Zwitterionic Polysaccharides of Shigella sonnei: Synthetic Study toward a Ready-for-Oligomerization Building Block Made of Two Rare Amino Sugars

Article abstract of DOI:10.1055/s-0037-1609719

Shigellosis is an endemic diarrheal disease caused by Gram negative bacteria named Shigella. The most exposed polysaccharides of Shigella sonnei display a zwitterionic disaccharide repeating unit (AB) made of two rare amino sugars: [4)-α- l -Alt p NAcA-(1→3)-β- d -Fuc p NAc4N-(1→]. An original synthesis of a ready-for-oligomerization AB disaccharide is reported. The targeted orthogonally protected disaccharide was synthesized from l -glucose and tetra- O -acetyl-β- d -glucosamine. The challenging introduction of the 4 _B -azido group masking the amino moiety of the AAT residue was performed at the disaccharide stage by a two-step procedure (triflation followed by nucleoaphilic displacement with NaN ₃). A post-glycosylation oxidation strategy was employed to access the altruronate moiety.

Full text of DOI:10.1055/s-0037-1609719

SYNTHESIS
0
0
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1
1
4
3
7
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2
1
0
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–M
paper
A
en
Synthesis
H. B. Pfister et al.
Paper
Zwitterionic Polysaccharides of Shigella sonnei: Synthetic Study
toward a Ready-for-Oligomerization Building Block Made of Two
Rare Amino Sugars
OH
Hélène B. Pfistera,b,c,1
Julie Paolettia,b,2
Ana Povedad,e
HO
O
OH
OH
O
OPMP
O
HO
HO
HO
HO
+
O
OBn
O
OH
O
NHC(O)CCl3
NH3+Cl–
O
Ph
HO
Jesus Jimenez-Barberod,e
Laurence A. Mulard*a,b
NHC(O)CCl3
a
Institut Pasteur, Unité de Chimie des Biomolécules, 28 rue
ClCH2C(O)O
BnO
N3
du Dr Roux, 75724 Paris Cedex 15, France
laurence.mulard@pasteur.fr
CNRS UMR3523, Institut Pasteur, 28 rue du Dr Roux, 75015
O
O
b
O
OPTFA
Paris, France
BnO C NHC(O)CCl3 NHC(O)CCl3
2
c
Université Paris Descartes Sorbonne Paris Cité, Institut Pas-
teur, 28 rue du Dr Roux, 75015 Paris, France
Molecular Recognition & Host-Pathogen Interactions Pro-
oligomerizable building block toward
oligosaccharides from S. sonnei
d
gram, CIC bioGUNE, Bizkaia Technological Park, Bldg 801A,
4
8160 Derio, Spain
e
Ikerbasque, Basque Foundation for Science, Maria Lopez de
Haro 3, 48013 Bilbao, Spain
Published as part of the Special Section on the 26th French–
Japanese Symposium on Medicinal and Fine Chemistry.
7
Received: 22.02.2018
causing organism, most vaccine strategies under develop-
ment aim at inducing protection against the exposed poly-
saccharide antigens. Among the most promising approach-
es, several detoxified LPS-based conjugate vaccines have
been investigated. Protective efficacy in children aged 2–4
years was demonstrated for the most advanced vaccine
candidate.8
Accepted after revision: 09.04.2018
Published online: 05.10.2018
DOI: 10.1055/s-0037-1609719; Art ID: ss-2018-z0103-op
Abstract Shigellosis is an endemic diarrheal disease caused by Gram
negative bacteria named Shigella. The most exposed polysaccharides of
Shigella sonnei display a zwitterionic disaccharide repeating unit (AB)
made of two rare amino sugars: [4)-α-L-AltpNAcA-(1→3)-β-D-Fucp-
NAc4N-(1→]. An original synthesis of a ready-for-oligomerization AB di-
saccharide is reported. The targeted orthogonally protected disaccha-
ride was synthesized from L-glucose and tetra-O-acetyl-β-D-
glucosamine. The challenging introduction of the 4 -azido group mask-
ing the amino moiety of the AAT residue was performed at the disac-
charide stage by a two-step procedure (triflation followed by nucleo-
As part of our ongoing effort toward the development of
a multivalent Shigella vaccine, synthetic oligosaccharide
haptens are designed to act as functional mimics of the O-SP
of selected bacteria. In this framework, we conceived the
first synthetic carbohydrate-based vaccine candidate
against Shigella flexneri 2a, the most prevalent Shigella sero-
B
philic displacement with NaN ). A post-glycosylation oxidation strategy
3
was employed to access the altruronate moiety.
9
type. The glycoconjugate of interest is built from a chemi-
cally synthesized 15mer oligosaccharide corresponding to
Key words amino sugars, glycosylation, oligosaccharide synthesis,
shigellosis, vaccine
10
three repeating units of the O-SP. It has recently entered a
phase I clinical trial.11 In addition to ongoing investigations
aimed at broadening S. flexneri coverage,12 herein, the tar-
get pathogen is Shigella sonnei. This Shigella species has only
one serotype, which is traditionally known as the prevalent
Shigellosis, caused by a diversity of Gram negative bac-
teria belonging to the genus Shigella, is a leading diarrheal
3
13
disease and a major cause of diarrheal deaths. As shed to
one in developed and transitional countries. However, the
14
light in recent epidemiological surveys, despite reduced
global distribution of S. sonnei is changing, and a growing
burden is predicted for this species.15 As other known Shi-
gella, S. sonnei is surrounded by an LPS embedded in its out-
er membrane. Yet, S. sonnei is to our knowledge the only
Shigella for which a capsular polysaccharide (CPS) has been
described.16 The two S. sonnei surface polysaccharides are
zwitterionic. Moreover, they display the same disaccharide
repeating unit made of two rare amino sugars (Figure 1), a
mortality, the burden of Shigella infection in children under
4
five years of age remains extremely high. Besides, the
5
growing spread of resistant strains is of increasing concern.
These findings emphasize the need for a Shigella vaccine.6
As the naturally acquired immunity against Shigella infec-
tion is in part directed against the O-specific polysaccharide
component (O-SP) of the lipopolysaccharide (LPS) of the
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

B
Synthesis
H. B. Pfister et al.
Paper
2
2
-acetamido-2-deoxy-L-altruronic acid (residue A) and a
-acetamido-4-amino-2,4,6-trideoxy-D-galactopyranose
The amine functionality is then installed by nucleophilic
displacement of an adequate leaving group at C-4 of the re-
sulting intermediate. In our efforts to design a synthetic
route to an AAT building block suitable for the synthesis of
S. sonnei oligosaccharides, we relied on D-glucosamine as
starting material. We reasoned that the Hanessian–Hullar
reaction (Scheme 1),21 i.e. the regioselective N-bromosuc-
cinimide-mediated oxidative opening of a benzylidene ace-
tal and concomitant bromination at C-6, would provide an
easy access to the desired 6-deoxy derivative by reduction
16,17
(AAT, residue B) 1,2-trans-linked to one another.
+H3N
O
O
O
HO
O
–O2C
NHAc
NHAc
A
B, AAT
Figure 1 Biological repeat of the surface polysaccharides – O-SP and
CPS, respectively – from S. sonnei: [4)-α-L-AltpNAcA-(1→3)-β-D-Fucp-
NAc4N-(1→]1
6,17
22
of the newly formed carbon–bromine bond.
Similarly to our previous work,18 the monosaccharide
donor and acceptor feature trichloroacetamide moieties at
C-2 to ensure appropriate anchimeric assistance during the
glycosylation steps.23 To fulfill the orthogonality require-
ment, the amine at position 4 of the AAT residue is masked
as an azido group.
In a previous publication, we described the first synthe-
sis of the biological repeating unit of the O-SP from S. son-
nei. The AB disaccharide was obtained as its propyl glyco-
18
side. Herein, we describe a new synthetic route to access
the orthogonally protected donor 1 (Scheme 1), a key build-
ing block designed for elongation at both ends, and in par-
ticular an original synthesis of a precursor of the AAT
monosaccharide.
In the synthesis described herein (Scheme 2), the
phthalimidoyl group was employed as temporary N-pro-
tecting group of the glucosamine precursor, as it is both sta-
ble to oxidative (Hanessian–Hullar benzylidene opening)
and reductive dehalogenation conditions. Therefore, start-
ing from tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-gluco-
ClCH2C(O)O
N3
O
O
BnO
O
OPTFA
BnO2C NHC(O)CCl3
NHC(O)CCl3
24
pyranose 2, the BF ·OEt -mediated glycosylation with p-
3
2
1
methoxyphenol gave glycoside 3 in pure β form with an ex-
cellent yield on a 50 gram scale. Conversion of the latter
into alcohol 4 by transesterification followed by benzylide-
nation proceeded in good overall yield. It is worth noting
that the use of DMF as co-solvent combined with a reduced
reaction time avoided the partial opening of the base-sensi-
tive phthalimidoyl ring into the corresponding carboxylic
acid during the basic methanolysis step.
OPTFA
+
N3
OBn
O
O
O
Ph
O
HO
OPG
NHC(O)CCl3
NHC(O)CCl3
Ref. 18
OTs
Br
OH
OH
Next, alcohol 4 was submitted to the key Hanessian–
HO
HO
O
O
O
AcO
AcO
BzO
PGO
22b
Hullar reaction. The published experimental conditions
OPG
NHC(O)CCl3
OPG
HO
NPhth
had to be adapted in order to obtain a consistent yield (75%)
of the benzoyl derivative 5 on a 5 gram scale. This was best
Published strategy:
Regioselective
tosylation at C-6
Strategy explored
in this paper:
Hanessian–Hullar reaction
achieved by increasing both the solvent polarity (CCl /TCE
4
3:1 → TCE) and temperature (100 °C → 130 °C). However,
OH
when the reaction was conducted on a 15 gram scale, the
desired intermediate 5 was obtained in admixture with an-
other compound. Silylation of the mixture by use of tert-
butyldimethylsilyl triflate gave monosaccharide 7, which
enabled the identification of the co-eluting side-product as
the dibromo analogue 6, resulting from the bromination of
the p-methoxyphenyl aglycon during the NBS-mediated
benzylidene opening. Such an outcome is not without prec-
O
Route A
HO
HO
Route B
OH
NH3+Cl–
Scheme 1 Strategies to disaccharide donor 1 by means of regioselec-
tive tosylation at C-6 (route A) and the Hanessian–Hullar reaction
route B) (PTFA = N-phenyltrifluoroacetimidoyl, PG = protecting group)
18
(
AAT is a constituent of several zwitterionic bacterial
polysaccharides. Increased interest in the latter in recent
years has led to numerous reports dealing with the synthe-
sis of AAT and AAT-containing oligosaccharides. In most
published syntheses based on easily available monosaccha-
ride precursors (reviewed before ), deoxygenation at C-6
relies on the regioselective introduction of a suitable leav-
ing group (tosylate, mesylate, iodide, etc.) and subsequent
displacement with hydride. Introduction of the amine pre-
cursor at C-4 often involves prior protection at C-2 and C-3.
19
25
edent. Since bromination of the aromatic ring of the p-
methoxyphenyl moiety was never observed when the Ha-
nessian–Hullar reaction was run on smaller scales, we hy-
pothesized that the NBS amount and/or reaction time
should be decreased for large-scale preparations. Further
optimization was not attempted. Indeed, under the Hanes-
sian–Hullar conditions established for alcohol 4, the silyl
ether 8, readily obtained from the former, was converted
into the expected bromo derivative 9 in excellent yield
2
0
19
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

