Synthetic approach to 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) α-disaccharides via a ketene dithioacetal

Article abstract of DOI:10.1016/S0957-4166(00)00371-2

A unique strategy for the synthesis of Kdo α-disaccharides based on the ketene dithioacetal 4 (precursor of Kdo) as a 'glycosyl donor' has been developed. Direct, fully stereoselective addition of 6-, 7-, or 8-OH unprotected sugar units to the exo-anomeri

Full text of DOI:10.1016/S0957-4166(00)00371-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3737–3746
Synthetic approach to 3-deoxy- -manno-oct-2-ulosonic acid
D
(Kdo) a-disaccharides via a ketene dithioacetal†
Jacek M*lynarski and Anna Banaszek*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 27 July 2000; accepted 14 September 2000
Abstract
A unique strategy for the synthesis of Kdo a-disaccharides based on the ketene dithioacetal 4 (precursor
of Kdo) as a ‘glycosyl donor’ has been developed. Direct, fully stereoselective addition of 6-, 7-, or 8-OH
unprotected sugar units to the exo-anomeric double bond in 4, promoted by trimethylsilyl triflate, led to
the corresponding O-disaccharides 12 with the dithioacetal residue intact. Subsequent hydrolysis of the
later afforded the title compounds in high yields. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
3-Deoxy-
polysaccharides (LPS) of Gram-negative bacteria.1 Kdo-a-(2“6)-GlcN disaccharide forms the
glycosidic linkage between lipid A and inner core region,2 which is composed of Kdo and
- and
D
-manno-oct-2-ulosonic acid (Kdo) is a key component of the core region lipo-
L
D
-glycero-
-manno-heptoses.3 Kdo units in this region are connected by a-(2“4) linkage,
D
forming trisaccharides,3 or by a-(2“8) linkage, as it occurs in the terminal part of LPS of
Chlamydia.4
Synthetic analogues of Kdo and its disaccharides have attracted interest as potential inhibitors
of Kdo incorporation into LPS inner core region.5 Numerous syntheses of di- and oligosaccha-
rides based on Kdo halides as glycosyl donors have been reported.6 They, however, suffer from
incomplete stereoselective outcome of the glycosylation reaction, often leading to the mixture of
a/b anomers. In addition, the C-2–C-3 elimination product is usually formed.6c
Introduction at C-3 of the Kdo glycosyl donor the phenylselenyl moiety as a stereocontrolling
auxiliary has allowed a-disaccharides to be achieved as sole products.7 This glycosylselenation
process involving phenylselenyl triflate as a reagent is quite capricious and one must take into
account a reductive removal of C-3 substituent in the final step of synthesis.
* Corresponding author. Fax: +48 22 632 66 81; e-mail: habaru@icho.edu.pl
†
This work was presented at the 13th International Conference on Organic Synthesis, Warsaw, Poland, July 2–5,
2000, Abstract OC B19.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00371-2

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J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
It occurred to us some time ago that replacement of ulosonic acid glycosyl donor by its
precursor would be of interest in the search for stereoselective synthesis of disaccharides.8 Such
a precursor would correspond to the simple exo-glycal, which has been reported9 to undergo
iodonium mediated addition of alcohols to form O-glycosidic linkage. Following this reasoning
we synthesized ketene dithioacetals of type 4, hoping that dithianyl group located at the end of
the exo-anomeric double bond should exert a steric hindrance for the attack from the dithianyl
ring side. Therefore a-glycosidic linkage should be formed exclusively. Successful preparation of
heptulosonic acid disaccharides in this way confirmed our expectations.8
2. Results and discussion
Ketene dithioacetal 4 being a precursor of Kdo molecule, was synthesized from -mannose by
D
a previously described route10 (Scheme 1). One step of this route deserves, however, some
comments: a mixture of products 2a and 3 was obtained upon the reductive cleavage of
5,7-O-benzylidene ring in 1 with triethylsilane (TES)–trifluoroacetic acid (TFA) system, whereas
such a reaction of the 4,6-O-benzylidene group in sugars leads to the 6-O-benzyl derivative as
a sole product.11
Scheme 1. Reagents and conditions: (a) TFA–TES, CH2Cl2, rt; (b) TbsCl, Im, CH2Cl2, DMAP, rt; (c) K2CO3,
MeOH, rt; (d) PCC, dichloroethane, 60°C; (e) 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-1,3-dithiane, KHMDS, THF,
−78°C“rt; (f) NBS, MeOH, CH2Cl2, rt
Fortunately, we found this unexpected product 3 to be very useful for the preparation Kdo
as a glycosyl acceptor in Kdo–Kdo disaccharide synthesis. With this aim compound 3,
after selective protection of the 7-OH group with tert-butyldimethylsilyl ether (Tbs) and
subsequent hydrolysis of the 1-OAc residue, underwent oxidative cyclization by treatment with
PCC in dichloroethane to give 2-deoxy-heptonolactone 6. This was reacted with the 1,3-dithi-
anyl anion generated from 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-1,3-dithiane and potassium

J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3739
bis(trimethylsilyl)amide (KHMDS) in THF,10 leading to ketene dithioacetal 7. Efficient transfor-
mation of 7 into the glycosyl acceptor 8 was performed in one step using N-bromosuccinimide
in methanol–dichloromethane.10 Under these conditions the Tbs group was simultaneously
removed.
