Glycosylations of Simple Acceptors with 2-O-Acyl l-Idose or l-Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring-Group Participation

Article abstract of DOI:10.1002/ejoc.201800318

Several l-idose and l-iduronic acid glycosyl donors (mostly thioglycosides but also halides and trichloroacetimidates) with acyl protecting groups at the C-2 position were prepared and evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide syntheses in the literature, the presence of C-2 acyl protecting groups in l-ido-configured glycosyl donors generally results in exclusive formation of 1,2-trans glycosidic linkages, a finding that has typically been attributed to neighbouring-group participation. However, glycosylations of simple alcohols with l-ido-configured donors (particularly thioglycosides), reported here, generally displayed incomplete stereocontrol and gave mixtures of the 1,2-trans and 1,2-cis products, suggesting that neighbouring-group participation has lesser importance in these reactions. Glycosyl donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for the desired α-l-anomer (1,2-trans) as the major product. Interestingly, glycosylations under the same reaction conditions with more complex monosaccharide acceptors gave exclusively the expected 1,2-trans products. The role of neighbouring-group participation in these glycosylations was explored with density functional theory (DFT) calculations, which revealed that the non-stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.

Full text of DOI:10.1002/ejoc.201800318

A Journal of
Accepted Article
Title: Glycosylations of Simple Acceptors with 2-O-Acyl L-Idose or L-
Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring
Group Participation
Authors: Shifaza Mohamed, Qi Qi He, Romain J. Lepage, Elizabeth H.
Krenske, and Vito Ferro
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800318
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10.1002/ejoc.201800318
European Journal of Organic Chemistry
Glycosylations of Simple Acceptors with 2-O-Acyl L-Idose or L-Iduronic Acid Donors
Reveal Only a Minor Role for Neighbouring Group Participation
Shifaza Mohamed,a Qi Qi He,a Romain J. Lepage,a,b Elizabeth H. Krenske,a and Vito Ferro*a
a
b
The University of Queensland
School of Chemistry and Molecular Biosciences
Brisbane, QLD 4072, Australia
E-mail: v.ferro@uq.edu.au
https://staff.scmb.uq.edu.au/staff/vito-ferro
Visiting PhD student from Griffith Institute for Drug Discovery
Griffith University
Brisbane, QLD 4111, Australia
Supporting information for this article is given via a link at the end of the document.
1
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Abstract
Several L-idose and L-iduronic acid glycosyl donors (mostly thioglycosides but also halides
and trichloroacetimidates) with acyl protecting groups at the C-2 position were prepared and
evaluated in glycosylation reactions with simple acceptors. In glycosaminoglycan oligosaccharide
syntheses in the literature, the presence of C-2 acyl protecting groups in L-ido-configured glycosyl
donors generally results in exclusive formation of 1,2-trans glycosidic linkages, a finding that has
typically been attributed to neighbouring group participation. However, glycosylations of simple
alcohols with L-ido-configured donors (particularly thioglycosides), reported here, generally
displayed incomplete stereocontrol and gave mixtures of the 1,2-trans and 1,2-cis products,
suggesting that neighbouring group participation has lesser importance in these reactions. Glycosyl
donors and reaction conditions were identified that gave improved, but not exclusive, selectivity for
the desired -L-anomer (1,2-trans) as the major product. Interestingly, glycosylations under the
same reaction conditions with more complex monosaccharide acceptors gave exclusively the
expected 1,2-trans products. The role of neighbouring group participation in these glycosylations
was explored with density functional theory (DFT) calculations, which revealed that the non-
stereoselective addition of the acceptor alcohol to the intermediate oxocarbenium ion is competitive
with the stereospecific addition of the acceptor to the acyloxonium ion intermediate.
1
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Introduction
Glycosaminoglycans (GAGs) are complex, highly sulfated polysaccharides that play
important roles in mammalian physiology as well as in numerous disease processes such as
angiogenesis, metastasis, inflammation and viral infections, to name a few. The monosaccharide L-
iduronic acid (IdoA) is a key component of the GAGs heparin, heparan sulfate (HS) and dermatan
sulfate (DS) where it is found (14)-linked to D-glucosamine (for heparin/HS)[1] or (13)-
linked to N-acetyl-D-galactosamine (for DS).[2] The unusual conformational flexibility of IdoA is
thought to contribute to the biological activity of GAGs by facilitating binding interactions with a
range of structurally diverse proteins.[2-3] The synthesis of IdoA building blocks[4] is of great current
interest for synthetic access to well-defined GAG oligosaccharides which are essential for
biological studies to identify therapeutically useful sequences and for elucidating structure-activity
relationships.[5]
As non-reducing end IdoA is found in GAGs only in -L-glycosidic linkages, generally the
IdoA or L-idose (Ido) glycosyl donors required for GAG oligosaccharide synthesis are prepared[4, 5b,
5c]
with an acyl protecting group at C-2 to ensure exclusive formation of the desired (1,2-trans)
glycosidic linkage. The 1,2-trans stereoselectivity has been generally thought to arise from
neighbouring group participation. Glycosylation reactions with glycosyl donors bearing a
“participating” acyl protecting group at C-2 are generally thought to occur via the initial formation
of a short-lived positively charged oxocarbenium ion formed upon dissociation of the anomeric
leaving group (Scheme 1).[6] Immediate intramolecular attack by the C-2 protecting group leads to
the formation of an acyloxonium ion intermediate which blocks approach of the acceptor from the
bottom face and thus prevents formation of the 1,2-cis glycosidic product. Direct nucleophilic
attack by the acceptor alcohol on C-1 of the acyloxonium ion gives the 1,2-trans glycosidic product
(Scheme 1, pathway a), while attack at the carbonyl carbon leads to the formation of an orthoester
byproduct (pathway d). The stereoselectivity of the reaction is also influenced by factors such as
2
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leaving group, solvent, activation system, additives and protecting groups on the donor and
acceptor. Occasionally, significant amounts of 1,2-cis-linked glycosides are also obtained (pathway
c), mostly when the acceptor alcohols are unreactive, and/or if the participating substituents at C-2
are poorly nucleophilic.[7]
Scheme 1. Mechanism for glycosylation with a glycosyl donor bearing an acyl participating group
at C-2 (adapted from ref.[6b]).
Many L-Ido-configured donors bearing acyl groups at C-2 and which adopt or are locked in
the 1C4 conformation in solution, have been utilized in GAG oligosaccharide synthesis[5] and in the
majority of cases the glycosyl acceptor has been a secondary alcohol on a suitably protected D-
glucosamine (or D-galactosamine) derivative. In these cases the glycosylation reactions generally
give the expected -L-linked 1,2-trans glycosylation products exclusively. There have also been
many examples of the synthesis of GAG oligosaccharides with an IdoA residue at the reducing
end,[8] generally as a glycoside of a reactive primary or secondary alcohol (e.g., methanol,
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isopropanol, etc) or as part of an aliphatic linker. The required glycosylation reactions of IdoA or
Ido glycosyl donors with acyl (participating) protecting groups at C-2 with such simple alcohols
have also generally been reported to give exclusively the desired -L-glycosides.[8] Interestingly,
however, there have been some cases where the reported stereochemical outcomes of the reactions
have been, unexpectedly, moderate to poor.[9] However, there have been no investigations into the
reasons for the observed selectivities, nor any systematic studies on these types of glycosylation
reactions. Herein, we describe the results of our own studies on the glycosylation reactions of a
variety of Ido or IdoA donors bearing participating protecting groups at C-2 with simple alcohol
acceptors. In most cases, a mixture of anomers was obtained rather than the expected 1,2-trans
glycoside, indicating that the reaction did not proceed exclusively via an acyloxonium ion
intermediate. We report DFT calculations that show that non-stereoselective attack by the acceptor
on the intermediate oxocarbenium ion is competitive with the stereoselective reaction of the
acceptor with the acyloxonium ion.
Results and discussion
Glycosylations using Glycosyl Halide Donors
As part of a broader project aimed at the synthesis of IdoA derivatives as probes for HS-
degrading enzymes involved in mucopolysaccharidosis disorders, synthetic access was required to
simple glycosides of Ido or IdoA. Initial efforts were directed towards the preparation of methyl -
L-idopyranosides such as 6 via the Koenigs–Knorr reaction (Scheme 2). The well-known Koenigs–
Knorr method uses heavy metal salts, mainly silver or mercury salts, as promoters and glycosyl
halides (usually bromides) as the glycosyl donors. Thus, bromide 3 was chosen as the target
glycosyl halide. Acetolysis of the 1,6-anhydrosugar 1[10] gave glycosyl acetate 2[11] in 98% yield
with an α/β anomeric ratio of 1.6:1. The anomeric configurations of Ido or IdoA glycosides
obtained throughout this study were determined by a combination of NMR techniques. Anomers
with the -L configuration generally displayed long range coupling from H-1 to H-3 which was
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readily discernible in COSY spectra, whereas their  anomeric counterparts did not. On the other
hand, only the  anomers displayed an nOe correlation between H-1 and H-5 in 1D NOESY
13
spectra. Another trend that was apparent for a  anomer was the chemical shift of C-5 in the C
NMR spectrum which was shifted significantly downfield relative to the  anomer, often by >5
ppm.