C
Synthesis
H. B. Pfister et al.
Paper
OAc
OAc
Br
Br
Ph
O
O
a
AcO
AcO
O
b, c
O
d
O
BzO
RO
O
AcO
AcO
O
BzO
HO
+
Br
OAc
OPMP
HO
OPMP
OPMP
O
NPhth
NPhth
NPhth
NPhth
NPhth
2
3
4
5
6
7
R = H
R = TBS
OMe
e
e
Br
Ph
O
O
d
BzO
TBSO
O
f
BzO
TBSO
O
O
TBSO
OPMP
OPMP
OPMP
NPhth
NPhth
NPhth
8
9
10
g, h
O
j
O
O
10
BzO
TBSO
HO
TBSO
+
TBSO
HO
OPMP
NHR
R = H
R = C(O)CCl3
OPMP
NHC(O)CCl3
13
OPMP
NHC(O)CCl3
1
1
1
2
14
i
Scheme 2 Route to an AAT precursor from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucosamine (2). Reagents and conditions: (a) PMP-OH,
BF ·OEt , DCE, 50 °C, 91%; (b) NaOMe, MeOH/DMF; (c) PhCH(OMe) , CSA, MeCN, 80 °C, 90% (2 steps); (d) NBS, BaCO , 1,1,2,2-tetrachloroethane, for 5,
3
2
2
3
8
1%, for 9, 96%; (e) TBSOTf, imidazole, THF, for 8, 90%; (f) Bu SnH, AIBN, toluene, 100 °C, 97%; (g) NaBH , i-PrOH/H O/THF; (h) AcOH, 110 °C, 83% (2
3
4
2
steps); (i) (Cl CCO) O, pyridine, 0 °C, 97%; (j) MeONa, MeOH, for 13, 29%, for 14, 27% (Phth = phthaloyl, PMP = p-methoxyphenyl, TBS = tert-butyldi-
3
2
methylsilyl).
(
96%) on an 8.5 gram scale. Bu SnH-mediated hydrodebro-
common, precedents for silyl migration to a vicinal alkoxide
3
28
mination of this key intermediate into the deoxy derivative
0 proceeded in good yield. We reasoned that owing to high
have been documented; a concerted mechanism was pro-
posed.2
8b
1
18
base-sensitivity, the uronate residue would not withstand
the cleavage conditions of the N-phthaloyl group. Therefore,
removal of the phthaloyl protecting group was achieved be-
fore glycosylation. Mild reaction conditions, involving first
the NaBH -mediated partial reduction of the phthalimide
In the original route, alcohol 13 was the selected precur-
sor for the introduction of the azido moiety at C-4 to access
the AAT building block. However, since the yield of conver-
sion of benzoate 12 into alcohol 13 did not meet our expec-
tations, an alternative route to a suitable precursor to the
AAT residue was explored.
26
4
1
0 followed by lactonization gave amine 11, which was
readily N-trichloroacetylated into the desired product 12 in
excellent yield. It should, however, be noted that purifica-
tion of intermediate 11 was necessary to obtain consistent
yields of trichloroacetamide 12 on a large scale. Attempts at
the selective debenzoylation at position 4 of the orthogo-
nally protected 12 resulted in partial silyl migration from
O-3 to O-4 to give a mixture of alcohol 13 and regioisomer
Toward this aim, the synthesis of fragments of the zwit-
terionic capsular polysaccharide from Streptococcus pneu-
moniae type 1 achieved by Wu et al. was particularly inspir-
ing.29 In this work, the azidation step necessary to generate
the AAT moiety was performed on a disaccharide substrate
encompassing a 4-O-triflyl leaving group at the non-reduc-
ing residue. Encouraged by that report, we set to synthesize
disaccharide 18, whereby a similar transformation would
provide the desired azide 20 (Scheme 3).
1
4, despite the implementation of reaction conditions
27
known to prevent silyl group migration. Although not so
a
BzO
HO
O
12
OPMP
NHC(O)CCl3
O
HO
O
BzO
1
1
5
O
OPMP
NHC(O)CCl3
O
OPMP
NHC(O)CCl3
c
OBn
O
d
b
OBn
O
O
O
O
Ph
O
Ph
OBn
O
OPTFA
O
NHC(O)CCl3
NHC(O)CCl3
18
Ph
O
17
NHC(O)CCl3
6
Cl–
N3
OH
N
O
O
O
O
TfO
O
OPMP
O
OPMP
NHC(O)CCl3
O
OPMP
NHC(O)CCl3
O
OPMP
NHC(O)CCl3
OBn
O
OBn
O
OBn
O
OBn
O
e
O
+
O
+
O
O
NHC(O)CCl3
Ph
O
Ph
O
Ph
O
Ph
O
NHC(O)CCl3
NHC(O)CCl3
NHC(O)CCl3
NHC(O)CCl3
19
20
21
22
Scheme 3 Synthesis of the azide derivative 20 from acceptor 15 and donor 16. Reagents and conditions: (a) Et N·3HF, THF, 84%; (b) TMSOTf, 4 Å MS,
3
DCE, 0 °C, 92%; (c) MeONa, MeOH, 50 °C, 88%; (d) Tf O, pyridine, 3 Å MS, CH Cl ; (e) NaN , 3 Å MS, DMF, for 20, 63%, for 21, 15%, for 22, 9%, over two
2
2
2
3
steps (Tf = trifluoromethanesulfonyl).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

D
Synthesis
H. B. Pfister et al.
Paper
To this end, orthogonal removal of the TBS group of
O
MsO
30
a
O
OPMP
NHC(O)CCl3
d
compound 12 under seemingly acidic conditions gave the
corresponding alcohol 15 (Scheme 3). TMSOTf-mediated
glycosylation of acceptor 15 with the known donor 1618
proceeded smoothly at 0 °C to provide disaccharide 17 in an
excellent 92% yield. Next, controlled basic methanolysis re-
OBn
O
O
Ph
O
NHC(O)CCl3
23
O
TsO
b
O
OPMP
NHC(O)CCl3
d
OBn
O
20
vealed the 4 -OH in disaccharide 18. In this reaction, short
18
O
B
Ph
O
reaction times were necessary to avoid side-product forma-
tion, otherwise observed (not described) and in particular
analogues wherein one of the trichloroacetamides was
transformed into a methyl carbamate (detected by mass
spectrometry). Such conversion was reported previously
under related conditions in the context of Shigella flexneri
NHC(O)CCl3
24
Cl
O
c
O
OPMP
NHC(O)CCl3
OBn
O
O
Ph
O
31
3
a oligosaccharide synthesis, and is thought to occur by
NHC(O)CCl3
25
32
means of an intermediate isocyanate.
Next, the transformation of alcohol 18 into azide 20 by
Scheme 4 Attempts to synthesize the azide derivative 20 from alcohol
18 via mesylate 23 and tosylate 24. Reagents and conditions: (a) MsCl,
pyridine, 50 °C (not described); (b) TsCl, pyridine, 50 °C, 28; (c) TfCl,
nucleophilic substitution of a 4 -triflate intermediate 19
B
was investigated (Scheme 3). It seemed a priori trivial as
DMAP, CH Cl , 0 °C, quant; d) NaN , 3 Å MS, DMF.
18
2
2
3
several groups, including ours, had previously validated
this two-step conversion, most commonly on monosaccha-
33
ride substrates, but also occasionally on disaccharide pre-
disfavored balance between triflate formation and substitu-
tion. This finding was surprising as this reaction sequence
is usually described as straightforward and was exploited
advantageously to obtain a large variety of rare monosac-
29,34
cursors.
However, conditions previously described in
the literature were unsuccessful in our hands. For example,
triflation of alcohol 18 in the presence of excess triflic an-
hydride and pyridine was not complete after stirring for 2
hours at 0 °C and could not be improved by raising the tem-
perature to room temperature.
charides.36 However, the difficult Tf O-mediated conversion
2
of hydroxyl groups into triflates, although seldom reported,
is not without precedent.37 Additionally, mesylate 23, to-
sylate 24, and the corresponding triflate 19 strongly differ
in terms of their reactivity. Whereas the mesylate and to-
sylate are poor leaving groups, our data suggest that the tri-
flate can react with a large variety of nucleophiles including
pyridine and chloride in the case of disaccharides instead of
disaccharides 21 and 25, respectively, but also water as sug-
gested by the isolation of alcohol 22. The identification of
the side product 22 hinted that residual water was highly
detrimental to the triflation reaction. Gratifyingly, com-
plete conversion of alcohol 18 into the corresponding tri-
flate 19 was achieved when molecular sieves were added to
the reaction mixture. In this case, the activation–nucleo-
philic inversion process gave the desired derivative 20 in a
reproducible 60–65% yield, although formation of the pyri-
dinium analogue 21 could not be avoided (~15%) (Scheme 3).
The product of triflation 19 and unreacted 18 were di-
rectly treated with excess sodium azide to give the desired
azide 20, albeit in only 15% yield, in addition to a large
amount of recovered alcohol 18 (59%) (Scheme 3). On the
one hand, when triflic anhydride and pyridine were used in
larger excess, a more polar compound, identified as pyridin-
ium 21, is formed in meaningful amounts. Due to the high
reactivity of the triflate intermediate 19, the reaction con-
ditions could not be pushed further without degradation of
the latter. On the other hand, using mesyl chloride or tosyl
chloride as sulfonyl agents, the reaction temperature could
be increased to 50 °C to force the reaction toward the for-
mation of the corresponding mesylate 23 and tosylate 24
(
Scheme 4). Unfortunately, nucleophilic displacement by
sodium azide at C-4 of these intermediates appeared un-
successful, even at high temperatures, and these alterna-
tives were abandoned. Interestingly, using excess triflyl
To our knowledge, all precedent reports on the 4 -OH
eq
to 4 -N conversion involving a disaccharide substrate have
ax
3
35
chloride as the source of triflate resulted in the isolation
dealt with nucleophilic inversion at the non-reducing resi-
of the 4 -chloro derivative 25 in excellent yield. The trifla-
due.2
9,34a
This is not the case in the present example. In this
B
tion–substitution was complete, which revealed the good
reactivity of the starting alcohol 18 under these conditions
while emphasizing the high leaving group propensity of the
formed triflate.
Taken altogether, these observations suggested that the
formation of the sulfonic ester intermediates is challenging,
especially in the case of the triflate, owing to the somewhat
context, we hypothesized that the L-altrose residue located
at position 3 could possibly interfere with the activation–
B
azidation protocol at the vicinal hydroxyl group. Aiming at
a better understanding of our experimental observations,
detailed NMR investigations assisted by molecular mechan-
ics calculations were undertaken. The available NMR data
(Table 1) revealed that the shapes of the chairs remain unal-
tered for the starting alcohol 18 as well as for the products
of triflate substitution at that same position, azido 20, pyri-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

E
Synthesis
H. B. Pfister et al.
Paper
dinium 21, alcohol 22, and chloride 25. All compounds fea-
ture well-defined chairs for the two residues A and B. How-
ever, molecular mechanics calculations suggest the pres-
ence of an important crowded environment around the 4B-
hydroxyl group in 18 (see Figure S1 in Supporting Informa-
tion). In fact, for tosylate 24, all J couplings are averaged
around 4.5 Hz (Table 1), suggesting that the tosylate moiety
HO
N3
ClCH C(O)O
N3
2
a, b, c
O
O
d
O
O
20
BnO
BnO2C
O
OPMP
BnO
O
OPMP
NHC(O)CCl3
BnO2C NHC(O)CCl3NHC(O)CCl3
NHC(O)CCl3
26
27
ClCH2C(O)O
BnO
N3
e
O
O
27
O
OH
BnO2C
NHC(O)CCl3
NHC(O)CCl3
28
provides additional steric conflicts around residue B. This
N3
4
ClCH2C(O)O
BnO
N3
ClCH2C(O)O
results in the destabilization of the C geometry, giving rise
1
f
O
O
O
O
28
1
O
OPTFA
+
BnO
BnO C
O
to a substantial percentage of the C alternative (see Figure
4
BnO C
NHC(O)CCl3
2
NHC(O)CCl3
2
NHC(O)CCl3
N
O
S2 in the Supporting Information). Conformational pertur-
bation, albeit to a lesser extent, of residue B in the mesylate
intermediate 23 also seems to occur (Table 1). Thus, steric
1
1:1
29
CCl3
Scheme 5 Synthesis of donor 1. Reagents and conditions: (a) 80% aq
AcOH, 60 °C; (b) TEMPO, BAIB, CH Cl /H O; (c) BnBr, K CO , DMF, 69%
2
2
2
2
3
interference may add to the less reactive tosylate 24 and
(
over 3 steps); (d) (ClCH CO) O, pyridine, 0 °C, 78%; (e) CAN,
2 2
4
mesylate 23, while the C conformation of the substituted
MeCN/H O, 82%; (f) PTFA-Cl, Cs CO , acetone, 93%.
1
2
2
3
B residue supports the high propensity of the reactive in-
termediate triflate for nucleophilic substitution.
Table 1 Key Vicinal Coupling Constants 3JHH (Hz) for the A and B Pyra-
nose Rings of Disaccharides 18, 23, and 24
suitable AB precursor. This strategy is compatible with late-
stage AB differentiation at position 4 , and therefore opens
B
the way to a large diversity of analogues. Such develop-
ments are supported by the conclusions issued from the
thorough NMR investigation of disaccharides 18–25 di-
Compound
Residue
J
18
8.3
23
24
versely modified at C-4 . It is noteworthy that donor 1 was
B
B
B
B
B
J
12
23
34
45
7.0
7.5
8.0
8.0
4.4
4.3
4.6
3.9
previously validated as a suitable building block for chain
J
J
J
10.4
8.4
18
elongation into S. sonnei oligosaccharides.
8.8
Anhydrous (anhyd) solvents – including toluene, CH Cl , THF, DMF,
2
2
MeOH, MeCN, DCE, 1,1,2,2-tetrachloroethane (TCE), and pyridine –
were delivered on molecular sieves and used as received. Reactions
requiring anhyd conditions were run under an argon atmosphere, and
dried glassware was used. The 3 or 4 Å MS were activated before use
by heating under high vacuum. Analytical TLC was performed with
silica gel 60 F254, 0.25 mm pre-coated TLC aluminum foil plates. Com-
pounds were visualized using UV254 and/or orcinol (1 mg/mL) in 10%
aq H SO with charring. Flash column chromatography was carried
A
A
A
A
J
J
J
J
12
23
34
45
<1
<1
2.6
2.7
9.9
<1
2.8
2.8
9.9
3.0
2.9
9.7
2
4
out using silica gel (particle size 40–63 μm). NMR spectra were re-
Next, acidic hydrolysis of the benzylidene acetal was
followed by chemo- and regioselective oxidation of the
primary position using the TEMPO/BAIB (BAIB = bis(ace-
toxy)iodobenzene) system. Subsequent conversion of the
generated carboxylic acid group into a benzyl ester gave the
disaccharide acceptor 26 (Scheme 5). Chloroacetylation of
the hydroxyl moiety provided the fully protected 27, which
was readily converted into hemiacetal 28 by means of a
CAN-mediated anomeric deprotection. Finally, the corre-
sponding donor was isolated as an equimolar mixture of the
known N-phenyltrifluoroacetimidate 1 and oxazoline 29,
which can be used as such in glycosylation reactions.18
In conclusion, a new synthetic route to access the or-
thogonally protected disaccharide donor 1 was reported.
The originality of the present synthesis stems from the
challenging instalment of the 4B amino moiety at an ad-
vanced stage by nucleophilic triflate displacement on a
corded at 303 K on a Bruker Avance spectrometer equipped with a
1
13
BBO probe at 400 MHz ( H) and 100 MHz ( C). Spectra were recorded
of samples in CDCl3 or DMSO-d . Chemical shifts δ are reported in
6
ppm relative to the residual solvent peak (CHCl ) in the case of CDCl
3
3
1
13
and DMSO-d6 at δ = 7.28/77.0, and δ = 2.50/39.52 for the H and
C
spectra, respectively. Elucidations of chemical structures were based
1
13
13
on H, COSY, DEPT-135, HSQC, decoupled HSQC, C, decoupled C,
and HMBC spectra. Signals are reported as s (singlet), d (doublet), t
(
triplet), dd (doublet of doublets), q (quartet), dt (doublet of triplets),
dq (doublet of quartets), ddd (doublet of doublets of doublets), and m
multiplet). The signals can also be described as broad (prefix b),
(
pseudo (prefix p), overlapped (suffix ) or partially overlapped (suffix
o
po). Of the two magnetically non-equivalent geminal protons at C-6,
the one resonating at lower field is denoted H-6a, and the one at high-
er field is denoted H-6b. Interchangeable assignments are marked
with an asterisk. Sugar residues are lettered as described in Figure 1
and identified by a subscript in the listing of signal assignments.
HRMS spectra were recorded on a WATERS QTOF Micromass instru-
+
ment in the positive-ion electrospray ionization (ESI ) mode. Solu-
tions were prepared using MeCN/H O (1:1) containing 0.1% formic
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

