Synthesis of the mixed acetal segment of S-glyceroplasmalopsychosine

Article abstract of DOI:10.1016/j.tet.2008.08.023

In this report the concept of converting carbohydrate to non-carbohydrate asymmetric molecules has been successfully exploited. The mixed acetal segment of glyceroplasmalopsychosine, a novel glycolipid, has been synthesized in a stereospecific manner using two simple sugar units. The glycosidation reaction between these two monosaccharides ensured the correct acetal stereocenter of the target molecule. Either olefin metathesis or heterogeneous Wittig reactions were used for constructing the long aliphatic chain of glyceroplasmalopsychosine.

Full text of DOI:10.1016/j.tet.2008.08.023

Tetrahedron 64 (2008) 9821–9827
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of the mixed acetal segment of S-glyceroplasmalopsychosine
*
Ajit K. Parhi, David R. Mootoo, Richard W. Franck
Department of Chemistry and Biochemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10021, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2008
Received in revised form 6 August 2008
Accepted 7 August 2008
Available online 12 August 2008
In this report the concept of converting carbohydrate to non-carbohydrate asymmetric molecules has
been successfully exploited. The mixed acetal segment of glyceroplasmalopsychosine, a novel glycolipid,
has been synthesized in a stereospecific manner using two simple sugar units. The glycosidation reaction
between these two monosaccharides ensured the correct acetal stereocenter of the target molecule.
Either olefin metathesis or heterogeneous Wittig reactions were used for constructing the long aliphatic
chain of glyceroplasmalopsychosine.
Dedicated to Professor Klaus Grohmann, our
friend and colleague, on the occasion of his
retirement from Hunter College of CUNY
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Glyceroplasmalopsychosine
Mixed acetal
Conversion of carbohydrate to non-
carbohydrate asymmetric molecules
Heterogeneous Wittig reaction
Olefin metathesis
Wilkinson’s catalyst
1. Introduction
Glyceroplasmalopsychosine is the most recent cationic sphingo-
lipid extracted from the white matter of bovine brain. Although
Long chain aldehydes, hexadecanal, and octadecanal, with or
without a double bond, are collectively called plasmal.1,2 They are
a common component of a novel type of glycosphingolipid (GSL) in
which a plasmal is conjugated to two hydroxyl groups of psycho-
sine or galactosylceramide through a cyclic acetal linkage. These
were originally isolated from human brain white matter and are
termed, respectively, plasmalopsychosine (PLPS)3 1 and plasmalo-
cerebroside.4 Recently Hikita5 et al. have isolated a novel glycolipid
‘glyceroplasmalopsychosine’ 2 from the white matter of bovine
brain. This unique glycolipid contains a glycerol moiety, a plasmal,
and psychosine where the plasmal is conjugated to the primary
hydroxyl group of the glycerol and the 6-hydroxyl of the psychosine
by an acetal linkage.6,7 Glyceroplasmalopsychosine exists as a pair
of stereoisomers whose structures depend on the mode of plasmal
conjugation, i.e., the way that O-plasmal conjugate is linked at C1 at
two primary hydroxyl groups at glycerol and galactose. The struc-
tures of both the isomers, which differ with respect to the asym-
metric C-1 carbon of the aldehyde are shown in Figure 1.
glyceroplasmalopsychosine is characterized by properties similar to
those of PLPS, it has certain properties distinct from them due to the
presence of an additional polar group, i.e., glycerol. The glycerol res-
idue may interact with galactosyl residue to achieve steric stability,
such that axes of two aliphatic chains, sphingosine and plasmal, are
orientedinparallel regardlessof theC1stereoisomerofplasmal. NMR
data indicate that two stereoisomers with regard to the asymmetric
C1 carbon of plasmal in glyceroplasmalopsychosine are detected in
a ratio of w1:1 whereas those of PLPS are found exclusively in only
one form8 (‘endo type’). This may reflect a difference in stability of the
plasmal linkage in these two compounds, i.e., the linkage in glycero-
plasmalopsychosine is much more unstable than that in PLPS.
The observation that glyceroplasmalopsychosine showed no
cytotoxic effect but only weak protein kinase C (PKC) inhibition in
contrast with strong cytotoxicity as well as PKC inhibitory activity
of psychosine,3 presented interesting questions concerning the
function of the glycerol and fatty aldehyde chain of glycolipid on
the membrane surface.
The intriguing biological properties and the challenge of
constructing the acetal linkage in a stereospecific manner make
glyceroplasmalopsychosine an interesting synthetic target. Herein
we report the first synthesis of the mixed acetal segment of
S-glyceroplasmalopsychosine 2A.
* Corresponding author. Tel.: þ1 212 772 5340; fax: þ1 212 772 5332.
