J
= 10.0 Hz, 1H, H-3a), 4.31−4.09 (m, 4H, H-2,3b,6′), 4.03−3.96 (m,
1H, H-1a), 3.79−3.68 (m, 2H, H-1b,5′), 2.36 (t, J = 7.2 Hz, 2H, CH2),
2.16−2.00 (m, 14H, 4 × OAc, CH2), 1.68−1.58 (m, 4H, 2 × CH2),
1.40−1.20 (m, 32H, 16 × CH2), 0.93−0.84 (m, 6H, 2 × CH3); 13C
NMR (100 MHz, CDCl3) δ 174.4, 170.8, 170.4, 170.3, 169.6 (CO);
100.7 (C-1′), 82.5 (CH), 72.5 (C-3′), 72.1 (C-5′), 71.5 (C-2′), 68.4
(C-4′), 67.9, 61.8, 61.4, 34.2, 33.2, 32.1, 31.8, 29.8, 29.6, 29.5, 29.4,
29.2, 29.1, 25.5, 25.0, 22.8, 22.7 (CH2); 20.9, 20.7, 14.3 (CH3); HRMS
(ESI) m/z [M + H]+ calcd for C41H72NO14 802.4953; found 802.4947.
(2R)-2-O-(2-Ethylhexanoyl)amino-1-O-palmitoyl-3-O-
(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)glycerol (15).
From 12 (151 mg, 0.22 mmol) and 2-ethylhexanoic acid, compound
15 was obtained as a paste (114 mg, 64%): Rf = 0.47 (petroleum
1
1/1); [α]D −11.0 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ
7.87−7.74 (m, 4H, Phth), 5.20 (t, J = 9.5 Hz, 1H, H-3′), 5.06 (t, J =
9.7 Hz, 1H, H-4′), 4.96 (dd, J = 9.2, 7.8 Hz, 1H, H-2′), 4.68 (d, J = 8.2
Hz, 1H, H-1′), 4.62−4.53 (m, 1H, H-2), 4.44−4.31 (m, 2H, H-3),
4.25 (dd, J = 12.3, 4.8 Hz, 1H, H-6′a), 4.18−4.07 (m, 2H, H-1a,6′b),
4.01 (dd, J = 11.8, 5.8 Hz, 1H, H-1b), 3.73 (ddd, J = 9.9, 4.7, 2.4 Hz,
1H, H-5′), 2.38−2.24 (m, 2H, CH2), 2.10, 2.05, 2.02, 1.99 (4 × s,
12H, 4 × OAc), 1.65−1.52 (m, 2H, CH2), 1.35−1.20 (m, 24H, 12 ×
CH2), 0.88 (t, J = 6.9 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
173.5, 170.8, 170.4, 169.6, 169.5, 163.6 (CO); 134.8, 128.9 (Cq);
123.8 (CH), 100.9 (C-1′), 84.5 (CH), 72.9 (C-3′), 72.0 (C-5′), 71.1
(C-2′), 68.5 (C-4′), 67.8, 62.4, 62.0, 34.1, 32.1, 29.8, 29.8, 29.6, 29.5,
29.4, 29.3, 24.9, 22.8 (CH2); 20.9, 20.8, 20.7, 14.3 (CH3); HRMS
(ESI) m/z [M + H]+ calcd for C41H60NO15 806.3963; found 806.3957.