F
Synthesis
H. B. Pfister et al.
Paper
+
+
acid. In the case of acid-sensitive compounds, solutions were pre-
HRMS (ESI ): m/z [M + Na] calcd for C28H25NO Na: 526.1478; found:
8
pared using MeOH/H O (1:1) to which was added 10 mM ammonium
526.1461.
2
acetate.
4-Methoxyphenyl 4-O-Benzoyl-6-bromo-2,6-dideoxy-2-phthalim-
4-Methoxyphenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-phthalimido-β-D-
ido-β-D-glucopyranoside (5)
glucopyranoside (3)
A solution of acetal 4 (2.5 g, 4.97 mmol) in anhyd TCE (40 mL) was
stirred over freshly activated powdered 4 Å MS for 30 min at r.t. under
an argon atmosphere. NBS (1.33 g, 7.45 mmol, 1.5 equiv) and BaCO3
(2.0 g, 9.9 mmol, 2.0 equiv) were added. Completion was reached af-
ter stirring for 1.5 h at 100 °C followed by 2 h at 130 °C. The reaction
mixture was filtered and concentrated in vacuo. Flash chromatogra-
phy (silica gel, toluene/EtOAc, 19:1 → 4:1) gave the bromide deriva-
tive 5.
A solution of tetraacetate 224 (61.7 g, 129 mmol) and p-methoxyphe-
nol (32.1 g, 258 mmol, 2.0 equiv) in anhyd DCE (600 mL) was stirred
over freshly activated powdered 4 Å MS for 30 min at r.t. under an ar-
gon atmosphere. The reaction mixture was cooled to 0 °C and
BF ·OEt (48 mL, 347 mmol, 3.0 equiv) was added. After stirring for 3
3
2
h at 50 °C, the reaction was quenched by addition of Et N. The sus-
pension was filtered and the filtrate was concentrated under reduced
3
pressure. Flash chromatography (silica gel, cyclohexane/EtOAc, 6:4 →
Yield: 2.36 g (4.05 mmol, 81%); white amorphous solid; R = 0.2 (tolu-
ene/EtOAc, 9:1).
f
1:1) yielded the 4-methoxyphenyl glycoside 3.
Yield: 63.5 g (117.3 mmol, 91%); white foam; R = 0.5 (CH Cl /Et O,
1
f
2
2
2
H NMR (400 MHz, CDCl ): δ = 8.09–8.06 (m, 2 H, HAr,Bz), 7.89–7.87
3
15:1).
(m, 2 H, HAr,Pht), 7.76–7.73 (m, 2 H, HAr,Pht), 7.61 (m, 1 H, HAr,Bz), 7.50–
1
H NMR (400 MHz, CDCl ): δ = 7.90–7.86 (m, 2 H, HAr,Pht), 7.78–7.75
7.48 (m, 2 H, HAr,Bz), 6.99–6.95 (m, 2 H, HAr,MP), 6.79–6.76 (m, 2 H,
HAr,MP), 5.82 (d, J1,2 = 8.4 Hz, 1 H, H-1), 5.23 (pt, J3,4 = J4,5 = 9.3 Hz, 1 H,
H-4), 4.73 (pt, 1 H, H-3), 4.59 (dd, J2,3 = 10.5 Hz, 1 H, H-2), 4.11 (ddd, 1
H, H-5), 3.75 (s, 3 H, CH3MP), 3.63 (dd, J5,6a = 2.5, J6a,6b = 11.3 Hz, 1 H, H-
6a), 3.54 (dd, 1 H, J5,6b = 7.7 Hz, H-6b).
3
(m, 2 H, HAr,Pht), 6.88–6.85 (m, 2 H, HAr,MP), 6.80–6.74 (m, 2 H, HAr,MP),
5
.89–5.85 (m, 2 H, H-1, H-3), 5.24 (t, J3,4 = J4,5 = 9.6 Hz, 1 H, H-4), 4.57
dd, J1,2 = 8.5, J2,3 = 10.6 Hz, 1 H, H-2), 4.34 (dd, J5,6a = 5.0, J6a,6b = 12.0
Hz, 1 H, H-6a), 4.18 (dd, J5,6b = 2.6 Hz, 1 H, H-6b), 3.96 (ddd, 1 H, H-5),
(
3
.74 (s, 3 H, CH3MP), 2.13, 2.07, 1.91 (3s, 9 H, CH3Ac).
13
C NMR (100 MHz, CDCl ): δ = 168.3 (2 C, COPht), 166.9 (COBz), 155.6,
3
13
C NMR (100 MHz, CDCl ): δ = 170.6, 170.2, 169.5 (3 C, COAc), 155.8,
150.6 (2 C, Cq,MP), 134.2, 123.6 (4 C, CAr,Pht), 133.8, 130.0, 128.6 (5 C,
CAr,Bz), 131.6 (2 C, Cq,Pht), 128.9 (Cq,Bz), 118.6, 114.6 (4 C, CAr,MP), 98.7 (C-
1), 75.3 (C-4), 74.0 (C-5), 70.3 (C-3), 57.1 (C-2), 55.6 (CH3MP), 31.1 (C-
6).
3
150.5 (2 C, Cq,MP), 134.4, 123.7 (4 C, CAr,Pht), 131.4 (2 C, Cq,Pht), 119.0,
114.5 (4 C, CAr,MP), 97.6 (C-1), 72.0 (C-5), 70.8 (C-3), 69.0 (C-4), 62.0 (C-
6), 55.6 (CH3MP), 54.6 (C-2), 20.7, 20.6, 20.4 (3 C, CH3Ac).
+
+
+
+
HRMS (ESI ): m/z [M + Na] calcd for C27H27NO11Na: 564.1482; found:
HRMS (ESI ): m/z [M + Na] calcd for C28H24NO BrNa: 604.0583;
8
564.1530.
found: 604.0607.
4
-Methoxyphenyl 4,6-O-Benzylidene-2-deoxy-2-phthalimido-β-D-
3-Bromo-4-methoxyphenyl 4-O-Benzoyl-6-bromo-3-O-tert-bu-
tyldimethylsilyl-2,6-dideoxy-2-phthalimido-β-D-glucopyranoside
glucopyranoside (4)
(7)
Triacetate 3 (20.0 g, 36.9 mmol) was dispersed in anhyd MeOH/DMF
(
9:1, 185 mL). NaOMe (25% in MeOH, 2.2 mL, 10.2 mmol, 0.3 equiv)
A solution of acetal 4 (15.0 g, 29.8 mmol) in anhyd TCE (250 mL) was
stirred at r.t. over freshly activated 4 Å powdered MS for 30 min under
an argon atmosphere. NBS (7.95 g, 44.7 mmol, 1.5 equiv) and BaCO3
(11.76 g, 60 mmol, 2.0 equiv) were added and the reaction mixture
was stirred at 100 °C for 90 min and then at 130 °C for 90 min. The
reaction mixture was filtered and the filtrate was concentrated in
vacuo. Purification by flash chromatography (silica gel, toluene/EtO-
Ac, 19:1 → 4:1) gave an admixture of the bromo derivatives 5 and 6
(11.9 g) as a pale yellow solid. A solution of alcohols 5 and 6 (10.8 g) in
THF (25 mL) was treated with TBSOTf (10.0 mL, 43 mmol, ~2.0 equiv)
and imidazole (4.38 g, 64 mmol, ~3.0 equiv). After stirring at r.t. for 15
h, MeOH was added and the reaction mixture was stirred for 10 min.
The organic phase was diluted with EtOAc, 1 L), washed with 10% aq
was added and the mixture was stirred for 30 min at r.t. The reaction
was quenched by slow addition of Dowex-H+ resin. The suspension
was filtered and the resin was thoroughly washed with CH Cl and
MeOH. Solvents were evaporated under reduced pressure. The residue
was dissolved in anhyd MeCN (185 mL), and benzaldehyde dimethy-
lacetal (17 mL, 111 mmol, 3.0 equiv) was added. A catalytic amount of
CSA was added until the pH was consistently 2 and then the resulting
mixture was heated for 30 min at 80 °C. At completion, the reaction
2
2
was quenched with Et N and volatiles were evaporated in vacuo. Flash
chromatography (silica gel, toluene/EtOAc, 9:1 → 8:2) gave acetal 4.
3
Yield: 16.8 g (33.5 mmol, 90%); white amorphous solid; R = 0.25 (tol-
uene/EtOAc, 9:1).
f
HCl (300 mL), sat. aq NaHCO (300 mL) and brine (300 mL), dried over
3
1
H NMR (400 MHz, CDCl ): δ = 7.90–7.88 (m, 2 H, HAr,Pht), 7.77–7.74
3
anhyd Na SO , and concentrated in vacuo. Flash chromatography (sili-
2
4
(
6
m, 2 H, HAr,Pht), 7.54–7.52 (m, 2 H, HAr,Ph), 7.42–7.39 (m, 3 H, HAr,Ph),
.88–6.85 (m, 2 H, HAr,MP), 6.79–6.75 (m, 2 H, HAr,MP), 5.82 (d, J1,2 = 8.5
Hz, 1 H, H-1), 5.62 (s, 1 H, CHPh), 4.73 (pt, J3,4 = 9.8 Hz, 1 H, H-3), 4.53
dd, J2,3 = 10.6 Hz, 1 H, H-2), 4.42 (dd, J5,6a = 4.2, J6a,6b = 10.3 Hz, 1 H, H-
a), 3.89 (t, J5,6b = 9.8 Hz, 1 H, H-6b), 3.78–3.70 (m, 5 H, H-4, H-5,
CH3MP).
ca gel, toluene/EtOAc, 98:2) gave the dibromo derivative 7 (3.10 g,
.99 mmol) and the desired bromide derivative 9 (6.51 g, 9.34 mmol)
3
as white foams.
(
6
Rf (7) = 0.5 (toluene/EtOAc, 95:5).
1
H NMR (400 MHz, CDCl ): δ = 8.10–8.08 (m, 2 H, HAr,Bz), 7.92–7.90
3
1
3
(m, 2 H, HAr,Pht), 7.81–7.79 (m, 2 H, HAr,Pht), 7.64 (m, 1 H, HAr,Bz), 7.53–
C NMR (100 MHz, CDCl ): δ = 168.1 (2 C, COPht), 155.7, 150.6 (2 C,
3
7.49 (m, 2 H, HAr,Bz), 7.29 (d, J = 2.9 Hz, 1 H, HAr,MP), 6.95 (dd, 1 H,
Cq,MP), 136.9 (Cq,Ph), 134.2, 123.6 (4 C, CAr,Pht), 131.6 (2 C, Cq,Pht), 129.4,
28.4, 126.3 (5 C, CAr,Ph), 118.6, 114.5 (4 C, CAr,MP), 102.0 (CHPh), 98.2
HAr,MP), 6.76 (d, J = 9.0 Hz, 1 H, HAr,MP), 5.72 (d, J1,2 = 8.7 Hz, 1 H, H-1),
1
5
9
.29 (pt, J3,4 = J4,5 = 9.5 Hz, 1 H, H-4), 4.89 (dd, 1 H, H-3), 4.60 (dd, J2,3
.8 Hz, 1 H, H-2), 4.06 (dt, 1 H, H-5), 3.82 (s, 3 H, CH3MP), 3.50 (d, J5,6a
=
=
(
(
C-1), 82.1 (C-4), 68.7 (C-3), 68.6 (C-6), 66.3 (C-5), 56.5 (C-2), 55.6
CH3MP).
J5,6b = 5.7 Hz, 2 H, H-6a, H-6b), 0.61 (s, 9 H, CH3tBu), –0.23, –0.39 (2s, 6
H, CH3Me).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