E-mail address: rfranck@hunter.cuny.edu (R.W. Franck).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.023

9822
A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
O
OH
O
H
C15H31
OH
HO
HO
O
HO
NH2
HO
Psychosine
C15H31
H
O
HN
H
O
H
O
NH2
H
O
C13H27
O
O
C13H27
HO
C13H27
OH
HO
OH
H
HO
HO
H
HO
Galactosylceremide
1 Plasmalopsychosine
OH
OH
H
HO
H
HO
O
H
O
H
H
C15H31
NH2
O
C15H31
NH2
HO
HO
O
HO
HO
H
O
O
C13H27
O
O
C13H27
OH
OH
2a S-acetal
Figure 1. Structures of psychosine, galactosylceramide, endo form of 4,6-PLPS (1), and both isomers of glyceroplasmalopsychosine (2a and 2b).
H
HO
HO
H
Glyceroplasmalopsychosine
2b R-acetal
2. Results and discussion
chain possibly by doing aldehyde chemistry or by alkene chemistry.
Conversion of the resulting 18-carbon chain to the saturated
aliphatic chain and global deprotection would then furnish the
desired final product 3.
Our retrosynthetic approach outlined in Scheme 1 is a classic
example of conversion of a carbohydrate to an asymmetric non-
carbohydrate molecule where chiral centers of the carbohydrate
are incorporated into the non-carbohydrate product. We envi-
sioned that the disaccharide 8 is a suitable intermediate for the
target compound 3 in that it may be elaborated to several of the
important functionalities of 3.
In particular the glycerol and acetal moieties could be derived
from this disaccharide 8. We reasoned that oxidative cleavage of the
C2–C3 bond of the lyxose unit in 8 and reduction of the product
would lead to diol 7 in which the C3, C4, and C5 of the lyxose unit
corresponds to the C1, C2, and C3, respectively, of the glycerol and
the C1 of the lyxose would now be converted to the acetal center
with a 2-carbon aliphatic chain. We hoped that the acetal stereo-
chemistry would be controlled by the C2 protecting group in the
lyxose donor during glycosidation reaction. So out of three existing
stereocenters of the lyxose donor we would exploit two, one for
retaining the glycerol stereochemistry and the other to influence
the glycosidation. The disaccharide 8 would be obtained from the
two monosaccharides, a lyxose donor 9 and a galactose acceptor 10.
After protecting the hydroxyl group of the glycerol in 7, the required
16-carbon aliphatic chain would be stitched to the existing aliphatic
Our synthesis began with the preparation of
D
-lyxose tri-
-lyxose.
chloroacetimidate donor 99 from commercially available
D
Acetylation of 11 followed by regioselective deacetylation of the
anomeric acetate using hydrazinium acetate produced the lactol 13
in 64% yield. The yield improved slightly by using benzyl amine in
THF.10 The trichloroacetimidation of lactol 13 smoothly furnished
the trichloroacetimidate 9 as a mixture of two anomers in 82% yield
(Scheme 2).
The synthesis of galactose acceptor 10 started from peracety-
lated galactose 14, which was glycosylated with benzyl alcohol
under BF3-etherate catalysis to give b
-glycoside 15 in 75% yield.11
Deacetylation using NaOCH3 followed by selective protection of the
primary OH with TIPS gave compound 17.12 Benzyl protection of
remaining OH groups of 17 followed by the removal of silyl
protection furnished the desired galactose derivative 10 in very
good overall yield (Scheme 3).
With both the coupling partners in hand, we were ready for the
key glycosidation step. Condensation of lyxose trichloroacetimidate
donor 9 and galactose acceptor 10 in the presence of catalytic
amount of TMSOTf produced exclusively
a-glycoside 19 in 86%
HO
HO
MeO
H
H
O
H
O
H
O
O
H
H
MeO
O
C15H31
OH
3
O
HO
HO
R
O
O
O
O
H
BnO
BnO
5
6
R = CH2
R = O
OH
4
O
O
BnO
C15H31
OBn
OBn
O
OH
O
OBn
H
BnO
BnO
BnO
OBn
OBn
OBn
AcO
10
O
PMBO
Glycerol
PMBO
HO
Fixed Stereochemistry
at acetal center
OH
OH
BnO
BnO
O
O
O
HO
AcO
AcO
O
O
OBn
OBn
BnO
O
Cl3C
O
8
9
BnO
OBn
7
NH
Attachment of
aliphatic chain
OBn
Scheme 1. Retrosynthetic analysis of S-glycero-S-plasmalgalactose.

A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
9823
AcO
AcO
AcO
HO
O
O
O
AcO
AcO
O
a
AcO
AcO
AcO
b or c
d
HO
HO
OAc
OH
AcO
OH
O
Cl3C
9
13
12
11
NH
Scheme 2. Synthesis of lyxose donor 9. Reagents and conditions: (a) Ac2O, DMAP, EtOAC; (b) NH2NH2$HOAc, DMF, 2 h, 64%; (c) benzyl amine, THF, 72%; (d) CCl3CN, DCM, 2 h, 82%.
