First total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol-a glycoglycerolipid of a marine alga with a high inhibitor activity against human Myt1-kinase

Article abstract of DOI:10.1016/j.carres.2009.05.022

The first total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-6′-amino-6′-deoxy-α-d-glucosyl)-sn-glycerol, a glycoglycerolipid isolated from a marine alga extract, is described. Starting from α-methylglucopyranoside the multistep strategy allows the stereoselective synthesis of the final compound using various protective group procedures as well as derivatization of partial molecule domains. The latter offers the development of lead structures for inhibitors of human Myt1-kinase.

Full text of DOI:10.1016/j.carres.2009.05.022

Carbohydrate Research 344 (2009) 1628–1631
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
First total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-60-amino-60-deoxy-
a-D-
glucosyl)-sn-glycerol—a glycoglycerolipid of a marine alga with a high inhibitor
activity against human Myt1-kinase
Christiane Göllner a, Claudia Philipp a, Bodo Dobner b, Wolfgang Sippl a, Matthias Schmidt a,
*
a Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str.4, 06120 Halle, Germany
b Department of Biochemical Pharmacy, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str.4, 06120 Halle, Germany
a r t i c l e i n f o
a b s t r a c t
The first total synthesis of 1,2-dipalmitoyl-3-(N-palmitoyl-60-amino-60-deoxy-
a glycoglycerolipid isolated from a marine alga extract, is described. Starting from
side the multistep strategy allows the stereoselective synthesis of the final compound using various pro-
tective group procedures as well as derivatization of partial molecule domains. The latter offers the
development of lead structures for inhibitors of human Myt1-kinase.
a
-
D
-glucosyl)-sn-glycerol,
Article history:
Received 16 March 2009
Received in revised form 15 May 2009
Accepted 28 May 2009
a-methylglucopyrano-
Available online 2 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glycoglycerolipid
Myt1-kinase
Glycosylation
1. Introduction
group for current measurements.5 All known selective (e.g., imatinib
and lapatinib) and non-selective kinase inhibitors (e.g., stauro-
Resulting from a systematic search of potential anti-cancer
agents from plants and marine organisms a range of constituents
were isolated which showed a high activity in a human Myt1-kinase
inhibition assay. Complex structure determination of the crude ex-
tract led to glycoglycerolipids including the most active compound
sporine and K-252a) work by binding the ATP binding site of the ki-
nases and therefore lead to inhibition of the enzyme activity of the
protein competitively. There are only a few studies that deal with
the interaction of glycolipids and kinases. Recently it could be shown
by X-ray crystallography and surface plasmon resonance thatsimple
glycolipids and fatty acid derivatives can bind to kinases and act as
activators and inhibitors depending on the structural variation.6
(IC50 of
g/mL) 1,2-dipalmitoyl-3-(N-palmitoyl-60-amino-60-
deoxy- -D
-glucosyl)-sn-glycerol (Scheme 1; compound 14).1
4
l
a
The human Myt1-kinase is a Thr-14 and Tyr-15 specific regula-
tor of Cdc2-kinase activity. The inhibitory phosphorylation of Cdc2
is important for timing the entry into mitosis. Various studies have
shown that premature activation of Cdc2 would lead to mitotic
dysfunction and apoptosis.2 Inhibition of Myt1-kinase is predicted
to cause premature activation of Cdc2.3,4 Therefore inhibitors of
Myt1-kinase are supposed to kill rapidly proliferating cells and
interfere with cell cycle checkpoints. Such inhibitors could repre-
sent an extension to conventional chemotherapy and could help
overcoming resistance.
The rapid development in the field of kinase inhibitors is demon-
strated by the commercial launch of imatinib and lapatinib recently.
So the current research activity is promoted and accelerated by the
development of suitable inhibitors as well as the conception of
appropriate biochemical assays.2,3 Thus, an innovative fluorescence
polarizationassayforWee1-andMyt1-kinaseswasdescribedbyRu-
dolph and Kristjansdottir that was established and expanded in our
For p38
copyranose can bind near the ATP binding site as well as in a lipid
binding site. Based on a comparison of p38 crystal structures and
our homology model of Myt1-kinase we can find structure analogies
in the areas of the binding sites. Therefore we hypothesize that sim-
ple glycolipids as well as the marine glycoglycerolipids have a simi-
lar binding mode in Myt1-kinase.
