Synthesis of deoxygenated disaccharide precursors for modified lipid II synthesis

Article abstract of DOI:10.1002/ejoc.200600515

The synthesis of novel deoxygenated disaccharide precursors for modified lipid II synthesis is described. The 3- and 4-deoxy-GlcNAc donors were obtained, respectively, by radical reduction of the iodo derivative by TBTH/AIBN and hydrogen reduction of the

Full text of DOI:10.1002/ejoc.200600515

FULL PAPER
DOI: 10.1002/ejoc.200600515
Synthesis of Deoxygenated Disaccharide Precursors for Modified Lipid II
Synthesis
De-Qun Sun,[a] Roger Busson,[a] and Piet Herdewijn*[a]
Keywords: Peptidoglycan / Deoxy--glucosamine / Disaccharide / Lipids / Reduction
The synthesis of novel deoxygenated disaccharide precur-
sors for modified lipid II synthesis is described. The 3- and
4-deoxy-GlcNAc donors were obtained, respectively, by radi-
cal reduction of the iodo derivative by TBTH/AIBN and hy-
drogen reduction of the triflate using a borohydride reagent
(nBu4NBH4). O-Glycosylation of the acceptor, promoted by
NIS/TMSOTf, led to the 3- and 4-deoxygenated disaccha-
rides.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
pounds that inhibit transglycosylases kill bacteria rapidly
(i.e., they are bactericidal) by a process that surpasses cess-
ation of glycan synthesis.[4] These three arguments, likewise,
could be used as arguments in the prediction that transgly-
cosylase inhibitors might have a lower frequency of resis-
tance formation than existing antibiotics. Therefore, infor-
mation on substrate specificity for the bacterial transglycos-
ylase reaction could be very helpful in the design of new
antibiotics.
Introduction
As antibiotic resistance is becoming an increasing medi-
cal problem, there is an urgent need for new anti-infectious
agents with new modes of action.[1] Because of its unique-
ness, the bacterial cell wall remains an attractive target for
new antibiotics. The major component of the bacterial cell
wall is the peptidoglycan, which is a carbohydrate polymer
that forms a network through peptide cross-links. Although
the cell walls of different bacterial strains have different
constitutions, the compositions of the peptidoglycan poly-
mer are strikingly similar as are their biosynthesis. Theore-
tically, any inhibitor of the peptidoglycan synthesis may
have the same impact on bacterial survival as known inhibi-
tors of the cross-linking reaction (β-lactam antibiotics).
The biosynthesis of peptidoglycan occurs in three stages
(Figure 1). Based on the current understanding at the mo-
lecular level, several intermediates of natural origin, such as
lipid I[2] and lipid II,[3] have been synthesized to study the
properties of the enzymes involved in peptidoglycan synthe-
sis. The transglycosylases, the enzymes involved in the poly-
merization of lipid II to give the glycan chain in the final
stage of the biosynthesis (stage III), have been difficult to
study due to the unavailability of appropriate substrates.
The transglycosylase reaction, though, is considered as an
interesting target for developing new antibiotics for several
reasons. First, these enzymes are located on the outer sur-
face of the bacterial membrane, which means that potential
antibiotics do not need to penetrate the whole bacterial
membrane. Secondly, several homologous transglycosylases
are found in each bacterial strain and inhibitors targeting
one of these enzymes could hit several others. Finally, com-
Figure 1. Transglycosylation reaction for peptidoglycan synthesis.
We have envisioned a synthetic strategy for the synthesis
of new types of lipid II precursors. The 3- and 4-hydroxy
groups of the GlcNAc (N-acetyl--glucosamine) moiety of
lipid II are considered the nucleophilic sites of the transgly-
cosylase reaction. Therefore, we have synthesized the 3- and
[a] Laboratory of Medicinal Chemistry, Rega Institute for Medical
Research, Katholieke Universiteit Leuven,
Minderbroedersstraat 10, 3000, Leuven, Belgium
Fax: +32-16-337340
E-mail: Piet.herdewijn@rega.kuleuven.be
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Deoxygenated Disaccharide Precursors for Modified Lipid II Synthesis
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4-deoxy analogs of the GlcNAc-MurNAc disaccharide (N-
Without isolation of 10 and 11, this mixture was then
acetyl--muramic acid) (i.e., 1a and 1b), which can be used submitted to a TMSOTf-promoted[13] reaction with ethane-
in the synthesis of new lipid II derivatives that could be thiol to give the β-anomeric 11 in a total yield of 74%.
potential inhibitors of transglycosylases.
Deprotection of 11 with sodium methoxide as catalyst in
MeOH followed by protection of the 4- and 6-OH functions
with a benzylidene group afforded compound 13 in 84%
yield. After quantitative acetylation, the 4-hydroxy group
Results and Discussion
The lipid II precursor is a disaccharide composed of of 14 was unmasked by a selective 4,6-benzylidene acetal
GlcNAc and MurNAc, with GlcNAc normally named the ring-opening reaction.[14] Excellent yield and selectivity was
donor and MurNAc the acceptor in the glycosylation reac- obtained using trifluorosulfonic (TfOH) acid and triethylsi-
tion (Scheme 1). The overall synthetic challenge for synthe- lane (TES) as reducing agent at a very low temperature.
sizing modified lipid II is the careful selection of protecting Small experimental changes to the originally described pro-
groups so that selective deprotection and activation reac- cedures for synthesizing 12–15 are mentioned in the Exp.
tions of functional groups in several stages of the synthetic Sect. Compound 15 was then converted into the iodosugar
process are possible giving the highest yield. The selection 17. However, radical reduction of the iodo derivative 17
of the protecting groups should allow easy global deprotec- using TBTH/AIBN as described for the synthesis of 2d[10]
tion in the final steps of the total synthesis and suitable did not work in our hands. As an alternative, we used the
protecting groups could also activate the glycosylation reac- method of Yang and co-workers[15] reported for the re-
tion, as reported by Wong and co-workers.[5] We prefer to duction of a sugar triflate with tetrabutylammonium
use the benzyl group (Bn) to protect the 6-hydroxy group borohydride in refluxing benzene. We carried out this reac-
of both the donor and acceptor. This is especially necessary tion in strictly anhydrous THF, and we successfully ob-
for the acceptor. When the 6-position was protected by tained the desired compound 2a by reduction of 16 with
other electron-withdrawing groups (acetyl), the coupling re- Bu4NBH4 at room temperature in an acceptable yield (52%
action with thioglycosides (2a, 2b, 2c) was seriously ham- for two steps).