OAc
OAc
O
AcO
AcO
OH
O
OTIPS
O
AcO
AcO
HO
HO
HO
HO
O
a
b
OAc
c
OBn
OBn
OBn
OAc
OAc
15
OH
OH
17
14
16
OTIPS
OH
O
BnO
BnO
BnO
BnO
O
d
e
OBn
OBn
10
OBn
OBn
18
Scheme 3. Synthesis of galactose acceptor 10. Reagents and conditions: (a) BF3$Et2O, BnOH, DCM, ꢀ78 ꢁC, 75%; (b) NaOCH3, MeOH; (c) TIPSCl, imidazole, DMF, 87%; (d) NaH, BnBr,
DMF, TBAI, 76%; (e) TBAF, THF, 92%.
yield.13 The protecting group manipulation started with depro-
tection of acetates groups in 19, followed by regioselective for-
mation of the lyxose C2–C3 acetonide 20 by exploiting the cis
relationship between these OH groups. The free C4 hydroxyl
group in lyxose unit of 20 was then protected as PMB ether to
produce 21 in very high overall yield. The deblocking of acetonide
using 9:1 AcOH/H2O furnished the desired diol 8 in 83% yield
(Scheme 4).
With the desired diol 8 in hand, the next key step was oxidative
cleavage of the C2–C3 bond of the lyxose unit of 8. Sodium meta-
periodate has been an attractive and popular reagent for the oxi-
dative cleavage of vicinal diols into dicarbonyls. Use of silica gel
supported sodium metaperiodate14 in oxidative cleavage has many
advantages such as running the reaction in dichloromethane and
without the need of purification. When the diol 8 was subjected to
the oxidative cleavage using silica gel supported metaperiodate,
dialdehyde 22 was obtained in quantitative yield. The dialdehyde
22 was then immediately reduced with NaBH4 to furnish the diol 7
in 90% yield over two steps (Scheme 4). The neutral conditions
employed in oxidative cleavage and subsequent reactions ensured
that there was no epimerization at the acetal center evident from
the proton and carbon NMR.
The key intermediate compound 7 has now all the important
functionalities of the target molecule 3. It has the required acetal
stereocenter along with 2-carbon aliphatic chain and the glycerol
moiety with correct C2 stereochemistry. The primary OH of
glycerol unit of 7 was then protected as p-methoxy benzylidene15
by treatment with DDQ in presence of molecular sieves. This re-
action afforded the desired product 23 as a mixture of two di-
astereomers (formed due to the attack of glycerol primary OH
from two faces of the carbocation at the benzylic carbon) in 72%
yield (Scheme 5).
Our next objective was the elongation of the 2-carbon acetal
chain, which was unveiled by the periodate cleavage to the18-
carbon aliphatic chain of the natural product. Olefin metathesis16
and Wittig reactions are the two options we employed. The re-
quired aldehyde 6 was prepared using Dess–Martin reagent17
where primary alcohol 23 was oxidized to aldehyde 6 in quanti-
tative yield. The choice of Dess–Martin reagent as oxidizing reagent
is particularly important to ensure that no epimerization occurred
at the acetal center during oxidation. For the olefin cross-metath-
esis, the required terminal alkene 5 can be prepared by two
methods. In the first method, Tebbe olefination18 produced the
required terminal olefin 5 in a modest 30% yield. In the second
AcO
O
AcO
AcO
OH
AcO
BnO
O
a
AcO
O
O
AcO
BnO
OBn
BnO
Cl3C
O
OBn
10
O
BnO
OBn
NH
19
OBn
9
O
O
HO
O
O
PMBO
O
HO
PMBO
O
O
HO
e
b, c
d
O
O
O
BnO
BnO
BnO
BnO
O
O
O
BnO
OBn
BnO
OBn
OBn
OBn
21
OBn
OBn
20
8
Scheme 4. Preparation of key intermediate compound-diol 8. Reagents and conditions: (a) TMSOTf, 4 Å molecular sieves, DCM, 82%; (b) NaOMe, MeOH, 94%; (c) DMP, p-TsOH,
acetone, 97%; (d) PMBCl, NaH, DMF, 94%; (e) AcOH/H2O (9:1), 60 ꢁC, 90%.

9824
A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
HO
17-carbon phosphonium salt 24 following the literature method.20
O
When aldehyde 6 was subjected to the heterogeneous Wittig pro-
tocol using phosphonium salt 24, compound 25 was obtained as
a mixture of isomers in 75% yield (Scheme 6).
The reduction of the internal double bond of 25 was achieved by
hydrogenation using Wilkinson’s catalyst21,22 to produce com-
pound 4 in quantitative yield (Scheme 7).
For global deprotection of 25 to produce the target compound 3,
we subjected 25 to hydrogenolysis and hydrogenation using
Pd(OH)2 as catalyst. Although our attempt to get a pure analytical
sample of the product was unsuccessful, the mass spectra con-
firmed the presence of product 3 (Scheme 8).