Searching for potential Myt1 inhibitors the isolated glycoglycer-
olipid represents an attractive target for neosynthesis and deriva-
tization of molecule domains. Development of analogues as lead
structures is in continuation of our work to glycolipids and is based
on our knowledge on neosynthesis of natural products. Here we
describe the first total synthesis of the title compound in 13 steps
which strategy is shown in Scheme 1.7–9
a kinase was shown that three molecules of n-octyl-b-D-glu-
a
2. Results and discussion
Starting point of our synthesis was the commercially available
and inexpensive
a-methylglucopyranoside 1 which is character-
* Corresponding author.
E-mail address: matthias.schmidt@pharmazie.uni-halle.de (M. Schmidt).
ized by stereoselective protection of the anomeric carbon atom.10
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.05.022

C. Göllner et al. / Carbohydrate Research 344 (2009) 1628–1631
1629
Cl
Cl
N3
O
BnO
BnO
O
N
h)
g)
OBn
N3
8
N3
O
BnO
BnO
O
BnO
Cl
BnO
7
BnO
OH
O
BnO
f)
O
9
O
O
i)
N3
N3
O
O
BnO
BnO
BnO
BnO
OH
BnO
BnO
6
10
OCH3
OH
j)
e)
N3
OMes
O
O
O
O
O
BnO
BnO
BnO
BnO
O
O
(CH2)14CH3
BnO
BnO
11
5
O
O
O
(CH2)14CH3
OCH3
d)
OH
k)
O
NH2
BnO
O
BnO
BnO
BnO
BnO
4
(CH2)14CH3
(CH2)14CH3
OCH3
OCH3
BnO
c)
OTrt
12
O
l)
O
O
O
BnO
BnO
H3C(H2C)14
NH
BnO
3
O
O
b)
BnO
BnO
O
(CH2)14CH3
OTrt
BnO
13
O
O
O
(CH2)14CH3
O
HO
m)
HO
O
O
OH
2
OCH3
a)
H3C(H2C)14
NH
O
O
OH
HO
HO
O
(CH2)14CH3
O
OH
HO
14
O
(CH2)14CH3
HO
OH
1
OCH3
O
Scheme 1. 13-step synthesis of the compound. Reagents and conditions: (a) TrCl, py, DMAP, 80 °C/4 h, 77%; (b) BnCl, NaH, 123 °C/2 h, 95%; (c) BF3–Et2O, CH2Cl2, rt/1 h, 92%;
(d) MsCl; TEA, CH2Cl2, ꢀ5 °C/1 h, 71%; (e) NaN3, DMF, 90 °C/8 h, 95%; (f) H2SO4/AcOH, 80 °C/4 h, 65%; (g) NaH, N,2,2-tris-(4-chlorphenyl)ketenimine, CH2Cl2, rt/5 h, 51%; (h)
(S)-1,2-isopropylideneglycerol, CH2Cl2, TMSOTf, ꢀ20 °C/0.5 h, 46%; (i) PPTS, MeOH, 65 °C/5 h, 82%; (j) DCC/palmitic acid, toluene, 50 °C/4 h, 67%; (k) triphenylphosphine, THF,
rt/24 h, 95%; (l) PyBOP/palmitic acid, CH2Cl2, rt/40 h, 87%; (m) PdOH, THF/IPA, 20 bar/24 h, 95%.