Following our purpose of employing ketene dithioacetal template 4 toward the synthesis of
varied Kdo disaccharides (Scheme 2), we investigated firstly the reaction with the known
6-O-unprotected glucose derivative 9 (Table 1). Direct addition of 9 to the double bond of
ketene dithioacetal afforded disaccharide 12a in high yield (Scheme 2, Table 1). The reaction
was conducted in dichloromethane at −78“−30°C using trimethylsilyl triflate (TmsOTf) as a
promoter.8 Similar results, and an even higher yield of the desired disaccharide 12b, were
obtained applying the 7-O-unprotected
L
-glycero-
-manno-heptose derivative 10.12
D
Scheme 2.
In contrast, glucosamine derivative 11 as a glycosyl acceptor needed more severe conditions,
i.e. higher temperature (ꢀ0°C), longer reaction time and a stoichiometric amount of TmsOTf
promoter. As a result disaccharide 12c was obtained in about 40% yield.
We were pleased to find that the addition of Kdo derivative 8 to Kdo precursor 4 proceeded
smoothly giving (2“8) linked disaccharide 12d in 72% yield.
In all reactions performed disaccharides were isolated as the only products, leaving the
dithianyl ring intact. This last one was easily transformed into the methyl ester by an oxidative
hydrolysis with 10-fold excess of NBS in aqueous THF solution (9:1),13 to give the a-linked Kdo
disaccharides 13a–d with full stereoselectivity (Scheme 2, Table 1). Evidently, the 1,3-dithianyl
ring due to its capacity fulfills a steric control on the addition reaction stage.
The a-configuration of the glycosidic linkage was established by comparison of NMR data
with those reported14 (Table 1). The distance between H-3ax and H-3eq (about 0.05 ppm)
established unambiguously a configuration. In the b anomers the distance is larger than 0.25
ppm. In one case (compound 13a) the configuration was additionally confirmed by NMR
identity of per-O-acetylated derivative 14 with the literature data.15
In summary, we have demonstrated the unique ketene dithioacetal precursor of Kdo as a
versatile ‘glycosyl donor’ for the fully stereoselective construction of Kdo a-disaccharides.
3. Experimental
3.1. General information
Optical rotations were measured with a JASCO Dip-360 Digital Polarimeter at room
1
temperature. H NMR spectra were recorded on Bruker AM-500 (500 MHz) spectrometers with
Me4Si as internal standard. High resolution mass spectra were taken on a Mariner PerSeptive

3740
J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
Table 1
Biosystems mass spectrometer with time-of-flight (TOF) detector. IR spectra were taken with a
Perkin–Elmer FT-IR-1600 spectrophotometer. Reactions were controlled using TLC on silica
[Merck alu-plates (0.2 mm)].
All reagents and solvents were purified and dried according to common methods. All organic
solutions were dried over MgSO4. Reaction products were purified by flash chromatography
using Merck’s Kieselgel 60 (240–400 mesh or 70–230 mesh).

J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3741
3.2. 1-O-Acetyl-3,4,6,7-tetra-O-benzyl-2-deoxy-
D
-manno-heptitol 2a and 1-O-acetyl-3,4,6-tri-
O-benzyl-2-deoxy- -manno-heptitol 3
D
To a vigorously stirred solution of benzylidene heptitol 110 (1.70 g, 2.70 mmol) in dry CH2Cl2
were added triethylsilane (2.0 mL, 12.55 mmol) and trifluoroacetic acid (0.86 mL, 11.30 mmol)
at 0°C under Ar. The temperature was allowed to rise to room temperature during 1 h with
stirring (TLC). The mixture was diluted with ethyl ether and washed with NaHCO3 and water.
