Protecting Group Dependence of Stereochemical Outcome of Glycosylation of 2-O-(Thiophen-2-yl)methyl Ether Protected Glycosyl Donors

Article abstract of DOI:10.1002/ejoc.201600071

A series of glycosyl donors possessing a (thiophen-2-yl)methyl ether protecting group at position 2 were synthesised and the effect of the protecting group pattern of other hydroxyls on the stereochemical outcome of glycosylation was investigated. Studies revealed optimal α-selectivity for glycosylation using a fully armed tri-benzylated donor, whilst other protecting group patterns were significantly less effective. Low-temperature NMR studies of both fully armed and fully disarmed donors revealed the intermediacy of cyclised sulfonium ion intermediates. Reaction conditions were developed which allowed removal of the (thiophen-2-yl)methyl ether protecting group either selectively, or together with benzyl ethers. Glycosyl donors with a 2-O-thiophenylmethyl ether protecting group undergo six-membered ring NGP, as demonstrated by low-T NMR studies, but the stereochemical outcome of glycosylation is highly dependent on other protecting groups.

Full text of DOI:10.1002/ejoc.201600071

DOI: 10.1002/ejoc.201600071
Full Paper
Control of Glycosylation
Protecting Group Dependence of Stereochemical Outcome of
Glycosylation of 2-O-(Thiophen-2-yl)methyl Ether Protected
Glycosyl Donors
Andrew J. A. Watson,[a] Stewart R. Alexander,[a] Daniel J. Cox,[c] and Antony J. Fairbanks*[a,b]
Abstract: A series of glycosyl donors possessing a (thiophen- tecting group patterns were significantly less effective. Low-
2-yl)methyl ether protecting group at position 2 were synthe- temperature NMR studies of both fully armed and fully dis-
sised and the effect of the protecting group pattern of other armed donors revealed the intermediacy of cyclised sulfonium
hydroxyls on the stereochemical outcome of glycosylation was ion intermediates. Reaction conditions were developed which
investigated. Studies revealed optimal α-selectivity for glycosyl- allowed removal of the (thiophen-2-yl)methyl ether protecting
ation using a fully armed tri-benzylated donor, whilst other pro- group either selectively, or together with benzyl ethers.
Introduction
straightforward, albeit less stereoselective, intermolecular glyc-
osylation processes.
The vital importance of oligosaccharides in a wide range of key
biological processes,[1] together with their inherent structural
complexity and remarkable structural diversity, has stimulated
the interest of generations of synthetic chemists.[2] The corner-
stone of oligosaccharide assembly is the linking of pre-formed
donor and acceptor building blocks by glycosylation. In this
regard the issue of control of anomeric stereochemistry during
glycosylation remains as a challenge for which, as yet, no uni-
versal solution has been found. Although 1,2-trans glycosidic
linkages can usually be synthesised with high levels of stereo-
control by five-membered ring neighbouring group participa-
tion (NGP) of 2-O-acyl-protected glycosyl donors,[3] the stereo-
controlled synthesis of 1,2-cis glycosidic linkages is considerably
more difficult.[4]
Multiple approaches have been investigated in the ongoing
search for a widely applicable stereoselective 1,2-cis glycosyl-
ation process.[5] These include intramolecular aglycon delivery
(IAD),[6] which, by the nature of the intramolecular glycosylation
process has the potential to provide 1,2-cis linkages with com-
plete control of anomeric stereochemistry. However the extra
inherent steps necessary for the temporary linking of donor and
acceptor have made these approaches less attractive than more
More recently the development of the use of new types of
NGP,[7] and in particular those involving six-membered ring in-
termediates, have shown significant promise that may lead to
a general solution applicable to the synthesis of all α-1,2-cis
glycosidic linkages (e.g. α-gluco, α-galacto etc). Boons and co-
workers[8] the lead proponents of this approach, first reported
highly selective glycosylations that centred upon the use of chi-
ral auxiliaries at the 2-position of glycosyl donors that operated
via 6-ring NGP to control the diastereoselectivity of glycosyl-
ation (Figure 1, a). Key to the high α-selectivity of these glycos-
ylations was the configuration of the stereogenic centre of the
auxiliary; the Ph group occupying an equatorial position in the
trans-decalin intermediate. Seeking to build upon these impor-
tant disclosures we[9] undertook studies that sought to combine
6-ring NGP with the participating effect of thiophene[10] with
the aim of discovering a simpler achiral protecting group for
position 2 that could give similar high levels of stereocontrol
(Figure 1, b). Subsequently Turnbull,[11] building on a previous
report[12] on the use of cyclic ꢀ-glycosyl donors, developed a
slightly different approach (Figure 1, c), in which preformed ꢀ-
configured cyclic oxathiane glycosyl donors, activated in a two-
step process involving oxidation and electrophilic substitution,
gave high levels of α-selectivity. Boons continued development
of this latter approach[13] and reported highly α-selective glyc-
osylations of oxathianes with a variety of glycosyl acceptors and
with differing protecting group patterns on the glycosyl donor.
[a] Department of Chemistry, University of Canterbury,
Private Bag 4800, Christchurch 8140, New Zealand
E-mail: antony.fairbanks@canterbury.ac.nz
Although the Boons and Turnbull approaches give high lev-
els of α-selectivity, the synthesis of the required donors, (bi-
cyclic or containing a chiral auxiliary), together with the double
activation procedure required for the oxathiane-derived donors
make them rather protracted. We therefore continued our in-
vestigations into the potential use of achiral substituted ethyl
ethers at the 2-position of glycosyl donors. Whilst initial investi-
www.chem.canterbury.ac.nz
[b] Biomolecular Interaction Centre, University of Canterbury,
Private Bag 4800, Christchurch 8140, New Zealand
[c] Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, UK,
Mansfield Road, Oxford, OX1 3TA, UK
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600071.
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Figure 1. α-Selective glycosylation processes involving 6-ring neighbouring group participation (NGP) via intermediate ꢀ-sulfonium ions. a) Glycosylation via
6-ring NGP of an OH-2 (S)-auxiliary; b) via 6-ring NGP of a 2-O-(thiophen-2-yl) methyl ether; c) via a pre-formed cyclic ꢀ-sulfonium ion derived from an
oxathiane; d) via 6-ring NGP of a 2-O-(trimethoxybenzenethiol) ethyl ether.
gations revealed that ethers containing iodine or selenium did chemical outcome of glycosylation reaction of donors possess-
not result in either increased levels of α-selectivity or effective ing the 2-O-(thiophen-2-yl)methyl ether protecting group
6-ring NGP, as evidenced by low-temperature NMR studies,[14] which we report herein, together with low-temperature NMR
recently we reported[15] the highly effective α-selective glyc- studies which reveal the extent to which these donors undergo
osylation of donors possessing a 2-O-(trimethoxybenzene- 6-ring NGP. We also report conditions developed for selective
thiol)ethyl ether protecting group (Figure 1, d).
protecting group removal.
Throughout all of these studies it has become apparent that
the stereochemical outcome of glycosylation is also dependent
on the protecting group pattern of other hydroxyls of the glyc-
osyl donor. Boons reported[8d] that donors with a 2-O-(S)-
(phenylthiomethyl)benzyl ether which possessed disarming
protecting groups resulted in more stereoselective glycosyl-
ation reactions. This “other” protecting group effect was ration-
alised by a proposed dynamic equilibrium between cyclic inter-
mediates and the acyclic glycosyl cation, and a Curtin–Hammett
scenario in which electron-donating protecting groups on the
donor led to increased reaction via the open chain form in a
non-stereoselective process.
Results and Discussion
Synthesis of Glycosyl Donors
In order to access a variety of differentially protected glycosyl
donors, all of which possessed the thiophenylmethyl ether pro-
tecting group at position 2, a divergent synthetic route based
on a common intermediate was devised. Although un-opti-
mised this approach did allow simple access to multiple donors
without the recourse to multiple parallel synthetic pathways,
and was therefore the most efficient for the purpose in hand.
Our preliminary study[9] into the use of the thiophene-based Thus the known 4,6-O-benzylidene-protected allyl glycoside 1
protecting group at position 2 had only involved fully armed was accessed following published procedures as the divergent
glycosyl donors. However if the effect observed by Boons was intermediate.[16] Benzylation of the 3-position of diol 1, by way
general then these donors should in fact be the least stereo- of an intermediate tin acetal, afforded the 3-O-benzyl ether 2a
selective amongst possible variants, i.e. the use of either par- in modest yield, allowing selective access to the 2-hydroxyl
tially or fully disarmed donors should result in more selective group (Scheme 1). Introduction of the thiophenylmethyl ether
glycosylation reactions. We therefore undertook further investi- protecting group was achieved by reaction of 2a with 2-
gations into the protecting group dependence of the stereo- (bromomethyl)thiophene 3[17] in the presence of sodium
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Scheme 1. Reagents and conditions: (i) Bu2SnO, MeOH, reflux, 2 h; (ii) BnBr, CsF, DMF, room temp., 16 h, 30 % over two steps; (iii) 3, NaH, DMF, 0 °C to r.t.,
16 h; 4a, 90 %; 4b, 80 %; (iv) Pd(PPh3)4, AcOH, r.t., 16 h; 5a, 76 %; 5b, 79 %; 5c, 69 %; 5d, 77 %; 5e, 99 %; (v) Cl3CCN, DBU, CH2Cl2, 16 h; 6a, 76 %; 6b, 73 %;
6c, 90 %; 6d, 75 %; 6e, 83 %; (vi) TBSCl, imidazole, DMAP, DMF, 60 °C, 16 h, 47 %; (vii) TBAF, THF, r.t., 16 h; (viii) Ac2O, pyridine, DMAP, r.t., 16 h, 93 % over two
steps; (ix) AcOH, water, 60 °C, 16 h; (x) Ac2O, pyridine, DMAP, r.t., 16 h, 77 % over two steps; (xi) AcOH, water, 80 °C, 1.5 h; (xii) Ac2O, pyridine, DMAP, r.t., 16 h,
48 % over two steps.
hydride in DMF to afford ether 4a. Removal of the allyl protect- acetone galactose as a glycosyl acceptor were undertaken
ing group at the anomeric centre proved more problematic (Table 1). It should be noted that the precise conditions used
than expected. Amongst several methods investigated, only the for glycosylation reactions involving 6-ring NGP can have a
reported procedure by Boons,[8b] which notably requires a stoi- marked effect on the stereochemical outcome of the reaction.
chiometric amount of Pd(PPh3)4, proved successful, and gave For this reason the activation procedure previously em-
hemiacetal 5a in good yield. Hemiacetal 5a was then converted ployed[14] was used for proper comparative purposes, even
into the trichloroacetimidate donor 6a by reaction with tri- though an alternative procedure may produce higher levels of
chloroacetonitrile and DBU (Scheme 1). Alternatively, selective α-selectivity.[19]
silylation of the 3-position of diol 1 by treatment with TBS chlor-
ide, imidazole and DMAP at 60 °C, gave the 3-O-silyl ether
2b.[18] Installation of the thiophenylmethyl ether group then
afforded ether 4b, which was followed by removal of the allyl
Table 1. Glycosylation of diacetone galactose with donors 6a–f.
protecting group to give hemiacetal 5b, and conversion to the
trichloroacetimidate donor 6b. Alternatively exchange of the
silyl protecting group of 4b for an acetate was achieved by
treatment of silyl ether 4b with TBAF and immediate acetyl-
ation with acetic anhydride/pyridine, to give acetate 4c. This
was converted into the mono-acetate-protected donor 6c using
analogous reaction sequences via hemiacetal 5c. In a similar
fashion removal of the 4,6-O-benzylidene protecting group of
4c, by treatment with 80 % aqueous acetic acid at 60 °C, and
immediate acetylation allowed access to the fully disarmed tri-
acetate-protected donor 6d, by way of intermediates 4d and
5d. Finally di-acetate-protected donor 6e was accessed from
Entry
Glycosyl
donor
Yield of
product [%]
α/ꢀ Ratio[a]
benzyl ether 4a, by an analogous route involving acid-catalysed
hydrolysis of the 4,6-O-benzylidene, acetylation, cleavage of the
anomeric allyl glycoside and conversion to the corresponding
trichloroacetimidate 6e (Scheme 1).
a
b
c
d
e
f
6a
6b
6c
6d
6e
6f
84
75
75
89
75
84
1:1.7
1:1.6
1.2:1
1.4:1
1:1.1
9:1
Glycosylation Reactions
With the required glycosyl donors in hand investigations into
the stereochemical outcome of their glycosylation using di-
[a] Anomeric ratios were determined by integration of appropriate peaks in
the 1H nmr spectra.