G
Synthesis
H. B. Pfister et al.
Paper
1
3
C NMR (100 MHz, CDCl ): δ = 165.4 (COBz), 152.1, 150.8 (2 C, Cq,MP),
74.6 (C-5), 70.2 (C-3), 57.5 (C-2), 55.6 (CH3MP), 31.2 (C-6), 25.3 (3 C,
CH3tBu), 17.5 (Cq,TBS), –4.5, –4.7 (2 C, CH3Me).
3
1
34.4, 123.6 (4 C, CAr,Pht), 133.7, 129.9, 128.6 (5 C, CAr,Bz), 133.7 (2 C,
Cq,Pht), 129.3 (Cq,Bz), 122.6, 117.2, 112.3 (3 C, CAr,MP), 111.6 (Cq,MP), 97.2
+
+
HRMS (ESI ): m/z [M + Na] calcd for C34H38BrNO SiNa: 718.1395;
8
(C-1), 75.1 (C-4), 74.8 (C-5), 70.2 (C-3), 57.4 (C-2), 55.7 (CH3MP), 31.1
C-6), 25.3 (3 C, CH3tBu), 17.5 (Cq,TBS), –4.5, –4.7 (2 C, CH3Me).
found: 718.1448.
(
+
+
HRMS (ESI ): m/z [M + Na] calcd for C34H37Br NO SiNa: 796.0553;
2
8
4-Methoxyphenyl 4-O-Benzoyl-3-O-tert-butyldimethylsilyl-2,6-
dideoxy-2-phthalimido-β-D-glucopyranoside (10)
found: 796.0585.
The bromide derivative 9 (4.02 g, 5.77 mmol) was dissolved in anhyd
4
2
-Methoxyphenyl 4,6-O-Benzylidene-3-O-tert-butyldimethylsilyl-
-deoxy-2-phthalimido-β-D-glucopyranoside (8)
toluene (37 mL). After degassing of the solution, Bu SnH (3.1 mL, 11.5
3
mmol, 2.0 equiv) and AIBN (190 mg, 1.15 mmol, 0.2 equiv) were add-
ed. The reaction mixture was stirred for 1 h at 100 °C. After that time,
A solution of alcohol 4 (3.05 g, 6.05 mmol) in THF (25 mL) was treated
with TBSOTf (3.0 mL, 13.3 mmol, 2.2 equiv), imidazole (1.24 g, 18.2
mmol, 3.0 equiv), and DMAP (103 mg, 0.61 mmol, 0.1 equiv). After
stirring of the mixture at r.t. for 1 h, MeOH was added and the reac-
tion mixture was stirred for 10 min. The organic phase was diluted
with CH Cl (150 mL), washed with 10% aq HCl (50 mL), sat. aq NaH-
CO (50 mL), and brine (50 mL), and then dried by passing through a
phase separator filter and concentrated in vacuo. Flash chromatogra-
phy (silica gel, cyclohexane/EtOAc, 9:1) gave the silyl derivative 8.
additional Bu SnH (1.3 mL, 4.92 mmol, 0.5 equiv) was added to drive
3
the reaction to completion. After 1 h, the reaction mixture was cooled
to r.t. and concentrated in vacuo. Flash chromatography (silica gel, tol-
uene/EtOAc, 98:2) gave the 6-deoxy derivative 10.
2
2
Yield: 3.45 g (5.58 mmol, 97%); white foam; R = 0.5 (toluene/EtOAc,
f
3
95:5).
1
H NMR (400 MHz, CDCl ): δ = 8.09–8.07 (m, 2 H, HAr,Bz), 7.89 (bs, 2 H,
3
HAr,Pht), 7.78–7.75 (m, 2 H, HAr,Pht), 7.63–7.59 (m, 1 H, HAr,Bz), 7.51–7.47
(m, 2 H, HAr,Bz), 6.87–6.84 (m, 2 H, HAr,MP), 6.76–6.74 (m, 2 H, HAr,MP),
Yield: 3.35 g (5.42 mmol, 90%); white amorphous solid; R = 0.5 (tolu-
ene/EtOAc, 95:5).
f
5.73 (d, J1,2 = 8.6 Hz, 1 H, H-1), 5.22 (dd, J4,5 = 9.6 Hz, 1 H, H-4), 4.82
1
H NMR (400 MHz, CDCl ): δ = 7.89 (bs, 2 H, HAr,Pht), 7.77–7.74 (m, 2 H,
(dd, J3,4 = 8.7 Hz, 1 H, H-3), 4.57 (dd, J2,3 = 10.3 Hz, 1 H, H-2), 3.88 (dq,
1 H, H-5), 3.74 (s, 3 H, CH3MP), 1.32 (d, J5,6 = 6.2 Hz, 3 H, H-6), 0.62 (s, 9
H, CH3tBu), –0.24, –0.38 (2s, 6 H, CH3Me).
3
HAr,Pht), 7.53–7.51 (m, 2 H, HAr,Ph), 7.41–7.37 (m, 3 H, HAr,Ph), 6.87–6.84
(m, 2 H, HAr,MP), 6.78–6.74 (m, 2 H, HAr,MP), 5.77 (d, J1,2 = 8.5 Hz, 1 H, H-
1
)
,
5
.
5
8
(
s
,
1
H
,
C
H
P
h
)
,
4
.
7
3
(
d
d
,
J
=
8
.
7
H
z
,
1
H
,
H
-
3
)
,
4
.
5
0
(
d
d
,
J
=
13
3
,
4
2
,
3
C NMR (100 MHz, CDCl ): δ = 165.5 (COBz), 155.5, 150.9 (2 C, Cq,MP),
3
10.1 Hz, 1 H, H-2), 4.41 (dd, J5,6a = 4.6, J6a,6b = 10.4 Hz, 1 H, H-6a), 3.87
134.2, 123.5 (4 C, CAr,Pht
Cq,Pht), 129.9 (Cq,Bz), 118.6, 114.5 (4 C, CAr,MP), 97.5 (C-1), 77.4 (C-4),
70.5 (C-5), 70.2 (C-3), 57.7 (C-2), 55.6 (CH3MP
(C-6), 17.5 (Cq,TBS), –4.5, –4.7 (2 C, CH3Me).
), 133.3, 129.8, 128.5 (5 C, CAr,Bz), 131.8 (2 C,
(
pt, J5,6b = 9.9 Hz, 1 H, H-6b), 3.76–3.72 (m, 4 H, H-5, CH3MP), 3.70 (dd,
J4,5 = 9.4 Hz, 1 H, H-4), 0.63 (s, 9 H, CH3tBu), –0.07, –0.24 (2s, 6 H,
CH3Me).
), 25.3 (3 C, CH3tBu), 17.8
13
C NMR (100 MHz, CDCl ): δ = 155.6, 150.7 (2 C, Cq,MP), 137.1 (Cq,Ph),
+
+
3
HRMS (ESI ): m/z [M + Na] calcd for C34H39NO SiNa: 640.2343;
found: 640.2341.
8
134.2, 123.4 (4 C, CAr,Pht), 131.7 (2 C, Cq,Pht), 129.1, 128.2, 126.4 (5 C,
CAr,Ph), 118.6, 114.5 (4 C, CAr,MP), 102.1 (CHPh), 98.1 (C-1), 82.6 (C-4),
9.6 (C-3), 68.8 (C-6), 66.4 (C-5), 57.7 (C-2), 55.6 (CH3MP), 25.4 (3 C,
CH3tBu), 17.7 (Cq,TBS), –4.2, –5.3 (2 C, CH3Me).
6
4
-Methoxyphenyl 2-Amino-4-O-benzoyl-3-O-tert-butyldimethyl-
silyl-2,6-dideoxy-β-D-glucopyranoside (11)
To solution of phthalimido 10 (7.02 g, 11.4 mmol) in i-
PrOH/THF/H O (6:1:1, 130 mL) was added NaBH (2.15 g, 56.8 mmol,
+
+
HRMS (ESI ): m/z [M + Na] calcd for C34H39NO SiNa: 640.2364;
found: 640.2343.
8
a
2
4
5
.0 equiv). After overnight stirring of the mixture at r.t., AcOH (70 mL)
4
-Methoxyphenyl 4-O-Benzoyl-6-bromo-3-O-tert-butyldimethyl-
was added and the mixture was stirred at 110 °C for 3 h. At comple-
tion, the reaction was quenched with Et N, diluted with H O (5 mL),
silyl-2,6-dideoxy-2-phthalimido-β-D-glucopyranoside (9)
3
2
A solution of acetal 8 (8.46 g, 13.7 mmol) in anhyd TCE (115 mL) was
stirred at r.t. over freshly activated 4 Å powdered MS for 30 min under
an argon atmosphere. NBS (3.66 g, 20.6 mmol, 1.5 equiv) and BaCO3
and extracted with CH Cl (3 × 10 mL). The organic phases were
pooled, washed with brine (5 mL), dried by passing through a phase
separator filter, and concentrated in vacuo. Flash chromatography
2 2
(5.41 g, 27.4 mmol, 2.0 equiv) were added and the reaction mixture
(silica gel, toluene/EtOAc/Et N, 9:1:0.5) gave amine 11.
3
was stirred for 3 h at 100 °C. The reaction mixture was filtered and
the filtrate was concentrated in vacuo. Flash chromatography (silica
gel, cyclohexane/EtOAc, 9:1) gave the bromide derivative 9.
Yield: 4.62 g (9.47 mmol, 83%); colorless oil; Rf = 0.3 (cyclohex-
ane/EtOAc, 8:2).
1
H NMR (400 MHz, CDCl ): δ = 8.08–8.05 (m, 2 H, HAr,Bz), 7.63–7.59
3
Yield: 9.20 g (13.2 mmol, 96%); white foam; R = 0.5 (toluene/EtOAc,
f
(m, 1 H, HAr,Bz), 7.50–7.47 (m, 2 H, HAr,Bz), 7.05–7.02 (m, 2 H, HAr,MP),
95:5).
6.87–6.83 (m, 2 H, HAr,MP), 5.12 (pt, 1 H, J3,4 = J4,5 = 9.2 Hz, H-4), 4.79 (d,
1
H NMR (400 MHz, CDCl ): δ = 8.10–8.08 (m, 2 H, HAr,Bz), 7.90 (bs, 2 H,
J1,2 = 8.0 Hz, 1 H, H-1), 3.84–3.79 (m, 4 H, H-3, CH3MP), 3.69 (dq, 1 H, H-
5), 3.19 (dd, J2,3 = 9.2 Hz, 1 H, H-2), 1.68 (bs, 2 H, NH ), 1.26 (d, J = 6.2
3
HAr,Pht), 7.79–7.77 (m, 2 H, HAr,Pht), 7.66–7.62 (m, 1 H, HAr,Bz), 7.53–7.49
2
5,6
(
5
(
1
m, 2 H, HAr,Bz), 6.96–6.92 (m, 2 H, HAr,MP), 6.77–6.73 (m, 2 H, HAr,MP),
.72 (d, J1,2 = 8.6 Hz, 1 H, H-1), 5.29 (dd, J4,5 = 9.7 Hz, 1 H, H-4), 4.89
dd, J3,4 = 8.6 Hz, 1 H, H-3), 4.60 (dd, J2,3 = 10.2 Hz, 1 H, H-2), 4.03 (ddd,
H, H-5), 3.74 (s, 3 H, CH3MP), 3.50 (m, 2 H, H-6a, H-6b), 0.62 (s, 9 H,
Hz, 3 H, H-6), 0.81 (s, 9 H, CH3tBu), 0.15, –0.11 (2s, 6 H, CH3Me).
13
C NMR (100 MHz, CDCl ): δ = 165.7 (COBz), 155.4, 151.4 (2 C, Cq,MP),
3
133.2, 129.8, 128.4 (5 C, CAr,Bz
102.8 (C-1), 76.4 (C-4), 75.7 (C-3), 70.6 (C-5), 58.3 (C-2), 55.6 (CH3MP
), 130.1 (Cq,Bz), 118.5, 114.5 (4 C, CAr,MP),
),
CH3tBu), –0.24, –0.29 (2s, 6 H, CH3Me).
1
25.7 (3 C, CH3tBu), 18.0 (Cq,TBS), 17.8 (C-6), –4.1, –4.3 (2 C, CH3Me).
3
C NMR (100 MHz, CDCl ) δ = 165.4 (COBz), 155.6, 150.9 (2 C, Cq,MP),
+
+
3
HRMS (ESI ): m/z [M + H] calcd for C26H38NO Si: 488.2468; found:
6
1
34.3, 123.5 (4 C, CAr,Pht), 133.7, 129.4, 128.6 (5 C, CAr,Bz), 131.7 (2 C,
488.2478.
Cq,Pht), 129.3 (Cq,Bz), 118.6, 114.5 (4 C, CAr,MP), 97.5 (C-1), 75.2 (C-4),
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