A modified method for tritylation of the primary hydroxyl group
with triphenylmethylchloride (TrCl) in absolute pyridine and cata-
lytic amounts of DMAP leads to compound 2 as considerable inter-
mediate for selective derivatization of position C6.11 Benzylation of
the secondary hydroxyl groups by use of a large excess of benzyl
chloride (BnCl) in the presence of sodium hydride resulted in 3.12
Afterwards the trityl protecting group was removed with trifluo-
roborane etherate complex yielding compound 4 with a free hy-
On the one hand the azido group can be reduced to give a deriv-
ative with an amino group, so it is a key intermediate for the syn-
thesis of amino glycosides. Otherwise the azido group can also be
used as protective group during the following glycosylation. A
requirement for glycosylation is deprotection of the anomeric C1
by acid hydrolysis of the methoxy group to get 7. This was reached
by a modified method with a mixture of sulfuric acid and acetic
acid under gentle conditions.16
droxyl group in position C6.13 Conversion into
5
with
The stereoselective glycosylation of 1-O-unsubstitued hexoses
depends on the base which is used. The reaction of derivative 7
as a-D-glucosyl donor with (S)-1,2-isopropylideneglycerol as
methanesulfonyl chloride14 affords the nucleophilic reaction with
sodium azide to give 6.15

1630
C. Göllner et al. / Carbohydrate Research 344 (2009) 1628–1631
acceptor substrate was accomplished by activating the remaining
free hydroxyl group by base-catalyzed addition of N,2,2-tris-(4-
chlorphenyl)ketenimine resulting in the ß-glycosyl imidate 8 in
sampled with a Fraction Collector C-660 (Büchi) by discontinuous
enhancement of polarity, for pressure we used a Pump Module
C-601 and a Pump Manager C-615 (Büchi). TLC was carried out on
silica gel plates (E. Merck 60 F254); zones were detected visually
by ultraviolet irradiation (254 nm) or by detection with spray
(solution of 0.5 g thymol and 5 ml concd sulfuric acid in 100 ml
ethanol) and heating at 130 °C for 10 min. All reagents were used
as purchased unless otherwise stated. Solvents were dried, accord-
ing to standard procedures. All reactions were carried out under an
atmosphere of dry argon. All chemicals were purchased from
Sigma–Aldrich Chemie GmbH (Germany).
good yields with a stereoselectivity of 8
vated intermediate reacted in an acid-catalyzed reaction with (S)-
1,2-isopropylideneglycerol to form 9 in a mixture of - and b-ano-
a
:8b = 26:74.17,18 This acti-
a
mers at the rate of 78:22 that can be separated by MPLC to obtain
both isomers. Thereby stereoselectivity of the glycosylation is
influenced by choice of the Lewis acid catalyst. Trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) as strong Lewis acid apparently
affords formation of the
a-glycoside as thermodynamic stable
form.19 A better separation of the anomers can be achieved by
immediate hydrolysis of the raw isopropylidene protecting group
using pyridiniumtosylate (PPTS) in methanol to give 10 caused
by the variation of the Rf-values concerning the anomer mixture
of 9 and 10, respectively. Acylation of the remaining free hydroxyl
groups was realized using palmitic anhydride which was synthe-
sized from the acid by DCC-method to get the intermediate 11 with
two hydrophobic acyl chains. Reduction of the azido group using
triphenylphosphine in absolute THF and hydrolysis yielded the
appropriate amino derivative 12. The next step comprised acyla-
tion of the remaining amino group with palmitic acid to insert
the last chain (13). Therefore benzotriazol-1-yl-oxytripyrrolidino-
phosphonium hexafluorophosphate (PyBOP) was used as coupling
reagent which is suitable as gentle alternative to acylation with
long-chain fatty acids. The final step was accomplished by catalytic
hydrogenation using PdOH in THF/isopropylalcohol v/v 9:1 mix-
ture under pressure to give the aspired product 14.
4.2. Chemistry
Synthesis of the compounds 2–7 was achieved by the modified
published methods. Experimental data correspond with the litera-
ture.11–16
4.2.1. (60-Azido-20,30,40-tri-O-benzyl-60-deoxy-b-
N,2,2-tri(p-chlorophenyl)ethanimidoate (8)
D-glucosyl)-
To a solution of 7 (5 g/8.7 mmol) in CH2Cl2 (50 ml) was added
NaH (3.48 g (60%)/87 mmol) and stirred for 0.5 h. To the reaction
mixture was added N-2,2-tris-(4-chlorphenyl)ketenimine17,18
(3.24 g/8.7 mmol) and stirred for 5 h at rt. The mixture was filtered,
concentrated and purified by MPLC (heptanes/diethylether) to give
3.78 g of 8 (51%) as a yellow syrup.
4.2.2. 3-O-(60-Azido-20,30,40-tri-O-benzyl-60-deoxy-
1,2-isopropylidene-sn-glycerol (9)
a-D-glucosyl)-
1H NMR studies of the synthetic compounds 14 enable us to
establish the absolute structures having the
ride at the glycerol sn-3 position. The data were completely in
accord with the data for the natural product.
a
-linked monosaccha-
The intermediate 8 (4 g/4.7 mmol) and (S)-1,2-isopropylidene-
glycerol (2.48 g/18.8 mmol) in CH2Cl2 (20 ml) were cooled at
ꢀ20 °C. To the reaction mixture was added trimethylsilyl trif-
luormethansulfonate as catalyst (1.8 mmol) and stirred for 0.5 h.