After solvent evaporation the residue was chromatographed on silica gel to give 7-O-benzyl
derivative 2a (52%); mp 47°C; [h]D −10.5 (c 1.00 in CHCl3); IR (film) winter alia: 3488, 3031, 2867,
1
1773, 1496, 1454, 1245, 1098 cm−1; H NMR (CDCl3): l 1.90–2.00 (m, 2H, 2×H-2), 1.96 (s, 3H,
Ac), 3.15 (d, 1H, OH-5, J 5.8 Hz), 3.56–3.69 (m, 2H), 3.70–3.82 (m, 2H), 3.82–3.92 (m, 2H),
4.10–4.20 (m, 2H), 4.30–4.80 (4×ABq, 4×2H, CH6 2Ph), 7.20–7.40 (m, 20H, Ar); HR-MS (ESI)
calcd for C37H42O7 [M+Na]+ 621.2823; found 621.2858.
Eluted second was 5,7-O-deprotected compound 3 (32%); colourless oil: [h]D −25.1 (c 0.98 in
1
CHCl3); IR (film) winter alia: 3465, 2875, 1733, 1497, 1454, 1245, 1096, 1058 cm−1; H NMR
(CDCl3): l 1.90–1.97 (m, 2H, 2×H-2), 1.97 (s, 3H, Ac), 2.29–2.32 (m, 1H, OH-7), 3.30 (d, 1H,
OH-5, J 5.3 Hz), 3.49–3.52 (m, 1H), 3.77 (dd, 1H, H-4, J 1.5, 3.0 Hz), 3.80–3.90 (m, 4H),
4.10–4.18 (m, 2H), 4.20–4.70 (3×ABq, 3×2H, CH6 2Ph), 7.20–7.35 (m, 15H, Ar); HR-MS (ESI)
calcd for C30H36O7 [M+Na]+ 531.2353; found 531.2364.
3.3. 3,4,6-Tri-O-benzyl-7-O-tert-butyldimethylsilyl-2-deoxy-
D
-manno-heptitol 5
To a solution of 3 (1.20 g, 2.36 mmol) in anhydrous CH2Cl2 (10 mL) were added triethyl-
amine (0.42 mL, 3.0 mmol), 4-dimethylaminopyridine (20 mg) and tert-butyldiphenylsilyl
chloride (380 mg, 2.5 mmol). The solution was stirred overnight at room temperature, then
evaporated. The crude product was redissolved in methanol (20 mL) and K2CO3 (500 mg) was
added. The resulting suspension was stirred at rt for 1 h (TLC). The mixture was then diluted
with CH2Cl2 and filtered through a short column of silica gel to give 5 (1.2 g, 87%) as a
colourless oil: [h]D −19.3 (c 1.15, CHCl3); IR (film) winter alia: 3461, 3031, 2929, 2857, 1454, 1253,
1
t
t
1094 cm−1; H NMR (CDCl3): l 0.07, 0.08 (2×s, 2×3H, BuMe2Si), 0.91 (s, 9H, BuMe2Si),
1.84–1.94 (m, 2H, 2×H-2), 1.95–1.98 (m, 1H, OH-1), 3.09 (d, 1H, OH-5, J 6.0 Hz), 3.55 (ddd,
1H, H-6, J 3.2, 5.4, 8.4 Hz), 3.68–3.72 (m, 2H, 2×H-1), 3.76 (m, 1H, H-5), 3.84 (dd, 1H, H-7a,
J 5.4, 11.1 Hz), 3.87–3.91 (m, 1H, H-3), 3.91 (dd, 1H, H-4, J 1.8, 3.5 Hz), 4.03 (dd, 1H, H-7b,
J 3.2, 11.0 Hz), 4.37–4.80 (3×ABq, 3×2H, CH6 2Ph), 7.20–7.35 (m, 15H, Ar); HR-MS (ESI) calcd
for C34H48O6Si [M+Na]+ 603.3112; found 603.3122.
3.4. 3,4,6-Tri-O-benzyl-7-O-tert-butyldimethylsilyl-2-deoxy- -manno-heptono-1,5-lactone 6
D
A mixture of PCC (1.80 g, 8.50 mmol) and heptitol 5 (1.30 g, 2.2 mmol) was stirred in
1,2-dichloroethane solution (30 mL) at 60°C for 1 h and then poured onto a column of silica gel
prepared in hexane. Elution with hexane–ether (3:2) gave lactone 6 with 90% yield. Colourless
oil: [h]D −7.3 (c 1.13, CHCl3); IR (film) winter alia: 3031, 2952, 2929, 2857, 1747, 1455, 1224, 1099
1
t
t
cm−1; H NMR (CDCl3): l 0.06, 0.07 (2×s, 2×3H, BuMe2Si), 0.90 (s, 9H, BuMe2Si), 2.91 (dd,
1H, H-2eq, J 6.8, 17.8 Hz), 2.96 (dd, 1H, H-2ax, J 10.8, 17.7 Hz), 3.28–3.86 (m, 2H, H-7a,
H-7b), 3.92 (ddd, 1H, H-3, J 1.8, 7.0, 10.8 Hz), 4.03 (dd, 1H, H-6, J 3.6, 12.8 Hz), 4.26 (dd, 1H,
H-5, J 1.5, 8.5 Hz), 4.37 (bs, 1H, H-4), 4.36–5.06 (3×ABq, 3×2H, CH2
6 Ph), 7.26–7.37 (m, 15H,
Ar); HR-MS (ESI) calcd for C34H44O6Si [M+Na]+ 599.2799; found 599.2806.