We have completed a building block that can, in principle, be
used for the total synthesis of glyceroplasmalopsychosine. We note
that the mixed acetal is very sensitive in our hands and may not
survive the conditions required for completion of the synthesis
(deprotection, activation of the anomeric hydroxyl, and glycosyl
transfer to a sphingosine). Thus, a modified plan, which places
a removable electron-withdrawing group adjacent to the acetal
center to stabilize it until every segment of the final product is
assembled has become our preferred route.
O
PMBO
H
PMBO
HO
H
O
b
O
O
O
a
BnO
BnO
O
O
BnO
OBn
OBn
H
BnO
OBn
OBn
22
8
H
O
O
PMBO
HO
H
O
c
H
OH
OH
O
O
O
BnO
BnO
BnO
23
O
O
OBn
OBn
BnO
MeO
OBn
OBn
7
Scheme 5. Oxidative cleavage followed by reduction and protection. Reagents and
conditions: (a) silica gel supported NaIO4, DCM, 2 h, quant; (b) NaBH4, MeOH, quant;
(c) DDQ, DCM, 4 Å molecular sieves, 72%.
method, exposing the aldehyde 6 to heterogeneous Wittig re-
action19 with PPh3MeBr using K2CO3 as base with a crown ether
phase transfer catalyst, the terminal olefin 5 was obtained in 75%
yield. The terminal olefin 5 was subjected to cross-metathesis with
1-heptadecene to produce the internal alkene 25 as a mixture of
isomers in 78% yield. Encouraged by the simplicity and cleanliness
of the heterogeneous Wittig reaction, we then prepared the
3. Conclusion
In conclusion, we have synthesized the mixed acetal segment of
glyceroplasmalopsychosine in a stereospecific manner. All the key
reactions including glycosidation, oxidative cleavage, oxidation,
metathesis, and heterogeneous Wittig reaction took place in very
H
H
O
O
O
H
H
O
O
O
H
H
O
a
HO
MeO
O
MeO
O
BnO
BnO
6
BnO
BnO
O
23
O
OBn
OBn
OBn
OBn
MeO
e
b or c
H
H
O
O
O
H
H
O
O
H
d
O
H2C
MeO
O
O
BnO
C15H31
OBn
BnO
BnO
O
O
BnO
OBn
PPh3 Br
OBn
25
OBn
C13H27
5
24
Scheme 6. Preparation of internal alkene 25. Reagents and conditions: (a) Dess–Martin periodinane, DCM, 1 h, quant; (b) Tebbe reagent, 0.5 M in toluene, THF, pyridine, 30%; (c)
PPh3MeBr, K2CO3, alumina, crown-6, THF, 70 ꢁC, 1 h, 75%; (d) 1-heptadecene, second generation Grubbs catalyst, DCM, 78%; (e) 24, K2CO3, alumina, crown-6, THF, 70 ꢁC, 1 h, 75%.
MeO
MeO
H
H
O
O
Wilkinson's catalyst
H2
O
O
O
H
O
H
O
O
Benzene
BnO
BnO
C15H31
OBn
BnO
BnO
C15H31
OBn
Quantitative Yield
O
O
OBn
OBn
25
4
Scheme 7. Preparation of mixed acetal 4.

A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
9825
MeO
OH
H
HO
O
O
H
O
H2 / Pd(OH)2
Ethanol
O
H
O
HO
HO
C15H31
OH
O
O
BnO
C15H31
OBn
O
OH
BnO
OBn
25
3
Scheme 8. Attempted synthesis of the final product 3.
good yield ensuring that the product is a pure material of known
configuration with respect to the acetal stereocenter.
HCl. Removal of the solvent afforded the crude product, which was
purified by flash column chromatography (EtOAc) to give the pure
product (908 mg, 94% yield) as white solid. 1H NMR (500 MHz,
4. Experimental
CDCl3) d: 7.37–7.25 (m, 20H), 4.95 (m, 3H), 4.82–4.72 (m, 3H), 4.65
(t, J¼11.5 Hz, 2H), 4.46 (m, 2H), 3.91 (t, J¼9 Hz, 1H), 3.82–3.80 (m,
4.1. General information
3H), 3.73 (m, 2H), 3.64 (br s, 1H), 3.54 (m, 3H), 3.49–3.46 (m, 1H),
2.45 (d, J¼5 Hz,1H), 2.13 (d, J¼3.5 Hz,1H), 2.07 (d, J¼3.5 Hz,1H); 13
C
NMR spectra were recorded at 300 MHz or 500 MHz (1H) and
75 MHz or 125 MHz (13C) in deuterated solvent. The assignment of
proton and carbon NMR peaks was supported by routine COSY and
for some cases by NOESY spectra. All air-moisture sensitive re-
actions were performed under a positive pressure of dry nitrogen.