Scheme 2. Preparation and glycosylations with halide and trichloroacetimidate L-ido glycosyl
donors.
Glycosyl acetate 2 was treated with 30% HBr in acetic acid at room temperature. However, the
desired bromide 3 proved to be unstable and could not be isolated due to hydrolysis to the
hemiacetal 4, which was isolated in 74% yield. Treatment of compound 2 with
bromotrimethylsilane[12] in anhydrous DCM at 0 °C also led to the hemiacetal 4. Despite earlier
reports[11, 13] of the successful synthesis of 3 using titanium tetrabromide, in our hands the bromide
3 was found to be highly reactive and unstable. Hung has also reported that a similar L-idosyl
bromide is unstable and is readily hydrolyzed to the hemiacetal.[14]
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The use of glycosyl chloride 5 as a glycosyl donor was then investigated. Although the
reactivity of glycosyl chlorides is lower than glycosyl bromides as glycosyl donors, their thermal
and chemical stabilities are higher. Compound 5 was synthesized according to the procedure
reported by Zhang and co-workers,[15] wherein acetate 2 was reacted with thionyl chloride and tin
tetrachloride, producing chloride 5 in good yield (88%, 10:1 α/β) which was then used directly in
the next step without further purification. Upon subjecting chloride 5 to Koenigs-Knorr reaction
conditions with Ag2CO3 as promoter, two products were obtained. The desired methyl glycoside 6
was isolated exclusively as the -anomer in 17% yield but the major product of the reaction was the
orthoester 7 (34%). The identities of the products were determined by NMR spectroscopy and mass
spectrometry (both m/z 433 [M + Na]+). The 1H NMR spectrum of the orthoester 7 had two sets of
signals due to the presence of two diastereoisomers in a ratio of 10:3. Hung has also reported the
formation of orthoester as the major product on subjecting a similar α-L-glycosyl chloride to
glycosylation with methanol using AgOTf as promoter.[14] Similarly, Whitfield[9b] reported that
glycosylation of methanol with a related IdoA-configured glycosyl bromide also gave orthoester as
the major product and interestingly, the -L-glycoside as a minor product with no trace of -L-
glycoside.
Sugar 1,2-orthoesters are often undesired byproducts in the Koenigs-Knorr glycosylation
with donors carrying 1,2-trans C-2 acetyl protecting groups. Formation of orthesters in this case
suggests that the reaction proceeds via an acyloxonium intermediate. Subsequent nucleophilic
attack on C-1 by methanol leads to the formation of the methyl glycoside 6 and the nucleophilic
attack on the newly formed acyloxonium carbon leads to the formation of the 1,2 orthoester 7.
Orthoesters can often be converted into their corresponding glycosides under Lewis acid
catalysis.[16] Treatment of 7 with a catalytic amount of TMSOTf in the presence of methanol led to
the isolation of methyl glycoside 6. However, due to partial conversion and decomposition of
6
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starting material, 6 was isolated in poor yield (25%). Jacquinet et al.[9a] have previously reported
that glycosylation of methanol with a related IdoA configured orthoester as a glycosyl donor results
in a mixture of anomeric methyl glycosides (/ = 2:1), suggesting that reaction through an
oxocarbenium ion intermediate is a viable pathway.
Glycosylation using Glycosyl Trichloroacetimidates
Glycosyl trichloroacetimidates are commonly used as powerful glycosyl donors owing to
their ease of synthesis and stability at room temperature.[17] The activation is accomplished using
catalytic amounts of Lewis acids such as TMSOTf or BF3.OEt2.[18] Hemiacetal 4 was thus
[19]
converted into the corresponding trichloroacetimidate donor 8
by treatment with
trichloroacetonitrile and cesium carbonate as the base (Scheme 2). Trichloroacetimidate 8 was
obtained in 48% yield as a mixture of anomers (2:1, α/β). However, the reaction was capricious and
yields within the range 35–48% were obtained upon scaling up. The use of other bases (K2CO3,
DBU) did not improve yields. In all cases TLC of the reaction did not indicate any significant
decomposition. Thus the low yield is presumably the result of decomposition of the
trichloroacetimidate during work up and purification. The subsequent glycosylation of donor 8 at 0
C with TMSOTf as the promoter gave the methyl glycoside 6 in good yield (83%) but with poor
selectivity (/ 1.2:1), suggesting that in this case reaction does not proceed exclusively via an
acyloxonium ion intermediate. Kusumoto and co-workers reported the exclusive formation of the α-
anomer of glycoside 6 in 72% yield using BF3.OEt2 as a promoter.[19a] Owing to the modest yield in
our hands for the synthesis of donor 8 this reaction was not pursued further and attention was turned
to thioglycoside donors.
Glycosylation using Thioglycoside Donors
Amongst the various glycosyl donors, thioglycosides are one of the most popular because of
their stability and ease of preparation.[20] Thioglycosides of L-idose and L-idoA derivatives are
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commonly used as glycosyl donors with various acceptors for GAG oligosaccharide synthesis.
When reacting L-ido configured thioglycoside donors containing participating protecting groups
with simple alcohols such as methanol, the formation of anomeric mixtures is not unprecedented.[9d]
Ethyl thioglycoside 9 was initially chosen for investigation and was prepared from compound 2 in
moderate yield (49%) by treatment with ethanethiol in the presence of BF3.OEt2 (Scheme 3).
Tabeur et al.[9c] and Codée et al.[21] have previously reported the synthesis of compound 9 in 95%
and 79% yield, respectively, under same reaction conditions. The moderate yield obtained, could be
attributed to the decomposition (detected by TLC) of either the starting material 2 or the
thioglycoside 9. Despite having a participating group at C-2, an anomeric mixture (2:1 α/β) was
[9c]
obtained. Phenylthioglycoside 10
was subsequently synthesized in 79% yield with anomeric
ratio of 10:1 α/β via the reaction of 2 with thiophenol and BF3.Et2O at 0 °C. This is a considerable
improvement in both yield and selectivity compared with the synthesis of 9.
Scheme 3. Synthesis of L-ido thioglycoside donors 9, 10 and 15 and glycosylation with 10.
Glycosylation of 10 with methanol in dichloromethane in the presence of NIS and catalytic
TMSOTf at room temperature, afforded methyl glycoside 6 in 79% yield with an anomeric ratio of -
3.3:1 α/β (Scheme 2). Further experiments were then performed in an effort to increase selectivity
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for the desired -anomer. Thus, the effect of reaction temperature on the anomeric selectivity of the
reaction was studied (Table 1). Decreasing the temperature to 0 °C gave a 1:1 mixture of anomers.
However, increasing the temperature to 35 °C led to a 10-fold increase in the -anomeric ratio
(30:1 α/β).
Fügedi and co-workers[22] have reported the direct synthesis of L-ido-configured
thioglycosyl donors via the 1,6-anhydrosugar 1 with exclusive  selectivity.[9d, 22] Anhydrosugar 1
was thus converted into the partially or fully protected derivatives 11[23] and 13[24] (Scheme 2).
Subsequent thiolysis of 11 and 13 with trimethyl(phenylthio)silane in the presence of zinc iodide
led to the formation of the thioglycosides 12[25] and 14 in excellent yield (77-81%) exclusively as
the  anomers.[25] The selectivities obtained for the preparation of 9, 10, 12 and 14, although not
directly comparable because of the nature of the starting materials, indicate that the nature of both
the nucleophile and the Lewis acid are important factors in determining anomeric selectivity in
reactions to form L-ido thioglycosides. Subsequent C-6 oxidation of compound 14 with 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) and iodobenzene diacetate (BAIB), followed by
esterification of the resulting carboxyl group with methyl iodide and potassium bicarbonate gave
the methyl ester 15 in good yield (68% over two steps).