3742
J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3.5. 2,6-Anhydro-4,5,7-tri-O-benzyl-8-O-tert-butyldimethylsilyl-1-(propane-1,3-diyl-dithio-
acetal)-1,3-dideoxy- -manno-oct-1-enitol 7
D
A solution of potassium bis(trimethylsilyl)amide (3.4 mL, 1.70 mmol ꢀ0.5 M solution in
toluene) was added dropwise to 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]-1,3-dithiane (620 mg,
1.70 mmol) dissolved in anhydrous THF (10 mL) at −78°C under Ar. The temperature was
maintained at −78°C for 1 h and then a solution of 6 (500 mg, 0.87 mmol) in THF (1–2
mL) was added dropwise. The reaction was stirred for ꢀ3 h while the temperature was
allowed to raise to rt. The reaction was then neutralized with TFA, and the crude product
was purified by flash chromatography (hexane–ether, 9:1) to give 350 mg of 7 (60%) as a
light yellow oil: [h]D +85.8 (c 1.23, CHCl3); IR (film) winter alia: 3030, 2952, 2927, 2856, 1596,
1
t
1454, 1355, 1237, 1098 cm−1; H NMR (CDCl3): l 0.08, 0.09 (2×s, 2×3H, BuMe2Si), 0.91 (s,
t
9H, BuMe2Si), 2.08–2.14 (m, 2H, H-2¦ax, H-2¦eq), 2.58 (dd, 1H, H-3ax, J 11.9, 14.0 Hz),
2.70–2.86 (m, 4H, H-1¦ax, H-1¦eq, H-3¦ax, H-3¦eq), 3.33 (ddd, 1H, H-3eq, J 1.1, 5.0, 14.0
Hz), 3.55 (dd, 1H, H-6, J 1.1, 9.0 Hz), 3.64 (ddd, 1H, H-4, J 2.2, 5.1, 11.9 Hz), 3.88–3.93
(m, 2H, H-8a, H-8b), 4.20–4.23 (m+bs, 2H, H-7, H-5), 4.38–5.06 (3×ABq, 3×2H, CH6 2Ph),
7.23–7.35 (m, 15H, Ar); HR-MS (ESI) calcd for C38H50O5S2 [M+Na]+ 701.2767; found
701.2742.
3.6. Methyl (methyl 4,5,7-tri-O-benzyl-3-deoxy-h- -manno-oct-2-ulopyranosid)onate 8
D
A solution of 7 (350 mg, 0.52 mmol) in CH2Cl2 (10 mL) was treated with methanol (3
mL) and NBS (280 mg, 1.56 mmol). The mixture was stirred at rt for ꢀ0.5 h, and then
filtered through a short column of silica gel and evaporated. The residue was purified by
chromatography (hexane–ether, 1:1) on silica to give the desired ester 8 as a colourless oil
(250 mg, 89%): [h]D +13.7 (c 0.83, CHCl3); IR (film) winter alia: 3529, 3031, 2923, 1749, 1454,
1
1273, 1162, 1085, 1063 cm−1; H NMR (CDCl3): l 2.23 (dd, 1H, H-3ax, J 11.8, 12.4 Hz),
2.32 (ddd, 1H, H-3eq, J 0.8, 4.4, 12.5 Hz), 2.30 (m, 1H, OH), 3.23 (s, 3H, OMe), 3.75 (dd,
1H, H-6, J 1.1, 8.9 Hz), 3.79 (s, 3H, CO2Me), 3.85–3.88 (m, 2H, H-8a, H-8b), 3.94 (m, 1H,
H-7), 4.00 (ddd, 1H, H-4, J 2.4, 4.6, 11.6 Hz), 4.06 (bs, 1H, H-5), 4.30–5.05 (3×ABq, 3×2H,
CH2
found 559.2305.