pered. Trichloroethoxycarbonyl (Troc) and phthalimido
(Phth) groups were used to protect the 2-amino group of Troc protecting group at the 2-amino function experiences
the donor and acceptor. a 40-fold enhancement of the glycosidation reaction as
Wong and co-workers[5] reported that a donor bearing a
Herein we describe the synthetic route for obtaining the compared with a building block having a Phth-protected 2-
3- and 4-deoxy donors 2a, 2b and 2c and the successful amino function. Therefore, we synthesized the 4-deoxy do-
synthesis of the protected disaccharides. The acceptor 3 can nor 2b (Scheme 4). Reduction of the 4-iodo derivative 19
be prepared by a somewhat improved procedure in five using TBTH/AIBN was again unsuccessful and 2b was ob-
steps from commercially available N-acetyl--glucosa- tained by the Bu4NBH4-mediated reduction of triflate 18.
mine.[6]
The method involving reduction of an iodo precursor[10]
Many methods for the deoxygenation of the hydroxy was investigated for the preparation of the 3-deoxy donor
groups of sugars have been described over the years.[7] The compound 2c (Scheme 5). Compound 21 was obtained in
3- and 4-hydroxy groups, respectively, of compounds 4 and good yield by iodination of 20. Reduction of the iodine
6, which can be prepared from -glucosamine,[8] were con- group of 21 by TBTH/AIBN was successful. However, a
verted into a series of thiocarbonyl derivatives, 7a–7c and mixture of 2c and 2f was obtained due to partial reductive
8a–8c. However, the Barton deoxygenation reaction[9] under elimination of the chlorine in the protecting group
radical conditions [tri-n-butyltin hydride (TBTH) with (Troc).[16] The ratio of 2c/2f could be turned in favor of the
AIBN as initiator] did not lead to the desired donor mole- desired compound 2c (over 5:1) by strictly controlling the
cules 2b and 2c (Scheme 2), whatever conditions we tried reaction time and the amount of TBTH used. After
(the thiocarbonyl derivatives 7a–c and 8a–c decomposed recrystallization from ethyl acetate and n-hexane, 2c was
during the reaction). This may be due to the presence of obtained as a pure compound in a yield of 89%. The suc-
the Troc protecting group and/or to competing reactions of cessful reduction of the iodo precursor at the 3-position
the SEt activating group in the anomeric position.
Hashimoto and co-workers[10] reported that the re- a difference in the stabilization of the radical intermediate.
duction of an iodosugar, such as the 4-iodo derivative of Several methods for O-glycosylation have been developed
(compound 21) and not at the 4-position might be due to
2d, using TBTH/AIBN in toluene can afford the 4-deoxy of which the thioglycoside methodology is one of the most
donor 2d in 87% yield (Scheme 3). Considering the harsher versatile and widespread.[12,17,18] This methodology em-
reaction conditions required to deprotect a pivaloyl (Piv) ploys a thioglycoside donor (e.g., having an alkylthio agly-
group in comparison to an acetyl (Ac) group, we selected con) which is O-glycosylated with a carbohydrate acceptor
2a as one of the desired donor molecules with a benzyl (Bn) in the presence of a thiophilic agent, which is generated by
at the 6-O position and an acetyl group at the 3-O position. a promoter system and transforms the aglycon into a good
Starting from 9[11] a mixture of the α and β anomers 10 and leaving group. There are several promoter systems for thiog-
11 was obtained in the first stage of the substitution reac- lycoside activation.[19–23] In our case the ICl/AgOTf method
tion of the 1-acetoxy group by an SEt group catalyzed by did not give the desired product and NIS/AgOTf afforded
BF3·OEt2.[12]
the disaccharide in yields lower than 30%. The NIS/
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D.-Q. Sun, R. Busson, P. Herdewijn
FULL PAPER
Scheme 1. Retrosynthetic analysis for the synthesis of the deoxygenated lipid II precursors.
Scheme 2. Attempts to obtain the deoxygenated sugars by the Barton reaction.
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Deoxygenated Disaccharide Precursors for Modified Lipid II Synthesis
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Scheme 3. Synthesis of the 4-deoxyglucosamine building block with a Phth protecting group at the amino function.
Scheme 4. Synthesis of the 4-deoxyglucosamine building block with a Troc protecting group at the amino function.
Scheme 5. Synthesis of the 3-deoxyglucosamine building block with a Troc protecting group at the amino function.
TMSOTf system gave yields of 43–47% (Scheme 6) in the
When the coupling reaction was carried out at –78 °C,
coupling reaction between different donors and the ac- yields lower than 40% were obtained (entry 1). Therefore,
ceptor under controlled reaction conditions (Table 1).
the reaction was studied at the higher temperature of
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D.-Q. Sun, R. Busson, P. Herdewijn
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Scheme 6. Synthesis of 3- and 4-deoxygenated lipid II precursors through coupling reaction promoted by NIS/TMSOTf.
Table 1. Study of the coupling reactions between the donors 2b and 2c and acceptor 3.
Entry Equiv. of acceptor
(mmol)
Equiv. of donor
Equiv. of promoter system
% Yield[c]
TMSOTf
NIS
Temp. (time)
1
2
3
4
5
6
7
8
1.0
3.0[a]
1.5[a]
1.5[a]
1.5[a]
1.5[a]
1.5[b]
1.3[b]
1.3[b]
0.2
0.2
0.2
0.1
0.1
0.2
0.3
0.3
3.5
2.0
2.0
2.0
2.0
2.0
2.0
1.3
–78 °C (3 h), r.t. (16 h)
34
1.0 (0.5)
1.0 (1.0)
1.0 (2.0)
1.0 (4.0)
1.0 (1.2)
1.0 (2.4)
1.0 (4.5)
–45 °C (20 min), 4 °C (10 h), r.t. (10 h)
–45 °C (20 min), 4 °C (12 h), r.t. (11 h)
–45 °C (20 min), 4 °C (7 h), r.t. (15 h)
–45 °C (30 min), 4 °C (10 h), r.t. (10 h)
–45 °C (30 min), –10 °C (10 h), r.t. (20 h) 18 (27)
–45 °C (1 h), –10 °C (7 h), r.t. (9 h)
–45 °C (2 h), –10 °C (14 h)
54 (79)
43 (64)
43 (59)
36 (68)
41 (85)
47 (61)
[a] Donor: 2c. [b] Donor: 2b. [c] Yields obtained after purification by column chromatography on silica; values in parentheses were
calculated on the basis of the amount of recovered acceptor.