Donor 15 was subjected to glycosylation using NIS-TMSOTf as the promoter at room
temperature (Scheme 3). However, only the starting material was isolated after several hours of
reaction. Glycosyl donor 15 is a disarmed donor, due to the presence of the electron-withdrawing
methyl ester at C-5. The more powerful promoter system of diphenyl sulfoxide (Ph2SO) and triflic
anhydride in the presence of the hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP) was then
investigated.[26] The glycosylation was performed according to the protocol reported by Crich and
Smith,[27] wherein a 1:1 mixture of thioglycoside and Ph2SO was cooled to −75 °C in DCM in the
presence of TTBP. This mixture was then treated with 1.1 equivalents of triflic anhydride (Tf2O),
and, after 5 min, the acceptor (methanol) was added and the reaction stirred at this temperature for
9
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30 min. Unfortunately, this strategy of glycosylation gave the α-methyl glycoside 16 in a poor yield
(10%) due to extensive decomposition of the glycosyl donor 15 as detected by TLC and it was
unclear whether any -glycoside had also formed during the reaction. This donor was therefore not
investigated further.
Scheme 4. Glycosylations with L-ido thioglycoside donors 15 and 17.
Having failed to obtain the desired α-L-methyl glycoside 16 in sufficient yield, glycosylation
using the armed non-oxidized analogue 14 was investigated. Firstly, the free 6-OH group was
protected with a temporary protecting group in order to avoid self-condensation of the substrate
under glycosylation conditions. The tert-butyldimethylsilyl (TBDMS) ether was chosen as a
temporary protecting group for 6-OH of 14 (Scheme 4). The silyl ether 17 obtained in 97% yield,
was subjected to glycosylation using NIS-TMSOTf as a promoter system at room temperature to
obtain the methyl glycoside 18 in an excellent yield of 90% with an anomeric ratio of 1:1 α/β.
During the glycosylation reaction, the C-6 silyl ether protecting group was also cleaved, possibly
during work-up. Attempts were then made to optimize the formation of the -anomer (summarized
in Table 1). Anomeric mixtures were obtained under all of the reaction conditions studied.
Decreasing the temperature of the reaction to 0 °C increased the time required for completion of the
reaction and also slightly increased the amount of -anomer formed (1.3:1). Upon increasing the
reaction temperature to 35 °C or 65 °C, the reaction time decreased and a slight decrease in the
fraction of -anomer was seen (1.2:1). However, the change in anomeric ratio was not significant in
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either case, in contrast to the reactions with donor 10 which showed a dramatic improvement in a
selectivity upon increasing the temperature.
A glycosylation reaction was next performed with glycosyl donor 19 (Scheme 5), obtained
as a gift from Alchemia Ltd and used as a building block used for their generic synthesis of
fondaparinux where it gives exclusively the  glycoside with mono- or disaccharide acceptors.[28]
The only previous report of this compound was in a patent application[28] where no analytical data
were given, and where the structure was depicted incorrectly as the β-L-glycoside. Compound 19
was thus fully characterized by 1D and 2D NMR and MS experiments, and confirmed to be the α-L-
glycoside. There was no correlation between H-1 and H-5 in the NOESY spectrum, while a W-
1
coupling between H-1 and H-3 was apparent in the H and COSY spectra. The thioglycoside 19
differs from the other donors considered earlier in having a locked conformation due to the 4,6-O-
isopropylidene protecting group. This feature might have an impact on the stereochemical outcome
of glycosylation as C-2 participation would likely result in a strained acyloxonium ion intermediate.
On subjecting the thioglycoside 19 to glycosylation at room temperature with NIS/TMSOTf an
anomeric mixture of the methyl glycoside 20 was obtained (1.7:1 / in 80% yield. The
isopropylidene group was removed under these reaction conditions, presumably post-glycosylation,
to afford methyl glycoside 20. A similar result was obtained upon reaction with n-butanol at room
temperature to give 21 in moderate yield (51%, 2:1 / Glycosylation of the more complex
monosaccharide acceptor 22[28] under the same conditions gave as anticipated, only the α-methyl
glycoside 23 in good yield (75%), although once again the isopropylidene group was removed.
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Scheme 5. Glycosylations with donors 19 and 24.
It was next decided to change the promoter system for glycosylation to NIS/TfOH and to
conduct the reaction at -78 C with warming up to -20 or 0 C as necessary. This protocol is
commonly used for HS oligosaccharide synthesis with thioglycoside donors[29] and it has recently
become the preferred method for thioglycoside activation in our laboratory (unpublished results).
Thus donor 19 was reacted under these conditions with methanol, resulting in the formation of 25 in
68% yield. The stereoselectivity (/ = 2:1) was similar but the isopropylidene group remained
intact. The reaction was then repeated with n-butanol and isopropanol as the acceptors, the latter to
see if there was any difference in selectivity when using a secondary alcohol other than one on a
monosaccharide acceptor. There has been a previous report of the glycosylation of an IdoA donor
with isopropanol resulting in a mixture of anomers.[9e] The reactions were also repeated using the
donor 24 wherein the C-2 participating group was replaced with a more sterically demanding
pivalate group, which has been reported[8a] to improve glycosylation outcomes with IdoA donors
compared with their acetate congeners. The results are summarized in Table 1. In all cases the
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glycoside was obtained in good yield (77-85%) but always as a mixture of anomers, although with
improved selectivity towards the desired  anomer. The best selectivity (/ = 5.6:1) was obtained
when using the less reactive secondary alcohol isopropanol as the acceptor combined with donor 24
containing the C-2 pivalate group. The NIS-TfOH promoter system was also applied to the
glycosylation of donor 10 with MeOH (Table 1, entry 4), but no advantage in selectivity was
observed.
Table 1: Summary of glycosylation outcomes with different thioglycoside donors.
Product
(% yield)
6 (80)
α/β
ratiob
1:1
Entry Donor Acceptor
Conditionsa
MeOH
MeOH
MeOH
MeOH
1
2
3
4
5
6
7
NIS-TMSOTf, 0 C, 3 h
NIS-TMSOTf, r.t., 2 h
NIS-TMSOTf, 35 C, 0.8 h
NIS-TfOH, -78 C to r.t., 24 h
Ph2SO/Tf2O
10
10
10
10
15
17
17
17
6 (79)
3.3:1
30:1
1.7:1
1:0
6 (82)
6 (n.d.)
16 (10)
18 (90)
18 (88)
MeOH
MeOH
MeOH
NIS-TMSOTf, r.t., 2 h
NIS-TMSOTf, 0 C, 6 h
NIS-TMSOTf, 35 C, 0.5 h
NIS-TMSOTf, DCE, 65 C, 0.5 h
NIS-TMSOTf, r.t., 1 h
1:1
1.3:1
MeOH
MeOH
MeOH
8
18 (78)
18 (72)
20 (80)
21 (51)
23 (75)
25 (68)
1.2:1
1.2:1
1.7:1
2:1
9
17
19
19
19
19
10
11
12
13
n-BuOH NIS-TMSOTf, r.t., 2 h
NIS-TMSOTf, r.t., 0.5 h
NIS-TfOH, -78 to 0 C, 3 h
NIS-TfOH, -78 to 0 C, 7 h
NIS-TfOH, -78 to 0 C, 7 h
1:0
22
MeOH
2:1
n-BuOH
i-PrOH
3.2:1
2.8:1
14
15
26 (82)
27 (77)
19
19
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n-BuOH
i-PrOH
3.8:1
5.6:1
16
17
NIS-TfOH, -78 to 0 C, 6 h
28 (85)
29 (78)
24
24
NIS-TfOH, -78 to 0 C, 6 h
b
1
aAll reactions carried out in DCM unless otherwise indicated. Anomeric ratio determined by H
NMR spectroscopy.
Although various L-idoA donors are known to give high stereoselectivity in reactions with
complex glycosyl acceptors, the formation of anomeric mixtures containing a high proportion of -
glycoside is not unprecedented in glycosylations with simple acceptors such as methanol or
isopropanol.[9] The results of our investigations described above provide numerous new examples of
this phenomenon, suggesting that glycosylations of L-idose and L-idoA donors bearing a
“participating group” do not always proceed via nucleophilic attack on the acyloxonium
intermediate. In order to gain insight into the relevance of the acyloxonium intermediate in these
glycosylations, we performed a density functional theory study. Calculations with the M06-2X
functional[30] were performed on the model system shown in Scheme 6 (details of the computational
methods are given in the supporting information). Here, the pyranose ring has the same substitution
pattern at C-2 and C-6 as in our thioglycosides 9 and 10, while the C-3 and C-4 substituents have
been replaced by H atoms for simplicity. Methanol is used as the glycosyl acceptor.
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Scheme 6. Energetics of several pathways for glycosylation of the model thioglycoside 30,
computed with M06-2X/6-311+G(d,p)//M06-2X/6-31G(d) in SMD implicit dichloromethane. G in
kcal/mol. Note that the structures drawn only depict the general stereochemical features and not the
exact conformations of the pyranose ring in each structure.