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Firstly, in contrast to expectations based upon the Boons re- 6a–e did produce more of the α-disaccharide than glycosyl-
port,[8d] it was found that the partially disarmed donor 6a, ation of the corresponding perbenzylated donor (α/ꢀ, 1:4).[9]
which possesses a 4,6-O-benzylidene and a 3-O-benzyl ether,
did not produce the disaccharide 7a as the predominantly the
α-product; rather the reaction was modestly ꢀ-selective
(Table 1, entry a). The analogous 4,6-O-benzylidene-protected
NMR Studies
donor 6b bearing a 3-O-silyl ether was also modestly ꢀ-select- The presence of the thiophenylmethyl ether at position 2 had
ive (Table 1, entry b). Glycosylation of donor 6c, which again clearly had an effect on the stereochemical outcome of glyc-
comprises a 4,6-O-benzylidene but with an acetate at position- osylation, albeit with very modest α-selectivity except in the
3, was non-selective, and disaccharide 7c was produced as a case of donor 6f. Whether this increased α-selectivity (relative
1.2:1 α/ꢀ mixture (Table 1, entry c). The fully disarmed donor to the 4:1 ꢀ-selective perbenzylated donor)[14] was the direct
6d, possessing acetates at positions 3-, 4- and 6-, showed only result of 6-ring NGP, or whether it may be due to other possible
very modest α-selectivity, and gave disaccharide 7d as a 1.4:1 effects, could be evidenced by NMR studies. Previous low-tem-
α/ꢀ mixture (Table 1, entry c), whilst the di-acetate-protected perature NMR experiments on activated glycosyl donors have
donor 6e was not selective (α/ꢀ, 1:1.1, Table entry e). All of provided evidence for NGP by the presence of cross correlations
these donors were therefore markedly less selective than the between C-1 on the donor and protons of the protecting group,
fully armed tri-benzyl-protected donor 6f, accessed as previ- as well as significant changes in the chemical shifts of H-1 and
ously reported,[9] which gave disaccharide 7f with good α-se- protecting group protons. NMR studies were therefore firstly
lectivity (α/ꢀ, 9:1, Table entry f). However, even though in the performed on donor 6f which had demonstrated the highest
other cases the α-stereoselectivity was poor, all of the donors levels of stereoselectivity. Donor 6f was activated in the ab-
Figure 2. Low-temperature NMR spectra of donor 6f; a) before and b) after activation at –78 °C in CD2Cl2. Changes in chemical shift were observed for H-1
and H-7 upon activation. Cross-correlations were seen between C-1 and H-7, and between C-7 and H-1 in the HMBC spectrum c).
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sence of acceptor at –78 °C in CD2Cl2 by the addition of a stoi-
In light of this evidence of 6-ring NGP, a similar NMR study
chiometric amount of TMSOTf, and NMR spectra were obtained was performed on the fully disarmed peracetylated donor 6d
(Figure 2).
(Figure 3), which had proved to be far less stereoselective in
terms of the outcome of glycosylation with diacetone galactose
(α/ꢀ, 1.4:1, Table entry d). Interestingly these studies revealed
very similar changes in the chemical shift of H-1 upon activa-
tion (Figure 3, b), together with cross correlations between C-1
and H-7 and between C-7 and H-1 in the HMBC spectrum (Fig-
ure 3, c), both of which provided strong evidence for the inter-
mediacy of cyclized intermediate 6d′. Again the observed value
of JH-1,H-2 was only 5.9 Hz. However the coupled HSQC spectrum
revealed that JH-1,C-1 was 157 Hz (see Supporting Information)
again supporting the supposition that 6d′ was ꢀ-configured.
The fact that both NMR studies had revealed very similar
A single compound was formed upon activation of donor 6f
(Figure 2) in which H-1 underwent a significant upfield shift
(Figure 2, b). The protons attached to the thiophene ring also
underwent a small shift. The HMBC spectrum revealed both
correlations between C-1 and H-7 (the thiophene proton adja-
cent to S) and also between H-1 and C-7 (Figure 2, c), providing
strong evidence for the formation of a cyclised intermediate,
tentatively drawn as sulfonium ion 6f′. However one piece of
evidence was not in support of this ꢀ-configured compound as
drawn; namely that the observed value of JH-1,H-2 was only
5.5 Hz, which did not match either of the values expected for
an α- or a ꢀ-configured intermediate in a 4C1 conformation. changes in the spectra of the fully armed donor 6f and the fully
Further investigation into the anomeric configuration of inter- disarmed donor 6d, which themselves produced very different
mediate 6f′ was undertaken by measuring the value of JH-1,C-1 stereochemical outcomes, is a further reminder that evidence
by means of a coupled HSQC spectrum (see Supporting Infor- that a cyclic intermediate is formed upon activation of a donor
mation), which was found to be 151 Hz. This low value implies does not mean that this is necessarily the reactive species
that H-1 was in an axial orientation,[20] and therefore that the through which glycosylation occurs. In terms of the protecting
intermediate was indeed ꢀ-configured. We conclude that the group dependence of the stereochemical outcome of glycosyl-
anomalous value measured for JH-1,H-2 may be due to the fact ation, similarly to our previous study,[14] we had in fact found
that 6f′ adopts a distorted conformation; a supposition that is the opposite outcome to that reported by Boons;[8d] i.e. that in
further supported by the somewhat low values of JH-2,H-3 and this case, using this activation procedure, the fully armed donor
JH-3,H-4 for 6f′, which were both found to be 7.6 Hz.
was the most stereoselective. Whilst the reasons for this dis-
Figure 3. Low-temperature NMR spectra of donor 6d; a) before and b) after activation at –78 °C in CD2Cl2. Changes in chemical shift were observed for H-1
upon activation. Cross-correlations were seen between C-1 and H-7, and between C-7 and H-1 in the HMBC spectrum c).
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crepancy are not obvious at this point in time, it is clear that a Conditions were discovered for the removal of the thiophenyl-
very fine balance exists during glycosylation, and the reaction methyl ether, either selectively in the presence of benzyl ethers,
pathway to product depends on a variety of factors. However or concomitantly with benzyl ether cleavage. These studies pro-
the formation of ꢀ-configured cyclised intermediates by 6-ring vide further insights into the utility of 6-ring NGP in the on-
NGP, as evidenced by the NMR study of the disarmed donor 6d, going search for a widely applicable 1,2-cis stereoselective glyc-
is not on its own sufficient to ensure high levels of α-stereo- osylation process. However, application of the thiophenyl-
selectivity.
methyl ether protecting group at position 2 for α-selective glyc-
osylation reactions appears to be limited to fully armed glycosyl
donors using the currently employed activation procedure.[19]
De-Protection Reactions
The utility of a stereo-directing protecting group is under-
pinned by the necessity of its eventual removal, either during
oligosaccharide synthesis to allow for chain extension at that
position, or during global de-protection in order to produce the
final target. The similarity of the thiophenylmethyl ether to a
benzyl ether implied that it may be removed under conditions
akin to those commonly used to cleave benzyl ethers. Disac-
charide 7f was therefore used as a substrate for the investiga-
tion of conditions that could be used to cleave both the benzyl
ethers and the thiophenylmethyl ether, and also to investigate
if selective cleavage of only the thiophenylmethyl ether was
possible.
Experimental Section
General Experimental: Melting points were recorded on an Elec-
trothermal melting point apparatus and are uncorrected. Proton
and carbon nuclear magnetic resonance (δH, δC) spectra were re-
corded on Agilent Technologies 400 MR (400 MHz) or Varian
VNMR500 (500 MHz) spectrometers. All chemical shifts are quoted
on the δ-scale in ppm using residual solvent as an internal standard.
High-resolution mass spectra were recorded with a Bruker maXis
3G UHR-TOF mass spectrometer. Thin-layer chromatography (TLC)
was carried out on Merck silica gel 60F254 aluminium-backed plates.
Visualization of the plates was achieved using a U.V. lamp (λmax
254 or 365 nm), and/or 5 % w/v ammonium molybdate in 2 sulf-
=
M
Birch reduction of 7f resulted in simultaneous cleavage of all uric acid. Flash column chromatography was carried out using
Sorbsil C60 40/60 silica. Unless preparative details are provided, all
reagents were commercially available or made following literature
procedures.
the benzyl ethers and the thiophenylmethyl ether to produce
the known disaccharide 8a (Scheme 2).[21] Alternatively reaction
of disaccharide 7f with an excess of trimethylsilyl iodide (TMSI)
in anhydrous CH2Cl2 also resulted in cleavage of all ethers, and
afforded disaccharide 8a in 85 % yield. Attention then turned
to selective cleavage of the thiophenylmethyl ether. Pleasingly,
the reaction of 8a with one equivalent of TMSI at 0 °C resulted
in selective cleavage of only the thiophenylmethyl ether, and
furnished the disaccharide 8b[6h] in 78 % yield (Scheme 2).
General Procedure for Glycosylation: To a flame-dried round-bot-
tomed flask containing activated 3 Å molecular sieves (0.100 g) was
added a solution of the trichloroacetimidate donor (≈ 75 mg,
≈ 0.125 mmol) and 1,2:3,4-di-O-isopropylidene-D-galactopyranoside
(65 mg, 2 equiv.) in freshly distilled CH2Cl2 (1 mL). The reaction was
cooled to –41 °C under N2 before TMSOTf (0.1 equiv.) was added.
The reaction was monitored by TLC (petroleum ether/EtOAc, 1:1)
until the product formation (Rf = 0.6) and consumption of the donor
(Rf = 0.9) were complete. The reaction was quenched with saturated
sodium hydrogen carbonate solution and filtered through Celite®.
The mixture was diluted with CH2Cl2, washed with saturated so-
dium hydrogen carbonate solution, and the aqueous layer ex-
tracted with CH2Cl2. The combined organic extracts were washed
with brine and dried (MgSO4) before concentrating under vacuum.
The residue was then purified by flash column chromatography
(typical eluent; petroleum ether/EtOAc, 6:1), to afford the di-
saccharide product.
Scheme 2. (i) Na, NH3(l)/THF, –100 °C, 1 h, 62 %; (ii) TMSI (4.5 equiv.), CH2Cl2,
16 h, 85 %; (iii) TMSI (1 equiv.), CH2Cl2, 0 °C, 0.5 h, 78 %.
Allyl 3-O-Benzyl-4,6-O-benzylidene-(α/ꢀ)-D-glucopyranoside 2a:
To a solution of diol 1 (10.79 g, 35 mmol) in MeOH (250 mL) was
added dibutyltin(IV) oxide (10.46 g, 1.2 equiv.) before the reaction
was heated to reflux. After 2 h the suspension became a solution
and was cooled to room temperature before concentrating under
Conclusions
A series of glycosyl donors possessing a thiophenylmethyl ether
protecting group at the 2-position were synthesized, in which
the protecting group pattern of the 3-, 4- and 6-hydroxyls was vacuum. The residue was the dissolved in DMF (100 mL) and to this
solution was added benzyl bromide (4.58 mL, 1.1 equiv.) and
cesium fluoride (6.91 g, 1.3 equiv.) before leaving to stir overnight.
The next day the reaction was concentrated under vacuum. The
residue was then partitioned between KF (satd. soln. 100 mL) and
CH2Cl2 (300 mL). The organic layer was then separated and dried
(MgSO4) before purifying by flash column chromatography (eluent;
petroleum ether/EtOAc, 3:1, Rf = 0.2). The product was then crystal-
lized from CH2Cl2/petroleum ether to afford benzyl ether 2a (4.17 g,
30 % yield) as a colorless solid; δH (400 MHz, CDCl3) [17:1 mixture
of α/ꢀ anomers observed, major α anomer quoted]: δ = 3.65 (app.
systematically varied. Glycosylation reactions were performed
which revealed that although reactions were more α-selective
than the corresponding perbenzylated donor, α-selectivity was
low, expect in the case of the tri-benzylated fully armed donor
6f. Low-temperature NMR studies on fully armed and fully dis-
armed donors revealed that in fact both underwent 6-ring NGP.
