Practical syntheses of optically active carbagalactose and their potential application to the carbocyclic analogues of KRN7000

Article abstract of DOI:10.1016/j.tetasy.2006.11.014

Carba-α- and β-d-galactose derivatives were efficiently prepared from a cyclohex-3-ene-1,2-diol derivative 1. Regioselective inversion of 2-OH, and stereoselective dihydroxylation of 1 were accomplished to provide a carba-β-d-galactose derivative 6 in a g

Full text of DOI:10.1016/j.tetasy.2006.11.014

Tetrahedron: Asymmetry 17 (2006) 3030–3036
Practical syntheses of optically active carbagalactose and their
potential application to the carbocyclic analogues of KRN7000
Seok-Ho Yu, Jeong-Ju Park and Sung-Kee Chung*
Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea
Received 19 October 2006; accepted 7 November 2006
Abstract—Carba-a- and b-D-galactose derivatives were efficiently prepared from a cyclohex-3-ene-1,2-diol derivative 1. Regioselective
inversion of 2-OH, and stereoselective dihydroxylation of 1 were accomplished to provide a carba-b-D-galactose derivative 6 in a good
yield and with a high stereoselectivity. Stereo-inversion of 1-OH of 6 via oxidation/reduction gave carba-a-D-galactose derivative 12 with
a high stereoselectivity. An efficient coupling of carba-a-galactose 12 with an aziridine derivative of sphingosine has been demonstrated
to give 1-O-carba-a-galactosyl sphingosine derivative 14.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
stereoisomers (carba-b-altrose, carba-b-mannose, carba-b-
idose, carba-b-talose), and this sequence of stereoinver-
sions is advantageous in that those four C3 and C4 stereo-
variants can also be utilized for the preparation of all
possible 1,2-olefin and 1,2-epoxides as well as the remain-
ing 12 stereoisomers (Fig. 1). However, due to the linear
sequence of stereoinversions, some of the stereoisomers
require relatively long synthetic routes. For example,
carba-a- and carba-b-galactoses have been synthesized
through 13–14 steps from cyclohex-3-ene-1,2-diol deriva-
tive 1 because they proceed through a serial inversion of
three to four stereocenters of carba-b-altrose.
Carbohydrate–protein interactions on cell surfaces are
known to initiate or mediate important cell–cell recogni-
tion processes such as immune responses, fertilization, cell
growth, cell–cell adhesion, viral infection, and inflamma-
tion.1 Currently, oligosaccharides or their analogues are
emerging as potential therapeutic agents,2 because they
are thought to be potential regulators of these biological
processes. Among many carbohydrate analogues, non-
hydrolyzable analogues such as carbasugar-based carbo-
hydrate mimetics3 are thought to be more desirable drug
candidates than natural sugars since they are expected
to provide a prolonged activity due to their stability
against ubiquitous glycosidases. Although there have been
reported3a–h,4 a number of synthetic routes to a variety of
carbasugars, paucity of efficient synthetic routes has ham-
pered their applications to various useful carbohydrate
mimetics.
As KRN-7000 (a-galactosyl ceramide) and its analogues
have been known as extremely exciting molecules display-
ing anticancer and immunomodulatory activities,6 we have
been interested in the synthesis and biological evaluation of
carbagalactose-based glycoconjugates. For efficient synthe-
ses of these glycomimetics such as carbasugar analogues of
KRN-7000, a more practical and concise synthetic route to
carbagalactose would be highly desirable. Although there
have been several reports for the synthesis of carbagalac-
tose, only Mehta’s norbornyl route7 appears to be practical
in terms of its overall yield and the number of synthetic
steps involved. However, it requires an expensive starting
material (i.e., 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-
diene) and a costly enzymatic resolution step8 of a key
intermediate, to its disadvantage. Since the optically active
1 [both (+) and (ꢀ) form] can be prepared practically (in a
bench scale synthesis, 15–20 g of each enantiomer can be
Recently, we have reported a divergent synthetic route to
obtain all optically active 16 (or 32) stereoisomers of car-
basugars (carba-aldohexopyranose).5 The synthetic route
comprises of sequential stereoinversions of 3- and/or 4-
OH of carba-b-altropyranose and subsequent stereochemi-
cal manipulations of 1 and/or 2-OH of the resulting four
*
Corresponding author. Tel.: +82 54 279 2103; fax: +82 54 279 3399;
e-mail: skchung@postech.ac.kr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.014

S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
3031
OTBDPS
OTBDPS
OH
OH
OMOM
OMOM
C1 and/or C2
stereo-inversion
carba-α-altrose
carba-β-allose
carba-α-allose
HO
cyclohex-3-ene-
1,2-diol deriv.
OH
carba-β-D-altrose deriv.
carba-α-mannose
carba-β-glucose
carba-α-glucose
C3 & C4
stereo-inversion
OTBDPS
carba-α-idose
carba-β-gulose
carba-α-gulose
O
OTBDPS
OMOM
BnO
OBn
C1 and/or C2
carba-α-talose
RO
OMOM
stereo-inversion
OTBDPS
carba-β-galactose
carba-α-galactose
OR
carba-β-D-mannose
carba-β-D-idose
carba-β-D-talose
C1 & C2 variants
BnO
OBn
1,2-epoxides & 1,2-olefins
C3 & C4 stereovariants
Figure 1. Syntheses of all 16 carbasugar stereoisomers.
readily prepared starting from ca. 50 g of 3-cyclohexene-1-
carboxylic acid, which is commercially available at a
reasonable price), a synthetic route starting from 1 was
envisioned as an efficient way to prepare optically active
carbagalactose derivatives.
compound 3 was replaced by a benzyl group to give com-
pound 5 by treatment with NaOMe in MeOH and subse-
quent benzylation of the 2-OH in 4 with NaH, BnBr,
TBAI in THF. It was gratifying to find that the dihydroxyl-
ation of compound 5 with OsO4 (cat.) and NMO in ace-
tone–water (8:1) gave preferentially carba-b-D-galactose
derivative 6 with a minor amount of carba-b-D-allose
derivative 7 (6:7 = 85:15, in 99% yield) (Scheme 1).