The computations indicate that the oxocarbenium ion 31 would rapidly cyclize to form
acyloxonium ion 32. Oxocarbenium ion 31 is predicted to adopt a 2,5B boat conformation, while
acyloxonium ion 32 is predicted to prefer a twisted O,3B boat (Figure 1). The barrier to cyclization
of 31 is almost negligible (TS1, G‡ ≈ 1 kcal/mol) and the cyclic acyloxonium ion 32 is 9.5
kcal/mol more stable than 31. Hence, in a rapidly equilibrating mixture of these two cationic
intermediates, the acyloxonium ion 32 would be the dominant, almost exclusive, component.
Figure 1. Structures of intermediates and transition states in the model glycosylation reaction of 30,
calculated with M06-2X/6-31G(d) in SMD implicit dichloromethane. Distances in Å.
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The reaction of acyloxonium ion 32 with methanol may proceed via the SN2 transition state
TS2 with a barrier of 12.8 kcal/mol (relative to 32). In TS2, the pyranose ring of 32 is changing
from the O,3B boat into a 1C4 chair. This process is stereospecific, leading to the 1,2-trans glycoside
-33. Intermediate 32 cannot directly react with methanol to give the anomeric glycoside -33. A
possible route to -33 would involve the conversion of 32 back to 31 followed by attack of
methanol on the lower face of the oxocarbenium carbon (TS4). Our computations indicate that once
32 has opened to 31, attack on either the top or bottom face by methanol does not pass through a
well-defined transition state. However, the approach of methanol to the bottom face of 31 has an
energy barrier of approximately 5.9 kcal/mol, some 3–4 kcal/mol higher than that for top-face
attack (2.1 kcal/mol). The transition states for the additions of methanol to the top and bottom faces
of 31 retain the 2,5B boat conformation of 31 (see Figure 1).
On the basis of the calculated barriers for TS2–TS4, the most favorable mechanism for the
glycosylation of the model thioglycoside involves addition to the oxocarbenium ion 31 (TS3).
Attack on the acyloxonium ion 32 (TS2) is about 1 kcal/mol higher in energy. The calculations
correctly predict that the 1,2-trans glycoside would be the favored product, but they overestimate
the level of selectivity. In our experiments with thioglycosides 10, 17, and 19 (Table 1), anomeric
mixtures with / ratios in the range 1:1–3:1 were obtained under most conditions, whereas the
estimated barrier for TS4 would predict much higher ratios. It is possible that the exact / ratio of
glycoside formed in any given reaction is influenced by factors not included in our model, such as
ion-pairing related phenomena and cage effects; these would vary with the reaction conditions and
are more difficult to quantify by computational means. Previous theoretical work on glucose-related
systems showed that solvent has an influence on the conformation of the ring, which in turn
controls the stereoselectivity of the reaction.[31] The effect of coordination of the counterion to the
oxocarbenium ion has also been investigated.[32] Another factor to consider is the effect of electron-
withdrawing substituents at C3 and C4, omitted in our model for simplicity, which could affect the
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stability of the cationic intermediates. What is clear, from both our experiments and our
calculations, is that contrary to the commonly invoked mechanistic argument, the glycosylations of
L-idose and L-idoA donors do not exclusively entail stereospecific attack by the acceptor on an
acyloxonium intermediate. Non-stereospecific addition to the oxocarbenium ion is predicted to be a
competitive, even dominant, pathway. We are currently studying the mechanisms of these
glycosylation reactions in further detail, including the role of the configuration at C5, and will
report our findings in due course.
Experimental section
General methods
General experimental details have been given previously.[33] DCM and BF3.OEt2 were distilled
from CaH2 and freshly used for glycosylation reactions. Methanol for glycosylation reactions was
distilled from magnesium turnings and stored over 3Å molecular sieves. n-Butanol and isopropanol
were dried over molecular sieves.
1,2,4,6-O-Tetra-O-acetyl-3-O-benzyl-L-idopyranose (2)
To a stirred solution of 1,6-anhydrosugar 1 (2.0 g, 8.0 mmol) in acetic anhydride (30 mL) under
nitrogen at 0 °C was added TFA (1 mL). The mixture was then stirred at r.t. for 24 h, quenched with
MeOH (10 mL) and concentrated under reduced pressure. Flash chromatography (hexane/EtOAc
1:1) of the crude material afforded tetraacetate 2 (3.4 g, 98%, 1.6:1 α/β) as a colourless oil. The 1H
1
NMR spectral data for the -anomer were in agreement with the literature.[11] 2α: H NMR (500
MHz, CDCl3): δ 6.05 (br s, 1H, H-1), 4.94-4.92 (m, 1H, H-2), 4.91-4.90 (m, 1H, H-4), 4.71, 4.69
(ABq, 2H, J = 11.8 Hz, CH2Ph), 4.51 (ddd, 1H, J5,6b = 6.4 Hz, J4,5 = 1.8 Hz, H-5), 4.24-4.17 (m,
2H, H-6a, H-6b), 3.76 (ddd, J2,3 = 2.9 Hz, J3,4 = 1.2 Hz, H-3); 13C NMR (125 MHz, CDCl3): δ 91.4
(C-1), 71.8 (C-3), 66.7 (C-4), 66.1 (C-2), 65.8 (C-5), 62.3 (C-6). The 1H and 13C NMR spectral data
for the -anomer were in agreement with the literature.[11] 2β: 1H NMR (500 MHz, CDCl3): δ 6.07
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(d, 1H, J1,2 = 1.8 Hz, H-1), 5.03-5.02 (m, 1H, H-2), 4.86-4.83 (m, 1H, H-4), 4.72, 4.67 (ABq, 2H, J
= 11.7 Hz, CH2Ph), 4.37 (ddd, 1H, J5,6a = 7.4 Hz, J5,6b = 5.8, J4,5 = 2.1 Hz, H-5), 4.18-4.12 (m, 2H,
H-6a, H-6b), 3.87 (t, 1H, J2,3 = J3,4 = 3.2 Hz, H-3); 13C NMR (125 MHz, CDCl3): δ 90.3 (C-1), 73.2
(C-3), 71.8 (C-5), 66.9 (C-2), 66.4 (C-4), 62.4 (C-6); ESMS: m/z 461.2 [M+Na]+.
2,4,6-Tri-O-acetyl-3-O-benzyl-L-idopyranose (4)
Compound 2 (0.3 g, 0.7 mmol) was dissolved in anhydrous DCM and activated 4 Å molecular
sieves were added and the mixture kept under nitrogen for 15 min. A solution of 30 % HBr in
acetic acid (0.5 mL) was then added, and the mixture was stirred at r.t. for 2 h. The reaction was
then quenched with cold sat. NaHCO3 (5 mL) and extracted with DCM (3 × 5 mL). The organic
layer was then washed with water, dried (MgSO4) and concentrated under reduced pressure. Flash
chromatography (hexane/EtOAc 1:1) of the crude mixture afforded hemiacetal 4 (0.2 g, 74%, 1.7:1
1
α/β) as colourless oil. 4: H NMR (500 MHz, CDCl3): δ 5.18 (d, 1H, J1,2 = 1.8 Hz, H-1), 4.90-
4.95 (m, 1H, H-4), 4.81-4.83 (m, 1H, H-2), 4.71-4.76 (m, 2H, CH2Ph), 4.54 (dd, 1H, J5,6 = 6.4, J4,5
= 1.7 Hz, H-5), 4.29-4.16 (m, 2H, H-6a, H-6b), 3.89-3.91 (m, 1H, H-3); 13C NMR (100 MHz,
CDCl3): 91.7 (C-1), 68.6 (C-4), 66.3 (C-2), 73.8 (CH2Ph), 62.8 (C-5), 72.1 (C-3), 62.7 (C-6); 4: δ
5.16 (br s, 1H, H-1), 4.90-4.92 (m, 1H, H-4), 4.71-4.76 (m, 2H, CH2Ph), 4.31 (d, J1,2 = 1.4 Hz, H-
2), 4.29-4.16 (m, 3H, H-5, H-6a, H-6b), 3.93 (dd, 1H, J2,3 = J3,4 = 3.0 Hz, H-3), 3.40 (d, 1H, J1,OH
=
9.3 Hz, OH); 13C NMR (100 MHz, CDCl3): 92.8 (C-1), 66.0 (C-4), 73.2 (CH2Ph), 73.1 (C-3), 72.0
(C-5), 62.7 (C-6); ESMS: m/z 419.2 [M+Na]+.