–45 °C. Based on the amount of acceptor, 1.3–1.5 equiv. of not go to completion. After the first stage of the deprotec-
the donor, 1.3–2.0 equiv. of the activator (NIS) and 0.1– tion procedure to remove the 6- and 6Ј-O-benzyl groups
0.3 equiv. of the promoter (TMSOTf) were used (entries 2– to generate 23a, removal of the residual zinc chloride was
8). The potential side-reaction (transesterification between necessary to avoid a side-reaction during the next step.
the protecting group of donor and acceptor caused by the Compound 23a was then treated with a zinc/copper couple
presence of TMSOTf) could be avoided by performing the in a solution of THF/Ac2O/AcOH to cleave the Troc group.
reaction for a longer period at a lower temperature (en- Acetylation in situ gave the target compound 1a in 61%
try 8). The 6-benzylated derivative 3 was used for the coup- yield.
ling reaction because this reaction did not work well when
the 6-position of the acceptor was protected with an acetyl
Conclusions
group.[6]
Synthetic strategies have been developed to obtain three
The 6-O-benzyl and 4Ј,6Ј-O-benzylidene acetal groups in
protected deoxygenated glucosamine donors 2a, 2b and 2c.
compound 22b were removed using anhydrous zinc chloride
The 4-deoxy and 3-deoxy donors 2c and 2b, respectively,
in Ac2O/AcOH[24] and the free hydroxy groups generated
were employed in a coupling reaction promoted by
were acetylated in situ. Without isolation of the intermedi-
TMSOTf/NIS to give the desired disaccharides 1a and 1b
ate 23b, zinc dust was added to the reaction mixture to
in moderate yields. The target compounds will be used to
cleave the Troc group from the deoxygenated glucosamine.
prepare deoxygenated lipid II analogs.
The free amino group was then acetylated to afford target
compound 1b in 73% yield. This one-pot reaction pro-
cedure gave a much lower yield (lower than 30%) of target
Experimental Section
compound 1a. The zinc chloride should be strictly anhy-
drous otherwise the deprotection of the benzyl group would ducted in an inert nitrogen atmosphere. Anhydrous solvents were
All reactions using air- or moisture-sensitive reagents were con-
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Deoxygenated Disaccharide Precursors for Modified Lipid II Synthesis
FULL PAPER
distilled prior to use. THF, toluene, 1,4-dioxane and Et2O were
distilled from sodium/benzophenone. CH2Cl2 and CH3CN were
distilled from CaH2, DMF was distilled from P2O5 and Pyr from
KOH. Precoated SIL G/UV254 plates were used for TLC and spots
DMAP (20 mg) in Ac2O (15 mL) and pyridine (9 mL) was stirred
at room temperature for 1 h. The mixture was evaporated and co-
evaporated with toluene under vacuum to give 14[26] as a white
solid. The solid was dried under high vacuum and used in the next
1
were examined with UV light and Ce(SO4)2/(NH4)6MoO4 spray. step without further purification. H NMR (200 MHz, CDCl3): δ
Silica (200–425 mesh) was used for column chromatography. Exact
mass spectra were acquired with a quadrupole time-of-flight mass
spectrometer equipped with a standard electrospray ionization
(ESI) interface. NMR spectra were recorded with 200 and
= 1.21 (t, J = 7.4 Hz, 3 H, CH3), 1.90 (s, 3 H, CH3), 2.63–2.76 (m,
2 H, CH2), 3.77–3.84 (m, 3 H, 2-H, 6,6Ј-H), 4.32–4.44 (m, 2 H, 4-
H, 5-H), 5.55 (s, 1 H, PhCH), 5.58 (d, J = 11 Hz, 1 H, 1-H), 5.93
(t, J = 9.4 Hz, 1 H, 3-H), 7.34–7.49 (m, 5 H, Ph), 7.72–7.91 (m, 4
H, Phth) ppm. 13C NMR (200 MHz, CDCl3): δ = 14.8 (CH3), 20.5
(CH3C=O), 24.3 (SCH2), 54.2 (C-2), 68.6 (C-6), 70.5 (C-3, C-5),
79.2 (C-4), 81.7 (C-1), 101.6 (PhCH), 123.1, 126.9, 128.3, 129.2,
131.2, 131.7, 134.2, 134.4, 136.9 (Carom), 167.5, 167.9 (2×CO,
Phth), 170.2 (AcCO) ppm.
1
500 MHz spectrometers at 25 °C. H and 13C resonances are refer-
enced to TMS; coupling constants (J) are reported in hertz (Hz).
NMR splitting patterns are designated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) and br. (broad). The acceptor 3
was prepared by a route based on the improved procedure of Lioux
et al.[6] Compounds 4,[8] 5,[8] 6[8] and 9[11] were prepared according
to literature procedures.
Ethyl 3-O-Acetyl-6-O-benzyl-2-deoxy-2-phthalimido-4-O-1-thio-β-
D-glucopyranoside (15): A mixture of crude 14 and 4-Å molecular
Ethyl 3,4,6-Tri-O-Acetyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopy-
sieves (MS) (3 g) in anhydrous CH2Cl2 (60 mL) was stirred at room
temperature for 30 min. The mixture was cooled to –78 °C and then
TES (1.34 mL, 9.0 mmol) and TfOH (0.54 mL, 6.0 mmol) were
added successively. After being stirred for 1 h at –78 °C, TLC
showed the reaction was complete. The reaction mixture was
quenched with NaHCO3 and a few drops of MeOH, then diluted
with CH2Cl2 and washed with saturated NaHCO3 and brine. The
organic layer was dried with anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by chromatography (SiO2, 3:1
n-hexane/ethyl acetate) to give 15[27] (1.37 g, 94% for two steps).
1H NMR (500 MHz, CDCl3), δ = 1.22 (t, J = 7.5 Hz, 3 H, CH3),
1.91 (s, 3 H, CH3C=O), 2.61–2.74 (m, 2 H, SCH2), 3.30 (br. s, 1
H, OH), 3.81–3.84 (m, 4 H, 2-H, 5-H, 6,6Ј-H), 4.31 (t, J = 10.5 Hz,
1 H, 4-H), 4.63 (AB pattern, 2J = 13.5 Hz, 2 H, OCH2Ph), 5.54
(d, J = 10.5 Hz, 1 H, 1-H), 5.73 (t, J = 10 Hz, 1 H, 3-H), 7.29–7.36
(m, 5 H, Ph), 7.69–7.84 (m, 4 H, Phth) ppm. 13C NMR (500 MHz,
CDCl3): δ = 14.8 (CH3), 20.5 (CH3C=O), 24.1 (SCH3), 53.7 (C-2),
70.1 (C-6), 70.9 (C-4), 73.5 (OCH2Ph), 74.2 (C-5), 78.5 (C-3), 80.7
(C-1), 123.4, 127.6, 127.6, 128.3, 131.1, 131.5, 134.0, 134.2, 137.7
(Carom), 167.3, 167.7 (2×CO), 171.0 (AcCO) ppm. MS: calcd. for
C25H27NO7S [M + Na] 508.1406; found 508.1407.
ranoside (11): BF3·Et2O (3.8 mL, 29.1 mmol) was added dropwise
to a solution of 9 (10.0 g, 20.9 mmol, β/α = 1.6:1) in EtSH (2.2 mL,
29.1 mmol) and anhydrous CH2Cl2 (100 mL) at 0 °C. Then the re-
action was stirred for 50 min at the same temperature and then at
room temperature for 4 h. The solution was evaporated under vac-
uum to give a mixture of 10 and 11 as a brown-red slurry. This
mixture was dissolved in anhydrous CH2Cl2 (100 mL) and then
EtSH (2.7 mL, 36.0 mmol) and TMSOTf (1.6 mL, 8.4 mmol) were
added successively at room temperature. After being stirred for
1.5 h, Et3N (5 mL) was added to quench the reaction. The solution
was evaporated under vacuum and the residue purified by
chromatography (SiO2, 1:1 n-hexane/ethyl acetate) to give 11[12a]
(7.4 g, 74% based on recovered 10); 0.43 g of 10 (the unreacted α
isomer of 9) was recovered.