6
Ph), 7.23–7.35 (m, 15H, Ar); HR-MS (ESI) calcd for C38H50O5S2 [M+Na]+ 559.2302;
3.7. 4,5,7,8-Tetra-O-benzyl-3-deoxy-1-(propane-1,3-diyl-dithioacetal)-h-
D
-manno-octopyranosyl-
(2“6)-(methyl 2,3,4-tri-O-benzyl-h- -glucopyranoside) 12a
D
Trimethylsilyl triflate (10 mL) was added to a stirred solution of enitol 410 (200 mg, 0.31
mmol) and glucose derivative 9 (150 mg, 0.35 mmol) in dry CH2Cl2 (5 mL) at −78°C under
Ar. The reaction mixture was stirred for 1 h while the temperature was allowed to rise to
−30°C. The reaction was then recooled to −78°C, and neutralized with a methanolic solution
of NH3. After evaporation of the solvents the crude product was purified by flash chro-
matography (hexane–ether, 3:2) giving dithiane 12a as a colourless oil (260 mg, 76%): [h]D
+22.5 (c 0.55, CHCl3); IR (film) winter alia: 3030, 2952, 2927, 2856, 1596, 1454, 1355, 1237,
1
1098 cm−1; H NMR (CDCl3): l 1.72–1.82 and 1.99–2.06 (2×m, 2×1H, H-2¦ax, H-2¦eq), 2.23
(dd, 1H, H-3eq, J 4.1, 12.4 Hz), 2.38 (dd, 1H, H-3ax, J 12.0, 12.1 Hz), 2.66–2.82 (m, 4H,

J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3743
H-1¦ax, H-1¦eq, H-3¦ax, H-3¦eq), 3.01 (dd, 1H, H-4%, J 8.8, 10.2 Hz), 3.18 (s, 3H, OMe),
3.32 (dd, 1H, H-2%, J 3.6, 9.6 Hz), 3.36 (dd, 1H, H-6a%, J 8.5, 9.9 Hz), 3.63 (dd, 1H, H-8b, J
4.4, 10.7 Hz), 3.75–3.81 (m, 2H, H-8a, H-5%), 3.29–4.93 (m, 3H, H-4, H-6, H-3%), 3.95 (ddd,
1H, H-7, J 1.9, 4.3, 9.0 Hz), 4.00 (dd, 1H, H-6%b, J 1.5, 10.0 Hz), 4.09 (bs, 1H, H-5), 4.41 (s,
1H, H-1), 4.51 (d, 1H, H-1%, Jꢀ3 Hz), 4.35–5.13 (7×ABq, 7×2H, CH
6 2Ph), 7.20–7.37 (m,
35H, Ar); HR-MS (ESI) calcd for C67H74O11S2 [M+Na]+ 1141.4565; found 1141.4618.
3.8. 4,5,7,8-Tetra-O-benzyl-3-deoxy-1-(propane-1,3-diyl-dithioacetal)-h-
D
-manno-octopyranosyl-
(2“7)-(methyl 2,3,4,6-tetra-O-benzyl- -glycero-h- -manno-heptopyranoside) 12b
L
D
Trimethylsilyl triflate (20 mL) was added to a stirred solution of enitol 410 (230 mg, 0.35
mmol) and heptose derivative 1012 (150 mg, 0.25 mmol) in dry CH2Cl2 (5 mL) at −78°C
under Ar. The reaction mixture was stirred for 1 h while the temperature was allowed to rise
to −40°C. The reaction was then recooled to −78°C, and neutralized with a methanolic
solution of NH3. Evaporation of the solvents and chromatography (hexane–ether, 3:2) gave
12b as a colourless oil (230 mg, 86%): [h]D +14.8 (c 1.00, CHCl3); IR (KBr) winter alia: 3437,
1
3029, 2900, 1952, 1496, 1453, 1362, 1111, 1060 cm−1; H NMR (CDCl3): l 1.74–1.84 and
2.00–2.08 (2×m, 2×1H, H-2¦ax, H-2¦eq), 2.27 (dd, 1H, H-3eq, J 4.2, 12.6 Hz), 2.42 (dd, 1H,
H-3ax, J 12.0, 12.5 Hz), 2.69–2.86 (m, 4H, H-1¦ax, H-1¦eq, H-3¦ax, H-3¦eq), 3.19 (s, 3H,
OMe), 3.62–3.67 (m, 2H), 3.70–3.73 (m, 2H), 3.74 (m, 1H, H-2¦), 3.80–3.87 (m, 3H), 3.97
(ddd, 1H, H-7, J 1.8, 4.7, 9.1 Hz), 4.07 (dd, 1H, J 6.3, 10.1 Hz), 4.10 (bs, 1H, H-5), 4.12
(dd, 1H, J 1.0, 4.9 Hz), 4.16 (t, 1H, H-4%, J 9.4 Hz), 4.41 (s, 1H, H-1), 4.75 (d, 1H, H-1%, J
1.7 Hz), 4.30–5.15 (8×ABq, 8×2H, CH6 2Ph), 7.20–7.37 (m, 40H, Ar); HR-MS (ESI) calcd for
C75H82O12S2 [M+Na]+ 1261.5145; found 1261.5175.