All solvents and reagents were purified prior to use according to
standard laboratory procedures. Low temperatures were recorded
as bath temperatures. Thin layer chromatography analyses were
carried out on precoated aluminum sheets of silica gel 60 F254. UV
light and vanillin, potassium permanganate or phosphomolybdic
acid spray was used to visualize the components on the TLC plates.
Flash column chromatography was carried out with silica gel 60
(230–400 mesh), using ACS reagent grade petroleum ether, ethyl
acetate, methylene chloride, hexane, chloroform, and ethyl ether.
NMR (125 MHz, CDCl3) d: 138.8, 138.6, 137.6, 128.6, 128.5, 128.4,
128.2, 128.0, 127.8, 127.7, 103.0, 100.2, 82.6, 79.8, 75.4, 74.5, 73.7,
73.2, 72.0, 71.2, 70.5, 68.0, 66.7, 63.1. HRMS calcd for C39H44NaO10
[MþþNa] 695.2832, found 695.2771.
4.1.3. 1,2,3,4-Tetra-O-benzyl-6-O-(2,3-O-isopropylidene-
a-D-
lyxopyranosyl)- -galactopyranoside: 20
b-D
To a stirred suspension of above compound (1 g, 1.48 mmol) in
15 mL of acetone was added 4.5 mL of dimethoxypropane and
50 mg of p-toluenesulfonic acid. After 12 h, at room temperature
60 mL of 1:1 hexane–diethyl ether was added, and the solution was
washed once with aqueous sodium bicarbonate solution and twice
with water, and concentrated in vacuo. The resulting material was
chromatographed (1:1 ethyl acetate/petroleum ether) over silica
gel to yield colorless oil (1.02 g, 97%). 1H NMR (500 MHz, CDCl3)
d:
4.1.1. 1,2,3,4-Tetra-O-benzyl-6-O-(2,3,4-tri-O-acetyl-
lyxopyranosyl)- -galactopyranoside: 19
2,3,4-Tri-O-acetyl- -lyxopyranosyl
(0.56 g, 1.35 mmol) and 1,2,3,4-tetra-O-benzyl-b-D
side 10 (0.69 g, 1.3 mmol) were dried together under high vacuum
for 2 h. To the flask containing the donor, acceptor, and some 4 Å
molecular sieves, 15 mL anhydrous DCM was added and the
a
-
D
-
7.43–7.33 (m, 20H), 5.04–4.9 (m, 3H), 4.86–4.69 (m, 5H), 4.63 (d,
J¼2.4 Hz, 1H), 4.5 (d, J¼7.7 Hz, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 3.97
(dd, J¼9.7, 7.7 Hz, 1H), 3.90 (dd, J¼11.5, 3.7 Hz, 1H), 3.86–3.82 (m,
2H), 3.78 (dd, J¼11.3, 4.6 Hz, 1H), 3.57 (dd, J¼9.8, 2.8 Hz, 1H), 3.54
(m, 1H), 3.44 (dd, J¼9.5, 6.0 Hz, 1H), 3.18 (d, J¼8.4 Hz, 1H), 1.54 (s,
b-D
D
trichloroacetimidate
9
-galactopyrano-
3H), 1.41 (s, 3H); 13C NMR (125 MHz, CDCl3)
d: 138.8, 138.6, 138.5,
137.8, 129.1,128.6,128.5,128.4,128.3,128.2,128.1,127.8, 127.7, 127.6,
109.6, 102.9, 98.7, 82.5, 79.8, 76.1, 75.4, 74.5, 74.3, 73.6, 73.3, 71.1,
67.5, 67.2, 63.5, 27.6, 25.7. HRMS calcd for C42H48NaO10 [MþþNa]
735.3145.35, found 735.3156.