(2R)-2-O-Amino-1-O-palmitoyl-3-O-(2′,3′,4′,6′-tetra-O-ace-
tyl-β-D-glucopyranosyl)glycerol (12). To a solution of 11 (0.38 g,
0.47 mmol) in MeOH (3 mL) was added N2H4·H2O (25.2 μL, 0.52
mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min
under Ar and then extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were washed with brine (20 mL), dried over MgSO4,
filtered, evaporated, and purified by column chromatography over
silica gel (petroleum ether/EtOAc 3/2) to afford 12 (0.31 g, 96%) as a
paste: Rf = 0.40 (petroleum ether/EtOAc 1/1); [α]D −46.7 (c 0.1,
1
ether/EtOAc 1/1); [α]D −38.0 (c 0.1, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.87 (s, 1H, NH), 5.25 (t, J = 9.4 Hz, 1H, H-3′), 5.09 (t, J =
9.7 Hz, 1H, H-4′), 5.01 (t, J = 8.7 Hz, 1H, H-2′), 4.57 (d, J = 7.7 Hz,
1H, H-1′), 4.47−4.39 (m, 1H, H-3a), 4.31−4.10 (m, 4H, H-2,3b,6′),
4.03−3.96 (m, 1H, H-1a), 3.78−3.69 (m, 2H, H-1b,5′), 2.36 (t, J = 7.2
Hz, 2H, CH2), 2.10, 2.09, 2.04, 2.02 (4 × s, 12H, 4 × OAc), 1.95−1.85
(m, 1H, CH), 1.69−1.57 (m, 4H, 2 × CH2), 1.52−1.39 (m, 2H, CH2),
1.37−1.20 (m, 28H, 14 × CH2), 0.95−0.84 (m, 9H, 3 × CH3); 13C
NMR (100 MHz, CDCl3) δ 174.4, 173.7, 170.8, 170.4, 170.2, 169.6
(CO); 100.7 (C-1′), 82.2 (CH), 72.5 (C-3′), 72.0 (C-5′), 71.5 (C-
2′), 68.3 (C-4′), 67.9, 61.8, 61.3 (CH2); 45.7 (CH), 34.3, 34.2, 32.2,
32.0, 29.8, 29.6, 29.5, 29.4, 29.2, 25.9, 24.9, 22.8 (CH2); 20.9, 20.8,
20.7, 14.2, 14.1, 12.1 (CH3); HRMS (ESI) m/z [M + H]+ calcd for
C41H72NO14 802.4953; found 802.4947.
1
CHCl3); H NMR (400 MHz, CDCl3) δ 5.22 (t, J = 8.7 Hz, 1H, H-
3′), 5.06 (t, J = 9.6 Hz, 1H, H-4′), 4.96 (dd, J = 9.6, 7.8 Hz, 1H, H-2′),
4.57 (d, J = 7.8 Hz, 1H, H-1′), 4.39−4.06 (m, 4H, H-3,6′), 4.04−3.90
D
dx.doi.org/10.1021/jo502128h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(2R)-1-O-Palmitoyl-2-O-palmitoylamino-3-O-(2′,3′,4′,6′-
tetra-O-acetyl-β-D-glucopyranosyl)glycerol (16). From 12 (189
mg, 0.28 mmol) and palmitic acid, compound 15 was obtained as a
white solid (192 mg, 76%): mp 74 °C: Rf = 0.57 (petroleum ether/
EtOAc 1/1); [α]D −42.3 (c 0.1, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.86 (s, 1H, NH), 5.24 (t, J = 9.5 Hz, 1H, H-3′), 5.09 (t, J =
9.7 Hz, 1H, H-4′), 5.02 (t, J = 9.6, 7.8 Hz, 1H, H-2′), 4.57 (d, J = 7.9
Hz, 1H, H-1′), 4.42 (dd, J = 12.2, 3.3 Hz, 1H, H-3a), 4.32−4.08 (m,
4H, H-2,3b,6′), 4.03−3.96 (m, 1H, H-1a), 3.78−3.69 (m, 2H, H-
1b,5′), 2.36 (t, J = 7.5 Hz, 2H, CH2), 2.18−2.01 (m, 14H, 4 × OAc,
CH2), 1.68−1.58 (m, 4H, 2 × CH2), 1.40−1.22 (m, 48H, 24 × CH2),
0.93−0.81 (m, 6H, 2 × CH3); 13C NMR (100 MHz, CDCl3) δ 174.4,
171.2, 170.8, 170.2, 169.5 (CO); 100.7 (C-1′), 82.1 (CH), 72.5 (C-
3′), 72.1 (C-5′), 71.4 (C-2′), 68.4 (C-4′), 67.8, 61.8, 61.3, 34.2, 33.3,
32.0, 29.8, 29.6, 29.5, 29.4, 29.2, 25.5, 24.9, 22.8 (CH2); 20.8, 20.7,
14.2 (CH3); HRMS (ESI) m/z [M + H]+ calcd for C49H88NO14
914.6205; found 914.6199.