2,4,6-Tri-O-acetyl-3-O-benzyl-L-idopyranosyl chloride (5)
To a stirred solution of the acetate 2 (1.8 g, 4.1 mmol) in anhydrous DCM (50 mL), thionyl chloride
(0.6 mL, 8.4 mmol) and stannic chloride (0.5 mL, 9.6 mmol) were added. The reaction mixture was
then stirred at r.t. for 90 min, neutralized with cold sat. NaHCO3 and extracted with DCM (2 × 10
mL). The combined organic layer was then dried (MgSO4) and concentrated under reduced pressure
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to obtain the crude glycosyl chloride 5 (1.5 g, 88%, 10:1 α/β) as colourless oil, used directly in the
1
next step without further purification. 5α: H NMR (500 MHz; CDCl3): δ 7.39-7.26 (m, 5H, Ph),
6.01 (br s, 1H, H-1), 5.13-5.12 (m, 1H, H-2), 4.92-4.90 (m, 1H, H-4), 4.81, 4.65 (ABq, 2H, J =
11.8 Hz, CH2Ph), 4.72-4.68 (m, 1H, H-5), 4.19 (d, J5,6 = 6.5 Hz, 2H, H-6), 3.76-3.74 (m, 1H, H-3),
13
2.08 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.05 (s, 3H, CH3); C NMR (125 MHz; CDCl3): δ 170.5,
169.9, 169.2 (3 × CO2CH3), 137.0, 128.6, 128.0, 127.6 (Ph), 88.5 (C-1), 72.2 (CH2Ph), 71.7 (C-3),
68.6 (C-2), 66.5 (C-4), 66.0 (C-5), 62.1 (C-6), 20.8 (×2), 20.7 ( 3 × CH3).
Glycosylation with glycosyl chloride 5
To the glycosyl chloride 5 (0.3 g, 0.7 mmol) in anhydrous toluene (10 mL) containing 3Å molecular
sieves, anhydrous methanol (0.7 mL) was added and the mixture heated to 70 °C. Ag2CO3 (260 mg,
0.94 mmol) was then added to the reaction mixture in 3 portions over 3 h and the reaction was
maintained at 70 °C for 24 h. The reaction mixture was then filtered and concentrated under
reduced pressure. The crude material was purified by flash chromatography (hexane/EtOAc 2:1) to
give the orthoester 7 (0.1 g, 34%) as colourless oil, Rf = 0.7. The 1H NMR spectrum was in accord
with the literature.[8c] 1H NMR (500 MHz; CDCl3): δ 7.38-7.37 (m, 5H, Ph), 5.52 (d, 1H, J1,2 = 2.7
Hz, H-1), 4.80-4.77 (m, 1H, H-4), 4.74, 4.64 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.15-4.10 (m, 3H, H-
5, H-6a, H-6b), 4.07-4.03 (m, 2H, H-3, H-2), 3.22 (s, 3H, OCH3), 2.05 (s, 3H, CH3), 2.04 (s, 3H,
CH3), 1.66 (s, 3H, CH3); 13C NMR (125 MHz; CDCl3): δ 170.6, 170.4 ( 2 × CO2CH3), 137.0, 128.6,
128.2, 127.9, 127.8, 123.8 [Ph, C(CH3)(OCH3)], 96.4 (C-1), 76.3 (C-3), 72.8 (CH2Ph), 71.6 (C-2),
67.8 (C-5), 65.8 (C-4), 62.9 (C-6), 49.1 (OCH3), 25.0, 20.8, 20.7 (3 × CH3); ESMS: m/z 433.0
[M+Na]+. Further elution gave methyl 2,4,6-tri-O-acetyl-3-O-benzyl-α-L-idopyranoside 6α (50 mg,
17%) as a colourless oil, Rf = 0.5. 1H NMR (500 MHz; CDCl3): δ 7.39-7.25 (m, 5H, Ph), 4.89-4.87
(m, 1H, H-2), 4.85-4.83 (m, 1H, H-4), 4.74, 4.65 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.71-4.69 (m 1H,
H-1), 4.43 (ddd, 1H, J4,5 = 1.5 Hz, J5,6b = 5.2 Hz, J5,6a = 7.2 Hz, H-5), 4.24-4.18 (m, 1H, H-6a), 4.14
13
(dd, 1H, B part of ABX, J6a,6b = 11.4 Hz, H-6b), 3.64 (dd, 1H, J = 1.0 Hz, J = 2.7 Hz, H-3); C
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NMR (125 MHz; CDCl3): δ 170.5, 170.0, 169.5 (3 × CO2CH3), 137.4, 128.4, 127.9 (Ph), 99.2 (C-
1), 72.3 (C-3), 72.1 (CH2Ph), 67.3 (C-2), 67.1 (C-4), 63.5 (C-5), 60.4 (C-6), 55.5 (OCH3), 20.9,
20.8, 20.7 (3 × CH3); HRMS (ESI); m/z [M+Na]+ calcd for C20H26O9Na: 433.1469, found:
433.1469.
2,4,6-Tri-O-acetyl-3-O-benzyl-α-L-idopyranosyl trichloroacetimidate (8)
To a mixture of hemiacetal 4 (0.2 g, 0.5 mmol) in anhydrous DCM (20 mL), under a nitrogen
atmosphere at 0 °C was added DBU (0.1 mL, 0.8 mmol) and trichloroacetonitrile (0.1 mL, 1.0
mmol). This mixture was then stirred at this temperature for 1 h and quenched with water (20 mL).
The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude material
obtained was purified by flash chromatography (hexane/EtOAc 2:1) to give the imidate 8 (0.13 g,
1
48%, 2:1 α/β) as colourless oil. 8α: H NMR (500 MHz; CDCl3): 8.66 (s, 1H, NH), 7.30-7.24 (m,
5H, Ph), 6.26 (s, 1H, H-1), 5.13-5.11 (m, 1H, H-2), 4.94-4.91 (m, 1H, H-4), 4.77, 4.67 (ABq, 2H, J
= 11.8 Hz, CH2Ph), 4.68-4.63 (m, 1H, H-5), 4.20 (dd, 1H, A part of ABX, J5,6a = 5.5 Hz, J6a,6b
=
11.7 Hz, H-6a), 4.15 (dd, 1H, B part of ABX, J5,6b = 7.3 Hz, H-6b), 3.81-3.78 (m, 1H, H-3), 2.09
(s, 6H, CH3), 1.99 (s, 3H, CH3); 13C NMR (125 MHz; CDCl3): 170.5, 170.0, 169.3 (3 × C=O),
160.4 (C=NH), 137.2, 128.3, 127.8, 127.6, 94.7 (C-1), 72.3 (CH2Ph), 71.5 (C-3), 66.5 (C-2), 66.1
(C-4), 65.4 (C-5), 62.4 (C-6), 20.8, 20.7, 20.6 (3 × CH3).
Ethyl 2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-L-idopyranoside (9)
To a mixture of peracetate 2 (0.2 g, 0.4 mmol) in anhydrous DCM (10 mL) at 0 °C was added
BF3.Et2O (0.18 mL, 6.4 mmol) and ethanthiol (40 μL, 0.5 mmol). The reaction mixture was then
stirred at this temperature for 2.5 h., washed with sat. NaHCO3, dried (MgSO4) and concentrated
under reduced pressure. The crude material obtained was purified by flash chromatography
(hexane/EtOAc 2:1) to give the thioglycoside 9 (86 mg, 49%, 2:1 α/β) as colourless oil. There are
1
some differences compared with the H NMR data reported in the literature;[9c] 13C NMR have not
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1
previously been reported. H NMR (500 MHz; CDCl3): δ 7.34-7.21 (m, 7H, Ph), 5.26 (br s, 1H, H-
1), 4.99 (d, 0.5H, J1,2 = 1.7 Hz, H-1), 4.97-4.96 (m, 1H, H-2), 4.96-4.94 (m, 0.5H, H-2), 4.83-
4.78 (m, 2.5H, H-4, H-4, H-5), 4.73, 4.61 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.22-4.11 (m, 3.5H,
H-5, H-6a, H-6b, H-6a, H-6b), 3.79 (dd, 0.5H, J2,3 = J3,4 = 2.7 Hz, H-3), 3.69-3.66 (m, 1H,
H-3), 2.76-2.54 (m, 3H, CH2CH3), 2.06, 2.05, 2.04, 2.03, 2.01, 2.00 (6 × s, 6 × 3H, COCH3), 1.28
(t, 4H, 4.7H, J = 7.6 Hz, CH2CH3); 13C NMR (125 MHz; CDCl3): 170.5, 170.4, 170.0, 169.9, 169.5
(6 × C=O), 137.1, 128.5, 128.3, 127.7, 127.6, 82.3 (C-1), 81.1 (C-1), 72.8 (C-5), 72.3 (CH2Ph,
C-3), 71.6 (C-3), 69.1 (C-2), 68.8 (C-2), 67.2 (C-5), 65.9 (C-4), 64.0 (C-4), 62.6 (C-6),
28.5, 25.8, 20.9, 20.7, 20.6 (6 × CH3), 15.0 (CH2CH3), 14.8 (CH2CH3); HRMS (ESI); m/z [M+Na]+
calcd for C21H28O8NaS: 463.1397, found: 463.1392.