3.9. 4,5,7,8-Tetra-O-benzyl-3-deoxy-1-(propane-1,3-diyl-dithioacetal)-h- -manno-octopyranosyl-
D
(2“6)-(methyl 3,4-di-O-benzyl-2-deoxy-2-N-acetamide-h- -glucopyranoside) 12c
D
Trimethylsilyl triflate (20 mL) was added to a stirred solution of enitol 410 (100 mg, 0.15
mmol) and glucosamine derivative 11 (62 mg, 0.15 mmol) in dry CH2Cl2 (3 mL) at −20°C
under Ar. The reaction mixture was stirred for 2 h while the temperature was allowed to rise
to 0°C and stirred for 2 h at this temperature. The reaction was then recooled to −20°C, and
neutralized with methanolic solution of NH3. Evaporation of the solvents and chromatogra-
phy (hexane–ether, 1:1) gave dithiane 12c as a colourless oil (65 mg, 39%): [h]D +60.8 (c
0.49, CHCl3); IR (film) winter alia: 3299, 3030, 2901, 1657, 1496, 1453, 1362, 1120, 1058 cm−1;
1H NMR (CDCl3): l 1.83 (s, 3H, NAc), 2.02–2.09 (m, 2H, H-2¦ax, H-2¦eq), 2.23 (dd, 1H,
H-3eq, J 4.2, 12.3 Hz), 2.40 (dd, 1H, H-3ax, J 12.0, 12.2 Hz), 2.71–2.86 (m, 4H, H-1¦ax,
H-1¦eq, H-3¦ax, H-3¦eq), 3.09 (s, 3H, OMe), 3.17 (dd, 1H, H-4%, J 9.0, 9.9 Hz), 3.42 (dd,
1H, H-6%b, J 8.9, 9.9 Hz), 3.60 (dd, 1H, H-3%, J 8.8, 10.4 Hz), 3.66 (dd, 1H, H-8b, J 4.7,
10.7 Hz), 3.73 (m, 1H, H-5%), 3.82 (dd, 1H, H-8a, J 1.8, 10.7 Hz), 3.88 (ddd, 1H, H-4, J 2.2,
4.5, 9.9 Hz), 3.89 (d, 1H, H-6, J 9.9 Hz), 3.97 (ddd, 1H, H-7, J 1.8, 4.5, 9.0 Hz), 4.02 (dd,
1H, H-6%a, J 1.1, 9.9 Hz), 4.11 (bs, 1H, H-5), 4.14 (dd, 1H, H-2%, J 3.7, 10.2 Hz), 4.36–5.11
(6×ABq, 6×2H, CH6 2Ph) and (s, 1H, H-1) and (d, 1H, H-1%), 5.26 (d, 1H, NH, J 9.4 Hz),
7.20–7.37 (m, 30H, Ar); HR-MS (ESI) calcd for C62H71O11NS2 [M+Na]+ 1092.4366; found
1092.4335.

3744
J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3.10. 4,5,7,8-Tetra-O-benzyl-3-deoxy-1-(propane-1,3-diyl-dithioacetal)-h-
D
-manno-octo-
pyranosyl-(2“8)-[methyl (methyl 4,5,7-tri-O-benzyl-3-deoxy-h-
D
-manno-oct-2-ulopyranosid)-
onate] 12d
Trimethylsilyl triflate (15 mL) was added to a stirred solution of enitol 410 (200 mg, 0.30
mmol) and Kdo derivative 8 (130 mg, 0.24 mmol) in dry CH2Cl2 at −78°C under Ar. The
reaction mixture was stirred for 2 h while the temperature was allowed to rise to −30°C. The
reaction was then recooled to −78°C, and neutralized with a methanolic solution of NH3,
then evaporated and the residue was chromatographed (hexane–ether, 3:2) to give 12d (200
mg, 72%). Colourless oil: [h]D +21.9 (c 0.63, CHCl3); IR (film) winter alia: 3030, 2898, 1748,
1
1496, 1453, 1361, 1109, 1062 cm−1; H NMR (CDCl3): l 1.72–1.81 and 1.95–2.03 (2×m,
2×1H, H-2¦ax, H-2¦eq), 2.20–2.26 (m, 3H, H-3eq, H-3%ax, H-3%eq), 2.42 (dd, 1H, H-3ax, J
12.1, 12.2 Hz), 2.64–2.90 (m, 4H, H-1¦ax, H-1¦eq, H-3¦ax, H-3¦eq), 3.12 (s, 3H, OMe), 3.38
(d, 1H, H-6%, J 9.0 Hz), 3.57 (dd, 1H, H-8%a, J 7.6, 11.0 Hz), 3.72 (dd, 1H, H-8a, J 4.2, 10.9
Hz), 3.74 (s, 3H, CO2Me), 3.80–3.85 (m, 3H), 3.90 (d, 1H, H-6, J 9.1 Hz), 3.96 (ddd, 1H,
H-7 or H-7%, J 1.8, 4.5, 9.0 Hz), 4.00 and 4.02 (2×bs, 2×1H, H-5 and H-5%), 4.19–4.26 (m,
2H), 4.33–5.08 (7×ABq, 7×2H, CH6 2Ph) and (s, 1H, H-1), 7.15–7.35 (m, 35H, Ar); HR-MS
(ESI) calcd for C70H78O13S2 [M+Na]+ 1213.4776; found 1213.4778.