Herein, we report a practical synthetic route to carba-
b-D-galactose derivatives (only five steps from 1) and its
conversion to a carba-a-D-galactose derivative with a high
stereoselectivity. We also describe a synthetic method for
preparing 1-O-carba-a-D-galactosyl sphingosine derivative,
which is similarly applicable to the syntheses of various
carba-a-D-galactosyl ceramide derivatives as carbocyclic
analogues of KRN7000.
Structural determinations of compounds 6 and 7 were car-
ried out by 1H NMR analysis summarized in Figure 2. For
compound 6, the coupling constants JH2–H3 = 9.3 Hz,
JH3–H4 = 2.8 Hz, and JH4–H5 = 2.4 Hz in benzene-d6 indi-
cate that H2 and H3 have axial orientations while H4 occu-
pies an equatorial position. The 1H–1H-homonuclear
COSY spectrum also corroborated the structure of
compound 6. For compound 7, the coupling constants
JH1–H2 = 9.3 Hz, JH2–H3 = 2.7 Hz, JH3–H4 = 2.6 Hz, and
JH4–H5 = 10.3 Hz in CDCl3 indicated that H1, H2, and
H4 have all axial orientations while H3 has an equatorial
orientation.
2. Result and discussion
2.1. Synthesis of carba-b-D-galactose derivative 6
In order to prepare carba-b-D-galactose from compound 1,
we needed to place the 3- and 4-OH on the same face as the
1-OH of 1 and to effect stereoinversion of the 2-OH. It was
expected that the 2-OH of compound 1 would be more sus-
ceptible to the Mitsunobu inversion because of its allylic
nature.9 As imagined, the stereochemistry of the 2-OH in
1 was selectively inverted under Mitsunobu conditions
(PPh3, DEAD, p-nitrobenzoic acid in THF) to provide
compound 2 in 71% yield. Then, we wanted to transform
2 into the carba-b-galactose configuration by stereoselec-
tive dihydroxylation of the 3,4-olefin moiety. Since the
effect of a neighboring group to an olefin is often crucial
to the stereoselectivity in a dihydroxylation reaction,10 we
decided to introduce the benzyl group onto the 2-OH for
a more pronounced effect on dihydroxylation. The 1-OH
of compound 2 was first protected as a MOM ether11 to
give compound 3 (93%), which could be orthogonally
removed later for selective inversion of the C1 stereochemis-
try to carba-a-galactose. Then, the p-nitrobenzoyl group in
2.2. Synthesis of the carba-a-galactose derivative 12
For the synthesis of a carba-a-galactose derivative, the ste-
reochemistry of 6 was inverted by an oxidation/reduction
protocol with PCC and L-SelectrideTM (Scheme 2). First,
removal of the TBDPS protecting group of the 6-OH in
6 and perbenzylation were carried out.12 Sequential treat-
ment of compound 6 with TBAF in THF (90%), and the
resulting triol 8 with NaH, BnBr, TBAI in THF (92%) pro-
vided a fully protected compound 9. The MOM group of 9
was removed by treatment with MeOH–water–concd HCl
(100:10:1) at reflux to provide an alcohol 10 in 94% yield.
Compound 10 was oxidized with PCC (3 equiv) to give 1-
keto derivative 11 (89%). Reduction of compound 11 with
L-SelectrideTM gave compound 12 with a high stereoselec-
tivity (12:10 > 40:1, in 82% yield). The structure of com-
pound 12 was assigned by 1H NMR analysis. The

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S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
OTBDPS
OTBDPS
OTBDPS
OH
OH
OMOM
OH
a
b
O-p-NO2Bz
O-p-NO2Bz
1
2
3
OTBDPS
OTBDPS
OMOM
OBn
OMOM
OH
c
d
5
4
OTBDPS
OMOM
OBn
OH
OTBDPS
OMOM
OBn
e
HO
HO
+
OH
carba-β-D-galactose
carba-β-D-allose
6
7
85 : 15
Scheme 1. Synthesis of carba-b-D-galactose derivative 6. Reagents and conditions: (a) PPh3, DEAD, 4-NO2C6H4CO2H, 0 ꢁC, 2 h, 71%; (b)
dimethoxymethane, P2O5 (4.5 equiv), rt, 2 h, 93%; (c) NaOMe (0.1 equiv), MeOH, rt, 50 min, 97%; (d) BnBr (2 equiv), NaH (2 equiv), Bu4NI (0.1 equiv),
THF, rt, 25 h, 91%; (e) OsO4 (cat.), NMO (2 equiv), acetone–water (8:1), rt, 22 h, 99%.
J = 10.3 Hz
J = 2.4 Hz
H
OH OR
OR
J = 2.6 Hz
HO
H
H
OMOM
H
OMOM
H
H
H
HO
J = 9.3 Hz
BnO
J = 9.2 Hz
OBn
H
J = 2.7 Hz
H
H
OH
J = 2.8 Hz
J =9.3 Hz
6
7
in 1H NMR (Benzene-D6)
in 1H NMR (CDCl3)
Figure 2. Structural determination of compounds 6 and 7.
coupling constants JH1–H2 = 3.2 Hz, JH2–H3 = 9.7 Hz, and
JH3–H4 = 2.3 Hz in CDCl3 indicate that H1 and H4 have
equatorial orientations, whereas H2 and H3 have axial
orientations.
amount of 12. When the ratio of 12:13 was raised to 4:1,
compound 14 was obtained in 85% yield without the for-
mation of 15, and un-reacted 12 was recovered quantita-
tively (Scheme 3).