Phenyl 2,4,6-tri-O-acetyl-3-O-benzyl-1-thio-L-idopyranoside (10)
Thiophenol (1.1 mL, 10.6 mmol) was added at 0 °C to a solution of 2 (4.2 g, 9.6 mmol) and freshly
distilled BF3.Et2O (3.6 mL, 28.8 mmol), in anhydrous DCM. After stirring for 5 h at 0 °C the
reaction mixture was quenched with sat. NaHCO3. The organic layer was then separated, dried
(MgSO4) and concentrated under reduced pressure. The crude material obtained was purified by
flash chromatography (hexane/EtOAc 1:1) to give thioglycoside 10 (3.7 g, 79%, 10:1 α/β) as a
colourless oil. The NMR spectral data were in accord with the literature.[9d] 101H NMR (500
MHz, CDCl3): δ 7.54-7.22 (m, 10H, Ph), 5.48 (br s, 1H, H-1), 5.16-5.14 (m, 1H, H-2), 4.99 (ddd,
1H, J4,5 = 1.5 Hz, J5,6b = 4.9 Hz, H-5), 4.88-4.86 (m, 1H, H-4), 4.82, 4.68 (ABq, 2H, J = 11.8 Hz,
CH2Ph), 4.25 (dd 1H, A part of ABX, J5,6a = 8.0 Hz, J6a,6b = 11.5 Hz, H-6a), 4.17 (dd, 1H, B part of
13
ABX, H-6b), 3.78-3.76 (m, 1H, H-3), 2.07, 2.05, 2.00 (3 × s, 3 × 3H, CH3); C NMR (125 MHz,
CDCl3): δ 170.6, 170.0, 169.5 (3 × C=O), 137.0, 135.8, 128.9, 128.5, 128.0, 127.7, 85.8 (C-1), 72.6
(CH2Ph), 71.4 9 (C-3), 68.7 (C-2), 67.1(C-4), 64.6 (C-5), 62.8 (C-6), 20.9, 20.8, 20.7 (3 × CH3);
HRMS (ESI); m/z [M+Na]+ calcd for C25H28O8NaS: 511.1397, found: 511.1392.
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Methyl 2,4,6-tri-O-acetyl-3-O-benzyl-L-idopyranoside (6)
To the glycosyl donor 10 (1.8 g, 3.7 mmol) and methanol (0.5 mL) in anhydrous DCM (180 mL) at
r.t., NIS (2.0 g, 8.8 mmol) followed by TMSOTf (0.7 mL of 1M TMSOTf in DCM, 0.7 mmol) were
added and stirred at this temperature for 2 h. The reaction mixture was then quenched with sat.
Na2S2O3 (50 mL) and the organic layer was washed with sat. NaHCO3, dried (MgSO4) and
concentrated under reduced pressure. The crude material obtained was dissolved in pyridine (10
mL) and acetic anhydride (2 mL) and stirred at r.t. for 18 h. The reaction mixture was then
concentrated under reduced pressure (×2 toluene). The crude material was then dissolved in DCM
and washed with sat. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude
material was purified by flash chromatography (hexane/EtOAc 3:1) to give the glycoside 6 (1.2 g,
79%, 3.3:1 α/β) as a colourless oil.
1,6-Anhydro-2-O-benzoyl-3-O-benzyl--L-idopyranose (11)
To a solution of 1[10] (4.5g, 17.8 mmol) in anhydrous DCM (20 mL) at 0 °C, were added anhydrous
pyridine (5 mL) and benzoyl chloride (2.8 mL) and the mixture was stirred at this temperature for 2
h and then quenched with water (5 mL). The organic layer was then washed with 1 M HCl (2 × 10
mL), sat. NaHCO3, dried (MgSO4), and concentrated under reduced pressure. The crude material
was then purified by flash chromatography (hexane/EtOAc 1:1) to give the anhydrosugar 11 (4.2 g,
66%) as white solid. m.p. 140-141 °C (hexane/EtOAc, lit.[14] 142-143 °C); [α]D +120.5 (c 0.7,
CHCl3; lit.[14] +127.5). The NMR spectral data were in accord with the literature.[14, 34] 1H NMR
(500 MHz, CDCl3): δ 8.07-8.03, 7.59-7.54, 7.46-7.41, 7.27-7.19 (m, 10H, Ph), 5.51 (d, 1H, J1,2
=
1.8 Hz, H-1), 5.05 (dd, 1H, J2,3 = 8.1 Hz, H-2), 4.77, 4.65 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.44 (dd,
1H, J4,5 = J5,6a = 4.5 Hz, H-5), 4.13 (d, 1H, J6a,6b = 7.7 Hz, H-6a), 3.97 (dd, 1H, J3,4 = 8.2 Hz, H-4),
3.85 (dd, 1H, H-3), 3.72 (dd, 1H, J5,6b = 5.1 Hz, H-6b); 13C NMR (100 MHz, CDCl3): 165.8 (C=O),
137.9, 133.4, 129.8, 129.4, 128.5, 128.4, 128.0, 127.8, 99.4 (C-1), 80.2 (C-3), 76.7 (C-2), 75.1 (C-
5), 74.6 (CH2Ph), 71.3 (C-4), 65.3 (C-6); ESMS: m/z 379.1 [M+Na]+.
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Phenyl 2-O-benzoyl-3-O-benzyl-1-thio--L-idopyranoside (12)
To a solution of 11 (0.3 g, 0.8 mmol) in anhydrous DCM (30 mL) were added
trimethyl(phenylthio)silane (0.6 mL, 1.8 mmol) and ZnI2 (0.7 g, 3.0 mmol). The mixture was stirred
at room temperature overnight and filtered through a pad of Celite. The filtrate was diluted with
DCM (50 mL), after which a solution of 1 M HCl in dioxane (5 mL) and water (10 mL) were
added. The mixture was stirred at r.t. for 10 min, the organic layer was washed with 2 M HCl, sat.
NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified
by flash chromatography (hexane/EtOAc 3:1) on silica gel to afford the thioglycoside 12 (0.3 g,
81%) as colourless oil. [α]D +5.9 (c 0.3, CHCl3; lit.[25] +8.8) There are some differences compared
with the reported 1H NMR data but the 13C NMR data was in accord with the literature.[25] 1H NMR
(500 MHz, CDCl3): δ 8.09-8.04, 7.59-7.51, 7.46-7.34, 7.33-7.22 (4 × m, 15H, Ph), 5.65 (br s, 1H,
H-1), 5.43-5.41 (m, 1H, H-2), 4.93, 4.63 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.76 (ddd, 1H, J4,5 = 1.7
Hz, J5,6a = 4.1 Hz, J5,6b = 7.3 Hz, H-5), 3.91 (dd, 1H, A part of ABX, J6a,6b = 11.7 Hz, H-6a), 3.73-
3.71 (m, 1H, H-4), 3.70 (dd, 1H, B part of ABX, H-6b), 3.66 (ddd, J = 1.1 Hz, J = 4.2 Hz, J = 3.1
Hz, H-3) ppm; 13C NMR (125 MHz, CDCl3): 165.6 (C=O), 137.7, 136.4 133.2, 131.5, 130.0, 128.8,
128.5, 128.2, 128.0, 127.9, 127.1, 86.0 (C-1), 73.9 (C-3), 72.2 (CH2Ph), 69.2 (C-2), 68.8 (C-4), 68.3
(C-5), 62.9 (C-6); ESMS: m/z 489.1 [M+Na]+.
1,6-Anhydro-2-O-benzoyl-3,4-di-O-benzyl--L-idopyranose (13)
To a mixture of the alcohol 11 (0.9 g, 2.5 mmol) and Ag2O (1.2 g, 5.2 mmol) in anhydrous DCM
containing 4Å molecular sieves at 0 °C under nitrogen was added benzyl bromide (0.4 mL, 3.1
mmol). The reaction temperature was then gradually warmed up to r.t., and the solution was kept
stirring for 2 days. The resulting mixture was filtered through Celite and the filtrate was
concentrated under reduced pressure. The crude residue was purified by flash chromatography
(hexane/EtOAc 3:1) to provide the dibenzyl ether 13 (0.57 g, 51% (80% based on starting material
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10.1002/ejoc.201800318
European Journal of Organic Chemistry
recovered)) as white solid, m.p. 83-85 °C (hexane/EtOAc); [α]D +38.9 (c 1.1, CHCl3). The NMR
spectral data were in accord with the literature.[24] 1H NMR (500 MHz, CDCl3): δ 8.03-8.00, 7.59-
7.53, 7.44-7.39, 7.38-7.14 (m, 15H, Ph), 5.49 (d, 1H, J1,2 = 1.8 Hz, H-1), 5.01 (dd, 1H, J2,3 = 8.4
Hz, H-2), 4.76, 4.75, 4.72, 4.65 (2 × ABq, 4H, J = 11.8 Hz, 2 × CH2Ph), 4.47 (dd, 1H, J4,5 = J5,6b
=
4.5 Hz, J5,6a = 0, H-5), 4.17 (d, 1H, J6a,6b = 7.6 Hz, H-6a), 3.96 (app t, 1H, J2,3 ~ J3,4 = 8.0 Hz, H-3),
13
3.86-3.82 (ddd, 1H, J4,6b = 1.1 Hz, H-4), 3.73-3.68 (m, 1H, H-6b); C NMR (125 MHz, CDCl3):
165.6 (C=O), 137.9, 137.8, 133.1, 129.7, 129.4, 128.4, 128.2, 128.1, 127.8, 127.7, 127.5, 127.4,
99.1 (C-1), 79.2 (C-4), 79.1 (C-3), 76.6 (C-2), 74.6 (PhCH2), 73.1 (PhCH2), 73.0 (C-5), 65.3 (C-6);
ESMS: m/z 469.0 [M+Na]+.