34.9, 33.8, 33.1, 32.9, 30.8, 30.6, 30.5, 30.2, 30.2, 26.6, 25.9, 23.8, 23.7
(CH2); 14.5 (CH3); HRMS (ESI) m/z [M + H]+ calcd for
C33H64NO10 634.4530; found 634.4525.
(2R)-2-O-(2-Ethylhexanoyl)amino-3-O-β-D-glucopyranosyl-1-
O-palmitoylglycerol (20). Deacetylation of 15 (85 mg, 0.106 mmol)
led to 20 as a paste (29 mg, 43% yield): Rf = 0.39 (CH2Cl2/MeOH
1
10/1); [α]D −29.7 (c 0.1, MeOH); H NMR (400 MHz, CD3OD) δ
4.37−4.21 (m, 3H, H-1′,3), 4.20−4.12 (m, 1H, H-2), 4.05 (dd, J =
11.1, 3.9 Hz, 1H, H-1a), 3.85 (d, J = 11.7 Hz, 1H, H-6′a), 3.75 (dd, J =
11.3, 6.2 Hz, 1H, H-1b), 3.71−3.60 (m, 1H, H-6′b), 3.44−3.24 (m,
3H, H-3′,4′,5′), 3.22−3.15 (m, 1H, H-2′), 2.34 (t, J = 7.3 Hz, 2H,
CH2), 2.03−1.90 (m, 1H, CH), 1.70−1.50 (m, 4H, 2 × CH2), 1.49−
1.17 (m, 30H, 15 × CH2), 1.06−0.81 (m, 9H, 3 × CH3); 13C NMR
(100 MHz, CD3OD) δ 175.7, 175.2 (CO); 104.9 (C-1′), 83.9, 78.0,
77.9, 75.0, 71.5 (CH); 69.0, 63.2, 62.7 (CH2); 46.6 (CH), 34.8, 33.3,
33.1, 30.8, 30.6, 30.5, 30.2, 26.9, 25.9, 23.7, 23.7 (CH2); 14.5, 14.4,
12.4 (CH3); HRMS (ESI) m/z [M + H]+ calcd for C33H64NO10
634.4530; found 634.4525.