3.11. General procedure for hydrolysis of the dithiane ring
Dithiane derivative (200 mg) was dissolved in a mixture of THF–water (9:1, 5 mL) and
NBS (10 equiv.) was added in one portion at rt. The mixture was stirred until TLC showed
disappearance of the substrate (0.5 h). The reaction was interrupted by addition of saturated
aqueous Na2SO3 and diluted with AcOEt. The organic layer was washed with brine, dried
and concentrated. The resulting crystals were redissolved in ether containing a few drops of
methanol and treated with a solution of CH2N2 in ether. After evaporation, the residue was
chromatographed to give the desired ester.
3.12. [Methyl (4,5,7,8-tetra-O-benzyl-3-deoxy-h-
D
-manno-oct-2-ulopyranosyl)onate]-
(2“6)-(methyl 2,3,4-tri-O-benzyl-h- -glucopyranoside) 13a
D
Based on the general procedure for hydrolysis of the dithiane ring, compound 12a was
converted into ester 13a (50%). Colourless oil: [h]D +31.5 (c 1.22, CHCl3); IR (film) winter alia
:
1
3030, 2923, 1750, 1496, 1454, 1361, 1064 cm−1; H NMR (CDCl3): l 2.23 (dd, 1H, H-3ax, J
11.9, 12.2 Hz), 2.30 (dd, 1H, H-3eq, J 4.2, 12.5 Hz), 3.09 (dd, 1H, H-4%, J 9.5, 9.9 Hz), 3.21
(s, 3H, OMe), 3.36 (dd, 1H, H-2%, J 3.6, 9.6 Hz), 3.52 (dd, 1H, H-6a%, J 7.4, 10.9 Hz),
3.61–3.66 (m, 3H), 3.67 (s, 3H, CO2Me), 3.80–3.84 (m, 2H), 3.60 (t, 1H, H-3%, J 9.4 Hz),
3.92 (ddd, 1H, H-4, J 2.3, 4.5, 11.5 Hz), 4.00 (ddd, 1H, H-7, J 1.9, 4.0, 9.2 Hz), 4.12 (bs,
1H, H-5), 4.51 (d, 1H, H-1%, J 3.7 Hz), 4.35–5.06 (7×ABq, 7×2H, CH6 2Ph), 7.19–7.35 (m,
35H, Ar); HR-MS (ESI) calcd for C65H70O13 [M+Na]+ 1081.4709; found 1081.4806.
Compounds 13a after hydrogenolysis (H2/Pd–C) and acetylation (Ac2O–Py) was trans-
formed into acetyl derivative 14, identical by the NMR data with that synthesized by a
previously elaborated methodology.15

J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
3745
3.13. [Methyl (4,5,7,8-tetra-O-benzyl-3-deoxy-h-
D
-manno-oct-2-ulopyranosyl)onate]-
-manno-heptopyranoside) 13b
(2“7)-(methyl 2,3,4,6-tetra-O-benzyl- -glycero-h-
L
D
Based on the general procedure for hydrolysis of the dithiane ring, compound 12b was
converted into ester 13b (53%). Colourless oil: [h]D +34.4 (c 1.39, CHCl3); IR (film) winter alia
:
3030, 2916, 1752, 1496, 1453, 1117, 1063 cm−1; 1H NMR (CDCl3): l 2.25 (dd, 1H, H-3ax, J 11.9,
12.5 Hz), 2.32 (dd, 1H, H-3eq, J 4.5, 12.6 Hz), 3.15 (s, 3H, OMe), 3.63 (s, 3H, CO2Me), 3.65
(dd, 1H, H-5%, J 1.0, 10.5 Hz), 3.69 (dd, 1H, H-8b, J 4.5, 10.8 Hz), 3.72–3.76 (m, 2H, H-2%,
H-7%a), 3.80–3.88 (m, 4H, H-8a, H-6, H-7%b, H-3%), 3.92 (ddd, 1H, H-4, J 2.1, 4.5, 11.7 Hz), 3.95
(dd, 1H, H-6%, J 0.8, 6.7 Hz), 4.03 (ddd, 1H, H-7, J 1.5, 3.8, 9.2 Hz), 4.15 (dd, 1H, H-4%, J 9.1,
9.5 Hz), 4.16 (bs, 1H, H-5), 4.73 (d, 1H, H-1%, J 1.5 Hz), 4.28–5.07 (8×ABq, 8×2H, CH6 2Ph),
7.19–7.36 (m, 40H, Ar); HR-MS (ESI) calcd for C73H78O14 [M+Na]+ 1201.5284; found
1201.5252.