Phenyl 2-O-benzoyl-3,4-di-O-benzyl-1-thio--L-idopyranoside (14)
To a solution of 13 (0.6 g, 1.4 mmol) in anhydrous DCM (20 mL) were added
trimethyl(phenylthio)silane (1.0 mL, 5 mmol) and ZnI2 (0.9 g, 2.8 mmol). The mixture was stirred
at r.t. for 18 h and filtered through a pad of Celite. The filtrate was diluted with DCM (20 mL), after
which a solution of 1 M HCl in dioxane (5 mL) and water (10 mL) were added. The mixture was
stirred at r.t. for 10 min, the organic layer was washed with 2 M HCl, sat. NaHCO3, dried (MgSO4)
and concentrated under reduced pressure. The crude residue was purified by flash chromatography
(hexane/EtOAc 6:1) to give the thioglycoside 14 (0.6 g, 77%) as a colourless oil; [α]D −110 (c 0.5,
CHCl3; lit.[22] −98). The NMR spectral data were in accord with the literature.[22] 1H NMR (500
MHz, CDCl3): δ 8.00-7.95, 7.55-7.19, 7.14-7.09 (m, 20H, Ph), 5.64 (br s, 1H, H-1), 5.48-5.46 (m,
1H, H-2), 4.92, 4.63 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.71 (ddd, 1H, J4,5 = 2.0 Hz, H-5), 4.48, 4.30
(ABq, 2H, J = 11.8 Hz, CH2Ph), 4.00 (dd, 1H, A part of ABX, J5,6a = 6.6 Hz, J6a,6b = 11.7 Hz, H-
6a), 3.97 (dd, 1H, J2,3 = 3.1 Hz, J3,4 = 1.1 Hz, H-3), 3.78 (dd, 1H, B part of ABX, J5,6b = 4.4 Hz, H-
6b), 3.57-3.53 (m, 1H, H-4); 13C NMR (125 MHz, CDCl3): 165.6 (C=O), 137.3, 137.2, 135.6,
133.3, 131.7, 130.0, 129.5, 129.0, 128.5, 128.4, 128.3, , 128.0 (×2), 127.9, 127.4, 85.9 (C-1), 74.5
24
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(C-4), 72.4, 72.1 ( 2 × CH2Ph), 70.5 (C-3), 69.2 (C-2), 68.3 (C-5), 62.9 (C-6); HRMS (ESI); m/z
[M+Na]+ calcd for C33H32O6NaS: 579.1812, found: 579.1795.
Methyl (phenyl 2-O-benzoyl-3,4-di-O-benzyl-1-thio--L-idopyranosid) uronate (15)
To a biphasic mixture of alcohol 14 (0.32 g, 0.6 mmol) in DCM/H2O 3:1 (18 ml) at r.t., TEMPO
(16 mg, 0.1 mmol) and BAIB (0.16 g, 0.5 mmol) were added and stirred vigorously for 2 h. 2M
Na2S2O3 (10 mL) was then added to the reaction mixture and the organic layer was separated. The
aqueous layer was then extracted with DCM (5 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The crude syrup obtained was dissolved in
anhydrous DMF (5 mL) and MeI (0.1 mL, 1.5 mmol) and KHCO3 (0.2 g, 1.6 mmol) was added and
stirred at r.t. for 4 h. The mixture was then concentrated under reduced pressure and the crude
material was dissolved in DCM, filtered and concentrated under reduced pressure. The crude
residue was then purified by flash chromatography (hexane/EtOAc 4:1) to give the methyl ester 15
1
(0.24 g, 68%) as colourless oil, [α]D −76.6 (c 1.5, CHCl3); H NMR (500 MHz, CDCl3): δ 7.96-7.91,
7.54-7.08 (m, 20H, Ph), 5.76 (br s, 1H, H-1), 5.44-5.41 (m, 1H, H-2), 5.31 (d, 1H, J4,5 = 2.4 Hz, H-
5), 4.88, 4.64 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.46, 4.40 (ABq, 2H, J = 11.8 Hz, CH2Ph), 3.97-3.93
13
(m, 2H, H-3, H-4), 3.76 (s, 3H, CO2CH3); C NMR (125 MHz, CDCl3): 169.7, 165.6 (2 × C=O),
137.3, 137.1, 135.6, 133.2, 131.0, 130.0, 129.3, 128.8, 128.5, 128.2, 128.0, 127.9, 127.7, 127.3,
85.9 (C-1), 74.5 (C-3), 72.5 (2 × CH2Ph), 71.1 (C-4), 68.9 (C-2), 68.7 (C-5), 52.5 (OCH3); HRMS
(ESI); m/z [M+Na]+ calcd for C33H32O6NaS: 607.1761, found: 607.1768.
Methyl (methyl 2-O-benzoyl-3,4-di-O-benzyl--L-idopyranosid) uronate (16)
To a solution of thioglycoside 15 (100 mg, 0.2 mmol), Ph2SO (340 mg, 0.5 mmol) and TTBP (130
mg, 0.5 mmol) in anhydrous DCM (5 mL) at −60 °C under an argon atmosphere, was added
trifluromethanesulfonic anhydride (40 μL, 0.2 mmol). The reaction mixture was then stirred at this
temperature for 5 min, after which a solution of methanol (0.1 mL) in anhydrous DCM (2 mL) was
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10.1002/ejoc.201800318
European Journal of Organic Chemistry
added. The mixture was stirred at −60 °C for 30 min, after which it was quenched with sat.
NaHCO3 (5 mL) and slowly warmed up to r.t. The organic layer was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc 3:1) to give the glycoside 16 (10 mg, 10%) as a colourless oil: 1H
NMR (500 MHz, CDCl3): δ 7.99-7.95, 7.52-7.46, 7.35-7.07 (m, 15H, Ph), 5.17-5.14 (m, 1H, H-5),
5.04-5.02 (m, 1H, H-1), 4.82 (d, 1H, J2,3 = 1.9 Hz, H-2), 4.82, 4.63 (ABq, 2H, J = 11.8 Hz, CH2Ph),
4.42, 4.33 (ABq, 2H, J = 11.8 Hz, CH2Ph), 3.89-3.86 (m, 2H, H-3, H-4), 3.74 (s, 3H, CO2CH3),
3.47 (s, 3H, OCH3); 13C NMR (125 MHz, CDCl3):  170.0 (C=O), 165.6 (C=O), 137.5, 137.4,
133.2, 130.0, 128.6, 128.4, 128.2 (×2), , 127.9, 127.8, 127.7, 99.7 (C-1), 74.3 (C-3), 72.4 (CH2Ph),
72.2 (CH2Ph), 71.9 (C-4), 68.1 (C-2), 67.8 (C-5); HRMS (ESI); m/z [M+Na]+ calcd for
C34H32O7Na: 607.1761, found: 607.1768.