resulting mixture was stirred for 1 h. TMSOTf (5 mL, 0.02 mmol) was
added dropwise at ꢀ25 ꢁC with N2 protection. The reaction mixture
was stirred for 3 h, during which time the temperature was gradu-
ally warmed to ambient temperature. Then the mixture was neu-
tralized with Et3N and filtered, concentrated to dryness to afford the
crude disaccharide, which was subjected to silica gel chromatog-
raphy (1:5 ethyl acetate/petroleum ether) to yield 716 mg product
4.1.4. 1,2,3,4-Tetra-O-benzyl-6-O-(2,3-O-isopropylidene-4-O-PMB-
a-D
-lyxopyranosyl)-
b-D-galactopyranoside: 21
Compound 20 (1.0 g, 1.4 mmol) was azeotroped with toluene
19 as white solid. 1H NMR (500 MHz, CDCl3)
d
: 7.43–7.34 (m, 20H),
(3ꢂ10 mL), dried under vacuum for 1 h, and dissolved in DMF
(8 mL). The solution was cooled to 0 ꢁC, sodium hydride (112 mg,
2.8 mmol, 60% dispersion in mineral oil) was added, and the re-
action mixture was stirred for 1 h. After addition of PMBCl (0.43 g,
2.8 mmol), the solution was warmed to room temperature and
stirred for 12 h. the reaction was quenched by the dropwise addi-
tion of water. The aqueous layer was extracted with ethyl acetate,
and the combined organic phases were washed with brine and
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash silica gel chromatography (1:4 EtOAc/petroleum ether)
afforded the pure product 21 (1.09 g, 94%). 1H NMR (500 MHz,
5.38 (dd, J¼9.8, 3.4 Hz, 1H), 5.25 (m, 1H), 5.20 (m, 1H), 5.0 (m, 3H),
4.89–4.80 (m, 3H), 4.7 (dd, J¼18.1, 12.0 Hz, 2H), 4.55 (d, J¼9.7 Hz,
1H), 4.53 (d, J¼1.8 Hz, 1H), 3.99–3.89 (m, 3H), 3.87 (d, J¼2.5 Hz, 1H),
3.76 (m, 1H), 3.62 (dd, J¼9.7, 2.8 Hz), 3.58 (m, 1H), 3.40 (dd, J¼9.5,
5.6 Hz,1H), 2.18 (s, 3H), 2.07 (s, 3H),1.99 (s, 3H); 13C NMR (125 MHz,
CDCl3) d: 169.9 (2),169.8,138.8,138.6,138.5,137.6,129.1,128.6,128.5
(2),128.4,128.3,128.2,128.0,127.7,127.6,102.8, 97.4, 82.6, 79.7, 75.4,
74.6, 73.8, 73.7, 73.3, 71.1, 69.7, 68.8, 67.1, 66.9, 60.0, 21, 20.9 (2).
HRMS calcd for C45H50NaO13 [MþþNa] 821.3149, found 821.3109.
4.1.2. 1,2,3,4-Tetra-O-benzyl-6-O-(
a-D
-lyxopyranosyl)-
b-
D-
CDCl3) d: 7.43–5.32 (m, 22H), 6.9 (m, 2H), 5.04–4.99 (m, 3H), 4.87–
galactopyranoside
4.60 (m, 8H), 4.53 (d, J¼7.7 Hz, 1H), 4.23 (t, J¼5.7 Hz, 1H), 3.98 (dd,
J¼9.7, 7.7 Hz, 1H), 3.94–3.91 (m, 2H), 3.89 (dd, J¼8.0, 4.3 Hz, 1H), 3.8
(s, 3H), 3.66–3.58 (m, 4H), 3.56–3.50 (m, 2H), 1.56 (s, 3H), 1.48 (s,
To a stirred solution of 19 (1.15 g, 1.44 mmol) in 90 mL of an-
hydrous methanol was added 1.2 mL of 0.5 M NaOCH3 solution. The
reaction mixture was stirred for 12 h and then neutralized with 1 N
3H); 13C NMR (125 MHz, CDCl3)
d: 159.5, 138.9, 138.7, 137.8, 130.5,

9826
A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
129.5, 128.6, 128.5, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 114.0,
109.3, 103.0, 98.5, 82.7, 79.9, 75.5, 75.4, 74.5, 74.4, 73.6, 73.4, 73.2,
71.9, 71.1, 66.4, 59.7, 55.5, 28.3, 26.6. HRMS calcd for C50H56NaO11
[MþþNa] 855.3720, found 855.3731.
0 ꢁC. DDQ (0.35 g, 1.55 mmol) in THF (3 mL) was added slowly.
The mixture was stirred for 3 h and filtered over Celite and
concentrated under reduced pressure. The residue was chromato-
graphed (3:2 ethyl acetate/petroleum ether) to give the product 23
(798 mg, 72%) as colorless oil. 1H NMR (500 MHz)
d: 7.45–7.29 (m,
4.1.5. 1,2,3,4-Tetra-O-benzyl-6-O-(4-O-PMB-
-galactopyranoside: 8
A solution of 21 (1.1 g, 1.32 mmol) in AcOH/H2O (10:1, 20 mL)
a
-
D
-lyxopyranosyl)-
b
-
22H), 6.92 (m, 2H), 5.8 (s,1H), 5.03–4.95 (m, 3H), 4.85–4.75 (m, 3H),
4.69 (d, J¼2.9 Hz,1H), 4.65 (d, J¼3.6 Hz,1H), 4.54–4.51 (m, 2H), 4.39
(m, 1H), 4.09 (m, 1H), 3.94 (m, 2H), 3.89 (m, 1H), 3.81 (m, 3H), 3.67
(dd, J¼10.4, 5.8 Hz, 1H), 3.57–3.52 (m, 4H), 3.46 (dd, J¼9.9, 5.6 Hz,
D
was heated to 60 ꢁC for 1.5 h. The reaction was cooled to room
temperature and then concentrated to give a white solid, which
was purified by silica gel chromatography (3:2 EtOAc/petroleum
ether) to furnish the pure product 22 (940 mg, 90%) as white solid.