3.14. [Methyl (4,5,7,8-tetra-O-benzyl-3-deoxy-h-
(2“6)-(methyl 3,4-di-O-benzyl-2-deoxy-2-N-acetamide-h-
D
-manno-oct-2-ulopyranosyl)onate]-
-glucopyranoside) 13c
D
Based on the general procedure for hydrolysis of the dithiane ring, compound 12c was
converted into ester 13c (53%). Colourless oil: [h]D +56.5 (c 0.46, CHCl3); IR (film) winter alia
:
3064, 3031, 2923, 1772, 1750, 1714, 1545, 1454, 1292, 1185, 1121, 1062 cm−1; H NMR (CDCl3):
l 1.84 (s, 3H, NAc), 2.25 (dd, 1H, H-3ax, J 11.9, 12.3 Hz), 2.32 (dd, 1H, H-3eq, J 4.3, 12.6 Hz),
3.14 (s, 3H, OMe), 3.69 (s, 3H, CO2Me), 3.22 (dd, 1H, H-4%, J 9.2, 9.4 Hz), 3.55–3.71 (m, 5H,
H-8a, H-3%, H-5%, H-6%a, H-6%b), 3.85 (dd, 1H, H-8b, J 1.8, 10.8 Hz), 3.90 (d, 1H, H-6, J 9.4 Hz),
3.92 (ddd, 1H, H-4. J 2.3, 4.5, 11.6 Hz), 4.02 (ddd, 1H, H-7, J 1.9, 4.06, 9.23 Hz), 4.13 (bs, 1H,
H-5), 4.16 (dd, 1H, H-2%, J 3.8, 10.3 Hz), 3.79 (d, 1H, H-1%, J 3.8 Hz), 4.35–5.05 (6×ABq, 6×2H,
1
CH
6 2Ph), 5.31 (d, 1H, NH, J 9.4 Hz), 7.20–7.37 (m, 30H, Ar); HR-MS (ESI) calcd for
C60H67O13N [M+Na]+ 1032.4505; found 1032.4557.
3.15. [Methyl (4,5,7,8–tetra-O-benzyl-3-deoxy-h-
(2“8)-[methyl (methyl 4,5,7-tri-O-benzyl-3-deoxy-h-
D
-manno-oct-2-ulopyranosyl)onate]-
-manno-oct-2-ulopyranosid)onate] 13d
D
Based on the general procedure for hydrolysis of the dithiane ring, compound 12d was
converted into ester 13d (50%). Colourless oil: [h]D +20.9 (c 0.84, CHCl3); IR (film) winter alia
:
1
3063, 3030, 2949, 2917, 2866, 1748, 1496, 1454, 1272, 1161, 1113, 1064 cm−1; H NMR (CDCl3):
l 2.17–2.24 (m, 3H, H-3ax, H-3%ax, H-3%eq), 2.35 (dd, 1H, H-3eq, J 4.3, 12.6 Hz), 3.06 (s, 3H,
OMe), 3.38 (d, 1H, H-6%, J 9.0 Hz), 3.69 (dd, 1H, H-8%a, J 6.6, 11.1 Hz), 3.63 and 3.71 (2×s,
2×3H, 2×CO2Me), 3.81–3.86 (m, 3H, H-4, H-4%, H-8%b), 3.88 (dd, 1H, H-8b, J 1.7, 10.8 Hz), 3.92
(d, 1H, H-6, J 9.4 Hz), 3.96 (ddd, 1H, H-7%, J 1.7, 6.6, 8.7 Hz), 3.98 (bs, 1H, H-5%), 4.02 (ddd,
1H, H-7, J 1.8, 3.9, 9.11 Hz), 4.06 (bs, 1H, H-5), 4.30–5.05 (7×ABq, 7×2H, CH6 2Ph), 7.15–7.35
(m, 35H, Ar); HR-MS (ESI) calcd for C68H74O15 [M+Na]+ 1153.4920; found 1153.4920.
Acknowledgements
We would like to thank Dr. B. Grzeszczyk (Institute of Organic Chemistry, Polish Academy
of Sciences) for generous gift of heptose derivative. An author (J.M.) thanks The Foundation
for Polish Science for a domestic grant for young scholars.

3746
J. M*lynarski, A. Banaszek / Tetrahedron: Asymmetry 11 (2000) 3737–3746
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