H
Synthesis
H. B. Pfister et al.
Paper
4-Methoxyphenyl 4-O-Benzoyl-3-O-tert-butyldimethylsilyl-2,6-
H-2, H-3), 3.70 (s, 3 H, CH3MP), 3.34 (m, 1 H, H-5), 2.97 (bq, J3,4 = J4,5 =
dideoxy-2-trichloroacetamido-β-D-glucopyranoside (12)
8.3 Hz, 1 H, H-4), 1.25 (d, J5,6 = 6.2 Hz, 3 H, H-6), 0.84 (s, 9 H, CH3tBu),
0
.12, 0.07 (2s, 6 H, CH3Me).
A solution of amine 11 (4.44 g, 9.10 mmol) in anhyd pyridine (35 mL)
was cooled to 0 °C and trichloroacetic anhydride (5.0 mL, 27.3 mmol,
13
C NMR (100 MHz, DMSO-d ): δ = 162.0 (NHCO), 155.2, 151.9 (2 C,
6
3.0 equiv) was added dropwise. After 10 min, the reaction was
Cq,MP), 118.5, 115.0 (4 C, CAr,MP), 102.3 (C-1), 93.6 (CCl ), 76.5 (C-4),
3
quenched with MeOH and volatiles were evaporated. The residue was
75.1 (C-3), 72.3 (C-5), 58.7 (C-2), 55.8 (CH3MP), 26.4 (3 C, CH3tBu), 18.4
(2 C, Cq,TBS, C-6), –3.1, –4.3 (2 C, CH3Me).
diluted with EtOAc and washed with 10% aq HCl, sat. aq NaHCO , and
3
brine. The organic phase was dried over anhyd Na SO , filtered, and
concentrated in vacuo. Flash chromatography (silica gel, cyclohex-
ane/acetone, 9:1) gave the trichloroacetamide precursor 12.
+
+
2
4
HRMS (ESI ): m/z [M + Na] calcd for C21H32NO SiCl Na: 550.0962;
6
3
found: 550.0941.
Yield: 5.60 g (8.84 mmol, 97%); white amorphous solid; R = 0.6 (tolu-
ene/EtOAc, 9:1).
f
4-Methoxyphenyl 4-O-Benzoyl-2,6-dideoxy-2-trichloroacetami-
do-β-D-glucopyranoside (15)
1
H NMR (400 MHz, CDCl ): δ = 8.08–8.06 (m, 2 H, HAr,Bz), 7.61 (m, 1 H,
3
To a solution of silyl ether 12 (3.54 g, 5.59 mmol) in anhyd THF (22
HAr,Bz), 7.51–7.47 (m, 2 H, HAr,Bz), 7.19 (d, JNH,2 = 7.6 Hz, 1 H, NH), 7.02–
mL) was added Et N·3HF (8.0 mL, 44.7 mmol, 8.0 equiv). After stirring
3
6.99 (m, 2 H, HAr,MP), 6.84–6.81 (m, 2 H, HAr,MP), 5.47 (d, J1,2 = 8.2 Hz, 1
for 2 d at r.t. under an argon atmosphere, the reaction was quenched
with MeOH and volatiles were evaporated. Flash chromatography (sil-
ica gel, toluene/EtOAc, 85:15) gave alcohol 15.
H, H-1), 5.13 (dd, J3,4 = 8.6, J4,5 = 9.4 Hz, 1 H, H-4), 4.61 (dd, J2,3 = 9.4 Hz,
1
H, H-3), 3.82–3.73 (m, 5 H, H-2, H-5, CH3MP), 1.30 (d, J5,6 = 6.3 Hz, 3
H, H-6), 0.80 (s, 9 H, CH3tBu), 0.09, –0.15 (2s, 6 H, CH3Me).
Yield: 2.43 g (4.68 mmol, 84%); white amorphous solid; R = 0.3 (tolu-
f
13
C NMR (100 MHz, CDCl ) δ = 165.6 (COBz), 162.1 (NHCO), 155.6,
3
ene/EtOAc, 9:1).
1
1
7
51.2 (2 C, Cq,MP), 133.4, 129.8, 128.5 (5 C, CAr,Bz), 129.9 (Cq,Bz), 118.8,
1
H NMR (400 MHz, CDCl ): δ = 8.06–8.04 (m, 2 H, HAr,Bz), 7.61 (m, 1 H,
1
3
14.5 (4 C, CAr,MP), 98.2 (C-1, JC,H = 164 Hz), 92.3 (CCl ), 77.1 (C-4),
3
HAr,Bz), 7.49–7.45 (m, 2 H, HAr,Bz), 7.27 (d, JNH,2 = 7.5 Hz, 1 H, NH), 7.04–
0.9 (C-3), 70.4 (C-5), 60.8 (C-2), 55.6 (CH3MP), 25.7 (3 C, CH3tBu), 17.9
7.00 (m, 2 H, HAr,MP), 6.86–6.83 (m, 2 H, HAr,MP), 5.41 (d, J1,2 = 8.4 Hz, 1
(Cq,TBS), 17.8 (C-6), –4.1, –4.3 (2 C, CH3Me).
H, H-1), 5.00 (pt, J3,4 = J4,5 = 9.3 Hz, 1 H, H-4), 4.44 (dt, J2,3 = 10.1 Hz, 1
H, H-3), 3.88–3.80 (m, 2 H, H-2, H-5), 3.78 (s, 3 H, CH3MP), 3.39 (d, J3,OH-
+
+
HRMS (ESI ): m/z [M + Na] calcd for C28H36NO Cl SiNa: 654.1224;
7
3
found: 654.1177.
=
5.4 Hz, 1 H, OH-3), 1.36 (d, J5,6 = 6.2 Hz, 3 H, H-6).
3
1
3
C NMR (100 MHz, CDCl ): δ = 166.6 (COBz), 162.6 (NHCO), 155.8,
3
4
-Methoxyphenyl 3-tert-Butyldimethylsilyl-2,6-dideoxy-2-tri-
chloroacetamido-β-D-glucopyranoside (13) and 4-Methoxyphenyl
-tert-Butyldimethylsilyl-2,6-dideoxy-2-trichloroacetamido-β-D-
1
1
7
51.1 (2 C, Cq,MP), 133.6, 129.9, 128.6 (5 C, CAr,Bz), 129.2 (Cq,Bz), 119.1,
14.6 (4 C, CAr,MP), 99.0 (C-1, 1JC,H = 164 Hz), 92.4 (CCl ), 77.3 (C-4),
3
4
1.0 (C-3), 70.4 (C-5), 59.9 (C-2), 55.6 (CH3MP), 17.7 (C-6).
glucopyranoside (14)
+
+
HRMS (ESI ): m/z [M + Na] calcd for C22H22NO Cl Na: 540.0360;
7
3
To a suspension of benzoate 12 (49 mg, 0.08 mmol) in MeOH (0.4 mL)
was added MeONa (25% in MeOH, 33 μL, 0.15 mmol, 2.0 equiv). After
stirring for 7 h at 50 °C, the reaction was quenched by addition of
found: 540.0336.
+
4-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-tri-
chloroacetamido-α-L-altropyranosyl-(1→3)-4-O-benzoyl-2,6-
dideoxy-2-trichloroacetamido-β-D-glucopyranoside (17)
Dowex-H resin. The reaction mixture was filtered and concentrated
in vacuo. Flash chromatography (silica gel, toluene/EtOAc, 95:5 → 9:1)
gave by order of elution the target alcohol 13 (29%) and regioisomer
A solution of acceptor 15 (2.47 g, 5.29 mmol, 1.0 equiv) and donor
14 (27%) as white amorphous solids
18
1
6 (3.79 g, 5.62 mmol, 1.2 equiv) in anhyd DCE (115 mL) was stirred
with freshly activated 4 Å MS for 30 min at r.t. under an argon atmo-
sphere. The reaction mixture was cooled to 0 °C and TMSOTf (85 μL,
Alcohol 13
Yield: 12 mg (0.02 mmol, 29%); white amorphous solid; R = 0.5 (tolu-
ene/EtOAc, 9:1).
f
0.47 mmol, 0.1 equiv) was added. After 15 min, the reaction mixture
was neutralized with Et N and the suspension was filtered and con-
3
1
H NMR (400 MHz, CDCl ): δ = 7.00–6.98 (m, 3 H, NH, H ), 6.84–6.82
centrated. Flash chromatography (silica gel, toluene/EtOAc, 19:1)
3
Ar
(
m, 2 H, H ), 5.17 (d, J = 8.2 Hz, 1 H, H-1), 4.00 (dd, J2,3 = 10.2, J3,4
=
yielded disaccharide 17.
Ar
1,2
8
2
.3 Hz, 1 H, H-3), 3.79 (s, 3 H, CH3MP), 3.73 (ddd, J2,NH = 7.0 Hz, 1 H, H-
), 3.52 (dq, 1 H, H-5), 3.36 (pt, J4,5 = 8.3 Hz, 1 H, H-4), 1.37 (d, J5,6 = 6.2
Yield: 4.33 g (4.31 mmol, 92%); white foam; R = 0.5 (toluene/EtOAc,
f
17:3).
Hz, 3 H, H-6), 0.94 (s, 9 H, CH3tBu), 0.19, 0.16 (2s, 6 H, CH3Me).
1
H NMR (400 MHz, CDCl ): δ = 8.07 (m, 2 H, HAr,Bz), 7.58–7.28 (m, 13
3
13
C NMR (100 MHz, CDCl ) δ = 162.4 (NHCO), 155.6, 151.1 (2 C, C ),
3
q
H, HAr,Bz, HAr,Bn, HAr,Ph), 7.06 (d, J2,NH = 7.0 Hz, 1 H, NH ), 7.00 (m, 2 H,
B
118.7, 114.6 (4 C, C ), 99.3 (C-1), 92.5 (CCl ), 77.5 (C-4), 73.5 (C-3),
A
r
3
HAr,MP), 6.83 (m, 2 H, HAr,MP), 6.62 (d, J2,NH = 8.3 Hz, 1 H, NH ), 5.52 (d,
A
72.8 (C-5), 59.1 (C-2), 55.6 (CH3MP), 25.9 (3 C, CH3tBu), 18.3 (C-6), 18.2
J1,2 = 8.3 Hz, 1 H, H-1 ), 5.42 (s, 1 H, CHPh), 5.26 (t, J = J4,5 = 9.1 Hz, 1
B
3,4
(Cq,TBS), –3.7, –4.5 (2 C, CH3Me).
H, H-4 ), 4.92 (bs, 1 H, H-1 ), 4.86 (d, J = 12.7 Hz, 1 H, CH2Bn), 4.76 (dd,
B
A
+
+
HRMS (ESI ): m/z [M + Na] calcd for C21H32NO SiCl Na: 550.0962;
J2,3 = 10.0 Hz, 1 H, H-3 ), 4.72 (d, 1 H, CH ), 4.51 (m, 1 H, H-5 ), 4.35
6
3
B 2Bn A
found: 550.0925.
(bdd, J2,3 = 2.7 Hz, 1 H, H-2 ), 4.00 (dd, J = 5.3, J6a,6b = 10.4 Hz, 1 H, H-
A 5,6a
6
a ), 3.91 (bt, 1 H, H-3 ), 3.81–3.78 (m, 4 H, H-5 , CH3MP), 3.60 (ddd, 1
A
A
B
Regioisomer 14
H, H-2 ), 3.51 (dd, J3,4 = 3.0, J4,5 = 9.8 Hz, 1 H, H-4 ), 3.36 (t, J5,6b = 10.5
B A
Hz, 1 H, H-6b ), 1.35 (d, J = 6.2 Hz, 3 H, H-6B).
Yield: 11 mg (0.02 mmol, 27%); white amorphous solid; R = 0.2 (tolu-
ene/EtOAc, 9:1).
A
5,6
f
13
C NMR (100 MHz, CDCl ): δ = 165.4 (CO ), 162.4 (NHCO ), 161.1
3 Bz B
1
(NHCO ), 155.8, 151.1 (2 C, Cq,MP), 138.8 (Cq,Bn), 137.2 (Cq,Ph), 133.4,
A
H NMR (400 MHz, DMSO-d ): δ = 8.89 (d, J
.92–6.90 (m, 2 H, HAr,MP), 6.86–6.84 (m, 2 H, HAr,MP), 5.24 (d, J4,OH-4
.0 Hz, 1 H, OH-4), 5.02 (d, J1,2 = 8.0 Hz, 1 H, H-1), 3.80–3.73 (m, 2 H,
= 8.7 Hz, 1 H, NH),
6
2,NH
129.7–125.3 (16 C, CAr,Ph, CAr,Bn, CAr,Bz, Cq,Bz), 118.7, 114.6 (4 C, CAr,MP),
6
7
=
1
02.3 (CHPh), 100.0 (C-1 ), 98.0 (C-1 ), 92.0, 91.9 (2 C, CCl3A,B), 77.6
A
B
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