1H NMR (200 MHz, CDCl3): δ = 1.22 (t, J = 7.4 Hz, 3 H, CH3),
1.87 (s, 3 H, CH3), 2.04 (s, 3 H, CH3), 2.11 (s, 3 H, CH3), 2.62–
2.73 (m, 2 H, SCH2), 3.87–3.91 (m, 1 H, 2-H), 4.14–4.36 (m, 2 H,
6,6Ј-H), 4.40 (t, J = 10.2 Hz, 1 H, 5-H), 5.18 (t, J = 9.8 Hz, 1 H,
3-H), 5.49 (d, J = 10.6 Hz, 1 H, 1-H), 5.84 (t, J = 10.2 Hz, 1 H, 4-
H), 7.70–7.90 (m, 4 H, Phth) ppm.
Ethyl 4,6-O-Benzylidene-2-deoxy-2-phthalimido-1-thio-β-D-glucopy-
Ethyl 3-O-Acetyl-6-O-benzyl-2-deoxy-2-phthalimido-4-O-(trifluoro-
ranoside (13): A solution of 11 (4.8 g, 10.0 mmol) in MeOH
(100 mL) was treated with NaOMe (30 wt.-% in MeOH, 115.0 µL,
2.0 mmol) at room temperature. After being stirred for 2 h, dry ice
was added to quench the reaction. Then the solution was concen-
trated in vacuo to give 12 as a white solid which was used in the
next step without further purification. Crude 12 was dissolved in
DMF (50 mL), then treated with pTsOH·H2O (0.46 g, 2.4 mmol)
and α,α-dimethoxytoluene (4.7 mL, 30.0 mmol). The reaction mix-
ture was stirred overnight at 70 °C. The solvent was evaporated
under vacuum and the residue dissolved in ethyl acetate (100 mL)
and washed with saturated NaHCO3 and brine. The organic layer
was dried with anhydrous Na2SO4, concentrated in vacuo and the
residue purified by chromatography (SiO2, 2:1 n-hexane/ethyl ace-
tate) to afford 13[25] (3.71 g, 84%) as white foam. 1H NMR
(200 MHz, CDCl3): δ = 1.21 (t, J = 7.4 Hz, 3 H, CH3), 2.67–2.73
(m, 2 H, SCH2), 2,782 (d, J = 3.2 Hz, 1 H, OH) 3.53–3.70 (m, 2
H, 6,6Ј-H), 3,798 (t, J = 9.4 Hz, 1 H, 2-H), 4.25–4.45 (m, 2 H, 3-
H, 4-H), 4.62 (m, 1 Hz, 5-H), 5.39 (d, J = 10.6 Hz, 1 H, 1-H), 5.59
(s, 1 H, PhCH), 7.35–7.53 (m, 5 H, Ph), 7.68–7.85 (m, 4 H,
Phth) ppm. 13C NMR (200 MHz, CDCl3): δ = 14.7 (CH3), 24.0
(CH2), 55.3 (C-2), 68.6 (C-6), 69.5 (C-3), 70.3 (C-5), 81.8 (C-1),
82.1 (C-4), 101.8 (PhCH), 123.3, 123.8, 126.3, 128.3, 129.3, 131.6,
134.2, 136.9 (Carom), 168.2 (2×CO) ppm.
methylsulfonyl)-1-thio-β-D-glucopyranoside (16): Tf2O (0.6 mL,
3.6 mmol) was added dropwise to a solution of pyridine (0.58 mL,
7.2 mmol) in anhydrous CH2Cl2 (8 mL) at 0 °C. After being stirred
for 10 min at the same temperature, a solution of 15 (0.87 g,
1.79 mmol) in anhydrous CH2Cl2 (8 mL) was added dropwise. The
reaction was stirred for another 30 min at 0 °C; TLC showed the
starting material had been completely consumed. Then the reaction
mixture was diluted with CH2Cl2 and washed with 0.1  HCl, satu-
rated NaHCO3 and brine. The organic layer was dried with anhy-
drous Na2SO4 and concentrated in vacuo to give 16 as a brown oil
which was dried under high vacuum and used in the next step with-
1
out further purification. H NMR (200 MHz, CDCl3): δ = 1.21 (t,
J = 7.4 Hz, 3 H, CH3), 1.93 (s, 3 H, CH3C=O), 2.57–2.74 (m, 2 H,
SCH2), 3.70–4.0 (m, 3 H, 2-H, 6,6Ј-H), 4.38 (t, J = 9.6 Hz, 1 H, 5-
H), 4.53–4.68 (AB, J = 11.8 Hz, 2 H, OCH2), 5.25 (t, J = 9.6 Hz,
1 H, 4-H), 5.52 (d, J = 10.6 Hz, 1 H, 1-H), 5.95 (t, J = 9.6 Hz, 1
H, 3-H) ppm. 13C NMR (200 MHz, CDCl3): δ = 14.8 (CH3), 20.1
(CH3C=O), 24.1 (SCH2), 54.0 (C-2), 67.6 (C-6), 70.7 (C-3), 73.5
(OCH2), 76.6 (C-4), 79.5 (C-5), 81.0 (C-1), 123.8, 125.3, 127.8,
128.2, 128.4, 129.0, 131.0, 134.4, 137.5 (Carom), 167.1 (2×CO),
169.9 (AcCO) ppm.
Ethyl 3-O-Acetyl-6-O-benzyl-2,4-dideoxy-2-phthalimido-1-thio-β-D-
Ethyl 3-O-Acetyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-
β-D-glucopyranoside (14): A solution of 13 (1.33 g, 3.0 mmol) and
xylopyranoside (2a): Crude 16 was dissolved in anhydrous THF
(60 mL) and treated with 4-Å MS (3 g) and nBu4NBH4 (1.41 g,
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FULL PAPER
5.37 mmol). The reaction mixture was stirred at room temperature
for 5 h until TLC showed the starting material 16 had been com-
pletely consumed. The reaction mixture was concentrated under
vacuum and the residue was dissolved in ethyl acetate and then
washed with cold water and brine. The organic layer was dried
with Na2SO4, concentrated in vacuo and the residue purified by
chromatography (SiO2, 3:1 n-hexane/ethyl acetate) to give 2a
(0.44 g, 52%) as a slightly yellow oil. 1H NMR (200 MHz, CDCl3):
δ = 1.20 (t, J = 7.8 Hz, 3 H, CH3), 1.69 (q, J = 11.72 Hz, 1 H, 4ax-
H), 2.26–2.36 (m, 1 H, 4eq-H), 2.58–2.78 (m, 2 H, SCH3), 3.52–
3.70 (m, 2 H, 6,6Ј-H), 3.88–3.96 (m, 1 H, 5-H), 4.25 (t, J = 10.3 Hz,
1 H, 2-H), 4.60 (s, 2 H, OCH2), 5.43 (d, J = 10.8 Hz, 1 H, 1-H),
5.66–5.79 (dt, 1 H, 3-H), 7.30–7.32 (m, 5 H, Ph), 7.77–7.88 (m, 4
H, Phth) ppm. 13C NMR (200 MHz, CDCl3): δ = 14.7 (CH3), 20.6
(CH3C=O), 23.9 (SCH2), 33.8 (C-4), 54.3 (C-2), 69.0 (C-3), 71.9
(C-6), 73.2 (OCH2), 74.9 (C-5), 80.98 (C-1), 123.4, 127.5, 128.3,
131.3, 131.6, 134.1, 137.9 (Carom), 167.7 (2×CO), 170.06
(AcCO) ppm. MS: calcd. for C25H27NO6S [M + Na] 492.1457;
found 492.1465.