However the stereochemical outcome of glycosylation of the
two donors was very different, showing that the formation of
ꢀ-configured cyclised intermediates by 6-ring NGP is not on
its own sufficient to ensure high levels of α-stereoselectivity. t, J = 9.6, 9.2 Hz, 1 H, 4-H), 3.73–3.92 (m, 4 H, 2-H, 3-H, 5-H & 6-H),
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4.05–4.10 (m, 1 H, 1 × OCH2CH=CH2), 4.22–4.31 (m, 2 H, 6′-H & 1 ×
OCH2CH=CH2), 4.46 (d, J = 7.4 Hz, 0.06 H, 1ꢀ-H), 4.81 (d, J = 11.2 Hz,
1 H, OCHH′Ph), 4.95–4.98 (m, 2 H, 1-H & OCHH′Ph), 5.23–5.35 (m, 2
H, OCH2CH=CH2), 5.58 (s, 1 H, CHPh), 5.89–5.98 (m, 1 H, OCH2CH=
OCH2Ph), 78.7 (d, C-2), 78.8 (d, C-3), 82.4 (d, C-4), 97.2 (d, C-1), 101.4
(d, CHPh), 118.4 (t, OCH2CH=CH2), 126.1, 126.4, 126.8, 127.1, 127.7,
128.1, 128.3, 128.4, 129.0, 133.7, 137.5 (11 × aromatic C), 138.9 (d,
OCH2CH=CH2), 141.1 (s, aromatic C) ppm. HRMS (ESI-TOF): calcd. for
CH2), 7.26–7.41 (m, 8 H, aromatic H), 7.49–7.51 (m, 2 H, aromatic H) C28H30O6SNa+: 517.1655, found 517.1656 [MNa+]. (Found: C, 68.13;
ppm. 13C NMR (100 MHz, CDCl3): δ = 62.9 (d, C-5), 68.9 (t, OCH2CH=
CH2), 69.1 (t, C-6), 72.6 (d, C-2), 75.0 (t, CH2Ph), 79.2 (d, C-3), 82.1 (d,
C-4), 98.1 (d, C-1), 101.4 (d, CHPh), 118.4 (t, OCH2CH=CH2), 126.1,
127.8, 128.1, 128.4, 128.5, 129.1, 133.5, 137.5 (8 × aromatic C), 138.6
(d, OCH2CH=CH2) ppm. HRMS (ESI-TOF): calcd. for C23H26O6H+:
399.1802, found 399.1815 [MH+].
H, 6.19. C28H30O6S requires C, 67.99; H, 6.11 %).
Allyl 2-O-(Thiophen-2-yl)methyl-3-O-tert-butyldimethylsilyl-
4,6-O-benzylidene-(α)-D-glucopyranoside (4b): NaH (0.38 g,
2 equiv. 60 % in mineral oil) was added to a solution of alcohol
2b (1.99 g, 4.7 mmol) in DMF (100 mL) at 0 °C. After 5 min, 2-
(bromomethyl)thiophene 3 (2.11 g, 2 equiv.) was added and the
reaction left to warm to room temperature overnight. The next day
analysis by TLC (petroleum ether/EtOAc, 7:1) showed complete con-
sumption of the starting material (Rf = 0.3). The reaction was then
quenched with MeOH (100 mL) before concentrating under vac-
uum. The crude material was then pre-adsorbed onto silica and
purified by flash column chromatography (eluent; petroleum ether/
EtOAc, 15:1, Rf = 0.4 in 9:1) to afford ether 4b (1.95 g, 80 % yield)
Allyl 4,6-O-Benzylidene-3-O-tert-butyldimethylsilyl-(α)-D-gluco-
pyranoside (2b):[18] To a solution of diol 1 (0.616 g, 2 mmol) in DMF
(15 mL) was added DMAP (0.049 g, 20 mol-%), imidazole (0.204 g,
1.5 equiv.) and TBDMS-Cl (0.362 g, 1.2 equiv.) before heating to
60 °C overnight. The next day analysis by TLC (petroleum ether/
EtOAc, 1:1) showed complete consumption of the starting material
(Rf = 0.1). The reaction was then concentrated under vacuum and
pre-adsorbed onto silica before purifying by flash column chroma- as a yellow oil. [α]D22 = –6.7 (c = 1.6 in CHCl3); δH (400 MHz, CDCl3)
tography (eluent; petroleum ether/EtOAc, 19:1, Rf = 0.3 in 7:1) to
[only the α anomer was observed]: δ = 0.03 (s, 3 H, SiCH3), 0.11 (s,
3 H, SiCH3), 0.88 [s, 9 H, SiC(CH3)3], 3.39–3.46 (m, 2 H, 2-H & 4-H),
afford silyl ether 2b (0.497 g, 47 % yield) as a colorless oil. [α]D22
=
+55.2 (c = 1.2 in CHCl3) [ref. [α]D22 = +74.8 (c = 0.82 in CHCl3)];[18] δH 3.66 (app. t, J = 10.0 Hz, 1 H, 6-H), 3.80–3.86 (m, 1 H, 5-H), 3.99–
(400 MHz, CDCl3) [only the α anomer was observed]: δ = 0.03 (s, 3
H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 3.43 (1 H, ap.
t, J = 9.2 Hz, 4-H), 3.58 (dd, 1 H, J = 8.8, 4.0 Hz, 2-H), 3.69–3.74 (m,
1 H, 1 × OCH2CH=CH2), 3.80–3.86 (1 H, m 5-H), 3.90 (1 H, ap. t, J =
9.2, 8.8 Hz, 3-H), 4.05–4.10 (m, 1 H, 6-H), 4.22–4.28 (m, 2 H, 6′-H &
1 × OCH2CH=CH2), 4.95 (d, 1 H, J = 3.6 Hz, 1-H), 5.23–5.35 (m, 2 H,
OCH2CH=CH2), 5.51 (s, 1 H, CHPh), 5.89–6.00 (m, 1 H, OCH2CH=CH2),
4.04 (m, 1 H, 1 × OCH2CH=CH2), 4.09–4.16 (m, 2 H, 3-H & 1 ×
OCH2CH=CH2), 4.22 (dd, J = 10.0, 4.4 Hz, 1 H, 6′-H), 4.64 (d, J =
2.8 Hz, 1 H, 1-H), 4.76 (d, J = 12.8 Hz, 1 H, 1 × OCH2Ar), 4.95 (d, J =
12.8 Hz, 1 H, 1 × OCH2Ar), 5.20–5.32 (m, 2 H, OCH2CH=CH2), 5.48 (s,
1 H, CHPh), 5.88–5.98 (m, 1 H, OCH2CH=CH2), 6.96–6.98 (m, 1 H,
aromatic H), 7.02 (m, 1 H, aromatic H), 7.30–7.31 (m, 1 H, aromatic
H), 7.34–7.38 (m, 3 H, aromatic H), 7.47–7.49 (m, 2 H, aromatic H);
7.35–7.39 (m, 3 H, aromatic H), 7.48–7.50 (m, 2 H, aromatic H); δC δC (100 MHz, CDCl3) –4.3 (q, SiCH3), –4.2 (q, SiCH3), 18.4 [s,
(100 MHz, CDCl3): δ = –4.5 (q, SiCH3), –4.2 (q, SiCH3), 18.5 [s,
SiC(CH3)3], 26.0 [3 × q, SiC(CH3)3], 62.9 (d, C-5), 68.9 (t, OCH2CH=
CH2), 69.1 (t, C-6), 73.2 (d, C-3), 73.8 (d, C-2), 81.9 (d, C-4), 98.3 (d,
SiC(CH3)3], 26.0 [3 × q, SiC(CH3)3], 62.5 (d, C-5), 68.4 (t, CH2Ar), 68.7
(t, OCH2CH=CH2), 69.2 (t, C-6), 71.7 (d, C-3), 80.1 (d, C-2), 82.7 (d, C-
4), 97.2 (d, C-1), 102.0 (d, CHPh), 118.4 (t, OCH2CH=CH2), 126.4,
C-1), 101.8 (d, CHPh), 118.3 (t, OCH2CH=CH2), 126.3, 128.2, 129.0, 126.4, 126.8, 127.2, 128.2, 129.1, 133.9 (7 × aromatic C), 137.5 (d,
133.6 (4 × aromatic C), 137.5 (d, OCH2CH=CH2) ppm. HRMS (ESI-
OCH2CH=CH2), 141.2 (aromatic C) ppm. HRMS (ESI-TOF): calcd. for
C27H38O6SSiNa+: 541.2054, found 541.2051 [MNa+]. (Found: C, 62.39;
H, 7.44. C27H38O6SSi requires C, 62.52; H, 7.38 %).
TOF): calcd. for C22H34O6SiNa+: 445.2017, found 445.2021 [MNa+].
2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-benzylidene-
(α/ꢀ)-
20 mmol) in DMF (300 mL) at 0 °C was added NaH (1.60 g, 2 equiv.
60 % dispersion in mineral oil). After 30 min 2-(bromomethyl)thio- 3 mmol) in THF (50 mL) was added TBAF·3water (1.04 g, 1.1 equiv.)
phene 3 (6.73 g, 1.9 equiv.) in DMF (100 mL) before allowing the before leaving to stir overnight. The next day analysis by TLC (petro-
D
-glucopyranoside (4a): To a solution of alcohol 2a (7.97 g, Allyl 2-O-(Thiophen-2-yl)methyl-3-O-acetyl-4,6-O-benzylidene-
(α)- -glucopyranoside (4c): To a solution of silyl ether 4b (1.56 g,
D
reaction to warm to room temperature. After 3 h, TLC (petroleum leum ether/EtOAc, 3:1) showed complete consumption of the start-
ether/EtOAc, 3:1) showed complete consumption of starting mate- ing material (Rf = 0.7) and formation of a new spot (Rf = 0.2). The
rial (Rf = 0.2). The reaction was then quenched with MeOH (150 mL)
reaction was then diluted with CH2Cl2 (200 mL), water (200 mL) and
before concentrating under vacuum. The residue was then parti- brine (200 mL). The organic layer was then separated and dried
tioned between CH2Cl2 (250 mL) and water (100 mL). The organic (MgSO4) before concentrating under vacuum. To the residue was
layer was separated and washed with water (100 mL) and brine
(100 mL) before drying (MgSO4) and concentrating under vacuum.