For neutralization eq. TEA was added and washed with a saturated
NaHCO3 solution and water. The organic layer was dried over
Na2SO4, filtered and concentrated. Purification was accomplished
by MPLC (CHCl3/MeOH) to give 1.32 g of 9 in yields of 46% as a
white waxy substance.
3. Conclusions
We describe the first total synthesis of 1,2-dipalmitoyl-3-(N-
palmitoyl-60-amino-60-deoxy-
a-
D-glucosyl)-sn-glycerol in a multi-
step strategy starting from
a-methylglucopyranoside. The strategy
1H NMR (CDCl3, 500 MHz): d 1.35 (s, 3H, ꢀCH3), 1.41 (s, 3H,
also allows the selective modification of defined structure moieties
of the synthesized glycoglycerolipid. The aim of our prospective
investigations is the systematical derivatization of the carbohy-
drate domain, variances of length of the fatty acids and substitu-
tion of the core-structure. The glycoglycerolipid 14, first isolated
from a marine alga extract, is described to inhibit human Myt1-ki-
nase. So the retrosynthesis of the final compound as well as deriv-
atization of partial molecule domains offers the development of
new lead structures for potent and bioavailable inhibitors of
Myt1-kinase. Because of their structure they should not show
ATP competition contrary to known unspecific kinase inhibitors,
for example, staurosporin and describe an innovative class of
Myt1-kinase inhibitors.20
0
ꢀCH3), 3.31 (dd, 1H, H-6, J5,6 5.5 Hz, J6,6 12.8 Hz), 3.39–3.47 (m,
2H, H-4, H-60), 3.51–3.56 (m, 2H, H-2, Hsn-1), 3.62 (dd, 1H, Hsn-1
,
0
0
0
J1,2 5.5 Hz, J1,1 10.7 Hz), 3.73 (dd, 1H, Hsn-3, J2,3 6.0 Hz, J3,3
8.5 Hz), 3.78–3.82 (m, 1H, H-5), 3.94 (t, 1H, H-3, J2,3 = J3,4 9.0 Hz),
0
0
0
4.06 (dd, 1H, Hsn-3 , J2,3 6.4 Hz, J3,3 8.2 Hz), 4.34 (m, 1H, Hsn-2),
4.86 (d, 1H, H-1, J1,2 3.4 Hz), 4.55–4.98 (m, 6H, –CH2–Ph), 7.21–
7.35 (m, 15H, –C6H5); MALDI TOF mass spectrum: m/z 612
(M+Na+). HRFABMS m/z 612.2663 [M+Na+]; (calcd for C33H39N3O7
612.2680). ½a 2D2
ꢁ
+58.50 (c 11.96, CHCl3).
4.2.3. 3-O-(60-Azido-20,30,40-tri-O-benzyl-60-deoxy-
sn-glycerol (10)
a-D-glucosyl)-
The glycoside 9 (1 g/1.7 mmol) was dissolved in MeOH (50 ml)
and pyridiniumtosylate (0.85 g/3.4 mmol) was added. The reaction
mixture was stirred for 5 h at 65 °C. Then the solution was concen-
trated and dissolved in CH2Cl2. The organic layer was washed with
water, dried over Na2SO4, filtered and concentrated. Purification
was achieved by MPLC (heptane/diethylether) to give 797 mg of
10 (82%) as a colourless waxy substance.
4. Experimental
4.1. General methods
Mass spectra (MS) were recorded off-line with nano-ESI (Prox-
eon emitters, Odense, Denmark) on a LTQ-Orbitrap XL (Thermo Fish-
er Scientific, San Jose, USA). 1H NMR spectra were obtained with a
Varian Inova 500 spectrometer operating at 500 MHz; all values
are reported in ppm (d) downfield from solvent. Polarimetric mea-
surements were accomplished by an Eloptron/Polartronic E (Sch-
mid+Haensch GmbH & Co.). Chromatography was performed on
silica gel (Merck Silica Gel 60, 40–63 mesh) by MPLC. Therefore col-
umns were prepared with a Cartriger C-670 (Büchi). Fractions were
1H NMR (CDCl3, 500 MHz): d 3.31 (dd, 1H, H-6, J5,6 5.7 Hz, J6,6
0
13.1 Hz), 3.39–3.46 (m, 3H, H-4, H-60, Hsn-1), 3.53 (dd, 1H, H-2,
J1,2 3.7 Hz, J2,3 9.7 Hz), 3.57–3.77 (m, 2H, Hsn-3), 3.79–3.87 (m, 1H,
0
H-5), 3.84–3.87 (m, 2H, Hsn-1 , Hsn-2), 3.93 (t, 1H, H-3, J2,3 = J3,4
9.0 Hz), 4.72 (d, 1H, H-1, J1,2 3.7 Hz), 4.55–4.95 (m, 6H, –CH2–Ph),
7.23–7.33 (m, 15H, –C6H5); MALDI TOF mass spectrum: m/z 572
(M+Na+). HRFABMS m/z 572.23673 [M+Na+]; (calcd for
C30H35N3O7 572.23672). ½a D22
ꢁ
+35.71 (c 0.56, CHCl3).