2.3. Synthesis of 1-O-carba-a-galactosyl sphingosine
derivative 14
3. Conclusion
With a good supply of carba-a-D-galactopyranose 12 in
hand, we investigated the synthesis of 1-O-carba-a-galactos-
yl sphingoshine derivative 14 via coupling of 12 with an
aziridine derivative of sphingosine 13.13 Compound 13 in
our hands was prepared from D-erythro-sphingosine by
tritylation, benzylation, detritylation, and cyclization with
TsCl, DMAP, Et3N in CH2Cl2 in good overall yield.14
The reaction of 12 and 13 with NaH in DMF gave the de-
sired product with varying yields depending on the ratio of
12 and 13 employed. When we used 1:1 ratio of 12 and 13,
the yield of the coupled product 14 was only 26% with a by-
product 15 (11%). As the reaction progresses under the
coupling conditions, obviously the starting material 12
and the desired product 14 were competing for 13. In order
to facilitate the formation of 14 we needed to increase the
We have successfully developed practical synthetic routes
to carba-a- and carba-b-galactose derivatives (6 and 12)
from cyclohex-3-ene-1,2-diol derivative 1. Since both
(+)- and (ꢀ)-forms of 1 are readily available, the described
synthetic strategy should be also applicable to all four
diastereomeric carbagalactoses (D- and L- of the a- and
b-forms). By using carba-a-galactose derivative 12, we have
also synthesized a carba-a-galactosyl sphingosine deriva-
tive 14. We are currently investigating the preparation of
various aziridine derivatives of all eight stereoisomers of
phytosphingosine14c and their couplings with carba-a-
galactose derivatives for the syntheses of a number of car-
bocyclic analogues of KRN7000 (a-Galactosyl ceramide).
Similarly, the optically active carbagalactose derivatives
are also being utilized for the syntheses of carbasugar

S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
3033
OH
OTBDPS
OMOM
OBn
OH
OH
OBn
OBn
a
b
HO
OMOM
OBn
OMOM
HO
BnO
OBn
carba-β-D-galactose
9
6
8
OBn
OBn
OBn
OBn
c
d
OH
OBn
BnO
BnO
O
BnO
11
10
e
OBn
OBn
OBn
OBn
OH
OBn
BnO
+
BnO
BnO
OH
12
10
> 40 : 1
Scheme 2. Synthesis of carba-a-galactose derivative 12. Reagents and conditions: (a) TBAF (1.1 equiv), THF, rt, 2 h, 90%; (b) BnBr (9 equiv), NaH
˚
(10 equiv), Bu4NI (0.3 equiv), THF, rt, 16 h, 92%; (c) MeOH–water–concd HCl (100:10:1), reflux, 20 h, 94%; (d) PCC (3 equiv), molecular sieves 4 A,
CH2Cl2, rt, 80 min, 89%; (e) L-SelectrideTM (4.3 equiv), THF, ꢀ20 ꢁC, 1 h, 82%.
BnO
BnO
OBn
BnO
BnO
OBn
a
TsN
+
(CH2)12CH3
NHTs
BnO
BnO
O
(CH3)12CH3
OH
OBn
OBn
12
13
14
+
OBn
BnO
BnO
OBn
(CH2)12CH3
(CH3)12CH3
TsN
NHTs
OBn
15
Scheme 3. Synthesis of carba-a-galactosyl sphingosine derivative 14. Reagents and conditions: (a) NaH (3 equiv), DMF, rt, 3 h, 85%.
BnO
O
glycomimetics for various physiologically important
glycoconjugates.
silica gel (70–230 mesh or 230–400 mesh). NMR spectra
were recorded on a Bruker AM 300, DPX 300, or DRX
500 spectrometer. Tetramethylsilane was used as the inter-
1
nal standard for H NMR. High resolution mass spectra
(FAB) were determined on a JMS-700 at the Korea Basic
Science Center, Daegu, Korea. Optical rotations were mea-
sured with a JASCO DIP-360 digital polarimeter. The stan-
dard extractive work-up procedure consisted of pouring
into a large amount of water, extracting with the organic
solvent indicated, washing the combined extracts succes-
sively with water and brine, drying the extract over an-
hydrous NaSO4 or MgSO4, and evaporating the solvent.
4. Experimental
4.1. General procedure
All non-hydrolytic reactions were carried out in an oven-
dried glassware under inert atmosphere of dry argon or
nitrogen. All commercial chemicals were used as obtained
without further purification, except for solvents, which
were purified and dried by standard methods prior to
use. Analytical TLC was performed on Merck 60 F254
silica gel plate (0.25 mm thickness) and visualization was
done with UV light, and/or by spraying with a 5% solution
of phosphomolybdic acid followed by charring with a heat
gun. Column chromatography was performed on Merck 60
4.2. (1R,2R,5S)-5-(tert-Butyl-diphenylsilanyloxymethyl)-2-
p-nitrobenzoyloxy-cyclohex-3-ene-1-ol 2
To a stirred mixture of compound 15a (2.0 g, 5.23 mmol),
triphenylphosphine (1.61 g, 6.14 mmol), 4-nitrobenzoic

3034
S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
acid (1.16 g, 6.94 mmol) in THF (100 ml) at ꢀ20 ꢁC was
added diethyl azodicarboxylate (1.00 g, 5.75 mmol). After
stirring for 2 h at 0 ꢁC, the reaction mixture was parti-
tioned between ethyl acetate and satd aq NaHCO3. The
organic layer was dried (MgSO4), concentrated, and
10H, 2Ph); 13C NMR (CDCl3): d 19.5, 27.0, 31.4, 39.8,
55.8, 67.7, 72.4, 83.6, 97.3, 127.9, 129.2, 129.9, 133.78,
133.84, 135.8; HRMS (FAB) m/z calcd for C25H35O4Si
427.2305, found 427.2307 (M++1).