The crude material was pre-adsorbed onto silica and purified by
added pyridine (3 mL), DMAP (0.04 g) and acetic anhydride (1.4 mL)
before leaving to stir overnight. The next day analysis by t.l.c
showed complete consumption of the previous material and forma-
flash column chromatography (eluent; petroleum ether/EtOAc, 9:1, tion of the product (Rf = 0.4). The reaction was concentrated under
Rf = 0.2) to afford ether 4a (8.80 g, 89 % yield) as a yellow oil that vacuum and pre-adsorbed onto silica before purifying by flash col-
solidified on standing; δH (400 MHz, CDCl3) [20:1 mixture of α/ꢀ umn chromatography (eluent; petroleum ether/EtOAc, 4:1) to afford
anomers observed, major α anomer quoted]: δ = 3.59–3.64 (m, 2
H, 2-H & 4-H), 3.68–3.73 (m, 1 H, 6-H), 3.86–3.92 (m, 1 H, 5-H), 4.03–
4.10 (m, 2 H, 3-H & 1 × OCH2CH=CH2), 4.18 (dd, J = 12.8, 5.2 Hz, 1
H, 1 × OCH2CH=CH2), 4.24–4.28 (m, 1 H, 6′-H), 4.56 (d, J = 8.2 Hz,
0.05 H, 1ꢀ-H), 4.76 (d, J = 3.6 Hz, 1 H, 1-H), 4.83–4.93 (m, 3 H, 1 ×
OCH2Ar & 2 × OCH2Ph), 4.99 (d, J = 12.8 Hz, 1 H, 1 × OCH2Ar), 5.23
acetate 4c (1.24 g, 93 % yield) as a pale yellow oil that solidified on
standing; m.p. 90–92 °C. [α]D22 = +38.1 (c = 1.0 in CHCl3); νmax
=
˜
(neat) 1736 (s, C=O) cm–1. δH (400 MHz, CDCl3) [only the α anomer
was observed]: δ = 2.08 [s, 3 H, C(O)CH3], 3.54 (app. t, J = 9.6 Hz, 1
H, 4-H), 3.63 (dd, J = 9.6, 4.0 Hz, 1 H, 2-H), 3.67–3.72 (m, 1 H, 6-H),
3.91–3.98 (m, 1 H, 5-H), 4.04 (dd, J = 12.8, 6.8 Hz, 1 H, OCH2CH=
(d, J = 10.0 Hz, 1 H, 1 × OCH2CH=CH2), 5.33 (d, J = 17.2 Hz, 1 H, 1 × CH2), 4.20 (dd, J = 13.0, 5.6 Hz, 1 H, OCH2CH=CH2), 4.24–4.27 (m, 1
OCH2CH=CH2), 5.56 (s, 1 H, CHPh), 5.89–5.99 (m, 1 H, OCH2CH=CH2),
6.95–7.00 (m, 2 H, aromatic H), 7.26–7.40 (m, 9 H, aromatic H), 7.48–
7.50 (m, 2 H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.7
(d, C-5), 68.3 (t, OCH2Ar), 68.7 (t, OCH2CH=CH2), 69.1 (t, C-6), 75.4 (t,
H, 6′-H), 4.79 (s, 2 H, OCH2Ar), 4.85 (d, J = 4.0 Hz, 1 H, 1-H), 5.22–37
(m, 2 H, OCH2CH=CH2), 5.46 (s, 1 H, CHPh), 5.57 (app. t, J = 10.0,
9.2 Hz, 1 H, 3-H), 5.89–5.99 (m, 1 H, OCH2CH=CH2), 6.97–7.01 (m, 2
H, aromatic H), 7.31–7.37 (m, 4 H, aromatic H), 7.42–7.45 (m, 2 H,
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aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.2 [q, C(O)CH3],
62.7 (d, C-5), 67.1 (t, CH2Ar), 68.8 (t, OCH2CH=CH2), 69.0 (t, C-6), 70.5
C(O)CH3], 20.9 [q, C(O)CH3], 62.4 (t, C-6), 67.9 (d, C-5), 67.9 (t, CH2Ar),
68.8 (t, OCH2CH=CH2), 69.9 (d, C-4), 75.5 (t, CH2Ph), 79.1 (d, C-2),
(d, C-3), 76.9 (d, C-2), 79.8 (d, C-4), 96.7 (d, C-1), 101.6 (d, CHPh), 79.3 (d, C-3), 96.2 (d, C-1), 118.6 (t, OCH2CH=CH2), 126.5, 126.8,
118.4 (t, OCH2CH=CH2), 126.3, 126.5, 126.8, 127.1, 128.3, 129.1, 133.6 127.2, 127.7, 127.9, 128.5, 133.5 (7 × aromatic C), 138.6 (d, OCH2CH=
(9 × aromatic C), 137.2 (d, OCH2CH=CH2), 140.6 (aromatic C), 169.8 CH2), 140.7 (aromatic C), 169.7 (s, C=O), 170.8 (s, C=O) ppm. HRMS
(s, C=O) ppm. HRMS (ESI-TOF): calcd. for C23H26O7SNa+: 469.1291, (ESI-TOF): calcd. for C25H30O8SNa+: 513.1554, found 513.1565
found 469.1295 [MNa+].
[MNa+].
Allyl 2-O-(Thiophen-2-yl)methy-3,4,6-triacetyl-(α)-
D
-gluco- 2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-benzylidene-
pyranoside (4d): 4,6-Benzylidene 4c (2.53 g, 5 mmol) was added
to 80 % AcOH (100 mL) and heated to 60 °C overnight. The next
day the reaction was cooled to room temperature before co-evapo-
rating with toluene (3 × 100 mL). The residue was then purified by
flash column chromatography (eluent; EtOAc/petrol, 2:1, Rf = 0.2)
the relevant fractions were then combined and concentrated under
vacuum. The residue was then dissolved in pyridine (10 mL) before
DMAP (0.13 g) and acetic anhydride (4.8 mL) were added. The reac-
tion was then left to stir overnight. The next day the reaction was
concentrated under vacuum and purified by flash column chroma-
tography (eluent; petroleum ether/EtOAc, 3:1, Rf = 0.2) to afford
(α/ꢀ)-D-glucopyranose (5a): To a solution of allyl glycoside 4a
(0.989 g, 2 mmol) in AcOH (20 mL) was added Pd(PPh3)4 (1.0 equiv.)
before leaving to stir at room temperature overnight. The next day
the reaction was diluted with CH2Cl2 (100 mL) before washing with
NaHCO3 (satd. soln. 2 × 100 mL) before the organic layer was dried
(MgSO4) and concentrated under vacuum. The crude material was
then pre-adsorbed onto silica before purifying by flash column
chromatography (eluent; petroleum ether/EtOAc, 2:1, Rf = 0.2) to
afford hemiacetals 5a (0.691 g, 76 % yield) as an off-white solid;
νmax (neat) 3386 (br., OH) cm–1; δH (400 MHz, CDCl3) [1:1.4 mixture
˜
of α/ꢀ anomers]: δ = 3.40–3.49 (m, 2 H, 2ꢀ-H & 5ꢀ-H), 3.61–3.81 (m,
triacetate 4d (1.71 g, 77 % yield) as a yellow oil. [α]D22 = +53.4 (c = 6 H, 2α-H, 3ꢀ-H, 4α-H, 4ꢀ-H, 6α-H & 6ꢀ-H), 4.00–4.11 (m, 2 H, 3α-
1.1 in CHCl3); νmax (neat) 1742 (s, C=O) cm–1; δH (400 MHz, CDCl3)
H & 5α-H), 4.29 (dd, J = 13.0 6.0 Hz, 1 H, 6′α-H), 4.35 (dd, J = 13.0
6.0 Hz, 1 H, 6′ꢀ-H), 4.80–4.85 (m, 3 H, 1ꢀ-H & 2 × OCH2Ph), 4.89–
5.01 (m, 5 H, 3 × OCH2Ar & 2 × OCH2Ph), 5.07 (d, J = 12.4 Hz, 1 H,
˜
[only the α anomer was observed]: δ = 2.01 [s, 3 H, C(O)CH3], 2.03
[s, 3 H, C(O)CH3], 2.08 [s, 3 H, C(O)CH3], 3.62 (dd, J = 9.6, 3.6 Hz, 1
H, 2-H), 3.99–4.06 (m, 3 H, 5-H, 6-H & 1 × OCH2CH=CH2), 4.15–4.20 OCH2Ar), 5.13 (d, J = 3.6 Hz, 1 H, 1α-H), 5.56–5.57 (br. s, 2 H, CHPh),
(m, 1 H, 1 × OCH2CH=CH2), 4.27 (dd, J = 12.0, 4.8 Hz, 1 H, 6′-H), 4.74
(d, J = 13.2 Hz, 1 H, 1 × OCH2Ar), 4.79 (d, J = 13.2 Hz, 1 H, 1 ×
OCH2Ar), 4.83 (d, J = 3.6 Hz, 1 H, 1-H), 4.97 (app. t, J = 10.0, 9.6 Hz,
1 H, 4-H), 5.23–5.36 (m, 2 H, OCH2CH=CH2), 5.45 (app. t, J = 10.0,
6.97–7.03 (m, 4 H, aromatic H), 7.27–7.41 (m, 22 H, aromatic H),
7.47–7.49 (m, 4 H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ =
62.7 (d, C-5α), 66.4 (d, C-5ꢀ), 68.4 (t, OCH2Ar), 68.8 (t, C-6), 69.1 (t,
C-6), 69.4 (t, OCH2Ar), 75.2 (t, OCH2Ph), 75.3 (t, OCH2Ph), 78.5 (d, C-
9.2 Hz, 1 H, 3-H), 5.88–5.98 (m, 1 H, OCH2CH=CH2), 6.96–7.00 (m, 2 3α), 78.9 (d, C-3ꢀ), 80.9 (d, C-4ꢀ), 81.6 (d, C-4α), 82.1 (d, C-2α), 82.6
H, aromatic H), 7.30–7.31 (m, 1 H, aromatic H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.8 [q, C(O)CH3], 20.9 [q, C(O)CH3], 21.0 [q,
C(O)CH3], 62.2 (t, C-6), 67.4 (m, C-5 & OCH2Ar), 68.9 (t, OCH2CH=
(d, C-2ꢀ), 92.5 (d, C-1α), 97.7 (d, C-1ꢀ), 101.3 (d, CHPh), 101.4 (d,
CHPh), 126.1, 126.2, 126.3, 126.6, 126.8, 126.9, 127.0, 127.3, 127.8,
128.2, 128.2, 128.4, 128.4, 128.5, 129.1, 129.1, 137.4, 137.5, 138.5,
CH2), 69.0 (d, C-4), 71.9 (d, C-3), 76.1 (d, C-2), 95.9 (d, C-1), 118.6 (t, 138.6, 140.5, 140.7 (24 × aromatic C) ppm. HRMS (ESI-TOF): calcd.
OCH2CH=CH2), 126.7, 126.9, 127.2, 133.4 (4 × aromatic C), 140.4 (d, for C25H26O6SNa+: 477.1342, found 477.1362 [MNa+].
OCH2CH=CH2), 170.0 (s, C=O), 170.2 (s, C=O), 170.7 (s, C=O) ppm.
2-O-(Thiophen-2-yl)methyl-3-O-tert-butyldimethylsilyl-4,6-O-
HRMS (ESI-TOF): calcd. for C20H26O9SNa+: 465.1190, found 465.1195
benzylidene-(α/ꢀ)-
glycoside 4b (1.30 g, 2.5 mmol) in AcOH (30 mL) was added
Allyl 2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-diacetyl- Pd(PPh3)4 (1.0 equiv.) before leaving to stir at room temperature
D-glucopyranose (5b): To a suspension of allyl
[MNa+].