C. Göllner et al. / Carbohydrate Research 344 (2009) 1628–1631
1631
4.2.4. 1,2-Dipalmitoyl-3-O-(60-azido-20,30,40-tri-O-benzyl-60-
deoxy- -glucosyl)-sn-glycerol (11)
H-2, J1,2 3.4 Hz, J2,3 9.7 Hz), 3.55 (dd, 1H, Hsn-1, J1,2 5.4 Hz, J1,1
0
0
a-
D
11.2 Hz), 3.62–3.77 (m, 3H, H-60, H-5, Hsn-1 ), 3.93 (t, 1H, H-3,
J2,3 = J3,4 9.0 Hz), 4.17 (dd, 1H, Hsn-3, J2,3 6.1 Hz, J3,3 12.0 Hz), 4.38
0
To a solution of 10 (440 mg/0.78 mmol) in toluene (10 mL) were
added palmitic acid anhydride (1.56 mmol) in toluene (10 ml), that
was prepared from palmitic acid by DCC-method in CCl4, and cat-
alytical amounts of DMAP. The reaction mixture was stirred at
50 °C. After 4 h DCC (160 mg/0.78 mmol) was added again and
the reaction mixture was stirred for 12 h at rt. The mixture was fil-
tered, washed with water and satd NH4Cl solution, dried over
Na2SO4 filtered and concentrated under diminished pressure. The
residue was purified by MPLC (heptane/diethylether) to give
548 mg of 11 (67%) as a white paste-like substance. 1H NMR
(CDCl3, 500 MHz): d 0.86 (t, 6H, –CH3, J 7.0 Hz), 1.10–1.30 (m,
48H, 2ꢂ–CH2–CH2–(CH2)12–CH3), 1.55–1.61 (m, 4H, 2ꢂ–CO–CH2–
CH2–),2.25–2.30 (m, 4H, 2ꢂ–CO–CH2–), 3.29 (dd, 1H, H-6, J5,6
0
0
0
(dd, 1H, Hsn-3 , J2,3 3.6 Hz, J3,3 11.9 Hz), 4.68 (d, 1H, H-1, J1,2
3.6 Hz), 4.60–4.95 (m, 6H, –CH2–Ph), 5.15–5.25 (m, 1H, Hsn-2),
5.59–5.64 (m, 1H, –NH–CO–), 7.17–7.32 (m, 15H, –C6H5); MALDI
TOF mass spectrum: m/z 1239 (M+H+). HRFABMS m/z
1238.95190 [M+H+]; (calcd for C78H127NO10 1238.95328). ½a 2D2
ꢁ
+13.57 (c 10.32, CHCl3).