(9.72 g, 20.0 mmol) in anhydrous CH2Cl2 (150 mL) was added
dropwise. Then the mixture was stirred at the same temperature for
an additional 30 min until TLC showed the starting material had
been completely consumed. The reaction mixture was evaporated
and co-concentrated with toluene below 30 °C in vacuo to give 20
as a white solid, which was dried under high vacuum for 2 h and
used in the next reaction without further purification.
Ethyl 4,6-O-Benzylidene-2,3-dideoxy-3-iodo-2-(2,2,2-trichloroe-
thoxycarbonylamino)-1-thio-β-D-glucopyranoside (21): Crude 20 was
dissolved in anhydrous ethylene glycol dimethyl ether (200 mL),
and treated with NaI (15.0 g, 100.0 mmol). The mixture was stirred
at room temperature overnight until TLC showed the starting ma-
terial 20 had been completely consumed. The reaction mixture was
diluted with ethyl acetate (300 mL) and washed with saturated
NaHCO3 and brine. The organic layer was dried with Na2SO4, con-
centrated in vacuo and the residue purified by chromatography
(SiO2, 4:1 n-hexane/ethyl acetate) to give 21 (10.78 g, 90.4% for two
1
steps) as a white foam. H NMR (200 MHz, CDCl3): δ = 1.29 (t,
J = 7.4 Hz, 3 H, CH3), 2.7–2.8 (q, J = 7.4 Hz, 2 H, SCH2), 3.08
Ethyl 3-O-Acetyl-6-O-benzyl-2-deoxy-2-(2,2,2-trichloroethoxycar- (dd, J = 3.2 and 8.4 Hz, 1 H, 4-H), 3.50 (dt, J = 3.5 and 9.3 Hz, 1
bonylamino)-4-O-(trifluoromethylsulfonyl)-1-thio-β-
D
-glucopyrano-
H, 2-H), 3.84–4.09 (m, 2 H, 5-H, 6Ј-H), 4.38 (dd, J = 4.4 and
9.5 Hz, 1 H, 6-H), 4.72–4.86 (m, 3 H, OCH2CCl3 and 1-H), 5.08
(t, J = 3.3 Hz, 1 H, 3-H), 5.38 (d, J = 9.2 Hz, 1 H, NH), 5.70 (s, 1
H, PhCH), 7.35–7.55 (m, 5 H, Ph) ppm. 13C NMR (200 MHz,
side (18): Tf2O (2.0 mL, 12.0 mmol) was added dropwise to a solu-
tion of pyridine (2.0 mL, 24.0 mmol) in anhydrous CH2Cl2 (30 mL)
at –10 to –15 °C. After being stirred for 5 min at the same tempera-
ture, a solution of 6 (4.23 g, 8.0 mmol) in anhydrous CH2Cl2 CDCl3): δ = 14.7 (CH3), 24.1 (SCH2), 41.6 (C-3), 52.0 (C-2), 68.3
(30 mL) was added dropwise at the same temperature. The reaction
was stirred for another 30 min at 0 °C until TLC showed the reac-
tion to be complete. The solution was diluted with CH2Cl2 and
washed with 0.1  HCl, saturated NaHCO3 and brine. The organic
layer was dried with anhydrous Na2SO4, concentrated in vacuo to
give 18 as a pink solid, which was dried under high vacuum for 2 h
and used in the next step without further purification.
(C-6), 69.8 (C-4), 74.7 (OCH2CCl3), 76.1 (C-5), 84.0 (C-1), 95.1
(CCl3), 101.4 (PhCH), 126.4, 128.4, 129.4, 136.8 (Carom), 153.6
(O=CN) ppm. MS: calcd. for C18H21Cl3NO5S [M + H] 595.9331;
found 595.9320.
Ethyl 4,6-O-Benzylidene-2,3-dideoxy-2-(2,2,2-trichloroethoxycar-
bonylamino)-1-thio-β-
(4.8 mL, 17.2 mol) in anhydrous toluene (5 mL) was slowly added
Ethyl 3-O-Acetyl-6-O-benzyl-2,4-dideoxy-2-(2,2,2-trichloroethoxy- dropwise to a solution of 21 (7.89 g, 13.2 mmol) and AIBN (80 mg)
D-xylopyranoside (2c): A solution of TBTH
carbonylamino)-1-thio-β-
D
-xylopyranoside (2b): Crude 18 was dis-
in anhydrous toluene (750 mL) at 115–120 °C under nitrogen. The
reaction was refluxed for 1.8 h. Then the solvent was removed un-
der vacuum to give a mixture of 2c and 2f, which was recrystallized
from n-hexane/ethyl acetate (6:1) to give 2c (4.03 g, 89% based on
recovered 21) as a white solid. From the mother liquor of n-hexane/
ethyl acetate, 2.15 g of 21 was recovered. Data for main product
2c: 1H NMR (200 MHz, CDCl3): δ = 1.29 (t, J = 7.4 Hz, 3 H,
CH3), 1.79 (q, J = 11.8 Hz, 1 H, 3ax-H), 2.61 (m, 1 H, 3eq-H),
2.74 (AB, J = 7.4 Hz, 2 H, SCH2), 3.45–3.52 (m, 1 H, 2-H), 3.62–
3.84 (m, 3 H, 4-H, 5-H and 6-H), 4.348 (dd, J = 4.6 and 10.6 Hz,
1 H, 6Ј-H), 4.49 (d, J = 10.2 Hz, 1 H, 1-H), 4.77 (s, 2 H, OCH2),
5.06 (d, J = 8 Hz, 1 H, NH), 5.56 (s, 1 H, PhCH), 7.36–7.51 (m, 5
solved in anhydrous THF (180 mL, freshly distilled) and treated
with nBu4NBH4 (6.1 g, 23.7 mmol) at 0 °C. The reaction mixture
was stirred at room temperature for 6 h until TLC showed the start-
ing material 18 had been completely consumed. The reaction solu-
tion was added to a cold saturated NaCl solution, the organic layer
was separated and the aqueous phase extracted four times with
EtOAc. The combined organic layers were dried with anhydrous
Na2SO4, the solvents evaporated under vacuum and the residue
purified by chromatography (SiO2, 3:2 n-hexane/ethyl acetate) to
give 2b (2.2 g, 53.6%) as a light yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 1.26 (t, J = 7.5 Hz, 3 H, CH3), 1.63 (q, J = 12 Hz, 1
H, 4ax-H), 2.03 (s, 3 H, CH3C=O), 2.15–2.17 (m, 1 H, 4eq-H), H, Ph) ppm. 13C NMR (200 MHz, CDCl3): δ = 14.8 (CH3), 24.1
2.68–2.76 (m, 2 H, SCH2), 3.49 (dd, J = 5 and 10 Hz, 1 H, 6-H),
3.61 (dd, J = 5 and 10 Hz, 1 H, 6Ј-H), 3.68 (q, J = 10 Hz, 1 H, 2-
H), 3.71–3.73 (m, 1 H, 5-H), 4.50 (d, J = 10 Hz, 1 H, 1-H), 4.56
(s, 2 H, OCH2CCl3), 4.67 and 4.81 (AB, J = 12 Hz, OCH2Ph), 5.03
(m, 1 H, 3-H), 5.41 (d, J = 10 Hz, 1 H, NH), 7.28–7.36 (m, 5
H, Ph) ppm. 13C NMR (500 MHz, CDCl3): δ = 14.7 (CH3), 20.8
(CH3C=O), 23.8 (SCH2), 33.6 (C-4), 55.4 (C-2), 71.4 (C-3), 71.9
(C-6), 73.3 (OCH2CCl3), 74.3 (OCH2Ph), 74.9 (C-5), 84.4 (C-1),
95.4 (CCl3), 127.4, 127.5, 128.2, 137.8 (Carom), 154.2 (NCOO),
170.7 (AcCO) ppm. MS: calcd. for C20H26Cl3NO6S [M + Na]
536.0444; found 536.0452.