(α/ꢀ)-
D
-glucopyranoside (4e): A suspension of 4,6-benzylidene 4a
overnight. The next day the reaction was diluted with CH2Cl2
(200 mL) before washing with NaHCO3 (satd. soln. 2 × 200 mL) be-
fore the organic layer was dried (MgSO4) and concentrated under
vacuum. The crude material was then pre-adsorbed onto silica be-
(3.96 g, 8 mmol) in 80 % AcOH (20 mL) was heated to 80 °C. After
90 min analysis by TLC (petroleum ether/EtOAc, 6:1) showed com-
plete consumption of starting material (Rf = 0.4). The reaction was
cooled to room temperature before co-evaporating with toluene fore purifying by flash column chromatography (eluent; petroleum
(3 × 100 mL). The crude material was then purified by flash column
chromatography (eluent; petroleum ether/EtOAc, 1:1, Rf = 0.7), the
relevant fractions were then combined and concentrated under
vacuum. The residue was then dissolved in pyridine (16 mL), to this
was added DMAP (0.10 g, 10 mol-%) and acetic anhydride (7.6 mL)
before leaving to stir overnight. The next day the reaction was con-
centrated under vacuum and pre-adsorbed onto silica before purify-
ing by flash column chromatography (eluent; petroleum ether/
EtOAc, 4:1, Rf = 0.3) to afford diacetate 4e (1.88 g, 48 % yield) as a
ether/EtOAc, 2:1, Rf = 0.2) to afford hemiacetals 5b (0.94 g, 79 %
yield) as a yellow oil; νmax (neat) 3417 (br., OH) cm–1; δH (400 MHz,
˜
CDCl3) [1:1 mixture of α/ꢀ anomers observed]: δ = 0.01 (s, 3 H,
SiCH3), 0.03 (s, 3 H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3),
0.87 [s, 9 H, SiC(CH3)3], 0.88 [s, 9 H, SiC(CH3)3], 3.02 (br. s, 2 H, OH),
3.28 (app. t, J = 8.0 Hz, 1 H, 2ꢀ-H), 3.39–3.51 (m, 4 H, 2α-H, 3α-H,
4α-H, 5ꢀ-H), 3.66 (app. t, J = 10.8, 10.0 Hz, 1 H, 6α-H), 3.75 (app. t,
J = 10.4, 9.6 Hz, 1 H, 6ꢀ-H), 3.83 (app. t, J = 8.8, 8.4 Hz, 1 H, 3ꢀ-H),
3.98–4.04 (m, 1 H, 5α-H), 4.07 (app. t, J = 8.8 Hz, 1 H, 4ꢀ-H), 4.25
pale yellow oil; νmax (neat) 1740 (s, C=O) cm–1; δH (400 MHz, CDCl3) (dd, J = 10.4, 4.8 Hz, 1 H, 6′α-H), 4.31 (dd, J = 10.4, 4.8 Hz, 1 H, 6′ꢀ-
˜
[25:1 mixture of α/ꢀ anomers observed, major α anomer quoted]:
H), 4.78 (d, J = 8.0 Hz, 1 H, 1ꢀ-H), 4.80 (d, J = 12.0 Hz, 1 H, 1 ×
δ = 1.91 [s, 3 H, C(O)CH3], 2.07 [s, 3 H, C(O)CH3], 3.63 (dd, J = 9.2 CH2Ar), 4.95 (d, J = 11.6 Hz, 1 H, 1 × CH2Ar), 4.97 (d, J = 12.4 Hz, 1
3.6 Hz, 1 H, 2-H), 3.88–4.07 (m, 4 H, 3-H, 5-H, 6-H & 1 × OCH2CH= H, 1 × CH2Ar), 5.02 (d, J = 3.6 Hz, 1 H, 1α-H), 5.04 (d, J = 11.6 Hz, 1
CH2), 4.13–4.24 (m, 2 H, 6′-H & 1 × OCH2CH=CH2), 4.47 (d, J = 7.4 Hz,
0.04 H, 1ꢀ-H), 4.64 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.77 (d, J = 3.2 Hz,
1 H, 1-H), 4.82 (d, J = 12.4 Hz, 1 H, CH2Ar), 4.89–4.94 (m, 2 H, 1 ×
CH2Ar & 1 × CH2Ph), 5.01 (app. t, J = 10.4 9.2 Hz, 1 H, 4-H), 5.23–
5.35 (m, 2 H, OCH2CH=CH2), 5.89–5.99 (m, 1 H, OCH2CH=CH2), 6.94–
6.97 (m, 1 H, aromatic H), 7.00–7.00 (m, 1 H, aromatic H), 7.26–7.35
(m, 6 H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8 [q,
H, 1 × CH2Ar), 5.48 (s, 1 H, CHPh), 5.49 (s, 1 H, CHPh), 6.96–6.99 (m,
2 H, aromatic H), 7.03–7.05 (m, 2 H, aromatic H), 7.28–7.38 (m, 8 H,
aromatic H), 7.45–7.49 (m, 4 H, aromatic H); δC (100 MHz, CDCl3)
–4.4 (q, SiCH3), –4.3 (q, SiCH3), –4.2 (q, SiCH3), –4.2 (q, SiCH3), 18.4
[s, SiC(CH3)3], 18.4 [s, SiC(CH3)3], 26.0 [3 × q, SiC(CH3)3], 26.0 [3 × q,
SiC(CH3)3], 62.7 (d, C-5α), 66.4 (d, C-5ꢀ), 68.4 (t, CH2Ar), 68.8 (t, C-
6ꢀ), 69.1 (t, C-6α), 69.4 (t, CH2Ar), 71.5 (d, C-4ꢀ), 74.3 (d, C-3ꢀ), 80.6
Eur. J. Org. Chem. 2016, 1520–1532
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(d, C-3α), 81.8 (d, C-2α), 82.1 (d, C-4α), 83.8 (d, C-2ꢀ), 92.6 (d, C-1α),
97.9 (d, C-1ꢀ), 102.0 (d, CHPh), 102.0 (d, CHPh), 126.1, 126.4, 126.4,
2.5 mmol) in AcOH (20 mL) was added Pd(PPh3)4 (1.0 equiv.) before
leaving to stir at room temperature overnight. The next day the
126.7, 126.8, 127.0, 127.0, 127.5, 128.2, 128.2, 129.1, 129.1, 137.3, reaction was diluted with CH2Cl2 (100 mL) before washing with
137.4, 140.5, 140.7 (16 × aromatic C) ppm. HRMS (ESI-TOF): calcd. NaHCO3 (satd. soln. 2 × 100 mL) before the organic layer was dried
for C24H34O6SSiNa+: 501.1738, found 501.1739 [MNa+].
(MgSO4) and concentrated under vacuum. The crude material was
then pre-adsorbed onto silica before purifying by flash column
chromatography (eluent; petroleum ether/EtOAc, 2:1, Rf = 0.2) to
2-O-(Thiophen-2-yl)methyl-3-O-acetyl-4,6-O-benzylidene-(α/ꢀ)-
D
-glucopyranose (5c): To a suspension of allyl glycoside (0.89 g,
afford hemiacetals 5e (1.11 g, 99 % yield) as an off white solid; νmax
˜
2.0 mmol) in AcOH (30 mL) was added Pd(PPh3)4 (1.0 equiv.) before
leaving to stir at room temperature overnight. The next day the
reaction was diluted with CH2Cl2 (200 mL) before washing with
NaHCO3 (satd. soln. 2 × 200 mL) before the organic layer was dried
(MgSO4) and concentrated under vacuum. The crude material was
then pre-adsorbed onto silica before purifying by flash column
chromatography (eluent; petroleum ether/EtOAc, 2:1, Rf = 0.2) to
(neat) 3372 (br., O–H), 1736 (s, C=O), 1715 (s, C=O) cm–1; δH
(400 MHz, CDCl3) [1.3:1 mixture of α/ꢀ anomers observed]: δ = 1.92
[s, 3 H, C(O)CH3], 1.93 [s, 3 H, C(O)CH3], 2.07 [s, 3 H, C(O)CH3], 2.07
[s, 3 H, C(O)CH3], 3.46 (dd, J = 8.8 8.0 Hz, 1 H, 2ꢀ-H), 3.57–3.66 (m,
3 H, 2α-H, 3ꢀ-H & 5ꢀ-H), 3.93 (app. t, J = 9.6 9.2 Hz, 1 H, 3α-H), 4.02
(dd, J = 12.4, 2.0 Hz, 1 H, 6α-H), 4.08–4.19 (m, 3 H, 5α-H, 6ꢀ-H & 6′
ꢀ-H), 4.22 (dd, J = 12.4, 4.8 Hz, 1 H, 6′α-H), 4.62–4.68 (m, 2 H, 2 ×
CH2Ph), 4.74 (d, J = 8.0 Hz, 1 H, 1ꢀ-H), 4.84–4.95 (m, 5 H, 2 × CH2Ph &
3 × CH2Ar), 5.02 (m, 2 H, 4α-H & 4ꢀ-H), 5.10 (d, J = 11.6 Hz, 1 H, 1 ×
CH2Ar), 5.14 (d, J = 3.6 Hz, 1 H, 1α-H), 6.95–6.98 (m, 2 H, aromatic
H), 7.00–7.03 (m, 2 H, aromatic H), 7.26–7.36 (m, 12 H, aromatic H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.9 [q, C(O)CH3], 20.9 [3 × q,
C(O)CH3], 62.4 (t, C-6ꢀ), 62.6 (t, C-6α), 67.9 (d, C-5α), 68.0 (t, CH2Ar),
69.0 (t, CH2Ar), 69.7 (d, C-4), 69.7 (d, C-4), 72.1 (d, C-5ꢀ), 75.4 (t,
CH2Ph), 75.5 (t, CH2Ph), 78.9 (d, C-3α), 79.3 (d, C-2α), 81.4 (d, C-3ꢀ),
82.5 (d, C-2ꢀ), 91.6 (d, C-1α), 97.5 (d, C-1ꢀ), 126.3, 126.7, 126.8, 126.9,
127.0, 127.4, 127.8, 128.0, 128.0, 128.5, 128.5, 138.3, 138.4, 140.4,
140.6 (16 × aromatic C), 169.7 (s, C=O), 169.8 (s, C=O), 171.0 (2 × s,
C=O) ppm. HRMS (ESI-TOF): calcd. for C22H26O8SNa+: 473.1241,
found 473.1243 [MNa+].
afford hemiacetals 5c (0.56 g, 69 % yield) as a yellow foam; νmax
˜
(neat) 3408 (br., OH), 1740 (s, C=O) cm–1; δH (400 MHz, CDCl3) [a 1:1
mixture of α/ꢀ anomers observed]: δ = 2.02 [s, 3 H, C(O)CH3], 2.08
[s, 3 H, C(O)CH3], 3.44 (dd, J = 8.8, 7.6 Hz, 1 H, 2ꢀ-H), 3.50–3.79 (6
H, 2α-H, 4α-H, 4ꢀ-H, 5ꢀ-H, 6α-H & H6ꢀ), 4.10–4.16 (m, 1 H, 5α-H),
4.28–4.35 (m, 2 H, 6′α-H & 6′ꢀ-H), 4.80 (d, J = 12.8 Hz, 1 H, 1 ×
OCH2Ar), 4.84 (d, J = 13.2 Hz, 1 H, 1 × OCH2Ar), 4.88 (d, J = 12.4 Hz,
1 H, 1 × OCH2Ar), 4.91 (d, J = 7.6 Hz, 1 H, 1ꢀ-H), 5.02 (d, J = 12.8 Hz,
1 H, 1 × OCH2Ar), 5.21 (d, J = 3.5 Hz, 1 H, 1α-H) 5.29 (app. t, J = 9.6,
9.2 Hz, 1 H, 3ꢀ-H), 5.46 (s, 2 H, 2 × CHPh), 5.51 (app. t, J = 10.0,
9.6 Hz, 1 H, 3α-H), 6.97–7.03 (m, 4 H, aromatic H), 7.30–7.45 (m, 12
H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1 [q,
C(O)CH3], 21.2 [q, C(O)CH3], 62.7 (d, C-5α), 66.5 (d, C-5ꢀ), 67.4 (t,
CH2Ar), 68.5 (t, CH2Ar), 68.7 (t, C-6), 69.0 (t, C-6), 70.6 (d, C-3α), 72.4
(d, C-3ꢀ), 77.3 (d, C-4α), 78.8 (d, C-2α), 79.2 (d, C-4ꢀ), 80.0 (d, C-2ꢀ),
91.9 (d, C-1α), 98.1 (d, C-1ꢀ), 101.5 (d, CHPh), 101.6 (d, CHPh), 126.3,
126.3, 126.4, 126.8, 126.9, 127.0, 127.2, 127.5, 128.3, 129.2, 137.0,
137.1, 139.9, 140.5 (14 × aromatic C), 170.1 (s, C=O), 170.1 (s, C=
O) ppm. HRMS (ESI-TOF): calcd. for C20H22O7SNa+: 429.0978, found
429.0986 [MNa+].