1H), 2.35 (t, 1H); 13C NMR (125 MHz, CDCl3)
d: 161.1, 139.1, 139.0,
138.9, 138.0, 129.5, 129.3, 129.2, 129.0 (2), 128.9 (2), 128.8, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 114.4, 105.0, 104.3, 103.5, 82.8, 80.1,
75.9, 75.7, 74.8, 73.9, 73.8, 73.7, 71.7, 68.6, 68.0, 66.2, 66.1, 62.5, 55.8.
HRMS calcd for C47H52NaO11 [MþþNa] 815.3407, found 815.3360.
1H NMR (500 MHz, CDCl3)
d: 7.40–7.25 (m, 22H), 6.88 (m, 2H), 5.01–
4.97 (m, 3H), 4.85–4.76 (m, 3H), 4.70 (d, J¼11.90 Hz, 1H), 4.66 (d,
J¼12.1 Hz, 1H), 4.60–4.53 (m, 2H), 4.50 (m, 1H), 3.95 (dd, J¼9.7,
7.9 Hz, 1H), 3.87–3.82 (m, 2H), 3.69 (m, 1H), 3.57 (m, 2H), 3.47 (m,
4.6. Dess–Martin oxidation
2H), 2.58 (d, 1H), 2.39 (d, 1H); 13C NMR (75 MHz, CDCl3)
d: 159.6,
138.9, 138.6, 137.7, 130.3, 129.5, 128.6, 128.5, 128.4 (2), 128.3 (2),
128.1, 127.8, 127.7,127.6, 114.2,103.0, 99.7, 82.7, 79.9, 75.4, 75.2, 74.5,
73.7, 73.5, 73.3, 72.4, 71.1, 70.7, 70.4, 66.6, 61.1, 55.5. HRMS calcd for
Dess–Martin periodinane (1.3 equiv) was added to a solution of
alcohol in DCM (4 mL/0.2 mmol of alcohol) under nitrogen. The re-
action mixture was stirred at room temperature for 1 h, to generate
amilkysuspension. Whenallstartingmaterialswereconsumed,a10%
solution of sodium hydrosulfite in a solution of saturated aqueous
NaHCO3 was added slowly to suspensions and stirred until two sep-
arate layer formed. The aqueous layer was extracted with DCM
(3ꢂ10 mL). The combined organic phases were dried over NaSO4,
filtered, and concentrated to give the crude aldehyde 6 as a colorless
oil, which was used for the next step without further purification.
C
47H52NaO11 [MþþNa] 815.3407, found 815.3378.
4.2. Procedure for glycol cleavage oxidation
To a vigorously stirred suspension of silica gel supported reagent
(2.0 g) in DCM (5 mL) in a 25 mL round-bottomed flask was added
a solution of the vicinal diol (1 mmol) in DCM (5 mL). The reaction
was monitored by TLC until disappearance of the starting material
(generally 2–3 h). The mixture was filtered through a sintered glass
funnel and the silica gel was thoroughly washed with chloroform
(3ꢂ10 mL). Removal of the solvent from the filtrate afforded the
aldehyde that was pure enough for the following step.
4.7. Procedure for heterogeneous Wittig reaction
Alkylphosphonium salt (1.2 equiv) was ground with anhydrous
ovendried K2CO3 (1.2 equiv)and basic alumina. THF (10 mL/mmol of
aldehyde) was added to the flask followed by the solution of alde-
hyde in THF (10 mL/mmol) and some crystals of crown-6 ether. The
color of the mixture turned yellow immediately after the addition of
the aldehyde, which was refluxed at 70 ꢁC for 1–2 h. After all the
starting materials were consumed, the reaction mixture was
allowed to come to the room temperature. The solids were filtered
and washed with THF. The combined solvents were concentrated
and the residue was subjected to chromatography to produce the
pure product in good yield.
4.3. NaBH4 reduction
The resulting aldehyde from the oxidative cleavage was dis-
solved in dry MeOH (5 mL/mmol of aldehyde). To the cooled so-
lution (0 ꢁC) of the aldehyde in MeOH, NaBH4 (excess) was added
and the reaction mixture was allowed to attain room temperature
slowly. The mixture was stirred overnight and was diluted with
H2O. The reaction mixture was extracted with chloroform and the
organic layer was washed with water. The combined organic phases
dried over Na2SO4, filtered, and concentrated in vacuo. Purification
by flash silica gel chromatography afforded the pure product.