chromatographed on silica gel to give compound 2
4.5. (1R,2S,5S)-5-(tert-Butyl-diphenylsilanyloxymethyl)-1-
methoxymethoxy-2-benzyloxy-cyclohex-3-ene 5
27
(1.96 g, 70.7%) as a colorless sticky oil. ½aꢁD ¼ ꢀ131:5
(c 1.0, CHCl3); 1H NMR (CDCl3): d 1.09 (s, 9H,
–C(CH3)3), 1.67 (ddd, J = 13.1, 10.9, 9.6 Hz, 1H, H6b),
2.25 (dt, J = 13.2, 4.3 Hz, 1H, H6a), 2.62 (m, 1H, H5),
3.63 (d, J = 5.9 Hz, 2H, H7a and H7b), 4.08 (ddd,
J = 10.9, 7.0, 3.9 Hz, 1H, H1), 5.54 (ddd, J = 7.0, 4.4,
2.6 Hz, 1H, H2), 5.74 (dt, J = 10.0, 2.6 Hz, 1H, H3), 5.90
(br d, J = 10.0 Hz, 1H, H4), 7.39–7.7 (m, 10H, 2Ph), 8.30
(m, 4H, 4-NO2Ph); 13C NMR (CDCl3): d 19.5, 27.0, 32.9,
38.9, 67.4, 70.2, 123.7, 125.0, 127.9, 130.0 (2s), 131.1,
133.4, 133.5, 133.7, 135.7, 135.8 (2s), 150.8, 165.4; HRMS
(FAB) m/z calcd for C30H34NO6Si 532.2155, found
532.2149 (M++1).
To a solution of compound 4 (1.37 g, 3.20 mmol) in dry
THF (30 ml) at 0 ꢁC was added NaH (280 mg, 55% in
paraffin liquid, 6.41 mmol). After stirring for 30 min at rt,
BnBr (0.76 ml, 6.41 mmol) and Bu4NI (118 mg, 0.32 mmol)
were added. After stirring for 25 h at rt, the reaction mix-
ture was carefully quenched with satd aq NaHCO3 and
worked up by a standard extractive procedure. The crude
product was chromatographed on silica gel to give com-
26
pound 5 (1.50 g, 91%) as a colorless oil. ½aꢁD ¼ ꢀ92:2 (c
1.0, CHCl3); 1H NMR (CDCl3): d 1.08 (s, 9H, –
C(CH3)3), 1.44 (app q, J = 11.0 Hz, 1H, H6b), 2.08 (dt,
J = 12.7, 4.4 Hz, 1H, H6a), 2.57 (m, 1H, H5), 3.43 (s,
3H, –OCH2OCH3), 3.56 (m, 2H, H7a and H7b), 3.86
(ddd, J = 11.8, 7.7, 3.8 Hz, 1H, H1), 4.08 (m, 1H, H2),
4.72 and 4.87 (m, 4H, –OCH2OCH3, –OCH2Ph), 5.74 (m,
2H, H3, H4), 7.27–7.70 (m, 15H, 3Ph); 13C NMR (CDCl3):
d 19.5, 27.0, 31.4, 39.5, 55.6, 67.7, 71.8, 79.8, 96.2, 127.6,
127.7, 127.9, 128.5, 129.9, 131.0, 133.8 (2S), 135.8 (2S),
139.0; HRMS (FAB) m/z calcd for C32H41O4Si 517.2774,
found 517.2773 (M++1).
4.3. (1R,2S,5S)-5-(tert-Butyl-diphenylsilanyloxymethyl)-1-
methoxymethoxy-2-p-nitrobenzoyloxy-cyclohex-3-ene 3
To a stirred mixture of compound 2 (1.90 g, 3.57 mmol) in
dimethoxymethane (20 ml) at rt was added P2O5 (2.00 g,
14.1 mmol) in portions over a period of 2 h. After comple-
tion of the reaction, satd aq NaHCO3 was added to the
reaction mixture until it became homogeneous. Ethyl ace-
tate was added to the mixture and the organic layer was
separated. An extractive workup followed by silica gel
chromatography gave compound 3 (1.92 g, 93.2%) as a col-
4.6. Methoxymethyl 2-O-benzyl-6-O-(tert-butyl-diphenyl)-
silyl-5a-carba-b-D-galactopyranoside 6 and methoxymethyl
2-O-benzyl-6-O-(tert-butyl-diphenyl)silyl-5a-carba-b-D-allo-
pyranoside 7
27
1
orless sticky oil. ½aꢁD ¼ ꢀ153:7 (c 1.0, CHCl3); H NMR
(CDCl3): d 1.05 (s, 9H, –C(CH3)3), 1.56 (m, 1H, H6b),
2.18 (dt, J = 12.9, 4.4 Hz, 1H, H6a), 2.59 (m, 1H, H5),
3.24 (s, 3H, –OCH2OCH3), 3.58 (app dd, J = 6.5, 1.9 Hz,
2H, H7a and H7b), 4.00 (ddd, J = 12.2, 8.1, 4.0 Hz, 1H,
H1), 4.64 and 4.71 (2d, each J = 6.98, 6.98 Hz, 2H,
–OCH2OCH3), 5.63 (m, 2H, H2 and H3), 5.86 (br d,
J = 10.3 Hz, 1H, H4), 7.34–7.70 (m, 10H, 2Ph), 8.26 (m,
4H, 4-NO2Ph); 13C NMR (CDCl3): d 19.5, 27.0, 31.0,
39.4, 55.6, 67.4, 75.8, 76.2, 95.7, 123.8, 125.5, 127.9,
129.9, 130.9, 133.1, 133.7 (2s), 135.8 (2s), 136.0, 150.8,
164.6; HRMS (FAB) m/z calcd for C32H38NO7Si
576.2418, found 576.2421 (M++1).