2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-benzylidene-
(α/ꢀ)-D-glucopyranosyl Trichloroacetimidate (6a): To a solution
of hemiacetals 5a (0.318 g, 0.7 mmol) in CH2Cl2 (10 mL) was added
trichloroacetonitrile (0.7 mL, 10 equiv.) and DBU (0.04 mL, 40 mol-
%) before leaving to stir overnight. The next day the reaction was
concentrated under vacuum and purified by flash column chroma-
tography (eluent; petroleum ether/EtOAc, 6:1, Rf = 0.4 & 0.3) to af-
ford trichloroacetimidate 6a (0.319 g, 76 % yield) as a yellow oil;
2-O-(Thiophen-2-yl)methyl-3,4,6-triacetyl-(α/ꢀ)-D-glucopyran-
ose (5d): Allyl glycoside 4d (1.67 g, 3.7 mmol) in AcOH (30 mL) was
added Pd(PPh3)4 (1.0 equiv.) before leaving to stir at room tempera-
ture overnight. The next day the reaction was diluted with CH2Cl2
(400 mL) before washing with NaHCO3 (satd. soln. 2 × 300 mL) be-
fore the organic layer was dried (MgSO4) and concentrated under
vacuum. The crude material was then pre-adsorbed onto silica be-
fore purifying by flash column chromatography (eluent; petroleum
ether/EtOAc, 2:1, Rf = 0.2) to afford hemiacetals 5d (1.15 g, 77 %
νmax (neat) 1671 (s, C=NH) cm–1; δH (400 MHz, CDCl3) [2.3:1 mixture
˜
of α/ꢀ anomers, major α anomer quoted]: δ = 3.69–3.81 (m, 3 H, 2-
H, 4-H & 6-H), 3.99–4.05 (m, 1 H 5-H), 4.11 (app. t, J = 9.6, 9.2 Hz, 1
H, 3-H), 4.32 (dd, J = 10.4, 4.8 Hz, 1 H, 6′-H), 4.85–4.95 (m, 4 H, 2 ×
OCH2Ar & 2 × OCH2Ph), 5.58 (s, 1 H, CHPh), 5.90 (d, J = 7.8 Hz, 0.44
H, Hꢀ) 6.38 (d, J = 3.6 Hz, 1 H, 1-H), 6.95–7.00 (m, 2 H, aromatic H),
7.27–7.33 (m, 4 H, aromatic H), 7.36–7.40 (m, 4 H, aromatic H), 7.48–
7.51 (m, 2 H, aromatic H), 8.62 (1 H, br. S, NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 65.2 (d, C-5), 68.2 (t, OCH2Ar), 68.8 (t, C-6),
75.4 (t, OCH2Ph), 78.1 (d, C-2), 78.1 (d, C-3), 81.5 (d, C-4), 94.9 (d, C-
1), 98.2 (s, CCl3), 101.4 (d, CHPh), 126.1, 126.3, 126.7, 126.8, 127.7,
128.1, 128.4, 128.4, 129.1, 137.2, 138.6, 140.6 (12 × aromatic C),
161.5 (s, C=NH) ppm. HRMS (ESI-TOF): calcd. for C27H26Cl3NO6SH+:
598.0619, found 598.0613 [MH+].
yield) as a yellow oil; ν
(neat) 3434 (br., OH), 1740 (s, C=O) cm–1
;
˜
max
δH (400 MHz, CDCl3) [1.1:1 mixture of α/ꢀ anomers]: δ = 1.97 [s, 3
H, C(O)CH3], 2.00 [s, 3 H, C(O)CH3], 2.01 [s, 3 H, C(O)CH3], 2.02 [s, 3
H, C(O)CH3], 2.07 [s, 6 H, 2 × C(O)CH3], 3.43 (app. t, J = 10.0, 7.6 Hz,
1 H, 2ꢀ-H), 3.64 (dd, J = 9.6, 2.6 Hz, 1 H, 2α-H), 3.68–3.72 (m, 1 H,
5ꢀ-H), 4.04–4.13 (m, 2 H, 6α-H & H6ꢀ), 4.19–4.29 (m, 3 H, 5α-H, 6′
α-H & H6′ꢀ), 4.79–4.86 (m, 5 H, 1ꢀ-H, 4 × OCH2Ar), 4.95–5.00 (m, 2
H, 4α-H, 4ꢀ-H), 5.13 (app. t, J = 9.6 Hz, 3ꢀ-H), 5.21 (d, J = 3.2 Hz, 1
H, 1α-H), 5.42 (app. t, J = 10.0, 9.2 Hz, 1 H, 3α-H), 6.95–7.00 (m, 3 H,
aromatic H), 7.28–7.32 (m, 3 H, aromatic H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.7 [q, C(O)CH3], 20.8 [q, C(O)CH3], 20.9 [2 × q, C(O)CH3],
20.9 [q, C(O)CH3], 21.0 [q, C(O)CH3], 62.1 (t, C-6), 62.3 (t, C-6), 67.5
(d, C-5α), 67.5 (t, OCH2Ar), 68.4 (t, OCH2Ar), 68.5 (C-4), 68.7 (C-4),
71.7 (d, C-5ꢀ), 71.9 (d, C-3α), 73.6 (d, C-3ꢀ), 76.5 (d, C-2α), 78.9 (d,
C-2ꢀ), 91.1 (d, C-1α), 97.5 (d, C-1ꢀ), 126.4, 126.8, 126.9, 127.0, 127.2,
127.5, 139.9, 140.4 (8 × aromatic C), 169.8 (s, C=O), 170.0 (s, C=O),
170.3 (2 × s, C=O), 170.9 (2 × s, C=O) ppm. HRMS (ESI-TOF): calcd.
for C17H22O9SNa+: 425.0877, found 425.0885 [MNa+].
O-[2-O-(Thiophen-2-yl)methyl-3-O-tert-butyldimethylsilyl-4,6-
O-benzylidene-(α/ꢀ)-D-glucopyranosyl] Trichloroacetimidate
(6b): To a solution of hemiacetals 5b (0.335 g, 0.7 mmol) in CH2Cl2
(10 mL) was added trichloroacetonitrile (0.7 mL, 10 equiv.) and DBU
(0.04 mL, 40 mol-%) before leaving to stir overnight. The next day
the reaction was concentrated under vacuum and purified by flash
column chromatography (eluent; petroleum ether/EtOAc, 9:1, Rf =
0.2) to afford trichloroacetimidate 6b (0.318 g, 73 % yield) as a col-
ourless oil; νmax (neat) 1671 (s, C=NH) cm–1; δH (400 MHz, CDCl3)
˜
[3.4:1 mixture of α/ꢀ anomers, major α anomer quoted]: δ = 0.05
(s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3), 0.87 [s, 9 H, SiC(CH3)3], 3.54 (app.
t, J = 9.6 Hz, 1 H, 4-H), 3.61 (dd, J = 9.2, 3.6 Hz, 1 H, 2-H), 3.70 (app.
t, J = 10.4, 9.6 Hz, 1 H, 6-H), 3.94–4.00 (m, 1 H, 5-H), 4.17 (app. t, J =
2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-diacetyl-(α/ꢀ)-
glucopyranose (5e): To a suspension of allyl glycoside 4e (1.21 g,
D-
Eur. J. Org. Chem. 2016, 1520–1532
www.eurjoc.org
1528
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
9.2 Hz, 1 H, 3-H), 4.29 (dd, J = 10.4, 5.2 Hz, 1 H, 6′-H), 4.83 (s, 2 H,
OCH2Ar), 5.52 (s, 1 H, CHPh), 5.92 (d, J = 7.8 Hz, 0.29 H, 1ꢀ-H), 6.35
(d, J = 3.6 Hz, 1 H, 1-H), 6.94–6.99 (m, 2 H, aromatic H), 7.26–7.28
(m, 1 H, aromatic H), 7.34–7.38 (m, 3 H, aromatic H), 7.47–7.51 (m,
2 H, aromatic H), 8.57 (br. s, 1 H, NH); δC (100 MHz, CDCl3) –4.4 (q,
SiCH3), –4.3 (q, SiCH3), 18.5 [s, SiC(CH3)3], 26.0 [3 × q, SiC(CH3)3], 65.3
(d, C-5), 68.1 (t, CH2Ar), 68.9 (t, C-6), 71.2 (d, C-3), 79.5 (d, C-2), 81.8
(d, C-4), 94.8 (d, C-1), 98.3 (s, CCl3), 101.9 (d, CHPh), 126.3, 126.3,
126.6, 126.9, 128.2, 129.1, 137.2, 140.4 (8 × aromatic C), 161.5 (s, C=
NH) ppm. HRMS (ESI-TOF): calcd. for C26H34Cl3NO6SSiH+: 622.1014,
found 622.1017 [MH+].
miacetals 5e (0.316 g, 0.7 mmol) in CH2Cl2 (10 mL) was added tri-
chloroacetonitrile (0.7 mL, 10 equiv.) and DBU (0.04 mL, 0.4 equiv.)
before leaving to stir overnight. The next day analysis by TLC (petro-
leum ether/EtOAc, 2:1) showed complete consumption of the start-
ing material (Rf = 0.2) and formation of two new spots (Rf = 0.4 &
0.6). The reaction was then concentrated under vacuum and puri-
fied by flash column chromatography (eluent; petroleum ether/
EtOAc, 4:1, Rf = 0.3) to afford trichloroacetimidate 6e (0.344 g, 83 %
yield) as a yellow oil; νmax (neat) 1742 (s, C=O), 1672 (s, C=N) cm–1
;
˜
δ
H (400 MHz, CDCl3) [3.8:1 mixture of α/ꢀ anomers observed, major
α anomer quoted]: δ = 1.95 [s, 3 H, C(O)CH3], 2.04 [s, 3 H, C(O)CH3],
3.82 (dd, J = 9.2, 3.6 Hz, 1 H, 2-H), 3.96 (app. t, J = 9.6, 9.2 Hz, 1 H,
3-H), 4.03–4.08 (m, 2 H, 5-H & 6-H), 4.18–4.22 (m, 1 H, 6′-H), 4.66 (d,
J = 12.0 Hz, 1 H, CH2Ar), 4.83–4.91 (m, 3 H, 3 × CH2Ar), 5.10 (app. t,
J = 10.0, 9.6 Hz, 1 H, 4-H), 6.43 (d, J = 3.6 Hz, 1 H, 1-H), 6.95–6.99
(m, 2 H, aromatic H), 7.26–7.36 (m, 7 H, aromatic H), 8.65 (s, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8 [q, C(O)CH3], 20.9 [q,
C(O)CH3], 62.0 (t, C-6), 67.8 (d, C-5), 68.9 (t, CH2Ar), 70.5 (d, C-4), 75.3
(t, CH2Ph), 78.2 (d, C-3), 78.6 (d, C-2), 91.2 (s, CCl3), 94.0 (d, C-1),
126.5, 126.8, 126.9, 127.9, 128.1, 128.5, 138.3, 140.3 (8 × aromatic
C), 161.1 (s, C=N), 169.7 (s, C=O), 170.8 (s, C=O) ppm. HRMS (ESI-
TOF): calcd. for C24H26Cl3NO8SNa+: 616.0337, found 616.0336
[MNa+].