(2R)-2-O-Oleoylamino-1-O-palmitoyl-3-O-(2′,3′,4′,6′-tetra-
O-acetyl-β-D-glucopyranosyl)glycerol (17). From 12 (151 mg,
0.22 mmol) and oleic acid, compound 17 was obtained as a white solid
(206 mg, 87%): mp 57 °C: Rf = 0.52 (petroleum ether/EtOAc 1/1);
(2R)-3-O-β-D-Glucopyranosyl-1-O-palmitoyl-2-O-palmitoyl-
aminoglycerol (21). Deacetylation of 16 (62 mg, 0.068 mmol) led to
21 as a white solid (31 mg, 61% yield): mp 177 °C: Rf = 0.24
1
[α]D −35.3 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ 8.83 (s,
1
(CH2Cl2/MeOH 20/1); [α]D −14.0 (c 0.1, MeOH); H NMR (400
1H, NH), 5.43−5.32 (m, 2H, CHCH), 5.24 (t, J = 9.5 Hz, 1H, H-
3′), 5.09 (t, J = 9.7 Hz, 1H, H-4′), 5.02 (dd, J = 9.6, 8.0 Hz, 1H, H-2′),
4.57 (d, J = 7.9 Hz, 1H, H-1′), 4.42 (dd, J = 12.2, 3.3 Hz, 1H, H-3a),
4.32−4.08 (m, 4H, H-2,3b,6′), 4.03−3.96 (m, 1H, H-1a), 3.78−3.69
(m, 2H, H-1b,5′), 2.36 (t, J = 7.5 Hz, 2H, CH2), 2.20−1.98 (m, 16H, 4
× OAc, 2 × CH2), 1.71−1.57 (m, 4H, 2 × CH2), 1.39−1.21 (m, 46H,
23 × CH2), 0.95−0.82 (m, 6H, 2 × CH3); 13C NMR (100 MHz,
CDCl3) δ 174.5, 170.8, 170.4, 170.3, 169.6 (CO); 130.1, 129.8
(CHCH); 100.7 (C-1′), 82.2 (CH), 72.5 (C-3′), 72.1 (C-5′), 71.4
(C-2′), 68.4 (C-4′), 67.8, 61.8, 61.3, 34.2, 33.3, 32.0, 29.9, 29.8, 29.6,
29.5, 29.4, 29.2, 27.3, 25.5, 25.0, 22.8 (CH2); 20.8, 20.7, 14.3 (CH3);
HRMS (ESI) m/z [M + H]+ calcd for C51H90NO14 940.6361; found
940.6356.
MHz, CD3OD) δ 4.39−4.22 (m, 3H, H-1′,3), 4.22−4.16 (m, 1H, H-
2), 4.08 (dd, J = 11.6, 3.5 Hz, 1H, H-1a), 3.90 (d, J = 12.0 Hz, 1H, H-
6′a), 3.78 (dd, J = 11.6, 6.3 Hz, 1H, H-1b), 3.69 (dd, J = 11.8, 5.2 Hz,
1H, H-6′b), 3.43−3.23 (m, 4H, H-2′,3′,4′,5′), 2.37 (t, J = 7.5 Hz, 2H,
CH2), 2.10 (t, J = 7.4 Hz, 2H, CH2), 1.69−1.58 (m, 4H, 2 × CH2),
1.49−1.10 (m, 48H, 24 × CH2), 0.96−0.86 (m, 6H, 2 × CH3); 13C
NMR (100 MHz, CD3OD) δ 175.1, 172.9 (CO); 104.6 (C-1′),
83.4, 77.5 74.6, 71.2 (CH); 68.9, 63.0, 62.5, 34.7, 33.6, 32.8, 30.5, 30.3,
30.2, 30.0 26.3, 25.6, 23.4 (CH2); 14.4 (CH3); HRMS (ESI) m/z [M
+ H]+ calcd for C41H80NO10 746.5782; found 746.5777.
(2R)-3-O-β-D-Glucopyranosyl-2-O-oleoylamino-1-O-
palmitoylglycerol (22). Deacetylation of 17 (125 mg, 0.133 mmol)
led to 22 as a white solid (35 mg, 34% yield): mp 162 °C: Rf = 0.32
General Procedure B for Deacetylation. Synthesis of (2R)-2-
O-acylamino-3-O-β-D-glucopyranosyl-1-O-palmitoylglycerol
(18−22). To a solution of acetylated compound (0.1 mmol) in 85%
EtOH (5 mL) was added N2H4·H2O (1.2 mmol). The mixture was
stirred at 50 °C overnight. The solution was poured into ice-cold brine
and extracted with CHCl3 (3 × 20 mL). The combined CHCl3 layers
were dried over MgSO4, filtered, evaporated, and purified by column
chromatography over silica gel (CH2Cl2/MeOH 30/1 to 20/1).