4.2.7. 1,2-Dipalmitoyl-3-(N-palmitoyl-60-amino-60-deoxy-
glucosyl)-sn-glycerol (14)
a-D-
The intermediate 13 (124 mg/0.1 mmol) was dissolved in 50 ml
THF/IPA (90:10) and removal of the O-benzyl groups was achieved
by palladium hydroxide-catalyzed hydrogenolysis (PdOH, 20 bar/
24 h). After filtration the solvents were evaporated and the residue
was purified by MPLC (CHCl3/MeOH) to provide 92 mg of the final
compound 14 (95%) as a white paste-like substance. 1H NMR
(CDCl3, 500 MHz): d 0.86 (t, 9H, –CH3, J 7.1 Hz), 1.21–1.29 (m,
72H, 36ꢂ–CH2–),1.60 (m, 6H, –CH2–CH2–CO–), 2.18–2.27 (m, 6H,
5.5 Hz, J6,6 13.0 Hz), 3.39–3.44 (m, 2H, H-4, H-60), 3.49–3.59 (m,
0
0
2H, H-2, Hsn-1), 3.73–3.79 (m, 2H, H-5, Hsn-1 ), 3.92 (t, 1H, H-3,
0
J2,3 = J3,4 9.3 Hz), 4.18 (dd, 1H, Hsn-3, J2,3 6.0 Hz, J3,3 12.0 Hz),
0
4.35–4.41 (m, 1H, Hsn-3 ), 4.72 (d, 1H, H-1, J1,2 3.3 Hz), 4.53–4.96
(m, 6H, –CH2–Ph), 5.21–5.25 (m, 1H, Hsn-2), 7.22–7.33 (m, 15H,
–C6H5); MALDI TOF mass spectrum: m/z 1049 (M+Na+). HRFABMS
–CH2CO–), 3.01 (dd, 1H, H-6, J5,6 7.4 Hz, J6,6 14.9 Hz), 3.07 (dd,
0
/z 1048.69763 [M+Na+]; (calcd for C62H95N3O9 1048.69605). ½a 2D2
0
0
m
ꢁ
1H, H-4, J3,4 9.6 Hz, J4,5 9.6 Hz), 3.46 (dd, 1H, H-60, J5,6 3.9 Hz, J6,6
+46.08 (c 4.34, CHCl3).
14.8 Hz), 3.56 (dd, 1H, H-2, J1,2 3.9 Hz, J2,3 9.5 Hz), 3.61 (dd, 1H,
0
Hsn-3, J2,3 6.0 Hz, J3,3 11.0 Hz), 3.71 (dd, 1H, H-3, J2,3 9.4, Hz, J3,4
4.2.5. 1,2-Dipalmitoyl-3-O-(60-amino-20,30,40-tri-O-benzyl-60-
9.7 Hz), 3.77 (dd, 1H, Hsn-3 , J2,3 4.6 Hz, J3,3 11.0 Hz), 4.02 (ddd,
0
0
0
0
deoxy-
a
-
D
-glucosyl)-sn-glycerol (12)
1H, H-5, J5,6 3.8 Hz, J5,6 7.4 Hz, J4,5 9.5 Hz), 4.11 (dd, 1H, Hsn-1, J1,2
0
0
0
0
To a solution of 11 (320 mg/0.312 mmol) in THF (20 mL) was
added triphenylphosphine (327 mg/1.25 mmol). The reaction mix-
ture was stirred at rt for 24 h. To the reaction mixture was added
water and stirred again for another 24 h at rt. The mixture was
evaporated, dissolved in heptane to remove triphenyloxide by fil-
tration, washed with brine, dried over Na2SO4 filtered and concen-
trated under diminished pressure. The residue was purified by
MPLC (CHCl3/MeOH) to give 297 mg of 12 (95%) as a white
paste-like substance. 1H NMR (CDCl3, 500 MHz): d 0.86 (t, 6H,
–CH3, J 7.0 Hz), 1.10–1.40 (m, 48H, 2ꢂ–CH2–CH2–(CH2)12–CH3),
1.65–1.83 (m, 4H, 2ꢂ–CO–CH2–CH2–), 2.25–2.40 (m, 4H, 2ꢂ–CO–
5.9 Hz, J1,1 11.9 Hz), 4.36 (dd, 1H, Hsn-1 , J1 ,2 4.2 Hz, J1,1 11.8 Hz),
4.78 (d, 1H, H-1, J1,2 4.1 Hz), 5.22 (m, 1H, Hsn-2), 5.83 (m, 1H,
–NH–CO–); MALDI TOF mass spectrum: m/z 990 (M+Na+).
HRFABMS m/z 968.8121 [M+H+]; (calcd for C57H110NO10
968.8130). ½a 2D2
ꢁ
+12.38 (c 0.32, CHCl3).
Acknowledgement
This work was supported by research funds from ‘Kultusminis-
terium des Landes Sachsen-Anhalt’.