I
Synthesis
H. B. Pfister et al.
Paper
(
6
6B).
C-3 ), 76.8 (C-4 ), 75.2 (C-4 ), 73.4 (C-3 ), 72.5 (CH2Bn), 70.5 (C-5B),
ica gel, toluene/EtOAc, 9:1 → 100% acetone by way of toluene/EtOAc
3:1) gave by order of elution the desired azido derivative 20 (63%) and
alcohol 22 (9%) as white solids, and the pyridinium 21 (15%) as a yel-
low solid.
B
A
B
A
8.5 (C-6 ), 59.7 (C-5 ), 59.3 (C-2 ), 55.6 (CH ), 53.0 (C-2 ), 17.8 (C-
A A B 3MP A
+
HRMS (ESI ): m/z [M + Na]+ calcd for C44H42NO12Cl Na: 1023.0767;
6
found: 1023.0720.
Azido Derivative 20
4-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-tri-
Yield: 326 mg (0.35 mmol, 63%); white solid; R = 0.3 (toluene/EtOAc,
f
chloroacetamido-α-L-altropyranosyl-(1→3)-2,6-dideoxy-2-tri-
chloroacetamido-β-D-glucopyranoside (18)
4:1).
1
H NMR (400 MHz, CDCl ): δ = 7.51–7.35 (m, 10 H, HAr,Bn, HAr,Ph), 7.02–
3
To a solution of benzoate 17 (4.59 g, 4.58 mmol) in MeOH (5 mL) was
added MeONa (25% in MeOH, 20 mL, 91.6 mmol, 20 equiv). After stir-
ring for 15 min at 50 °C, the reaction mixture was diluted with CH Cl
and MeOH and the reaction was quenched with Dowex-H resin. The
reaction mixture was filtered and concentrated in vacuo. Flash chro-
matography (silica gel, toluene/EtOAc, 3:1) gave alcohol 18.
6.97 (m, 2 H, HAr,MP), 6.95 (d, J2,NH = 6.6 Hz, 1 H, NH ), 6.84–6.80 (m, 2
B
H, HAr,MP), 6.69 (d, J2,NH = 8.1 Hz, 1 H, NH ), 5.61 (s, 1 H, CHPh), 5.39 (d,
A
J1,2 = 8.4 Hz, 1 H, H-1 ), 4.93 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.89 (s, 1 H, H-
2
2
B
+
1A), 4.80 (d, 1 H, CH2Bn), 4.77 (ddpo, J2,3 = 10.8, J3,4 = 3.6 Hz, 1 H, H-3B),
4.70 (pdtpo, J4,5 = J5,6b = 10.2 Hz, 1 H, H-5 ), 4.44 (dd, J = 2.8 Hz, 1 H,
A
2,3
H-2 ), 4.39 (dd, J = 5.3, J6a,6b = 10.5 Hz, 1 H, H-6a ), 4.00 (pt, J = 2.7
A
5,6a
A
3,4
Hz, 1 H, H-3 ), 3.87 (dq, J = 1.0 Hz, 1 H, H-5 ), 3.80 (pt , H-6b , 1 H),
Yield: 3.61 g (4.02 mmol, 88%); white amorphous solid; R = 0.3 (tolu-
ene/EtOAc, 7:3).
A
4,5
B
po
A
f
3
.79 (spo, 3 H, CH3MP), 3.75 (bdpo, 1 H, H-4 ), 3.73–3.67 (m, 2 H, H-2 ,
B
B
H-4 ), 1.46 (d, J = 6.4 Hz, 3 H, H-6B).
A
5,6
1
H NMR (400 MHz, CDCl ): δ = 7.53–7.30 (m, 10 H, HAr,Bn, HAr,Ph), 6.99–
3
13
C NMR (100 MHz, CDCl ): δ = 162.6 (NHCO ), 161.1 (NHCO ), 155.9,
6
.97 (m, 2 H, HAr,MP), 6.91 (d, J2,NH = 7.4 Hz, 1 H, NH ), 6.85–6.82 (m, 2
3
B
A
B
1
51.0 (2 C, Cq,MP), 138.6 (Cq,Bn), 136.4 (Cq,Ph), 129.8–126.3 (10 C, CAr,Ph,
H, HAr,MP), 6.73 (d, J2,NH = 8.3 Hz, 1 H, NH ), 5.62 (s, 1 H, CHPh), 5.31 (d,
A
1
CAr,Bn), 119.6, 114.6 (4 C, CAr,MP), 102.5 (CHPh), 100.0 (C-1 JC,H = 170
Hz), 98.5 (C-1B, JC,H = 166 Hz), 92.0, 91.9 (2 C, CCl3A,B), 77.0 (C-4 ), 75.7
J1,2 = 8.4 Hz, 1 H, H-1 ), 4.99 (s, 1 H, H-1 ), 4.90 (d, J = 12.1 Hz, 1 H,
A,
B
A
1
CH2Bn), 4.80 (d, 1 H, CH2Bn), 4.74 (ddd, 1 H, H-5 ), 4.48 (dd, J = 2.8 Hz,
A
A
2,3
(
C-3 ), 73.4 (C-3 ), 72.9 (CH ), 70.0 (C-5 ), 68.9 (C-6 ), 59.7 (C-5 ),
1
H, H-2 ), 4.39 (dd, J5,6a = 5.2 Hz, J6a,6b = 10.4 Hz, 1 H, H-6a ), 4.23 (dd,
B A 2Bn B A A
A
A
5
6.7 (2 C, C-2 , C-4 ), 55.6 (CH ), 52.8 (C-2 ), 17.5 (C-6 ).
J2,3 = 10.3, J3,4 = 8.4 Hz, 1 H, H-3 ), 4.04 (pt, J = 2.7 Hz, 1 H, H-3 ), 3.83
B B 3MP A B
B
3,4
A
+
+
(
pt, J5,6b = 10.3 Hz, 1 H, H-6b ), 3.79 (s, 3 H, CH3MP), 3.74 (ddd, J4,5 = 8.2
HRMS (ESI ): m/z [M + Na] calcd for C37H37N O Cl Na: 944.0569;
5 10 6
A
Hz, 1 H, H-4 ), 3.64–3.52 (m, 2 H, H-2 , H-5 ), 3.34 (t, J = 8.9 Hz, 1 H,
found: 944.0453.
A
B
B
4,5
H-4 ), 1.42 (d, J = 6.1 Hz, 3 H, H-6B).
B
5,6
13
C NMR (100 MHz, CDCl ) δ = 162.0 (NHCO ), 161.2 (NHCO ), 155.8,
Pyridinium Derivative 21
3
B
A
151.2 (2 C, Cq,MP), 138.2 (Cq,Bn), 137.0 (Cq,Ph), 129.3–126.3 (10 C, CAr,Ph
,
Yield: 80 mg (0.08 mmol, 15%); yellow solid; R = 0.3 (toluene/EtOAc,
f
CAr,Bn), 118.9, 114.6 (4 C, CAr,MP), 102.5 (CHPh), 99.7 (C-1 ), 98.6 (C-1 ),
75:25).
A
B
9
2.3, 91.8 (2 C, CCl3A, CCl3B), 80.5 (C-3 ), 76.5 (C-4 ), 75.0 (C-4 ), 73.4
1
B
A
B
H NMR (400 MHz, DMSO-d ): δ = 9.38 (d, J
= 7.8 Hz, 1 H, NHB),
6
2,NH
(C-3 ), 73.0 (CH ), 71.9 (C-5 ), 68.7 (C-6 ), 59.8 (C-5 ), 58.5 (C-2 ),
A 2Bn B A A B
9
.34 (d, J2,NH = 8.8 Hz, 1 H, NH ), 9.19–9.18 (m, 2 H, HAr,Pyr), 8.50 (m, 1
A
55.6 (CH3MP), 52.6 (C-2 ), 17.8 (C-6 ).
A B
H, HAr,Pyr), 8.02–7.99 (m, 2 H, HAr,Pyr), 7.53–7.27 (m, 10 H, HAr,Bn,Ph),
7.04–7.00 (m, 2 H, HAr,MP), 6.93–6.90 (m, 2 H, HAr,MP), 5.68 (s, 1 H,
CHPh), 5.50 (dd, J4,5 = 2.0 Hz, 1 H, H-4 ), 5.32 (d, J = 8.5 Hz, 1 H, H-
+
+
HRMS (ESI ): m/z [M + Na] calcd for C37H38N O Cl Na: 919.0505;
found: 919.0475.
2
11
6
B
1,2
1B), 5.04 (s, 1 H, H-1 ), 4.82 (dd, J = 11.1, J3,4 = 5.6 Hz, 1 H, H-3 ), 4.62
A
2,3
B
4-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-tri-
(dq, 1 H, H-5
B
), 4.39 (ddpo, J5,6a = 4.2 Hz, 1 H, H-6a
A
), 4.90 (dpo, 1 H,
chloroacetamido-α-L-altropyranosyl-(1→3)-4-azido-2,4,6-tride-
oxy-2-trichloroacetamido-β-D-galactopyranoside (20), 4-
Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-trichlo-
roacetamido-α-L-altropyranosyl-(1→3)-4-pyridinium-2,4,6-tride-
oxy-2-trichloroacetamido-β-D-galactopyranoside chloride (21)
and 4-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-
trichloroacetamido-α-L-altropyranosyl-(1→3)-2,6-dideoxy-2-tri-
chloroacetamido-β-D-galactopyranoside (22)
CH2Bn), 4.80 (d, J = 12.8 Hz, 1 H, CH2Bn), 4.35 (ddd, 1 H, H-2
4.11 (m, 2 H, H-4 , H-5 ), 4.00 (dd, J2,3 = 2.5 Hz, 1 H, H-2 ), 3.83 (t, J5,6b
= J6a,6b = 9.6 Hz, 1 H, H-6b ), 3.72 (s, 3 H, CH3MP), 3.59 (bs, 1 H, H-3 ),
B
), 4.14–
A
A
A
A
A
1.12 (d, J5,6 = 6.5 Hz, 3 H, H-6
).
B
13
C NMR (100 MHz, DMSO-d ): δ = 162.4 (NHCO ), 161.8 (NHCO ),
6
B
A
155.8, 151.2 (2 C, Cq,MP), 147.4, 145.9 (3 C, CAr,Pyr), 138.7 (Cq,Bn), 138.1
(
(
Cq,Ph), 129.4–126.6 (12 C, C ), 118.9, 114.6 (4 C, CAr,MP), 101.5
Ar,Bn,Ph,Pyr
CHPh), 101.0 (C-1B, JC,H = 168 Hz), 99.9 (C-1A, 1JC,H = 173 Hz), 93.1,
1
A solution of alcohol 18 (500 mg, 0.56 mmol) dissolved in anhyd
92.8 (2 C, CCl3A, CCl3B), 75.3 (C-4 ), 73.8 (C-3 ), 72.5 (C-3 ), 72.2 (C-
A A B
CH Cl (6.3 mL) was stirred over freshly activated powdered 3 Å MS
4B), 72.0 (CH2Bn), 69.2 (C-5 ), 68.5 (C-6 ), 59.8 (C-5 ), 56.3 (CH3MP),
2
2
B
A
A
for 30 min at r.t. under an argon atmosphere. The reaction mixture
was cooled to 0 °C and anhyd pyridine (270 μL, 3.34 mmol, 6.0 equiv)
was added followed by triflic anhydride (280 μL, 1.67 mmol, 3.0
equiv), and then the reaction mixture was stirred at r.t. for 2.5 h. After
that time, the reaction mixture was diluted with cold CH Cl (300 mL)
53.7 (C-2 ), 53.3 (C-2 ), 16.0 (C-6 ).
B
A
B
+
+
HRMS (ESI ): m/z [M] calcd for C42H42N O Cl : 958.1002; found:
3
10
6
958.0667.
2
2
Compound 22
Yield: 46 mg (0.05 mmol, 9%); white solid; R = 0.2 (toluene/EtOAc,
and washed with cold 10% aq HCl (100 mL), sat. aq NaHCO (100 mL),
3
and brine (200 mL), dried over anhyd Na SO , filtered, and concen-
f
2
4
75:25).
trated in vacuo. NaN (360 mg, 5.56 mmol, 10 equiv) was suspended
3
1
in anhyd DMF (1.7 mL) and stirred over freshly activated powdered 3
Å MS for 30 min at r.t. under an argon atmosphere. The reaction mix-
ture was cooled at 0 °C. Then, the above residue was added to the sus-
pension, which was stirred at r.t. for 1 h, filtered over a 0.2 μm filter,
and concentrated under reduced pressure. Flash chromatography (sil-
H NMR (400 MHz, DMSO-d ): δ = 9.28 (d, J
= 6.1 Hz, 1 H, NHA),
6
2,NH
8.96 (d, J2,NH = 9.2 Hz, 1 H, NH ), 7.49–7.24 (m, 10 H, HAr,Bn, HAr,Ph),
B
6.95–6.92 (m, 2 H, HAr,MP), 6.88–6.85 (m, 2 H, HAr,MP), 5.64 (s, 1 H,
CHPh), 4.97 (dpo, J1,2 = 8.0 Hz, 1 H, H-1 ), 4.96 (s, 1 H, H-1 ), 4.80 (d, J =
12.3 Hz, 1 H, CH2Bn), 4.75 (d, J4,OH = 5.8 Hz, 1 H, OH-4 ), 4.59 (dpo, 1 H,
B
A
B
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