(2R)-3-O-β-D-Glucopyranosyl-2-O-hexanoylamino-1-O-
palmitoylglycerol (18). Deacetylation of 13 (105 mg, 0.14 mmol)
led to 18 as a white solid (30 mg, 44% yield): mp 94 °C: Rf = 0.43
1
(CH2Cl2/MeOH 10/1); [α]D −18.0 (c 0.1, MeOH); H NMR (400
MHz, CD3OD) δ 5.32 (s, 2H, CHCH), 4.37−4.20 (m, 3H, H-1′,3),
4.19−4.11 (m, 1H, H-2), 4.04 (d, J = 10.0 Hz, 1H, H-1a), 3.85 (d, J =
11.3 Hz, 1H, H-6′a), 3.79−3.71 (m, 1H, H-1b), 3.68−3.58 (m, 1H, H-
6′b), 3.40−3.22 (m, 3H, H-3′,4′,5′), 3.19 (t, J = 7.9 Hz, 1H, H-2′),
2.40−2.28 (m, 2H, CH2), 2.14−1.94 (m, 4H, 2 × CH2), 1.67−1.52
(m, 4H, 2 × CH2), 1.48−1.10 (m, 46H, 23 × CH2), 0.97−0.80 (m,
6H, 2 × CH3); 13C NMR (100 MHz, CD3OD) δ 175.2, 173.2 (C
O); 130.9, 130.8 (CHCH); 104.9 (C-1′), 83.7, 78.0, 77.9, 75.0, 71.6
(CH); 69.0, 63.4, 62.7, 34.9, 33.8, 33.1, 30.8, 30.7, 30.5, 30.4, 30.2,
28.2, 26.6, 26.0, 23.8 (CH2); 14.5 (CH3); HRMS (ESI) m/z [M + H]+
calcd for C43H82NO10 772.5939; found 772.5933.
1
(CH2Cl2/MeOH 8/1); [α]D −32.0 (c 0.1, MeOH); H NMR (400
MHz, CD3OD) δ 4.35−4.20 (m, 3H, H-1′,3), 4.19−4.12 (m, 1H, H-
2), 4.04 (dd, J = 11.4, 3.9 Hz, 1H, H-1a), 3.86 (d, J = 11.7 Hz, 1H, H-
6′a), 3.75 (dd, J = 11.4, 6.1 Hz, 1H, H-1b), 3.67−3.61 (m, 1H, H-6′b),
3.40−3.24 (m, 3H, H-3′,4′,5′), 3.22−3.15 (m, 1H, H-2′), 2.34 (t, J =
7.4 Hz, 2H, CH2), 2.07 (t, J = 7.4 Hz, 2H, CH2), 1.70−1.55 (m, 4H, 2
× CH2), 1.45−1.22 (m, 28H, 14 × CH2), 0.97−0.85 (m, 6H, 2 ×
CH3); 13C NMR (100 MHz, CD3OD) δ 175.2, 173.2 (CO); 104.9
(C-1′), 83.7, 78.0, 77.9, 75.0, 71.6 (CH); 69.0, 63.3, 62.7, 34.9, 33.7,
33.1, 32.4, 30.8, 30.6, 30.5, 30.2, 26.3, 25.9, 23.7, 23.4 (CH2); 14.5,
14.3 (CH3); HRMS (ESI) m/z [M + H]+ calcd for C31H60NO10
606.4217; found 606.4212.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H, 13C, Dept-135, COSY, and HMQC NMR spectra
of all described compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(2R)-3-O-β-D-Glucopyranosyl-2-O-octanoylamino-1-O-
palmitoylglycerol (19). Deacetylation of 14 (95 mg, 0.12 mmol) led
to 19 as a white solid (35 mg, 47% yield): mp 96 °C Rf = 0.26
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: joanne.xie@ppsm.ens-cachan.fr.