(SCH3), 36.2 (C-3), 50.6 (C-2), 68.9 (C-6), 73.9 (C-4), 74.6
(OCH2CCl3), 75.9 (C-5), 86.5 (C-1), 95.3 (CCl3), 101.6 (PhCH),
126.1, 128.4, 129.2, 137.1 (Carom), 153.8 (O=CN) ppm. MS: calcd.
for C18H22Cl3NO5S [M + Na] 492.0182; found 492.0190.
Benzyl O-[3-O-Acetyl-6-O-benzyl-2,4-dideoxy-2-(2,2,2-trichloroe-
thoxycarbonylamino)-β-
benzyl-2-deoxy-3-O-[ -1-(2-phenylsulfonylethyloxycarbonyl)ethyl]-
α- -glucopyranoside (22a): A mixture of 2b (3.0 g, 5.84 mmol), 3
D-xylopyranosyl]-(1Ǟ4)-2-acetylamino-6-
D
D
(2.9 g, 4.50 mmol) and 4-Å MS (3 g) in anhydrous CH2Cl2 (20 mL)
was stirred at room temperature under nitrogen for 30 min and
then the mixture was cooled to –45 °C. NIS (1.31 g, 5.84 mmol)
was added in one portion, followed by dropwise addition of
TMSOTf (0.26 mL, 1.35 mmol). After being stirred for an ad-
ditional 2 h at the same temperature, the reaction was kept at 0 °C
for 14 h. Then the reaction mixture was treated with saturated
Na2S2O3 (10 mL). After being stirred until the brown color had
Ethyl 4,6-O-Benzylidene-2-deoxy-2-(2,2,2-trichloroethoxycarbonyla-
mino)-3-O-(trifluoromethylsulfonyl)-1-thio-β-D-glucopyranoside (20):
Tf2O (7.0 mL, 40.0 mmol) was added dropwise to a solution of
pyridine (6.5 mL, 80.0 mmol) in anhydrous CH2Cl2 (200 mL) at
0 °C. After being stirred for 15 min, a solution of compound 4
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Deoxygenated Disaccharide Precursors for Modified Lipid II Synthesis
FULL PAPER
disappeared, the mixture was diluted with CH2Cl2 (200 mL) and
washed with saturated NaHCO3 and brine. The organic layer was
dried with anhydrous Na2SO4, concentrated in vacuo and the resi-
due purified by chromatography (SiO2, 1:4 ethyl acetate/dichloro-
methane) to give 22a (2.32 g, 47.2%) as a white foam (0.65 g of 3
was recovered). 1H NMR (500 MHz, CDCl3): δ = 1.169 (d, J =
6.6 Hz, 3 H, CH3), 1.500 (q, J = 12.1 Hz, 1 H, 4ЈA-H), 1.97 (s, 3
H, 2-AcMe), 2.02 (s, 3 H, 3Ј-AcMe), 2.12 (dd, J = 5.4 and 12.1 Hz,
1 H, 4ЈB-H), 3.37 (m, 1 H, 6A-H), 3.40–3.53 (m, 5 H, 2Ј-H, 6ЈA-
H, 3-H, CH2-S), 3.57 (m, 2 H, 5-H and 6ЈB-H), 3.66 (m, 2 H, 6B-
H and NHCOO), 3.78 (m, 1 H, 2-H), 3.91 (t, J = 9.3 Hz, 1 H, 4-
H), 4.11 (d, J = 8.5 Hz, 1 H, 1Ј-H), 4.34 (d, J = 12.2 Hz, 1 H,
TrocA), 4.36–4.52 (m, 7 H, 3-OCH, 3Ј-H, 5Ј-H, TrocB, 1-BnA,
OCH2-C), 4.57 (m, 2 H, 1-BnB and 6Ј-BnA), 4.63 (d, J = 12.2 Hz,
1 H, 6-BnA), 4.71 (d, J = 12.5 Hz, 1 H, 6-BnB), 4.83 (d, J = 12.0 Hz,
1 H, 6Ј-BnB), 5.36 (d, J = 3.4 Hz, 1 H, 1-H), 7.24–7.69 (m, 18 H,
3×Bn, Phm, Php), 7.90 (d, J = 7.5 Hz, 2 H, Pho), 8.94 (br., 1 H,
NHAc) ppm. 13C NMR (500 MHz, CDCl3): δ = 18.2 (CH3), 20.8
(3Ј-AcMe), 22.9 (2-AcMe), 33.4 (C-4Ј), 54.1 (C-2), 54.7 (CH2-S), 56,3
(C-2Ј), 58.0 (O-CH2-C), 67.2 (C-6), 70.0 (C-5), 70.2 (1-Bn-CH2),
70.4 (C-3Ј), 70.6 (C-5Ј), 71.7 (C-6Ј), 73.3 (Troc-CH2), 73.6 (6Ј-Bn-
CH2), 74.2 (6-Bn-CH2), 74.6 (3-OCH), 75.3 (C-3), 77.2 (C-4), 95.7
(CCl3), 96.4 (C-1), 100.5 (C-1Ј), 127.5, 127.6, 127.7, 127.9, 128.2,
128.3, 128.9, 129.3, 129.4, 134.0, 137.1, 137.5, 137.6, 138.9 (Carom),
154.1 (NCOO), 170.2 (2-AcC O ), 170.6 (3Ј-AcC O), 175.5
(COO) ppm. MS: calcd. for C51H59Cl3N2O16S [M + H] 1093.2729;
found 1093.2750.