J
Synthesis
H. B. Pfister et al.
Paper
1
CH2Bn), 4.55 (dddpo, 1 H, H-5 ), 4.37 (m, 1 H, H-2 ), 4.32 (ddpo, J5,6a
=
H NMR (400 MHz, CDCl ): δ = 7.53–7.30 (m, 10 H, HAr,Bn, HAr,Ph), 7.01–
A
A
3
5
9
3
.5, J6a,6b = 10.1 Hz, 1 H, H-6a ), 4.29–4.22 (m, 1 H, H-2 ), 4.10 (dd, J =
6.98 (m, 2 H, HAr,MP), 6.90 (d, J2,NH = 6.8 Hz, 1 H, NH ), 6.85–6.81 (m, 2
A
B
B
.7 Hz, 1 H, H-4 ), 3.93 (dd, J2,3 = 10.9, J3,4 = 8.0 Hz, 1 H, H-3 ), 3.76–
H, HAr,MP), 6.73 (d, J2,NH = 8.7 Hz, 1 H, NH ), 5.61 (s, 1 H, CHPh), 5.47 (d,
A
B
A
.66 (mpo, 4 H, H-6b , H-5 , H-4 , H-3 ), 3.71 (s, 3 H, CH3MP), 1.23 (d,
J1,2 = 8.4 Hz, 1 H, H-1 ), 4.96 (dpo, J = 12.8 Hz, 1 H, CH2Bn), 4.91 (dddpo,
A
B
B
A
B
J5,6 = 5.9 Hz, 3 H, H-6B).
J4,5 = 10.0 Hz, 1 H, H-5 ), 5.04 (s , 1 H, H-1 ), 4.82 (ddpo, J2,3 = 10.6, J3,4 =
A po A
1
3
3.6 Hz, 1 H, H-3
J3,4 = 8.4 Hz, 1 H, H-2 ), 4.37 (dd, J
5,6a
B
), 4.78 (d, J = 12.8 Hz, 1 H, CH2Bn), 4.44 (dd, J2,3 = 2.6,
C NMR (100 MHz, DMSO-d ): δ = 162.2 (NHCO ), 162.0 (NHCO ),
6
B
A
= 5.4 Hz, J6a,6b = 10.5 Hz, 1 H, H-
1
55.3, 151.9 (2 C, Cq,MP), 139.0 (Cq,Bn), 138.3 (Cq,Ph), 129.3–126.6 (10 C,
A
1
6a
A
), 4.32 (dd, J4,5 = 0.6 Hz, 1 H, H-4
B
), 4.01–3.97 (m, 2 H, H-5
B
, H-3 ),
A
CAr,Ph, CAr,Bn), 118.9, 115.0 (4 C, C
1
), 101.5 (CHPh), 100.9 (C-1 , J
=
Ar,MP
A
C,H
1
3.80–3.70 (mpo, 3 H, H-2
B
, H-4
A
, H-6b
A
), 3.79 (spo, 3 H, CH3MP), 1.46 (d,
64 Hz), 100.7 (C-1 , J = 164 Hz), 93.8, 93.0 (2 C, CCl3A, CCl3B), 79.8
B
C,H
J
=
6
.
2
H
z
,
3
H
,
H
-
6
)
.
(C-3 ), 75.9 (C-4 ), 74.2 (C-4 ), 71.2 (2 C, CH , C-3 ), 70.5 (C-5 ), 68.7
5
,
6
B
B A B 2Bn A B
13
(C-6 ), 58.7 (C-5 ), 55.8 (CH3MP), 52.9 (2 C, C-2B, C-2 ), 17.0 (C-6 ).
C NMR (100 MHz, CDCl ): δ = 162.6 (NHCO ), 161.1 (NHCO ), 155.9,
3 B A
A
A
A
B
+
+
150.9 (2 C, Cq,MP), 138.8 (Cq,Bn), 137.1 (Cq,Ph), 129.2–126.3 (10 C, CAr,Bn
,
HRMS (ESI ): m/z [M + NH ] calcd for C37H42N O Cl : 914.1024;
4
3
11
6
1
CAr,Ph), 119.6, 114.6 (4 C, C
), 102.4 (CHPh), 101.2 (C-1 , J = 170
found: 914.0950.
Ar,MP
A
C,H
1
Hz), 98.6 (C-1 , J = 168 Hz), 91.9, 91.8 (2 C, CCl3A,B), 77.0 (C-4 ), 76.5
B
C,H
A
(
5
C-3 ), 73.8 (C-3 ), 72.6 (CH ), 69.7 (C-5 ), 68.8 (C-6 ), 64.8 (C-4 ),
B A 2Bn B A B
4
-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-tri-
chloroacetamido-α-L-altropyranosyl-(1→3)-4-p-toluenesulfonyl-
,4,6-trideoxy-2-trichloroacetamido-β-D-glucopyranoside (24)
To a suspension of alcohol 18 (100 mg, 0.11 mmol) in anhyd pyridine
0.4 mL) was added p-toluenesulfonyl chloride (32 mg, 0.17 mmol, 1.5
9.9 (C-5 ), 55.6 (CH ), 55.0 (C-2 ), 52.6 (C-2 ), 18.1 (C-6 ).
A 3MP B A B
+
+
HRMS (ESI ): m/z [M + Na] calcd for C37H37N O Cl Na: 937.0165;
found: 937.0134.
2
2
10
7
(
4
-Methoxyphenyl Benzyl 3-O-Benzyl-2-deoxy-2-trichloroacet-
amido-α-L-altropyranosyluronate-(1→3)-4-azido-2,4,6-trideoxy-
-trichloroacetamido-β-D-galactopyranoside (26)
equiv) and the reaction mixture was stirred at 50 °C for 7 d. After that
time, the reaction mixture was concentrated in vacuo. Flash chroma-
tography (silica gel, toluene/EtOAc, 9:1 → 7:3) gave tosylate 24.
2
A suspension of acetal 20 (819 mg, 0.89 mmol) in 80% aq AcOH (4.2
mL) was stirred for 3 h at 60 °C. At completion, the solvents were
evaporated and co-evaporated with toluene. The residue was dis-
solved in CH Cl /H O (2:1, 15 mL). TEMPO (28 mg, 0.18 mmol, 0.2
Yield: 32.6 mg (0.031 mmol, 28%); white solid; R = 0.4 (toluene/EtOAc,
f
7:3).
1
H NMR (400 MHz, CDCl ): δ = 7.79–6.79 (m, 18 H, HAr,Bn, HAr,Ph, HAr,MP),
3
2
2
2
7
4
4
.22 (d , 1 H, NH ), 6.80 (d , 1 H, NH ), 5.61 (s, 1 H, CHPh), 5.29 (d, J
=
o
B
po
A
1,2
equiv) and BAIB (713 mg, 2.21 mmol, 2.5 equiv) were added. After
.4 Hz, 1 H, H-1 ), 5.11 (s, 1 H, H-1 ), 4.85 (d, J = 11.9 Hz, 1 H, CH2Bn),
B
A
stirring at r.t. for 2 h, the reaction was quenched with 10% aq Na SO3
2
.72 (d, 1 H, CH2Bn), 4.51–4.44 (m, 3 H, H-2 , H-5 , H-4 ), 4.33 (dd, 1 H,
A
A
B
and the biphasic mixture diluted with CH Cl (80 mL). The aqueous
2
2
J5,6a = 5.2 Hz, J6a,6b = 10.4 Hz, H-6a ), 4.24 (pt, 1 H, J = J3,4 = 4.6 Hz, H-
A
2,3
phase was separated and extracted twice with CH Cl (80 mL). The
2
2
3B), 4.14 (ddd, 1 H, J2,NH = 8.6 Hz, H-2 ), 4.04 (pt, 1 H, J = J3,4 = 2.6 Hz,
B
2,3
combined organic phases were washed with brine (80 mL), dried over
anhyd Na SO , filtered, and concentrated under reduced pressure. To a
H-3 ), 3.94 (dq, J = 3.7, J5,6 = 7.0 Hz, 1 H, H-5 ), 3.77 (s, 3 H, CH3MP),
A
4,5
B
2
4
3
.78–3.71 (mpo, 2 H, H-4 , H-6b ), 2.42 (s, 3 H, CH3Ts), 1.123 (d, J5,6 =
A A
solution of the crude material in anhyd DMF (13 mL) were added ben-
7.0 Hz, 3 H, H-6B).
zyl bromide (420 μL, 3.54 mmol, 4.0 equiv) and K CO (245 mg, 1.77
2
3
13
C NMR (100 MHz, CDCl ): δ = 162.0 (NHCO ), 161.3 (NHCO ), 155.3,
mmol, 2.0 equiv). After stirring at r.t. for 2 h, the reaction mixture was
diluted with H O (30 mL) and extracted with CH Cl (100 mL). The or-
3
B
A
1
1
9
50.6, 145.7, 138.2, 137.3, 133.3, 130.1–125.3 (15 C, CAr,Ph, CAr,Bn, CAr,Ts),
2
2
2
17.7, 114.6 (4 C, CAr,MP), 102.2 (CHPh), 97.2 (C-1 ), 97.1 (C-1 ), 91.93,
ganic phases were pooled, washed with brine (50 mL), dried over an-
hyd Na SO , filtered, and concentrated in vacuo. Flash chromatogra-
A
B
1.87 (2 C, CCl3A, CCl3B), 78.9 (C-4 ), 77.2 (C-4 ), 73.4 (C-3 ), 73.3
B
A
A
2
4
(
CH2Bn), 72.8 (C-3 ), 71.9 (C-5 ), 68.8 (C-6 ), 59.8 (C-5 ), 55.6 (CH3MP),
phy (silica gel, toluene/EtOAc, 4:1) gave benzyl ester 26.
B
B
A
A
5
3.0 (C-2 ), 51.7 (C-2 ), 21.4 (CH3Ts), 19.0 (C-6B).
A B
Yield: 574 mg (0.61 mmol, 69%); white solid; R = 0.2 (toluene/EtOAc,
4:1).
f
+
+
HRMS (ESI ): m/z [M + Na] calcd for C37H41N O Cl Na: 1073.0593;
6
11
6
found: 1073.0585.
1
H NMR (400 MHz, DMSO-d ): δ = 9.85 (d, J
= 8.6 Hz, 1 H, NHA),
6
2,NH
8
.78 (d, J2,NH = 9.1 Hz, 1 H, NH ), 7.42–7.25 (m, 10 H, HAr,Bn), 6.91–6.89
B
4
-Methoxyphenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-tri-
(m, 2 H, HAr,MP), 6.86–6.83 (m, 2 H, HAr,MP), 5.34 (d, J = 5.1 Hz, 1 H, OH-
chloroacetamido-α-L-altropyranosyl-(1→3)-4-chloro-2,4,6-tride-
oxy-2-trichloroacetamido-β-D-galactopyranoside (25)
4A), 5.27 (d, J1,2 = 6.5 Hz, 1 H, H-1 ), 5.21 (dpo, 1 H, CH2Bn-6), 5.01 (d, J1,2
=
A
8.3 Hz, 1 H, H-1 ), 4.68 (d, J = 5.1 Hz, 1 H, H-5 ), 4.57 (d, J = 11.6 Hz, 1
B
A
Alcohol 18 (50 mg, 56 μmol) was dissolved under argon in anhyd CH2-
Cl2 (0.4 mL). The reaction mixture was cooled to 0 °C and DMAP (20
mg, 0.17 mmol, 3.0 equiv) was added followed by triflic chloride (9
μL, 0.08 mmol, 1.5 equiv) and the reaction mixture was stirred for 3 h
at 0 °C. More triflic chloride (9 μL, 0.08 mmol, 1.5 equiv) was added
and the reaction mixture was stirred for another 3 h at 0 °C. After that
time, the reaction mixture was diluted with CH Cl (45 mL), washed
H, CH2Bn-3), 4.46 (d, J = 11.6 Hz, 1 H, CH2Bn-3), 4.34–4.31 (mpo, 1 H, H-
4A), 4.29 (ddpo, J2,3 = 10.8, J3,4 = 3.6 Hz, 1 H, H-3 ), 4.20 (dd, J = 2.1 Hz,
B
2,3
1 H, H-2 ), 4.02–4.07 (m, 2 H, H-2 , H-4 ), 3.72–3.69 (m, 2 H, H-5 , H-
A
B
B
B
3A), 3.70 (s, 3 H, CH3MP), 1.17 (d, J5,6 = 6.3 Hz, 3 H, H-6B).
13
C NMR (100 MHz, DMSO-d ): δ = 169.5 (C-6 ), 162.1 (NHCO ), 162.0
6
A
B
(
NHCO ), 155.3, 151.6 (2 C, Cq,MP), 138.7 (Cq,Bn-3), 136.0 (Cq,Bn-6), 129.0–
A
2
2
127.8 (10 C, C
), 118.7, 114.9 (4 C, CAr,MP), 100.6 (C-1B, 1J = 164
C,H
Ar,Bn
1
with H O (10 mL) and brine (10 mL), dried by passing through a phase
2
Hz), 99.5 (C-1 , J = 171 Hz), 93.5, 93.4 (2 C, CCl3A,B), 76.9 (C-3 ), 76.1
A
C,H
B
separator filter, and concentrated in vacuo. Flash chromatography
(
C-3 ), 75.1 (C-5 ), 71.1 (CH
), 69.2 (C-5 ), 66.8 (CH2Bn-6), 65.5, 65.4
A
A
2Bn-3
B
(silica gel, toluene/EtOAc, 9:1 → 3:1) gave the 4-chloro derivative 25.
(
2 C, C-4 , C-4 ), 55.8 (CH ), 53.0 (C-2 ), 52.6 (C-2 ), 17.8 (C-6 ).
A
B
3MP
B
A
B
Yield: 51 mg (56 μmol, 100%); colorless oil; R = 0.2 (toluene/EtOAc,
+
+
f
HRMS (ESI ): m/z [M + NH ] calcd for C37H41N O Cl : 955.0964;
4 6 11 6
4:1).
found: 955.0974.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