1
(CH2Cl2/MeOH 10/1); [α]D −21.7 (c 0.1, MeOH); H NMR (400
MHz, CD3OD) δ 4.37−4.19 (m, 3H, H-1′,3), 4.19−4.12 (m, 1H, H-
2), 4.04 (dd, J = 11.4, 3.8 Hz, 1H, H-1a), 3.86 (d, J = 11.6 Hz, 1H, H-
6′a), 3.75 (dd, J = 11.4, 6.2 Hz, 1H, H-1b), 3.63 (dd, J = 9.8, 7.2 Hz,
1H, H-6′b), 3.40−3.24 (m, 3H, H-3′,4′,5′), 3.22−3.16 (m, 1H, H-2′),
2.34 (t, J = 7.4 Hz, 2H, CH2), 2.07 (t, J = 7.4 Hz, 2H, CH2), 1.69−1.54
(m, 4H, 2 × CH2), 1.48−1.22 (m, 32H, 16 × CH2), 1.01−0.81 (m,
6H, 2 × CH3); 13C NMR (100 MHz, CD3OD) δ 175.2, 173.2 (C
O); 104.9 (C-1′), 83.7, 78.0, 77.9, 75.0, 71.6 (CH); 69.0, 63.3, 62.7,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.C. gratefully acknowledges China Scholarship Council
(CSC) for a doctoral scholarship.
E
dx.doi.org/10.1021/jo502128h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(19) Bartoszewicz, A.; Kalek, M.; Stawinski, J. Tetrahedron 2008, 64,
8843−8850.
(20) (a) Schenk, S.; Weston, J.; Anders, E. J. Am. Chem. Soc. 2005,
127, 12566−12576. (b) But, T. Y. S.; Toy, P. H. Chem.Asian J.
2007, 2, 1340−1355.
REFERENCES
■
(1) Shirahashi, H.; Murakami, N.; Watanabe, M.; Nagatsu, A.;
Sakakibara, J.; Tokuda, H.; Nishino, H.; Iwashima, A. Chem. Pharm.
Bull. 1993, 41, 1664−1666.
(2) (a) Murakami, C.; Kumagai, T.; Hada, T.; Kanekazu, U.;
Nakazawa, S.; Kamisuki, S.; Maeda, N.; Xu, X.; Yoshida, H.; Sugawara,
F.; Sakaguchi, K.; Mizushina, Y. Biochem. Pharmacol. 2003, 65, 259−
267. (b) Maeda, N.; Hada, T.; Murakami-Nakai, C.; Kuriyama, I.;
Ichikawa, H.; Fukumori, Y.; Hiratsuka, J.; Yoshida, H.; Sakaguchi, K.;
Mizushina, Y. J. Nutr. Biochem. 2005, 16, 121−128. (c) Maeda, N.;
Matsubara, K.; Yoshida, H.; Mizushina, Y. Mini-Rev. Med. Chem. 2011,
11, 32−38. (d) Colombo, D.; Scala, A.; Taino, I. M.; Toma, L.;
Ronchetti, F.; Tokuda, H.; Nishino, H.; Nagatsu, A.; Sakakibara, J.
Cancer Lett. 1998, 123, 83−86. (e) Sun, Y.; Zhang, J.; Li, C.; Guan, H.;
Yu, G. Carbohydr. Res. 2012, 355, 6−12. (f) Tanaka, R.; Sakano, Y.;
Nagatsu, A.; Shibuya, M.; Ebizuka, Y.; Goda, Y. Bioorg. Med. Chem.
Lett. 2005, 15, 159−162.
(3) Kinjo, Y.; Tupin, E.; Wu, D.; Fujio, M.; Garcia-Navarro, R.;
Benhnia, M. R.; Zajonc, D. M.; Ben-Menachem, G.; Ainge, G. D.;
Painter, G. F.; Khurana, A.; Hoebe, K.; Behar, S. M.; Beutler, B.;
Wilson, I. A.; Tsuji, M.; Sellati, T. J.; Wong, C.-H.; Kronenberg, M.
Nat. Immunol. 2006, 7, 978−986.