To a solution of 5 (1.40 g, 2.71 mmol) and 4-methylmor-
pholine-N-oxide (NMO, 635 mg, 5.42 mmol) in acetone–
water (28 ml, 6:1) at rt was added a catalytic amount of
OsO4. After stirring for 22 h, Na2SO3 (3.41 g, 27.1 mmol)
was added and the resulting mixture was further stirred
for 30 min at rt. The reaction mixture was extractively
worked up with ethyl acetate, and chromatographed on
silica gel to give compound 6 (1.26 g, 84.6%) and
compound 7 (219 mg, 14.7%) as colorless oils.
27
Compound 6: ½aꢁD ¼ þ29:2 (c 1.0, CHCl3); 1H NMR
4.4. (1R,2S,5S)-5-(tert-Butyl-diphenylsilanyloxymethyl)-1-
methoxymethoxy-2-ol-cyclohex-3-ene 4
(C6D6): d 1.28 (s, 9H, –C(CH3)3), 1.53 (m, 1H, H5), 1.82
(m, 2H, H5aa and H5ab), 3.31 (s, 3H, –OCH2OCH3),
3.42 (dd, J = 9.3, 2.8 Hz, 1H, H3), 3.67 (app td, J = 9.3,
7.1 Hz, 1H, H1), 3.73 (dd, J = 9.8, 5.8 Hz, 1H, H6a), 3.85
(t, J = 9.2 Hz, 1H, H2), 3.98 (dd, J = 9.7, 7.7 Hz, 1H,
H6b), 4.24 (t, J = 2.4 Hz, 1H, H4), 4.67–5.08 (4d, each
J = 6.7, 11.8, 6.7, 11.8 Hz, 4H, –OCH2OCH3, –OCH2Ph),
7.25–7.91 (m, 15H, 3Ph); 13C NMR (C6D6): d 19.5, 27.1,
28.3, 39.3, 55.2, 65.1, 69.2, 75.1, 75.3, 78.8, 83.3, 96.0,
128.7, 130.0, 134.0, 134.1, 136.0, 136.1, 139.8; HRMS
(FAB) m/z calcd for C32H43O6Si 551.2829, found
551.2831 (M++1).
To a stirred solution of compound 3 (1.97 g, 3.42 mmol) in
MeOH (20 ml) at rt was added NaOMe (25% in MeOH,
80 ll, 0.35 mmol). After stirring for 50 min, acetic acid
(41 mg) was added and the resulting mixture was concen-
trated. The residue was partitioned between ethyl acetate
and satd aq NaHCO3. An extractive workup followed by
silica gel chromatography gave compound 4 (1.41 g,
26
96.6%) as a colorless sticky oil. ½aꢁD ¼ ꢀ105:7 (c 1.0,
CHCl3); 1H NMR (CDCl3): d 1.04 (s, 9H, –C(CH3)3),
1.67 (app q, J = 11.8 Hz, 1H, H6b), 2.08 (dt, J = 12.5,
4.2 Hz, 1H, H6a), 2.54 (m, 1H, H5), 3.45 (s, 3H,
–OCH2OCH3), 3.46–3.56 (m, 3H, H1, H7a, and H7b),
4.13 (m, 1H, H2), 4.75 and 4.80 (2d, J = 7.0 Hz, 2H,
–OCH2OCH3), 5.60–5.70 (m, 2H, H3, H4), 7.34–7.66 (m,
27
Compound 7: ½aꢁD ¼ þ0:64 (c 1.0, CHCl3); 1H NMR
(CDCl3): d 1.07 (m, 10H, –C(CH3)3, H5ab), 1.85 (dt,
J = 13.2, 4.3 Hz, 1H, H5aa), 2.16 (m, 1H, H-5), 2.38 (br
s, 2H, OH’s), 3.30 (dd, J = 9.3, 2.7 Hz, 1H, H2), 3.37 (s,

S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
3035
3H, –OCH2OCH3), 3.60 (dd, J = 10.3, 2.6 Hz, 1H, H4),
3.67 (dd, J = 10.0, 7.0 Hz, 1H, H6a), 3.81 (dd, J = 10.0,
4.4 Hz, 1H, H6b), 3.98 (ddd, J = 11.5, 9.4, 4.7 Hz, 1H,
H1), 4.20 (t, J = 2.6 Hz, 1H, H3), 4.68–4.85 (m, 4H,
–OCH2OCH3, –OCH2Ph), 7.27–7.70 (m, 15H, 3Ph); 13C
NMR (CDCl3): d 19.3, 27.0, 30.5, 37.8, 55.5, 67.0, 71.1,
72.5, 73.2, 74.9, 82.0, 96.8, 127.9 (2s), 128.0, 128.6, 130.0,
132.9, 133.1, 135.7, 138.4; HRMS (FAB) m/z calcd for
C32H43O6Si 551.2829, found 551.2821 (M++1).