O-[2-O-(Thiophen-2-yl)methyl-3-O-acetyl-4,6-O-benzylidene-
(α/ꢀ)-D-glucopyranosyl] Trichloroacetimidate (6c): To a solution
of hemiacetals 5c (0.203 g, 0.5 mmol) in CH2Cl2 (10 mL) was added
trichloroacetonitrile (0.5 mL, 10 equiv.) and DBU (0.03 mL, 40 mol-
%) before leaving to stir overnight. The next day the reaction was
concentrated under vacuum and purified by flash column chroma-
tography (eluent; petroleum ether/EtOAc, 4:1, Rf = 0.3) to afford
trichloroacetimidate 6c (0.249 g, 90 % yield) as a yellow oil; νmax
˜
(neat) 1727 (s, C=O), 1672 (s, C=NH) cm–1; δH (400 MHz, CDCl3) [a
2.2:1 mixture of α/ꢀ anomers observed, major α anomer quoted]:
δ = 2.08 [s, 3 H, C(O)CH3], 3.64 (app. t, J = 10.0, 9.6 Hz, 1 H, 4-H),
3.71 (app. t, J = 10.4, 10.0 Hz, 1 H, 6-H), 3.82 (dd, J = 10.0, 3.2 Hz, 1
H, 2-H), 4.06–4.11 (m, 1 H, 5-H), 4.32 (dd, J = 10.4, 4.8 Hz, 1 H, 6′-
H), 4.77 (d, J = 12.8 Hz, 1 H, 1 × CH2Ar), 4.83 (d, J = 13.2 Hz, 1 H,
1 × CH2Ar), 5.48 (s, 1 H, CHPh), 5.60 (app. t, J = 10.0, 9.6 Hz, 1 H, 3-
H), 6.46 (d, J = 3.2 Hz, 1 H, 1-H), 6.97–7.00 (m, 2 H, aromatic H),
7.31–7.37 (m, 4 H, aromatic H), 7.43–7.45 (m, 2 H, aromatic H), 8.65
(s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.1 [q, C(O)CH3],
65.2 (d, C-5), 67.2 (t, CH2Ar), 68.7 (t, C-6), 70.2 (d, C-3), 75.8 (d, C-2),
79.0 (d, C-4), 91.0 (s, CCl3), 94.1 (d, C-1), 101.6 (d, CHPh), 126.2, 126.7,
126.8, 127.3, 128.3, 129.2, 136.9, 139.9 (8 × aromatic C), 161.6 (s, C=
N ) , 1 6 9 . 8 ( s , C = O ) p p m . H R M S ( E S I -T O F ) : c a l c d . f o r
2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-benzylidene-
(α/ꢀ)-
D
-glucopyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-D-
galactopyranose (7a): The general procedure for glycosylation
with trichloroacetimidate 6a (75 mg, 0.125 mmol) and diacetone
galactose (65 mg, 2 equiv.) gave disaccharide 7a as a yellow oil
(73 mg, 84 % yield); δH (400 MHz, CDCl3) [1:1.7 mixture of α/ꢀ ano-
mers observed]: δ = 1.33 [s, 3 H, (C)CH3], 1.34 [s, 6 H, 2 × (C)CH3],
1.45 [s, 3 H, (C)CH3], 1.46 [s, 3 H, (C)CH3], 1.52 [s, 3 H, (C)CH3], 1.55
[s, 6 H, 2 × (C)CH3], 3.36–3.43 (m, 1 H, 5bꢀ-H), 3.49 (app. t, J = 8.8,
7.6 Hz, 1 H, 2bꢀ-H), 3.58–3.79 (m, 9 H, 2bα-H, 3bꢀ-H, 4bα-H, 4bꢀ-H,
6aα -H6aꢀ -H6bα-H, 6bꢀ-H & 6′a-H), 3.89–3.95 (m, 1 H, 5bα-H), 4.01–
4.12 (m, 4 H, 3bα-H, 5aα-H, 5aꢀ-H, & 6′a-H), 4.23–4.37 (m, 6 H, 2aα-
H, 2aꢀ-H, 4aα-H, 4aꢀ-H, 6′bα-H & 6′bꢀ-H), 4.57 (d, J = 7.6 Hz, 1 H,
1bꢀ-H), 4.60–4.64 (m, 2 H, 3aα-H & 3aꢀ-H), 4.82–4.92 (m, 8 H, 1bα-
H, 4 × OCH2Ph, 3 × OCH2Ar), 5.22 (d, J = 12.0 Hz, 1 H, OCH2Ar), 5.52–
5.58 (m, 4 H, 1aα-H, 1aꢀ-H, 2 × CHPh), 6.95–6.97 (m, 2 H, aromatic
H), 7.00–7.02 (m, 1 H, aromatic H), 7.11–7.12 (m, 1 H, aromatic H),
7.26–7.32 (m, 10 H, aromatic H), 7.36–7.39 (m, 8 H, aromatic H),
7.46–7.50 (m, 4 H, aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.6 [q, (C)CH3], 24.8 [q, (C)CH3], 25.1 [q, (C)CH3], 25.1 [q, (C)CH3],
26.1 [q, (C)CH3], 26.2 [2 × q, 2 × (C)CH3], 26.3 [q, (C)CH3], 62.6 (d, C-
5bα), 66.2 (d, C-5bꢀ), 67.2 (2 × d, 2 × C-5a), 67.4 (t, C-6a), 67.7 (t,
OCH2Ar), 68.9 (t, OCH2Ar), 69.0 (t, C-6b), 69.1 (t, C-6b), 70.3 (t, C-6a),
70.6 (d, C-2a), 70.8 (d, C-2a), 70.9 (2 × d, 2 × C-3a), 71.0 (d, C-4a), 71.5
(d, C-4a), 75.3 (t, OCH2Ph), 75.4 (t, OCH2Ph), 78.7 (d, C-3bα), 78.9 (d,
C-3bꢀ), 80.5 (d, C-4bꢀ), 81.3 (d, C-4bα), 81.4 (d, C-2bꢀ), 82.2 (d, C-
2bα), 96.4 (d, C-1aα), 96.5 (d, C-1aꢀ), 98.6 (d, C-1bα), 101.3 (d, CHPh),
101.4 (d, CHPh), 105.0 (d, C-1bꢀ), 108.8 [s, (C)CH3], 108.8 [s, (C)CH3],
109.4 [s, (C)CH3], 109.6 [s, (C)CH3], 126.0, 126.1, 126.2, 126.6, 126.8,
126.8, 127.3, 127.7, 127.7, 128.1, 128.2, 128.3, 128.4, 128.4, 129.0,
129.0, 137.5, 137.6, 138.7, 139.0, 141.0, 141.1 (22 × aromatic C) ppm.
HRMS (ESI-TOF): calcd. for C37H44O11SNa+: 719.2497, found 719.2498
[MNa+].
C
22H22Cl3NO7SNa+: 572.0075, found 572.0077 [MNa+].
O-[2-O-(Thiophen-2-yl)methy-3,4,6-triacetyl-(α/ꢀ)-
D
-gluco-
pyranosyl] Trichloroacetimidate (6d): To a solution of hemiacetals
5d (0.423 g, 1.05 mmol) in CH2Cl2 (15 mL) was added trichloroaceto-
nitrile (1.05 mL, 10 equiv.) and DBU (0.06 mL, 0.4 equiv.) before
leaving to stir overnight. The next day analysis by TLC (petroleum
ether/EtOAc, 2:1) showed complete consumption of the starting
material (Rf = 0.2) and formation of a new spot (Rf = 0.4). The reac-
tion was then concentrated under vacuum and purified by flash
column chromatography (eluent; petroleum ether/EtOAc, 3:1, Rf =
0.2) to afford trichloroacetimidate 6d (0.433 g, 75 % yield) as a yel-
low oil; νmax (neat) 1743 (s, C=O), 1674 (s, C=N) cm–1; δH (400 MHz,
˜
CDCl3) [4.9:1 mixture of α/ꢀ anomers observed, major α anomer
quoted]: δ = 2.03 [s, 6 H, 2 × C(O)CH3], 2.05 [s, 3 H, C(O)CH3], 3.81
(dd, J = 9.6, 3.6 Hz, 1 H, 2-H), 4.07 (dd, J = 12.4, 1.6 Hz, 1 H, 6-H),
4.16–4.20 (m, 1 H, 5-H), 4.27 (dd, J = 12.4, 4.4 Hz, 1 H, 6′-H), 4.75 (d,
J = 13.2 Hz, 1 H, 1 × CH2Ar), 4.81 (d, J = 12.8 Hz, 1 H, 1 × CH2Ar),
5.07 (app. t, J = 10.4, 9.6 Hz, 1 H, 4-H), 5.46 (app. t, J = 10.0, 9.6 Hz,
1 H, 3-H), 5.83 (d, J = 7.8 Hz, 0.21 H, 1ꢀ-H), 6.47 (d, J = 3.6 Hz, 1 H,
1-H), 6.96–7.00 (m, 2 H, aromatic H), 7.30–7.31 (m, 1 H, aromatic H),
8.67 (s, 1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.8 [q,
C(O)CH3], 20.8 [q, C(O)CH3], 21.0 [q, C(O)CH3], 61.7 (t, C-6), 67.3 (t,
CH2Ar), 68.1 (d, C-4), 70.1 (d, C-5), 71.4 (d, C-3), 75.1 (d, C-2), 91.0 (s,
CCl3), 93.4 (d, C-1), 126.8, 126.8, 127.3, 139.9 (4 × aromatic C), 161.2
(s, C=N), 169.8 (s, C=O), 170.1 (s, C=O), 170.6 (s, C=O) ppm. HRMS
(ESI-TOF): calcd. for C19H22Cl3NO9SNa+: 567.9973, found 567.9993
[MNa+].
2-O-(Thiophen-2-yl)methyl-3-O-tert-butyldimethylsilyl-4,6-O-
benzylidene-(α/ꢀ)-
D
-glucopyranosyl-(1→6)-1,2:3,4-di-O-iso-
propylidene- -galactopyranose (7b): The general procedure for
D
glycosylation with trichloroacetimidate 6b (78 mg, 0.125 mmol) and
diacetone galactose gave disaccharide 7b as a colourless oil (68 mg,
75 % yield); δH (400 MHz, CDCl3) [1:1.6 mixture of α/ꢀ anomers
observed]: δ = –0.01 (s, 3 H, SiCH3), –0.01 (s, 3 H, SiCH3), –0.07 (s, 3
O-[2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-diacetyl-(α/ꢀ)-
D
-glucopyranosyl] Trichloroacetimidate (6e): To a solution of he-
Eur. J. Org. Chem. 2016, 1520–1532
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Full Paper
H, SiCH3), –0.07 (s, 3 H, SiCH3), 0.85 [s, 9 H, SiC(CH3)3], 0.86 [s, 9 H,
SiC(CH3)3], 1.31 [s, 3 H, (C)CH3], 1.32 [s, 3 H, (C)CH3], 1.33 [s, 2 × 3
H, 2 × (C)CH3], 1.44 [s, 3 H, (C)CH3], 1.46 [s, 3 H, (C)CH3], 1.50 [s, 3
H, (C)CH3], 1.57 [s, 3 H, (C)CH3], 3.31–3.48 (m, 5 H, 2bα-H, 2bꢀ-H,
2[-O-(Thiophen-2-yl)methy-3,4,6-triacetyl-(α/ꢀ)-
D
-glucopyrano-
syl]-(1→6)-1,2:3,4-di-O-isopropylidene-
D
-galactopyranose (7d):
The general procedure for glycosylation with trichloroacetimidate
6d (69 mg, 0.125 mmol) and diacetone galactose (65 mg, 2 equiv.)