134.1, 137.0, 137.2, 137.5, 138.9 (Carom), 153.5 (NCOO), 170.5 (2-
AcCO), 175.4 (COO) ppm. MS: calcd. for C49H55Cl3N2O15S [M +
H] 1049.2467; found 1049.2461.
Benzyl O-[(3,6-O-Acetyl-2,4-dideoxy-2-acetylamino)-β-
anosyl]-(1Ǟ4)-2-acetylamino-6-O-acetyl-2-deoxy-3-O-[ -1-(2-phen-
ylsulfonylethyloxycarbonyl)ethyl]-α- -glucopyranoside (1a): A mix-
D-xylopyr-
D
D
ture of 22a (2.24 g, 2.05 mmol) and anhydrous ZnCl2 (2.85 g,
20.5 mmol) in a solution of Ac2O/AcOH (3:1, 36 mL) was stirred
at room temperature overnight (15 h). The reaction mixture was
co-evaporated with toluene in vacuo to give a brown oil, which was
dissolved in CH2Cl2 (300 mL) and saturated NaHCO3 (100 mL).
Then the organic layer was separated and washed with saturated
NaHCO3 (pH Ͼ 7) and brine (pH = 7). The organic layer was
dried with anhydrous Na2SO4 and concentrated in vacuo to give
23a as a light brown oil as intermediate (MS: calcd. for
C41H51Cl3N2O18S [M + H] 997.2001; found 997.1990). Compound
23a was dissolved in a solution of Ac2O/AcOH/THF (3:2:1, 30 mL)
and then treated with a zinc/copper couple (5.0 g, 76.5 mmol). The
mixture was stirred at room temperature overnight (26 h). The mix-
ture was filtered through a pad of Celite and washed with acetone.
The filtrate was concentrated in vacuo and the residue purified by
chromatography (SiO2, ethyl acetate and 95:5 ethyl acetate/meth-
anol) to afford 1a (1.08 g, 61%) as a white foam (0.34 g of 23a was
recovered). 1H NMR (500 MHz, CDCl3): δ = 1.222 (d, J = 7.0 Hz,
3 H, CH3), 1.60 (q, J = 12.0 Hz, 1 H, 4ЈA-H), 1.95, 1.99, 2.05,
2.07, 2.12 (5×s, 15 H, 5×AcMe), 2.10 (obs m, 1 H, 4ЈB-H), 3.48–
3.60 (m, 2 H, 3-H, 5-H), 3.62–3.84 (m, 5 H, 2-H, 4-H, 5Ј-H, CH2-
S), 3.93 (q, J = 8.5 Hz, 1 H, 2Ј-H), 4.03–4.30 (m, 5 H, 6A-H, 6B-
H, 6ЈA-H, 6ЈB-H, 14-H), 4.34–4.70 (m, 5 H, O-CH2-C, 3-OCH, 1-
Bn-CH2), 4.91 (dt, J = 5.0 and 10.8 Hz, 1 H, 3Ј-H), 5.29 (d, J =
3.2 Hz, 1 H, 1-H), 6.25 (d, J = 7.8 Hz, 1 H, 2Ј-NHAc), 7.31 (m, 5
H, Bn), 7.60–7.75 (m, 4 H, Phm+p, 2-NHAc), 7.95 (dd, J = 2.2 and
8.4 Hz, 2 H, Pho) ppm. 13C NMR (500 MHz, CDCl3): δ = 18.0
(CH3), 20.5, 20.7, 20.7(3×OAcMe), 22.8, 22.9 (2×NHAcMe), 32.8
(C-4’), 53.8 (C-2), 54.2 (C-2), 54.6 (CH2-S), 58.0 (O-CH2-C), 61.9
(C-6), 65.1 (C-6’), 69.3 (C-5’), 69.5 (C-5), 70.2 (1-Bn-CH2), 70.5
(C-3Ј), 74.5 (C-3), 74.8 (3-OCH), 77.7 (C-4), 96.2 (C-1), 101.5 (C-
1’), 127.6, 127.8, 128.0, 128.3, 129.5, 134.1, 137.4, 138.9 (Carom),
170.5, 170.5, 170.7, 170.8, 171,3 (5×AcCO), 175.4 (COO) ppm. MS:
calcd. for C408H52N2O17S [M + H] 865.3064; found 865.3068.
Benzyl O-[4,6-O-Benzylidene-2,3-dideoxy-2-(2,2,2-trichloroethoxy-
carbonylamino)-1-β-
D-xylopyranosyl]-(1Ǟ4)-2-acetylamino-6-ben-
zyl-2-deoxy-3-O-[ -1-(2-phenylsulfonylethyloxycarbonyl)ethyl]-α-D-
D
glucopyranoside (22b): A mixture of 2c (0.71 g, 1.5 mmol), 3 (0.64 g,
1.0 mmol) and 4-Å MS (3 g) in anhydrous CH2Cl2 (10 mL) was
stirred at room temperature under nitrogen for 20 min and then the
mixture was cooled to –45 °C. NIS (0.45 g, 2.0 mmol) was added
in one portion and then TMSOTf (40 µL, 0.2 mmol) was added
dropwise. After being stirred for an additional 20 min at the same
temperature, the reaction was kept at 4 °C for 10 h and then for
11 h at room temperature. Then the reaction mixture was treated
with 10% Na2S2O3 (10 mL). After being stirred until the brown
color had disappeared, the mixture was diluted with CHCl3
(100 mL) and washed with brine. The organic layer was dried with
anhydrous Na2SO4, concentrated in vacuo and the residue purified
by chromatography (SiO2, 2:3 n-hexane/ethyl acetate) to give 22b
(0.45 g, 43%) as a white foam (0.21 g of 3 was recovered). 1H NMR
Benzyl O-(4,6-O-Acetyl-2,3-dideoxy-2-acetylamino-β-
syl)-(1Ǟ4)-2-acetylamino-6-O-acetyl-2-deoxy-3-O-[
sulfonylethyloxycarbonyl)ethyl]-α- -glucopyranoside (1b): A mixture
of 22b (1.05 g, 1.0 mmol) and anhydrous ZnCl2 (1.39 g, 10 mmol)
D-xylopyrano-
D
-1-(2-phenyl-
D