NMR (CDCl3): d 1.59 (app q, J = 12.2 Hz, 1H, H5ab),
1.72 (dt, J = 12.3, 4.4 Hz, 1H, H5aa) 1.83 (m, 1H, H5),
2.03 (br s, 1H, –OH), 3.37 (dd, J = 8.8, 5.1 Hz, 1H, H6a),
3.46 (dd, J = 9.6, 2.3 Hz, 1H, H3), 3.55 (t, J = 9.1 Hz,
1H, H6b), 3.57 (m, 1H, H1), 3.84 (t, J = 9.3 Hz, 1H, H2),
4.17 (br s, 1H, H4), 4.46–5.08 (m, 8H, 4 · –OCH2Ph),
7.33 (m, 20H, 4Ph); 13C NMR (CDCl3): d 29.8, 38.4,
71.4. 72.6. 73.1. 74.0. 75.2. 75.3. 76.2. 84.5. 85.5. 128.0,
128.1, 128.2, 128.3, 128.4, 128.47, 128.54, 128.7, 128.9,
129.1, 129.2, 138.9, 139.2, 139.5, 140.1; HRMS (FAB) m/
z calcd for C35H39O5 539.2797, found 539.2794 (M++1).
4.7. Methoxymethyl 2-O-benzyl-5a-carba-b-D-galacto-
pyranoside 8
4.10. (2R,3S,4S,5R)-2,3,4-Tri-benzyloxy-5-benzyloxy-
methyl-cyclohexanone 11
To the solution of compound 6 (1.24 g) in THF (25 ml) at
0 ꢁC was added tetrabutylammonium fluoride (1 M in
THF, 2.48 ml, 2.48 mmol). After stirring for 2 h at rt, the
reaction mixture was concentrated and chromatographed
on silica gel (sequential elution with CH2Cl2 to remove
TBDPS-F followed by elution with ethyl acetate) to give
the desired triol compound 8 (634 mg, 90.2%) as a colorless
foam. ½aꢁD ¼ þ51:3 (c 1.0, CHCl3); H NMR (CDCl3): d
1.61 (m, 1H), 1.80 (m, 2H), 3.38 (m, 4H), 3.57–3.79 (m,
4H), 4.10 (pseudo t, J = 2.4 Hz, 1H, H4), 4.63–4.99 (m,
4H, –OCH2OCH3, –OCH2Ph), 7.24–7.37 (m, 5H, Ph);
13C NMR (CDCl3): d 28.0, 38.3, 55.7, 64.4, 70.6, 74.5,
75.5, 78.8, 82.7, 96.2, 128.1, 128.8, 139.0; HRMS (FAB)
m/z calcd for C16H25O6 313.1651, found 313.1648 (M++1).
To a stirred mixture of 10 (850 mg, 1.58 mmol), molecular
˚
sieves 4 A (powder, 1 g) in CH2Cl2 (30 ml) at rt, was added
PCC (1.02 g, 4.73 mmol). After stirring for 80 min, the
reaction mixture was filtered through a silica gel column
and washed with EtOAc–n-hexane (1:4–1:2). The filtrate
was concentrated to give 11 (753 mg, 1.40 mmol,
27
1
27
1
89.0%) as a colorless oil. ½aꢁD ¼ þ10:1 (c 1.0, CHCl3); H
NMR (CDCl3): d 2.05 (m, 1H, H5), 2.24 (dd, J = 13.6,
3.8 Hz, 1H, H6a) 2.56 (t, J = 13.8 Hz, 1H, H6b), 3.36
(dd, J = 8.9, 5.2 Hz, 1H, H7a), 3.58 (t, J = 8.9 Hz, 1H,
H7b), 3.70 (dd, J = 10.2, 2.3 Hz, 1H, H3), 4.29 (br s, 1H,
H4), 4.46–5.08 (m, 9H, H2, 4 · –OCH2Ph), 7.36 (m, 20H,
4Ph); 13C NMR (CDCl3): d 38.3, 38.4, 70.2, 73.4, 73.9,
74.0, 75.2, 75.3, 84.57, 84.65, 127.7, 127.8, 128.0, 128.1,
128.3, 128.5 (2S), 128.7, 138.1, 138.2, 138.7, 139.0; HRMS
(FAB) m/z calcd for C35H37O5 537.2641, found 537.2643
(M++1).
4.8. Methoxymethyl 2,3,4,6-tetra-O-benzyl-5a-carba-b-D-
galactopyranoside 9
To a solution of compound 8 (611 mg, 1.96 mmol) in dry
THF (35 ml) at 0 ꢁC, was added NaH (860 mg, 55% in par-
affin liquid, 19.7 mmol). After stirring for 25 min at rt,
BnBr (2.09 ml, 17.6 mmol) and Bu4NI (217 mg, 0.59 mmol)
were added. After stirring for 16 h at rt, the reaction mix-
ture was carefully quenched with satd aq NaHCO3 and
worked up by a standard extractive procedure. The crude
4.11. 2,3,4,6-Tetra-O-benzyl-5a-carba-a-D-galactopyranose
12
To a stirred solution of compound 11 (4.0 g, 7.45 mmol) in
THF (250 ml) at 0 ꢁC, was slowly added L-SelectrideTM
(32.4 ml, 1 M solution in THF, 32.4 mmol) over 25 min
with a syringe. After 1 h, the reaction mixture was carefully
quenched by dropwise addition of 5% KOH (2.5 ml). The
reaction mixture turned to be turbid and a white precipitate
was formed. To the resulting mixture at 0 ꢁC, H2O2 (4 ml)
was slowly added and stirred for 1 h and 30 min. The
resulting mixture was filtered, washed with CH2Cl2, and
the filtrate was concentrated. The residue was dissolved
in ethyl acetate, washed with water and brine, dried
(MgSO4), concentrated, and chromatographed to give
product was chromatographed on silica gel to give com-
27
pound 9 (1.05 g, 92.0%) as a colorless oil. ½aꢁD ¼ þ29:7 (c
1
1.0, CHCl3); H NMR (CDCl3): d 1.59–1.75 (m, 3H, H5,
H5aa, H5ab), 3.32 (dd, J = 9.0, 5.0 Hz, 1H, H6a), 3.35 (s,
3H, –OCH2OCH3), 3.41 (dd, J = 9.7, 2.4 Hz, 1H, H3),
3.50 (t, J = 9.0 Hz, 1H, H6b), 3.58 (ddd, J = 11.1, 9.2,
5.3 Hz, 1H, H1), 3.91 (t, J = 9.4 Hz, 1H, H2), 4.11 (br s,
1H, H4), 4.42–5.05 (m, 10H, –OCH2OCH3, 4 · –OCH2Ph),
7.29 (m, 20H, 4Ph); 13C NMR (CDCl3): d 28.9, 37.7, 55.5,
70.8, 73.1, 73.4, 74.6, 74.8, 76.0, 78.7, 83.3, 84.9, 96.8,
127.4, 127.6, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5,
128.6, 138.4, 139.0, 139.3, 139.6; HRMS (FAB) m/z calcd
for C37H43O6 583.3060, found 583.3059 (M++1).