The alkene 25 was prepared by heterogeneous Wittig reaction
given above in 70% yield calculated from the crude aldehyde 6
(from 60 mg of aldehyde 6: yield 53 mg, 70%) as colorless oil. 1H
NMR (500 MHz, CDCl3) d: 7.39–7.24 (m, 22H), 6.85 (m, 2H), 5.76 (s,
4.4. Diol 7 (prepared from oxidative cleavage of 8 followed
by reduction)
1H), 5.68 (m,1H), 5.43 (m, 1H), 5.25 (m,1H), 5.0–4.94 (m, 3H), 4.79–
4.73 (m, 3H), 4.65 (m, 2H), 4.48 (m, 1H), 4.34 (m, 1H), 4.06 (m, 1H),
3.94–3.88 (m, 2H), 3.8 (m, 1H), 3.77 (s, 3H), 3.68 (m, 1H), 3.54 (m,
3H), 2.10 (m, 2H), 1.25 (aliphatic chain), 0.87 (t, 3H); 13C NMR
The oxidative cleavage of 8 afforded the crude aldehyde 22,
which was immediately reduced with NaBH4 to afford the diol 6
(from 500 mg of 8 yield 451 mg, 90%).
(125 MHz, CDCl3) d: 161.1, 139.1, 138.7, 138.6, 137.8, 136.6, 128.9,
128.8, 128.7, 128.6, 128.4, 128.1, 128.0, 126.6, 114.3, 104.8, 103.4, 99.1,
82.8, 80.1, 75.8, 75.3, 75.1, 74.7, 73.6, 73.3, 71.1, 68.3, 68.1, 65.8, 65.2,
65.0, 55.5, 32.5, 30.3, 29.9, 29.6, 28.5, 23.0, 14.7. HRMS calcd for
1H NMR (500 MHz, CDCl3)
d: 7.39–7.27 (m, 22H), 6.90 (m, 2H),
5.0–4.93 (m, 3H), 4.84–4.75 (m, 3H), 4.66 (d, J¼11.9 Hz, 2H), 4.59
(m, 2H), 4.52 (d, J¼7.7 Hz, 1H), 4.49 (m, 1H), 3.94 (dd, J¼9.7, 7.7 Hz,
1H), 3.87 (dd, J¼9.8, 6.4 Hz, 1H), 3.81 (m, 6H), 3.66–3.62 (m, 3H),
C
63H86NO10 [MþþNH4þ] 1016.6252, found 1016.6248.
3.55–3.45 (m, 5H); 13C NMR (75 MHz, CDCl3)
d: 159.6, 138.8, 138.6,
4.8. Wilkinson’s hydrogenation product, mixed acetal: 4
137.7, 130.1, 129.6, 128.5, 128.4 (2), 128.3, 128.1, 127.8, 127.7, 127.6,
114.2, 103.2, 102.9, 83.9, 82.6, 82.2, 79.8, 77.8, 75.5, 74.6, 73.8, 73.6,
72.1, 71.4, 66.2, 66.1, 62.3, 62.1, 55.5. HRMS calcd for C47H54NaO11
[MþþNa] 817.3564, found 817.3544.
To the solution of alkene 25 (20 mg, 0.015 mmol) in 1 mL of an-
hydrous benzene was added Wilkinson’s catalyst (15 mg). The
resulting mixture was stirred overnight under an atmosphere of H2
(balloon) after which the solution was evaporated to dryness in
vacuo. The residue was purified by column chromatography (10: 1,
PE/EtOAc) to afford the pure product (15 mg). 1H NMR (500 MHz,
4.5. p-Methoxy benzylidene derivative: 23
Molecular sieves (3 g) were finely ground and suspended in
CDCl3) d: 7.37–7.28 (m, 22H), 6.89 (m, 2H), 5.77 (s,1H), 5.02–4.94 (m,
dichloromethane (15 mL). Compound
dichloromethane (15 mL) was added and the mixture was cooled to
7
(1.11 g, 1.4 mmol) in
3H), 4.81–4.73 (m, 3H), 4.67–4.62 (m, 2H), 4.51–4.43 (m, 2H), 4.36 (t,
1H), 4.07 (m,1H), 3.95–3.90 (m, 2H), 3.87 (m,1H), 3.82–3.78 (m, 4H),

A.K. Parhi et al. / Tetrahedron 64 (2008) 9821–9827
9827
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3.68–3.61 (m, 1H), 3.56–3.49 (m, 3H), 1.56 (m, 2H), 1.27 (aliphatic
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: 161.1, 139.3, 139.1,
d
138.2,128.9,128.8,128.7,128.6,128.4,128.2,128.1,114.3,104.9,104.2,
103.5, 82.9, 80.2, 75.8, 75.3, 75.4, 74.9, 74.2, 74.1, 74.0, 73.9, 73.7, 71.5,
68.6, 68.4, 66.5, 65.8, 65.7, 55.8, 33.7, 32.5, 30.3, 30.2, 30.0, 29.9, 25.2,
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The research was supported by NIH grant GM60271 to CUNY.
The Hunter Chemistry Department infrastructure is supported by
RCMI NIH RR03037.
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