(4) (a) Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Tetrahedron
1994, 50, 2771−2784. (b) Morita, M.; Motoki, K.; Akimoto, K.;
Natori, T.; Sakai, T.; Sawa, E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.;
Fukushima, H. J. Med. Chem. 1995, 38, 2176−2187.
(5) (a) Schnaar, R. L.; Suzuki, A.; Stanley, P. In Essentials of
Glycobiology, 2nd ed.; Varki, A., Cummings, R. D., Esko, J. D., Freeze,
H. H., Stanley, P., Bertozzi, C. R., Hart, G. W., Etzler, M. E., Eds.; Cold
Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2009;
Chapter 10. (b) Schnaar, R. L. Arch. Biochem. Biophys. 2004, 426,
163−172.
(6) (a) Long, X.; Deng, S.; Mattner, J.; Zang, Z.; Zhou, D.; McNary,
N.; Goff, R. D.; Teyton, L.; Bendelac, A.; Savage, P. B. Nat. Chem. Biol.
2007, 3, 559−564. (b) Wu, D.; Fujio, M.; Wong, C.-H. Bioorg. Med.
Chem. 2008, 16, 1073−1083.
(7) Banchet-Cadeddu, A.; Henon, E.; Dauchez, M.; Renault, J.-H.;
́
Monneaux, F.; Haudrechy, A. Org. Biomol. Chem. 2011, 9, 3080−3104
and references therein.
(8) Lee, T.; Cho, M.; Ko, S.-Y.; Youn, H.-J.; Baek, D. J.; Cho, W.-J.;
Kang, C.-Y.; Kim, S. J. Med. Chem. 2007, 50, 585−589.
(9) Malhotra, R. Biochem. Anal. Biochem. 2012, 1, 108.
(10) Li, X.; Wu, Y.-D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428−
1438.
(11) Chandrasekhar, S.; Rao, C. L.; Reddy, M. S.; Sharma, G. D.;
Kiran, M. U.; Naresh, P.; Chaitanya, G. K.; Bhanuprakash, K.;
Jagadeesh, B. J. Org. Chem. 2008, 73, 9443−9446.
(12) Chen, F.; Ma, B.; Yang, Z.-C.; Lin, G.; Yang, D. Amino Acids
2012, 43, 499−503.
(13) (a) Malapelle, A.; Ramozzi, R.; Xie, J. Synthesis 2009, 888−890.
(b) Gong, Y. C.; Sun, H. B.; Xie, J. Eur. J. Org. Chem. 2009, 6027−
6033. (c) Gong, Y.; Peyrat, S.; Sun, H.; Xie, J. Tetrahedron 2011, 67,
7114−7120. (d) Song, Z.; He, X.-P.; Chen, G.-R.; Xie, J. Synthesis
2011, 2761−2766. (e) Peyrat, S.; Xie, J. Synthesis 2012, 44, 1718−
1724. (f) Noel, O.; Xie, J. Synthesis 2013, 45, 134−140. (g) Peyrat, S.;
Cheng, K.; Xie, J. Synthesis 2013, 45, 2737−2744. (h) Zhang, H.-L.;
Zang, Y.; Xie, J.; Chen, G.-R.; He, X.-P.; Tian, H. Sci. Rep. 2014, 4,
5513.
(14) Ishida, J.; Hinou, H.; Naruchi, K.; Nishimura, S.-I. Bioorg. Med.
Chem. Lett. 2014, 24, 1197−1200.
(15) van Boeckel, C. A. A.; Visser, G. M.; van Boom, J. H.
Tetrahedron 1985, 41, 4557−4565.
(16) Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 5232−5234.
(17) Mannock, D. A.; Lewis, R. N.; McElhaney, R. N. Chem. Phys.
Lipids 1987, 43, 113−127.
(18) Janwitayanuchit, W.; Suwanborirux, K.; Patarapanich, C.;
Pummangura, S.; Lipipun, V.; Vilaivan, T. Phytochemistry 2003, 64,
1253−1264.
F
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