compound 12 (3.10 g, 77.2%) as a colorless oil together
25
with recovered 11 (217 mg, 5.4 %). ½aꢁD ¼ þ20:8 (c 1.0,
CHCl3); 1H NMR (CDCl3): d 1.64 (m, 2H, H5aa and
H5ab), 2.32 (m, 1H, H5), 2.62 (br s, 1H, –OH), 3.34 (dd,
J = 8.9, 5.1 Hz, 1H, H6a), 3.54 (t, J = 9.2 Hz, 1H, H6b),
3.80 (dd, J = 9.7, 2.3 Hz, 1H, H3), 3.94 (dd, J = 9.7,
3.2 Hz, 1H, H2), 4.20 (app q, J = 2.9 Hz, 1H, H1), 4.23
(pseudo t, J = 1.8 Hz, 1H, H4), 4.77–5.05 (m, 8H, 4 ·
–OCH2Ph), 7.36 (m, 20H, 4Ph); 13C NMR (CDCl3): d
27.8, 35.3, 67.4, 70.8, 72.9, 73.1, 73.2, 74.7, 75.7, 80.3,
81.2, 127.4, 127.5, 127.6, 127.8, 127.86, 127.95, 128.0,
128.3, 128.5, 128.6, 128.7, 138.6, 138.7, 139.2, 139.7;
HRMS (FAB) m/z calcd for C35H39O5 539.2797, found
539.2795 (M++1).
4.9. 2,3,4,6-Tetra-O-benzyl-5a-carba-b-D-galactopyranose
10
The solution of compound 9 (1.02 g, 1.76 mmol) in
MeOH–water–concd HCl (100:10:1, 40 ml) was refluxed
for 20 h. The reaction mixture was concentrated and parti-
tioned between ethyl acetate and satd aq NaHCO3. The
organic layer was dried (MgSO4), concentrated, and
chromatographed to give compound 10 (887 mg, 93.7%)
27
1
as a colorless sticky oil. ½aꢁD ¼ ꢀ12:6 (c 1.0, CHCl3); H

3036
S.-H. Yu et al. / Tetrahedron: Asymmetry 17 (2006) 3030–3036
4.12. (2S,3R,4E)-3-Benzyloxy-1-(20,30,40,60-tetra-O-benzyl-
5a-carba-a-D-galactopyranosyloxy)-2-(p-toluenesulfonyl-
amino)-4-octadecene 14
´
Ed. 1999, 38, 2300–2324; (d) Petitou, M.; Herault, J.-P.;
Bernat, A.; Driguez, P.-A.; Duchaussoy, P.; Lormeau, J.-C.;
Herbert, J.-M. Nature 1999, 398, 417–422; (e) Sinay, P.
Nature 1999, 398, 377–378; (f) Carbohydrate Mimics.
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH:
Weinheim, 1998; (g) Carbohydrates in Drug Design; Witczak,
Z. J., Nieforth, K. A., Eds.; Marcel Dekker: New York, 1997.
3. (a) Ogawa, S. Trends Glycosci. Glycotechnol. 2004, 16, 33–53;
(b) Compain, P.; Martin, O. R. Bioorg. Med. Chem. 2001, 9,
3077–3092; (c) Ogawa, S.; Ohmura, M.; Hisamatsu, S.
Synthesis 2001, 312–316; (d) Ogawa, S.; Hirai, K.; Odagiri,
T.; Matsunaga, N.; Yamazaki, T.; Nakajima, A. Eur. J. Org.
Chem. 1998, 1099–1109; (e) Suami, T. Top. Curr. Chem. 1990,
154, 257–283; (f) Suami, T.; Ogawa, S. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 21–90; (g) Carbohydrates in Drug
Design; Witczak, Z. J., Nieforth, K. A., Eds.; Marcel Dekker:
New York, 1997; pp 433–469; (h) Carbohydrate Mimics.
Concepts and Methods; Chapleur, Y., Ed.; Wiley-VCH:
Weinheim, 1998; pp 87–106; (i) Postema, M. H. D.
C-Glycoside Synthesis; CRC Press: Boca Raton, FL, 1995;
(j) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier/Pergamon: Oxford, 1995.
To carbasugar derivative 12 (1.31 g, 2.43 mmol) in DMF
(4 ml) at 0 ꢁC, was added NaH (55%, 108 mg, 2.47 mol).
After stirring for 20 min, aziridine derivative 13 (315 mg,
0.60 mmol) in DMF (2 ml) was added with a syringe. After
stirring for 1.5 h at rt, the reaction mixture was partitioned
between CH2Cl2 and satd aq NaHCO3. The organic layer
was dried (MgSO4), concentrated, and chromatographed
to give the coupled product 14 (540 mg, 0.51 mmol,
85.0%) as an oil, together with recovered 12 (1.03 g,
1.91 mmol).