Phenyl 2-O-benzoyl-3,4-di-O-benzyl-6-O-tert-butyldimethylsilyl-1-thio-α-L-idopyranoside (17)
To a solution of compound 14 (0.6 g, 1.1 mmol) in anhydrous pyridine (10 mL), TBDMSCl (0.3 g,
2.0 mmol) and a catalytic amount of DMAP (10 mg) were added and the mixture stirred at r.t. for
24 h. The reaction mixture was then concentrated under reduced pressure (×2 toluene). The crude
mixture was then left on the high vacuum for 24 h to give the silyl ether 17 (0.7 g, 97%) as a
1
colourless oil. The crude material obtained was used without further purification. H NMR (500
MHz, CDCl3):  7.96-7.91, 7.55-7.13 (m, 20H, Ph), 5.60 (d, 1H, J1,2 = 2.0 Hz, H-1), 5.42 (ddd, J2,4
= 0.9 Hz, J2,3 = 3.4 Hz, H-2), 4.89, 4.63 (ABq, 2H, J = 12.0 Hz, CH2Ph), 4.63-4.59 (m, 1H, H-5),
4.48, 4.41 (ABq, 2H, J = 11.5 Hz, CH2Ph), 3.98 (dd, 1H, J3,4 = 3.6 Hz, H-3), 3.91 (dd, 1H, A part of
ABX, J5,6a = 6.3 Hz, J6a,6b = 10.0 Hz, H-6a), 3.87 (dd, 1H, B part of ABX, J5,6b = 6.1 Hz, H-6b),
3.63 (dd, 1H, J4,5 = 3.2 Hz, H4), 0.88 (s, 9H, C(CH3)3), 0.06 (s, 3H, CH3), 0.05 (s, 3H, CH3).
General procedure for NIS-TMSOTf promoted glycosylation: To the glycosyl donor (1 eq.) and
acceptor (5 eq.) in anhydrous DCM (10 ml) at the required temperature, NIS (2 eq.) followed by
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cat. TMSOTf (0.1 eq.) were added and the mixture was stirred until the reaction was complete. The
reaction mixture was then quenched with sat. Na2S2O3 (10 mL) and the organic layer was washed
with sat. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude material
was purified by flash chromatography (hexane/EtoAc 3:1) to obtain the glycoside.
Methyl 2-O-benzoyl-3,4-di-O-benzyl-L-idopyranoside (18)
Glycosylation with methanol of glycosyl donor 17 via the general procedure for NIS-TMSOTf gave
18 (r.t.: 90%, 1:1 α/β; 0 °C: 88%, 1.3:1 α/β; 35 °C: 78%, 1.2:1 α/β; 65 °C: 72%, 1.2:1 α/β) as a
colourless oil. 1H NMR (500 MHz, CDCl3): m, 4H), 7.56-7.51 (m, 2H), 7.39-7.27
(m, 14H), 7.27-7.21 (m, 7H), 7.19-7.15 (m, 2H), 7.15-7.11 (m, 2H); 18  5.23-5.21 (m, 1H, H-2),
4.89-4.88 (br s, 1H, H-1), 4.86, 4.65 (ABq, 2H, J = 11.8 Hz, CH2Ph), 4.49, 4.27 (ABq, 2H, J = 11.8
Hz, CH2Ph), 4.26-4.22 (m, 1H, H-5), 4.03-3.98 (m, 1H, H-6a), 3.91 (dd, 1H, J2,3 = J3,4 = 3.1 Hz, H-
3), 3.74 (dd 1H, B part of ABX, J5,6b = 4.4 Hz, J6a,6b = 11.8 Hz, H-6b), 3.53-3.51 (m, 1H, H-4), 3.46
(s, 3H, OCH3); 18  5.21 (dd, 1H, J1,2 = 2.5 Hz, J2,3 = 5.7 Hz, H-2), 4.92 (d, 1H, H-1), 4.81, 4.72
(ABq, 2H, J = 11.8 Hz, CH2Ph), 4.58, 4.39 (ABq, 2H, J 11.8 Hz, CH2Ph), 4.16 (dd, 1H, J3,4 = 5.5
Hz, H-3), 4.09-4.05 (m, 1H, H-5), 4.03-4.05 (m, 1H, H-6a), 3.86 (dd, B part of ABX, 1H, J5,6b = 4.5
13
Hz, J6a,6b = 11.8 Hz, H-6b), 3.59 (dd, 1H, J4,5 = 3.7 Hz, H-4), 3.52 (s, 3H, (OCH3); C NMR (125
MHz, CDCl3):  166.2, 165.6, 137.6, 137.4, 137.3, 133.2, 130.0, 129.9, 128.5 (x2), 128.4 (x2),
128.3, 128.0 (×2), 127.9 (×2); 18  99.5 (C-1), 74.4 (C-4), 72.1 (2 × CH2Ph), 71.7 (C-3), 68.4 (C-
4), 67.2 (C-5), 62.9 (C-6), 55.6 (OCH3); 18 98.9 (C-1), 75.6 (C-4), 75.0 (C-5), 73.7 (C-3), 72.9,
72.2 (2 × CH2Ph), 69.8 (C-2), 62.8 (C-6), 57.2 (OCH3); HRMS (ESI); m/z [M+Na]+ calcd for
C28H30O7Na: 501.1884, found: 501.1899.
4’-Methyphenyl
2-O-benzoyl-3-O-benzyl-4,6-O-isopropylidene-1-thio--L-idopyranoside
(19)[28]
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White solid; m.p. 119.6 – 120.7 C; []D –88.7 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.1
(dd, 2H, J = 1.3, 8.2 Hz, H-Ar), 7.54 (tt, 1H, J = 1.3, 7.4 Hz, H-Ar), 7.46 – 7.30 (m, 9H, H-Ar),
7.08 (d, 2H, J = 8.2 Hz, H-Ar), 5.70 (s, 1H, H-1), 5.49 (dd, 1H, J1,2 = 1.1 Hz, J2,3 =2.4 Hz, H-2),
4.97, 4.66 (ABq, 2H, JA,B = 11.7 Hz, CH2Ph), 4.37 (ddd, 1H, J4,5 = J5,6b = 1.7 Hz, J5,6a = 2.3 Hz, H-
5), 4.18 (dd, 1H, J5,6a = 2.3 Hz, J6a,6b = 12.9 Hz, H-6a), 4.02 (dd, 1H, J4,5 = 2.3 Hz, J3,4 = 0.8 Hz, H-
4), 3.97 (dd, 1H, J5,6b = 1.7 Hz, J6a,6b = 12.9 Hz, H-6b), 3.76 (dt, 1H, J2,3 = 2.4 Hz, J3,4 = 0.8 Hz, H-
13
3), 2.31 (s, 3H, SPhCH3), 1.46 (s, 3H, CH3), 1.45 (s, 3H, CH3); C NMR (100 MHz, CDCl3): δ
165.5 (C=O), 137.4, 137.0, 133.2, 132.7, 130.8, 130.0, 129.7, 129.6, 128.6, 128.4, 128.2, 127.9,
127.8 (C-Ar), 98.5 (C(CH3)2), 86.2 (C-1), 73.7 (C-3), 72.4 (CH2Ph), 68.1 (C-2), 66.7 (C-4), 63.1
(C-6), 60.4 (C-5), 29.3 (SPhCH3), 21.0 (CH3), 18.4 (CH3); LRMS: m/z = 538.1 [M+NH4]+, 543.1
[M+Na]+, 559.1 [M+K]+.
Methyl 2-O-benzoyl-3-O-benzyl-L-idopyranoside (20)
Glycosylation with methanol of glycosyl donor 19 via the general procedure for NIS-TMSOTf gave
1
20 (80%, 1.7:1 α/β) as a colourless oil. H NMR (500 MHz, CDCl3):  8.02-7.97, 7.60-7.54, 7.46-
7.41, 7.35-7.25 (m, Ph), 5.31 (ddd, 0.6H, J = 1.0 Hz, J1,2 = 2.1 Hz, J2,3 = 4.3 Hz, H-2β), 5.22-5.26
(m, 1H, H-2α), 4.89 (d, 0.6H, H-1β), 4.86 (br s, 1H, H-2α), 4.82, 4.63 (ABq, 2H, J = 12.1 Hz, α-
CH2Ph), 4.75, 4.66 (ABq, 1.2H, J = 11.9 Hz, β-CH2Ph), 4.27 (ddd, 1H, J = 1.0 Hz, J4 ,5 = 4.2 Hz,

J = 5.7 Hz, H-5α), 4.07 (ddd, 0.6H, J = 2.2 Hz, J = 6.7 Hz, H-5β), 4.62-3.82 (m, 3.8H, H-6α, H-6β,
13
H-3β), 3.79-3.74 (m, 2.6H, H-3α, H-4α, H-4β), 3.53 (s, 1.8H, OCH3β), 3.46 (s, 3H, OCH3α); C
NMR (125 MHz, CDCl3):  165.5 (2 × C=O), 137.6, 137.3, 133.6, 133.4, 129.8, 129.7, 129.2,
128.6, 128.5, 128.5, 128.1, 127.9,127.8, 127.7, 99.8 (C-1α), 99.3 (C-1β), 76.3, 75.1, 74.9, 72.9,
69.3, 68.2, 68.1, 68.0, 66.8, 57.2 (OCH3), 55.7 (OCH3); HRMS (ESI); m/z [M+Na]+ calcd for
C21H24O7Na: 411.1414, found: 411.1423.
n-Butyl 2-O-benzoyl-3-O-benzyl-L-idopyranoside (21)
28
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