(500 MHz, CDCl3): δ = 1.23 (d, J = 6 Hz, 3 H, CH3), 1.29 (q, J = in a solution of Ac2O/AcOH (3:1, 15 mL) was stirred at room tem-
11.8 Hz, 1 H, 3ЈA-H), 1.973 (s, 3 H, 2-AcMe), 2.25 (dt, J = 4.5 and perature overnight. The reaction mixture was co-evaporated with
12.4 Hz, 1 H, 3ЈB–H), 3.26 (dt, J = 4.9 and 9.8 Hz, 1 H, 5Ј-H), toluene in vacuo to give 23b as an oil as intermediate, which was
3.41 (dd, J = 3.1 and 10.6 Hz, 1 H, 6A-H), 3.44–3.54 (m, 5 H, 2Ј- dissolved in a solution of THF/Ac2O/AcOH (3:2:1, 15 mL) and
H, 4Ј-H, 3-H, CH2-S), 3.58 (td, J = 2.7 and 10.0 Hz, 1 H, 5-H),
6.69 (t, J = 10.3 Hz, 1 H, 6ЈA-H), 3.70 (obs m, 1 H, 6B-H), 3.79
(dt, J = 11.2 and 3.9 Hz, 1 H, 2-H), 3.86 (t, J = 9.5 Hz, 1 H, 4-H),
4.19 (d, J = 8.0 Hz, 1 H, 1Ј-H), 4.24 (d, J = 9.5 Hz, 1 H, NHCOO),
4.35 (dd, J = 4.9 and 10.3 Hz, 1 H, 6ЈB-H), 4.37 (d, J = 12.0 Hz,
then treated with zinc dust (2.61 g, 40.0 mmol). The mixture was
stirred at room temperature overnight until TLC showed the inter-
mediate 23b had been completely consumed. The mixture was fil-
tered through a pad of Celite and washed with acetone. The filtrate
was concentrated in vacuo and the residue was purified by
1 H, TrocA), 4.40–4.60 (m, 6 H, 3-OCH, 1-BnA+B, 6-BnA, O-CH2- chromatography (SiO2, 1:4 n-hexane/ethyl acetate and 95:5 ethyl
1
C), 4.79 (d, J = 12.2 Hz, 1 H, 6-BnB), 4.87 (d, J = 12.2 Hz, 1 H,
acetate/methanol) to afford 1b (0.634 g, 73%) as a white foam. H
TrocB), 5.35 (d, J = 3.4 Hz, 1 H, 1-H), 5.51 (s, 1 H, O-CH-O), 7.25– NMR (500 MHz, [D6]acetone): δ = 1.18 (d, J = 7.1 Hz, 3 H, CH3),
7.62 (m, 17 H, 3×Bn, Phm), 7.63–7.68 (m, 2 H, NH-AC, Php), 7.92 1.77 (q, J = 12.1 Hz, 1 H, 3ЈA-H), 1.98, 1.20, 2.03, 2.05, 2.09 (5×s,
(m, 2 H, Pho) ppm. 13C NMR (500 MHz, CDCl3): δ = 18.5 (CH3),
15 H, 5×AcMe), 2.41 (dt, J = 12.2 and 4.6 Hz, 3ЈB-H), 3.64–3.77
23.0 (2-AcMe), 34.3 (C-3Ј), 51.2 (C-2’), 54.1 (C-2), 54.8 (CH2-S), (m, 4 H, 2-H, 3-H, CH2-S), 3.80 (dm, J = 9.5 Hz, 1 H, 5Ј-H), 3.86
58.0 (O-CH2-C), 67.8 (C-6), 68.9 (C-6’), 69.9 (C-5), 70.3 (C-5’, 1- (dd, J = 4.7 and 10.0 Hz, 1 H, 5-H), 3.90–4.00 (m, 2 H, 2Ј-H and
Bn-CH2), 73.9 (Troc–CH2), 74.5 (3-OCH, 6-Bn-CH2), 75.3 (C-4’),
75.8 (C-3), 78.6 (C-4), 95.5 (CCl3), 96.5 (C-1), 101.7 (O-CH-O),
4-H), 4.10 (d, J = 12.2 Hz, 1 H, 6A-H), 4.15 (dd, J = 4.9 and
12.2 Hz, 1 H, 6ЈA-H), 4.34 (dd, J = 4.8 and 12.2 Hz, 1 H, 6B-H),
102.4 (C-1’), 126.1, 127.7, 128.0, 128.3, 128.6, 129.1, 129.4, 129.8, 4.44–4.60 (m, 5 H, 6ЈB-H, O-CH2-C, 3-OCH, 1-BnA), 4.66 (d, J =
Eur. J. Org. Chem. 2006, 5158–5166
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D.-Q. Sun, R. Busson, P. Herdewijn
FULL PAPER
Fraser-Reid, K. Tatsuta, J. Thiem), Springer, Heidelberg, Ger-
many, 2001, vol. 1, pp. 232–251.
[8] a) U. Ellervik, H. Grundberg, G. Magnusson, J. Org. Chem.
1998, 63, 9323–9338; b) M. Schultz, H. Kunz, Tetrahedron:
Asymmetry 1993, 4, 1205–1220.
[9] Preparative Carbohydrate Chemistry (Ed.: S. Hanessian), Mar-
cel Dekker, New York, 1996, chapter 8, and references cited
therein.
7.5 Hz, 1 H, 1Ј-H), 4.68 (d, J = 11.7 Hz, 1 H, 1-BnB), 4.84 (dt, J
= 4.8 and 10.5 Hz, 1 H, 4Ј-H), 5.26 (s, 1 H, 1-H), 7.28 (m, 1 H,
Bnp), 7.35 (m, 4 H, Bnm, Pho), 7.53 (d, J = 8.6 Hz, 1 H, 2Ј-NHAc),
7.72 (t, J = 7.5 Hz, 2 H, Phm), 7.98 (d, J = 8.0 Hz, 2 H, Bno), 8.24
(br. s, 1 H, 2-NHAc) ppm. 13C NMR (500 MHz, [D6]acetone): δ =
18.5 (CH3), 20.69, 20.85 (2×), 22.98, 23.17 (5×AcMe), 34.54 (C-3Ј),
50.34 (C-2’), 55.30 (C-2, CH2-S), 59.59 (O-CH2-C), 63.0 (C-6),
63.20 (C-6’), 66.9 (C-4’), 70.2 (C-5), 70.3 (1-Bn-CH2), 75.8 (3-
OCH), 75.9 (C-5’), 76.2 (C-3), 77.3 (C-4), 96.5 (C-1), 102.8 (C-1’),
128.4, 128.6, 128.2, 129.1, 130.3, 134.7, 138.6, 140.9 (Carom), 170.1,
170.6, 171.0, 171.3, 172.8 (5×AcCO), 176.4 (COO) ppm. MS: calcd.
for C40H52N2O17S [M + H] 865.3064 and [M + Na] 887.2883;
found 865.3020 and 887.2853.
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Received: June 14, 2006
Published Online: September 14, 2006
5166
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Eur. J. Org. Chem. 2006, 5158–5166