25
Compound 14: ½aꢁD ¼ þ13:1 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) and 1H–1H homonuclear COSY
NMR (500 MHz, CDCl3): d 0.92 (t, J = 7.0 Hz, 3H, –CH@
CHCH2(CH2)11CH3), 1.29 (m, 22H, –CH@CHCH2-
(CH2)11CH3), 1.45 (br t, J = 13.0 Hz, 1H, H5ab), 1.52
(m, 1H, 1H, H5aa), 1.98 (app q, J = 7.5 Hz, 2H, H6a
and H6b), 2.07 (m, 1H, H50), 2.37 (s, 3H, Ph–CH3),
3.29 (dd, J = 8.5, 5.0 Hz, H60a), 3.44 (m, 1H, H2), 3.48
4. (a) Boyd, D. R.; Sharma, N. D.; Llamas, N. M.; Malone, J.
F.; O’Dowd, C. R.; Allen, C. C. R. Org. Biomol. Chem. 2005,
´
3, 1953–1963; (b) Gomez, A. M.; Moreno, E.; Valverde, S.;
Lopez, J. C. Eur. J. Org. Chem. 2004, 1830–1840, and
(t, J = 9.0 Hz, 1H, H60 ), 3.59 (dd, J = 9.5 Hz, 1H, H1a),
´
b
references cited therein; (c) Hudlicky, T.; Entwistle, D. A.;
Pitzer, K. K.; Thorpe, A. J. Chem. Rev. 1996, 96, 1195–1220.
5. (a) Yu, S.-H.; Chung, S.-K. Tetrahedron: Asymmetry 2004,
15, 581–584; (b) Yu, S.-H.; Chung, S.-K. Tetrahedron:
Asymmetry 2005, 16, 2729–2747.
6. (a) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai,
T.; Sawa, E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.;
Kukushima, H. J. Med. Chem. 1995, 38, 2176–2187; (b)
Miyamoto, K.; Miyake, S.; Yamamura, T. Nature 2001, 413,
531–534; (c) Yang, G.; Schmieg, J.; Tsuji, M.; Franck, R. W.
Angew. Chem., Int. Ed. 2004, 43, 3818–3822; (d) Goff, R. D.;
Gao, Y.; Mattner, J.; Zhou, D.; Yin, N.; Cantu, C., III;
Teyton, L.; Bendelac, A.; Savage, P. B. J. Am. Chem. Soc.
2004, 126, 13602–13603.
3.67 (pseudo q, J = 2.5 Hz, 1H, H10), 3.82 (dd, J = 10.0,
2.5 Hz, 1H, H30), 3.85 (dd, J = 10.0, 5.5 Hz, 1H, H1b),
3.89 (dd, J = 9.5, 2.5 Hz, 1H, H20), 3.95 (dd, J = 8.0,
5.5 Hz, 1H, H3), 4.1 (br s, 1H, H40), 4.16–5.00 (m, 10H,
5 · –OCH2Ph), 5.19 (dd, J = 15.5, 8.0 Hz, 1H, H4), 5.44
(d, J = 6.0 Hz, 1H, NH), 5.59 (dt, J = 15.5, 6.5 Hz, 1H,
H5), 7.14–7.72 (m, 29H, 5 · Ph, tosyl); 13C NMR (CDCl3):
d 14.3, 21.7, 22.9, 27.2, 29.3, 29.5, 29.6, 29.7, 29.90, 29.94,
32.1, 32.6, 35.9, 57.7, 68.9, 70.8, 73.1, 73.4, 74.8, 76.0, 79.5,
80.2, 81.7, 126.7, 127.4, 127.6, 127.8, 127.9, 128.1, 128.4,
128.5, 128.6, 129.6, 136.8, 138.3, 138.6, 138.7, 139.0,
138.4, 139.8, 143.1; MS (FAB) m/z 1087 (M++Na); HRMS
(FAB) m/z calcd for C67H86NO8S 1064.6074, found
1064.6077 (M++1).
7. (a) Mehta, G.; Mohal, N.; Lakshimnath, S. Tetrahedron Lett.
2000, 41, 3505–3508; (b) Mehta, G.; Talukdar, P.; Mohal, N.
Tetrahedron Lett. 2001, 42, 7663–7666.
8. Berger, B.; Rabiller, C. G.; Ko¨nigsberger, K.; Faber, K.;
Griengl, H. Tetrahedron: Asymmetry 1990, 1, 541–546.
9. Boyd, D. R.; Sharma, N. D.; Llamas, N. M.; Malone, J. F.;
O’Dowd, C. R.; Allen, C. C. R. Org. Biomol. Chem. 2005, 3,
1953–1963.
Acknowledgment
This work was supported by the Korea Research Founda-
tion Grant funded by the Korean Government
(MOEHRD) (KRF-2005-070-C00078).
10. Arjona, O.; Dios, A.; Plumet, J.; Saez, B. J. Org. Chem. 1995,
60, 4932–4935.
11. (a) Yardley, J. P.; Fletcher, H. Synthesis 1976, 276; (b)
Chung, S. K.; Yu, S. H. Korean J. Med. Chem. 1996, 6, 35–46.
12. Although the 6-OTBDPS group may be utilized further in the
synthesis of carba-a-galactose, the 6-OBn derivative was
thought to be better for its application to KRN7000
analogues.
13. Tsunoda, H.; Ogawa, S. Liebigs Ann. 1995, 267–277.
14. (a) Chung, S. K.; Lee, J. M. Tetrahedron: Asymmetry 1999,
10, 1441–1444; (b) Lee, J. M.; Lim, H. S.; Chung, S. K.
Tetrahedron: Asymmetry 2002, 13, 343–347; (c) Park, J. J.;
Chung, S. K., unpublished results.
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