K
Synthesis
H. B. Pfister et al.
Paper
4
-Methoxyphenyl Benzyl 3-O-Benzyl-4-O-chloroacetyl-2-deoxy-2-
trichloroacetamido-α-L-altropyranosyluronate-(1→3)-4-azido-
,4,6-trideoxy-2-trichloroacetamido-α/β-D-galactopyranose (27)
(C-1B, 1JC,H = 173 Hz), 75.6 (C-3 ), 73.0 (C-5 ), 71.9 (CH2Bn-3), 71.7 (C-
B
A
3 ), 68.5 (C-4 ), 68.1 (CH
), 65.2 (C-5 ), 65.1 (C-4 ), 54.3 (C-2 ),
A
A
2Bn-6
B B A
2
50.9 (C-2 ), 40.7 (CH2ClAc), 17.3 (C-6B).
B
+
+
A solution of alcohol 26 (609 mg, 0.65 mmol) in anhyd pyridine (1.6
HRMS (ESI ): m/z [M + Na] calcd for C32H32N O Cl Na: 929.9816;
5 11 7
mL) was cooled to 0 °C. Chloroacetic anhydride (166 mg, 0.97 mmol,
found: 929.9755.
1.5 equiv) was added. After stirring for 15 min at that temperature,
the reaction was quenched by addition of MeOH and the solvents
were evaporated. Flash chromatography (silica gel, toluene/EtOAc,
β-Anomer
Rf = 0.4 (cyclohexane/acetone, 3:2).
9:1) gave chloroacetate 27.
1
H NMR (partial, 400 MHz, CDCl ): δ = 7.47–7.19 (m, 10 H, H ), 7.03
3
Ar
Yield: 516 mg (0.51 mmol, 78%); white solid; R = 0.5 (toluene/EtOAc,
f
(d, J2,NH = 7.4 Hz, 1 H, NH ), 6.79 (d, J
= 6.6 Hz, 1 H, NH ), 5.80 (m, 1
B
2,NH
A
4:1).
H, H-4 ), 5.37 (d, J = 7.0 Hz, 1 H, H-1 ), 5.28 (s, 2 H, CH2Bn-6), 4.80 (m,
A
1,2
A
1
6
H NMR (400 MHz, DMSO-d ): δ = 8.98 (d, J2,NH = 8.4 Hz, 1 H, NHA),
1 H, H-5 ), 4.71 (pt, J = J1,OH = 8.2 Hz, 1 H, H-1 ), 4.59 (d, J = 11.5 Hz,
A
1
,
2
B
8
.81 (d, J2,NH = 9.2 Hz, 1 H, NH ), 7.45–7.22 (m, 10 H, HAr,Bn), 6.91–6.88
B
1 H, CH2Bn-3), 4.33 (d, J = 11.5 Hz, 1 H, CH2Bn-3), 4.29 (m, 1 H, H-3 ), 4.13
B
(s, 2 H, CH2ClAc), 3.94 (m, 1 H, H-2 ), 3.82 (m, 1 H, H-2 ), 3.61 (dt, J
1.2 Hz, 1 H, H-5 ), 1.32 (d, J = 6.4 Hz, 3 H, H-6B).
(m, 2 H, HAr,MP), 6.85–6.83 (m, 2 H, HAr,MP), 5.69 (pt, J = 3.2 Hz, 1 H, H-
=
A
B
4,5
4A), 5.31 (dpo, J1,2 = 6.8 Hz, 1 H, H-1 ), 5.31–5.24 (mpo, 2 H, CH2Bn-6),
A
B
5,6
5
.00 (dpo, J1,2 = 6.4 Hz, 1 H, H-1 ), 4.99 (m , 1 H, H-5 ), 4.57 (d, J = 11.3
B po A
13
C NMR (partial, 100 MHz, CDCl ): δ = 167.3 (C-6 ), 166.6 (COClAc),
3
A
Hz, 1 H, CH2Bn-3), 4.40 (dpo, 1 H, CH2Bn-3), 4.40, 4.35 (2d, J = 15.4 Hz, 2 H,
163.5, 162.2 (2 C, NHCOA,B), 136.3 (Cq,Bn-3), 134.5 (Cq,Bn-6), 129.2–128.4
CH2ClAc), 4.31 (ddpo, J2,3 = 10.6 Hz, 1 H, H-3 ), 4.15 (pd, J = 3.4 Hz, 1 H,
B
1
1
(
10 C, C ), 98.2 (C-1 , J = 168 Hz), 95.4 (C-1 , J = 163 Hz), 77.0
Ar
A
C,H
B
C,H
H-4 ), 4.11–3.97 (m, 3 H, H-2 , H-2 , H-3 ), 3.73–3.69 (mpo, 1 H, H-5B),
B
A
B
A
(
C-3 ), 72.1 (CH
), 65.5 (C-5 ), 56.0 (C-2 ), 40.6 (CH2ClAc), 17.4 (C-
B
2Bn-3
B
B
3.69 (spo, 3 H, CH3MP), 1.18 (d, J5,6 = 6.4 Hz, 3 H, H-6B).
6B).
13
C NMR (100 MHz, DMSO-d ): δ = 167.9 (C-6 ), 167.1 (COClAc), 162.2
6
A
+
+
HRMS (ESI ): m/z [M + Na] calcd for C32H32N O Cl Na: 929.9816;
found: 919.9755.
5
11
7
(
NHCO ), 162.1 (NHCO ), 155.3, 151.5 (2 C, Cq,MP), 137.8 (Cq,Bn-3), 135.7
B
A
(
C
), 129.1–128.1 (10 C, CAr,Bn), 118.7, 114.9 (4 C, CAr,MP), 100.5 (C-
q,Bn-6
1B, 1JC,H = 164 Hz), 99.3 (C-1A, 1J = 171 Hz), 93.5, 93.2 (2 C, CCl3A
,
C,H
Benzyl 3-O-Benzyl-4-O-chloroacetyl-2-deoxy-2-trichloroacetami-
do-α-L-altropyranosyluronate)-(1→3)-4-azido-2-trichloroacet-
amido-2,4,6-trideoxy-β-D-galactopyranosyl N-
Phenyltrifluoroacetimidate (1) and 2-Trichloromethyl-[(benzyl 3-
O-benzyl-4-O-chloroacetyl-2-deoxy-2-trichloroacetamido-α-L-al-
tropyranosyluronate)-(1→3)-4-azido-1,2,4,6-tetradeoxy-β-D-ga-
lactopyranose]-[2,1]-oxazoline (29)
CCl3B), 77.4 (C-3 ), 73.9 (C-3 ), 72.5 (C-5 ), 71.9 (CH2Bn-3), 68.9 (2 C, C-
B
A
A
5B, C-4 ), 67.4 (CH
), 65.5 (C-4 ), 55.8 (CH ), 53.2 (C-2 ), 53.0 (C-
A
2Bn-6
B 3MP B
2A), 41.4 (CH2ClAc), 17.8 (C-6B).
+
+
HRMS (ESI ): m/z [M + NH ] calcd for C39H42N O Cl : 1031.0680;
4
6
12
7
found: 1031.0594.
Benzyl 3-O-Benzyl-4-O-chloroacetyl-2-deoxy-2-trichloroacetami-
do-α-L-altropyranosyluronate-(1→3)-4-azido-2,4,6-trideoxy-2-
trichloroacetamido-α/β-D-galactopyranose (28)
Hemiacetal 28 (548 mg, 0.60 mmol) was dissolved under argon in ac-
etone (7 mL). N-Phenyl-2,2,2-trifluoroacetamidoyl chloride (190 μL,
1
.20 mmol, 2.0 equiv) was added followed by Cs CO (216 mg, 0.66
2 3
The fully protected disaccharide 27 (402 mg, 0.40 mmol) was sus-
mmol, 1.1 equiv). After stirring at r.t. for 2 h, the reaction mixture was
filtered and the filtrate was concentrated under reduced pressure.
Flash chromatography of the crude material (silica gel, cyclohex-
pended in H O/MeCN (3:1, 16 mL) and cooled to 0 °C; then a solution
2
of CAN (542 mg, 0.99 mmol, 2.5 equiv) in H O was added. The tem-
2
perature of the reaction mixture was allowed to slowly reach r.t. After
stirring for 90 min, the reaction was quenched by the addition of sat.
ane/EtOAc/Et N, 4:1:0.3) gave an equimolar mixture of oxazoline 29
3
and N-phenyltrifluoroacetimidate 1.
aq NaHCO (50 mL). The mixture was extracted with EtOAc, 180 mL)
3
Yield: 561 mg (0.56 mmol, 93%); 29/1 = 1:1; white foam.
Analytical data for the two compounds were as described previous-
and the organic phase was washed with H O (50 mL) and brine (50
2
mL), dried over anhyd Na SO , filtered, and concentrated in vacuo. Pu-
2
4
18
ly.
rification by flash chromatography (silica gel, toluene/EtOAc, 8:2 →
:3) gave hemiacetal 28.
7
Molecular Mechanics
Yield: 295 mg (0.32 mmol, 82%); α/β = 3:1, white foam.
Molecular mechanics calculations were performed with the MAE-
STRO software using the OPLS3 force field. All the starting geome-
tries, calculations, and analysis were performed using the corre-
sponding modules within the MAESTRO package.
α-Anomer
Rf = 0.5 (cyclohexane/acetone, 3:2).
1
H NMR (400 MHz, CDCl ): δ = 7.47–7.19 (m, 10 H, H ), 7.00 (d, J
=
=
3
Ar
2,NH
9
3
5
1
.0 Hz, 1 H, NH ), 6.89 (d, J
.1 Hz, 1 H, H-4 ), 5.41 (d, J1,2 = 7.3 Hz, 1 H, H-1 ), 5.28 (s, 2 H, CH2Bn-6),
.25 (pt, J1,2 = J1,OH = 3.4 Hz, 1 H, H-1 ), 4.79 (d, 1 H, H-5 ), 4.55 (d, J =
1.5 Hz, 1 H, CH2Bn-3), 4.43 (m, 1 H, H-2 ), 4.34 (d, J = 11.5 Hz, 1 H,
= 7.1 Hz, 1 H, NH ), 5.79 (pt, J = J4,5
B
2,NH A 3,4
A
A
Funding Information
B
A
B
This work has received funding from the Institut Pasteur, the ME-
NESR, France (ENS Cachan, PhD fellowship to H. P.) and the European
Commission Seventh Framework Program (FP7/2007–2013) under
Grant agreement No. 261472-STOPENTERICS, which included a fel-
CH2Bn-3), 4.28 (dd, J2,3 = 10.7, J3,4 = 3.7 Hz, 1 H, H-3 ), 4.15 (dqpo, J
=
B
4,5
0.8 Hz, 1 H, H-5 ), 4.13 (s, 2 H, CH2ClAc), 4.00 (dd, J = 10.0 Hz, 1 H, H-
B
2
,
3
3A), 3.95 (dd, J = 3.7 Hz, 1 H, H-4 ), 3.89 (dd, J = 7.3 Hz, 1 H, H-2 ), 3.14
B
A
(
dd, J2,OH = 1.2 Hz, 1 H, OH-1), 1.24 (d, J5,6 = 6.5 Hz, 3 H, H-6B).
lowship to J.P.
E
u
or
p
e
a
n
C
o
m
mosin
S
e
v
e
n
ht
Fra
m
e
w
o
kr
P
orgra
m
2(
6
1
4
7
2
S-
T
O
P
E
N
T
E
R
C
I
S)
13
C NMR (100 MHz, CDCl ): δ = 167.3 (C-6 ), 166.8 (COClAc), 162.3
3
A
(
NHCO ), 161.9 (NHCO ), 136.4 (Cq,Bn-3), 134.5 (Cq,Bn-6), 129.2–128.4
A
B
1
(10 C, CAr), 97.3 (C-1 , J = 167 Hz), 92.4, 92.1 (2 C, CCl3A, CCl3B), 91.4
A
C,H
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–M

L
Synthesis
H. B. Pfister et al.
Paper
Acknowledgment
(11) (a) van der Put, R. M.; Kim, T. H.; Guerreiro, C.; Thouron, F.;
Hoogerhout, P.; Sansonetti, P. J.; Westdijk, J.; Stork, M.;
Phalipon, A.; Mulard, L. A. Bioconjugate Chem. 2016, 27, 883. (b)
https://clinicaltrials.gov/ct2/show/NCT02797236
The authors thank F. Bonhomme (CNRS UMR 3523) for the HRMS
spectra.
(
12) (a) Boutet, J.; Blasco, P.; Guerreiro, C.; Thouron, F.; Dartevelle, S.;
Nato, F.; Canada, F. J.; Arda, A.; Phalipon, A.; Jimenez-Barbero, J.;
Mulard, L. A. Chem. Eur. J. 2016, 22, 10892. (b) Hu, Z.; Bongat
White, A. F.; Mulard, L. A. Chem. Asian J. 2017, 12, 419.
Supporting Information
Supporting information for this article is available online at
(
13) Kotloff, K. L.; Winickoff, J. P.; Ivanoff, B.; Clemens, J. D.;
Swerdlow, D. L.; Sansonetti, P. J.; Adak, G. K.; Levine, M. M. Bull.
World Health Organ. 1999, 77, 651.
https://doi.org/10.1055/s-0037-1609719.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
14) Holt, K. E.; Baker, S.; Weill, F. X.; Holmes, E. C.; Kitchen, A.; Yu, J.;
Sangal, V.; Brown, D. J.; Coia, J. E.; Kim, D. W.; Choi, S. Y.; Kim, S.
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