References
0
CH2–), 2.71 (dd, 1H, H-6, J5,6 6.0 Hz, J6,6 13.0 Hz), 2.95 (dd, 1H, H-
60, J5,6 3.0 Hz, J6,6 13.0 Hz), 3.33 (t, 1H, H-4, J3,4 = J4,5 9.2 Hz), 3.47
(dd, 1H, H-2, J1,2 3.7 Hz, J2,3 10.0 Hz), 3.53–3.58 (m, 1H, H-5), 3.53
0
0
1. Zhou, B.-N.; Tang, S.; Johnson, R. K.; Mattern, M. P.; Lazo, J. S.; Sharlow, E. R.;
Harich, K.; Kingston, D. G. I. Tetrahedron 2005, 61, 883–887.
2. Squire, C. J.; Dickson, J. M.; Ivanovic, I.; Baker, E. N. Structure 2005, 13, 541–550.
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1999, 5113–5123.
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139–147.
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Annual Conference of the German Pharmaceutical Society, Bonn, D, Oct 8–11,
2008; A65.
11. Tennant-Eyles, R. J.; Davis, B. G.; Fairbanks, A. J. Tetrahedron: Asymmetry 2000,
11, 231–243.
0
0
0
(dd, 1H, Hsn-1, J1,2 6.0 Hz, J1,1 11.0 Hz), 3.72 (dd, 1H, Hsn-1 , J1 ,2
6.0 Hz, J1,1 11.0 Hz), 3.93 (t, 1H, H-3, J2,3 = J3,4 9.2 Hz), 4.18 (dd,
0
0
0
0
1H, Hsn-3, J2,3 6.0 Hz, J3,3 12.0 Hz), 4.39 (dd, 1H, Hsn-3 , J2,3 3.0 Hz,
J3,30 12.0 Hz), 4.69 (d, 1H, H-1, J1,2 3.7 Hz), 4.59–4.97 (m, 6H,
–CH2–Ph), 5.20–5.25 (m, 1H, Hsn-2), 7.24–7.67 (m, 15H, –C6H5);
MALDI TOF mass spectrum: m/z 1001 (M+H+). HRFABMS m/z
1000.72382 [M+H+]; (calcd for C62H97NO9 1000.72361).
½ ꢁ
a 2D2
+37.62 (c 3.19, CHCl3).
4.2.6. 1,2-Dipalmitoyl-3-(N-palmitoyl-60-amino-20,30,40-tri-O-
benzyl-60-deoxy-
-glucosyl)-sn-glycerol (13)
a-D
To a solution of 12 (200 mg/0.2 mmol) in CH2Cl2 (10 ml) were
added PyBOP (100 mg/0.2 mmol) and palmitic acid (50 mg/
0.2 mmol). The reaction mixture was stirred for 21 h at rt. CH2Cl2
was evaporated under diminished pressure and the residue was
purified by MPLC (heptanes/diethylether) to give 216 mg of 13
(87%) as a white waxy substance. 1H NMR (CDCl3, 500 MHz): d
0.86 (t, 9H, –CH3, J 7.0 Hz), 1.12–1.42 (m, 72H, 3ꢂ–CH2–CH2–
(CH2)12–CH3), 1.51–1.64 (m, 4H, 3ꢂ–CO–CH2–CH2–), 2.07–2.12
(m, 2H, –NH–CO–CH2–), 2.25–2.30 (m, 4H, 2ꢂ–CH2–COO–), 3.26
(t, 1H, H-4, J3,4 = J4,5 9.4 Hz), 3.31–3.35 (m, 1H, H-6), 3.45 (dd, 1H,
12. Koto, S.; Morishima, M.; Miyata, Y.; Zen, I. Bull. Chem. Soc. Jpn. 1976, 49, 2639–
2640.
13. Dax, K.; Wolflehner, H.; Weidmann, H. Carbohydr. Res. 1978, 65, 132–138.
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15. Takagi, Y.; Tsuchiya, T.; Umezawa, S. Bull. Chem. Soc. Jpn. 1973, 46, 1261–1262.
16. Kavadias, G.; Dextraze, P.; Massé, R.; Belleau, B. Can. J. Chem. 1978, 56, 2086–2092.
17. Stevens, C. L.; Freemann, R. C.; Noll, K. J. Org. Chem. 1965, 30, 3718–3720.
18. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19, 731–732.
19. Grundler, G.; Schmidt, R. R. Liebigs Ann. Chem. 1984, 1826–1847.
20. Philipp, C.; Göllner, C.; Rüttinger; H.H.; Sippl, W.; Schmidt, M. Abstracts of
Papers, Annual Conference of the German Pharmaceutical Society, Bonn, D, Oct
8–11, 2008; B40.