3bα-H, 4bꢀ-H & 5bꢀ-H), 3.63–3.81 (m, 6 H, 3bꢀ-H, 6aα-H, 6aꢀ-H, 6bα- gave disaccharide 7d as a yellow oil (72 mg, 89 % yield) as a yellow
H, 6bꢀ-H & 6′aα-H), 3.86–3.92 (m, 1 H, 5bα-H), 4.05–4.11 (4 H, 4bα- oil; νmax (neat) 1744 (s, C=O) cm–1; δH (400 MHz, CDCl3) [1.4:1 mix-
˜
H, 5aα-H, 5aꢀ-H & 6′aꢀ-H), 4.23–4.35 (m, 6 H, 2aα-H, 2aꢀ-H, 4aα-H, ture of α/ꢀ anomers observed]: δ = 1.32 & 1.33 [s, 2 × 6 H, (C)CH3],
4aꢀ-H, 6bα-H & 6bꢀ-H), 4.54 (d, J = 7.6 Hz, 1 H, 1bꢀ-H), 4.59–4.63 (m, 1.44, 1.46, 1.52 & 1.56 [s, 4 × 3 H, (C)CH3], 1.97, 1.99, 2.01, 2.02,
2 H, 3aα-H & 3aꢀ-H), 4.78–4.90 (m, 4 H, 1bα-H & 3 × CH2Ar), 5.16 (d,
J = 11.6 Hz, 1 H, 1 × CH2Ar), 5.47 (s, 1 H, CHPhα), 5.48 (s, 1 H,
CHPhꢀ), 5.52 (d, J = 5.2 Hz, 1 H, 1aα-H), 5.55 (d, J = 5.2 Hz, 1 H, 1aꢀ-
2.07 & 2.07 [s, 6 × 3 H, C(O)CH3], 3.43 (dd, J = 9.6, 7.6 Hz, 1 H, 2bꢀ-
H), 3.60 (dd, J = 10.4, 3.6 Hz, 1 H, 2bα-H), 3.62–3.66 (m, 1 H, 5bꢀ-H),
3.71–3.78 (m, 3 H, 6aα-H, 6′aα-H & 6aꢀ-H), 4.01–4.15 (m, 6 H, 5aα-H,
H), 6.93–6.97 (m, 2 H, aromatic H), 7.03 (d, J = 3.2 Hz, 1 H, aromatic 5aꢀ-H, 5bα-H, 6bα-H, 6bꢀ-H & 6′aꢀ-H), 4.22–4.34 (m, 6 H, 2aα-H, 2aꢀ-
H), 7.12 (d, J = 3.2 Hz, 1 H, aromatic H), 7.25–7.29 (m, 2 H, aromatic
H), 7.34–7.37 (m, 6 H, aromatic H), 7.46–7.48 (m, 4 H, aromatic H);
δC (100 MHz, CDCl3) –4.3 (q, SiCH3), –4.3 (q, SiCH3), –4.2 (q, SiCH3),
H, 4aα-H, 4aꢀ-H, 6′bα-H & 6′bꢀ-H), 4.55 (d, J = 7.6 Hz, 1 H, 1bꢀ-H),
4.60–4.63 (m, 2 H, 3aα-H & 3aꢀ-H), 4.73–4.82 (m, 3 H, 3 × OCH2Ar),
4.88–5.07 (m, 4 H, 1bα-H, 4bα-H, 4bꢀ-H & 1 × OCH2Ar), 5.10 (app. t,
–4.2 (q, SiCH3), 18.4 [s, SiC(CH3)3], 18.5 [s, SiC(CH3)3], 24.6 [q, (C)CH3], J = 9.6, 9.2 Hz, 1 H, 3bꢀ-H), 5.40 (app. t, J = 9.6 Hz, 1 H, 3bα-H), 5.50
24.7 [q, (C)CH3], 25.1 [q, (C)CH3], 25.1 [q, (C)CH3], 26.0 [q, SiC(CH3)3], (d, J = 4.8 Hz, 1 H, 1aα-H), 5.56 (d, J = 5.6 Hz, 1 H, 1aꢀ-H), 6.93–7.04
26.0 [q, SiC(CH3)3], 26.1 [q, (C)CH3], 26.2 [q, (C)CH3], 26.2 [q, (C)CH3], (m, 4 H, aromatic H), 7.28–7.30 (m, 2 H, aromatic H) ppm. 13C NMR
26.3 [q, (C)CH3], 62.5 (d, C-5bα), 66.1 (d, C-5bꢀ), 66.5 (d, C-5aα), 67.3
(d, C-5aꢀ), 67.5 (t, C-6aα), 67.6 (t, OCH2Ar), 68.7 (t, OCH2Ar), 68.9 (t,
(100 MHz, CDCl3): δ = 20.8 [q, C(O)CH3], 20.8 [q, C(O)CH3], 20.9 [q,
C(O)CH3], 20.9 [q, C(O)CH3], 21.0 [q, C(O)CH3], 21.0 [q, C(O)CH3], 24.5
C-6bꢀ), 69.2 (t, C-6bα), 70.1 (t, C-6aꢀ), 70.6 (d, C-2a), 70.8 (d, C-2a), [q, (C)CH3], 24.7 [q, (C)CH3], 25.1 [q, (C)CH3], 25.1 [q, (C)CH3], 26.1
70.9 (d, C-3a), 70.9 (d, C-3a), 71.2 (d, C-4a), 71.5 (d, C-4a), 71.6 (d, C-
4bα), 74.1 (d, C-3bꢀ), 79.9 (d, C-3bα), 81.8 (d, C-2bα), 82.0 (d, C-4bꢀ),
[q, (C)CH3], 26.2 [q, (C)CH3], 26.2 [q, (C)CH3], 26.3 [q, (C)CH3], 62.1 (t,
C-6bα), 62.2 (t, C-6bꢀ), 66.4 (d, C-5bα), 66.8 (t, OCH2Ar), 67.3 (d, C-
82.5 (d, C-2bꢀ), 96.5 (2 × d, C-1aꢀ & C-1aα), 98.7 (d, C-1bα), 101.9 (d, 5aα), 67.6 (d, C-5aꢀ), 67.7 (t, C-6aα), 67.9 (t, OCH2Ar), 68.7 (d, C-4bα),
CHPh), 101.9 (d, CHPh), 105.0 (d, C-1bꢀ), 108.7 [s, (C)CH3], 108.8 [s, 68.7 (d, C-4bꢀ), 70.5 (t, C-6aꢀ), 70.5 (d, C-2aꢀ), 70.7 (d, C-2aα), 70.8
(C)CH3], 109.4 [s, (C)CH3], 109.6 [s, (C)CH3], 125.8, 126.2, 126.4, 126.5, (d, C-3aα), 70.9 (d, C-3aꢀ), 71.0 (d, C-4aα), 71.5 (d, C-4aꢀ), 71.7 (d, C-
126.5, 126.7, 127.0, 127.5, 128.2, 128.2, 129.0, 129.1, 137.4, 137.6, 5bꢀ), 71.8 (d, C-3bα), 73.4 (d, C-3bꢀ), 75.9 (d, C-2bα), 76.9 (d, C-2bꢀ),
140.8, 141.1 (16 × aromatic C) ppm. HRMS (ESI-TOF): calcd. for
96.4 (d, C-1aα), 96.5 (d, C-1aꢀ), 97.3 (d, C-1bα), 104.5 (d, C-1bꢀ), 108.7
[s, (C)CH3], 108.9 [s, (C)CH3], 109.4 [s, (C)CH3], 109.7 [s, (C)CH3], 126.2,
126.5, 126.6, 126.8, 127.0, 127.5, 140.4, 140.9 (8 × aromatic C), 169.8
[s, C(O)CH3], 170.0 [s, C(O)CH3], 170.3 [s, C(O)CH3], 170.3 [s, C(O)CH3],
170.8 [s, C(O)CH3], 170.8 [s, C(O)CH3] ppm. HRMS (ESI-TOF): calcd.
for C29H40O14SNa+: 667.2031, found 667.2085 [MNa+].
C36H52O11SSiNa+: 743.2892, found 743.2911 [MNa+].
2-O-(Thiophen-2-yl)methyl-3-O-acetyl-4,6-O-benzylidene-
(α/ꢀ)-
D
-glucopyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-D-
galactopyranose (7c): The general procedure for glycosylation
with trichloroacetimidate 6c (69 mg, 0.125 mmol) and diacetone
galactose (65 mg, 2 equiv.) gave disaccharide 7c as a yellow oil
2-O-(Thiophen-2-yl)methyl-3-O-benzyl-4,6-O-diacetyl-(α/ꢀ)-
D-
(61 mg, 75 % yield); νmax (neat) 1728 (s, C=O) cm–1; δH (400 MHz,
glucopyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene- -galacto-
D
˜
CDCl3) [1.2:1 mixture of α/ꢀ anomers observed]: δ = 1.32 [s, 9 H,
3 × (C)CH3], 1.34 [s, 3 H, (C)CH3], 1.45 [s, 3 H, (C)CH3], 1.47 [s, 3 H,
(C)CH3], 1.53 [s, 3 H, (C)CH3], 1.57 [s, 3 H, (C)CH3], 2.02 [s, 3 H,
C(O)CH3], 2.07 [s, 3 H, C(O)CH3], 3.42–3.58 (m, 4 H, 2bꢀ-H, 4bα-H,
4bꢀ-H & 5bꢀ-H), 3.61 (dd, J = 9.6, 3.6 Hz, 1 H, 2bα-H), 3.66–3.83 (m,
pyranose (7e): The general procedure for glycosylation with tri-
chloroacetimidate 6e (74 mg, 0.125 mmol) and diacetone galactose
(65 mg, 2 equiv.) gave disaccharide 7e as a yellow oil (65 mg, 75 %
yield); ν
(neat) 1742 (s, C=O) cm–1; δH (400 MHz, CDCl3) [1:1.1
˜
max
mixture of α/ꢀ anomers observed]: δ = 1.32–1.34 [m, 12 H, 4 ×
5 H, 6bα-H, 6bꢀ-H, 2 × 6a-H & 6′a-H), 3.93–4.00 (m, 1 H, 5bα-H), 4.04– (C)CH3], 1.44 [s, 3 H, (C)CH3], 1.46 [s, 3 H, (C)CH3], 1.51 [s, 3 H, (C)CH3],
4.14 (m, 3 H, 2 × 5a-H & 6′a-H), 4.21–4.39 (m, 6 H, 2 × 2a-H, 2 × 4a- 1.56 [s, 3 H, (C)CH3], 1.88 [s, 3 H, C(O)CH3], 1.92 [s, 3 H, C(O)CH3],
H, 6′bα-H & 6′bꢀ-H), 4.61–4.66 (m, 3 H, 1bꢀ-H & 2 × 3a-H), 4.76 (d, 2.06 [s, 6 H, 2 × C(O)CH3], 3.49–3.59 (m, 3 H, 2bꢀ-H, 3bꢀ-H & 5bꢀ-H),
J = 13.2 Hz, 1 H, 1 × OCH2Ar), 4.84 (d, J = 13.2 Hz, 1 H, 1 × OCH2Ar),
3.63 (dd, J = 9.6, 4.0 Hz, 1 H, 2bα-H), 3.70–3.78 (m, 3 H, 2 × 6a-H &
4.91 (d, J = 12.8 Hz, 1 H, 1 × OCH2Ar), 4.98 (d, J = 3.6 Hz, 1 H, 1bα- 1 × 6′a-H), 3.91 (app. t, J = 9.2 Hz, 1 H, 3bα-H), 3.97–4.15 (m, 6 H,
H), 5.08 (d, J = 12.8 Hz, 1 H, 1 × OCH2Ar), 5.25 (app. t, J = 9.6, 9.2 Hz,
1 H, 3bꢀ-H), 5.44 (s, 1 H, CHPh), 5.45 (s, 1 H, CHPh), 5.50–5.58 (m, 3
H, 2 × 1a-H & 3bα-H), 6.94–7.00 (m, 3 H, aromatic H), 7.06–7.06 (m,
1 H, aromatic H), 7.28–7.36 (m, 8 H, aromatic H), 7.40–7.44 (m, 4 H,
aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.2 [q, C(O)CH3],
21.2 [q, C(O)CH3], 24.6 [q, (C)CH3], 24.8 [q, (C)CH3], 25.1 [q, (C)CH3],
25.1 [q, (C)CH3], 26.1 [q, (C)CH3], 26.2 [q, (C)CH3], 26.2 [q, (C)CH3],
26.3 [q, (C)CH3], 62.7 (d, C-5bα), 66.1 (d, C-5bꢀ), 66.2 (t, OCH2Ar),
66.4 (d, C-5a), 67.3 (d, C-5a), 67.5 (t, C-6a), 68.0 (t, OCH2Ar), 68.8 (t,
C-6bꢀ), 69.1 (t, C-6bα), 70.4 (d, C-3bα), 70.6 (t, C-6a), 70.8 (d, C-2a),
5bα-H, 2 × 5a-H, 2 × 6b-H & 1 × 6′a-H), 4.20–4.34 (m, 6 H, 2 × 2a-H,
2 × 4a-H & 2 × 6′b-H), 4.48 (d, J = 7.6 Hz, 1 H, 1bꢀ-H), 4.59–4.64 (m,
4 H, 2 × 3a-H & 2 × OCH2Ph), 4.84–4.93 (m, 6 H, 1bα-H, 2 × OCH2Ph &
3 × OCH2Ar), 4.97–5.04 (m, 2 H, 4bα-H & 4bꢀ-H), 5.26 (d, J = 11.6 Hz,
1 H, OCH2Ar), 5.51 (d, J = 5.2 Hz, 1 H, 1aα-H), 5.58 (d, J = 4.6 Hz, 1
H, 1aꢀ-H), 6.94–6.96 (m, 2 H, aromatic H), 7.00–7.01 (m, 1 H, aromatic
H), 7.11–7.12 (m, 1 H, aromatic H), 7.25–7.34 (m, 12 H, aromatic H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.9 [2 × q, 2 × C(O)CH3], 21.0
[2 × q, 2 × C(O)CH3], 24.6 [q, (C)CH3], 24.8 [q, (C)CH3], 25.1 [q,
(C)CH3], 25.2 [q, (C)CH3], 26.1 [q, (C)CH3], 26.2 [2 × q, 2 × (C)CH3],
70.8 (d, C-2a), 70.9 (d, C-3a), 70.9 (d, C-3a), 71.5 (2 × d, 2 × C-4a), 72.2 26.3 [q, (C)CH3], 62.4 (t, C-6b), 62.5 (t, C-6b), 66.5 (d, C-5bα), 67.5 (d,
(d, C-3bꢀ), 76.7 (d, C-2bα), 78.1 (d, C-4bα), 78.9 (d, C-4bꢀ), 79.6 (d, C-
2bꢀ), 96.4 (d, C-1aα), 96.5 (d, C-1aꢀ), 98.2 (d, C-1bα), 101.5 (d, CHPh),
C-5a), 67.5 (d, C-5a), 67.6 (t, C-6a), 67.8 (t, OCH2Ar), 68.6 (t, OCH2Ar),
69.6 (d, C-4b), 69.7 (d, C-4b), 70.4 (t, C-6a), 70.6 (d, C-2a), 70.7 (d, C-
101.6 (d, CHPh), 105.1 (d, C-1bꢀ), 108.7 [s, (C)CH3], 108.9 [s, (C)CH3], 2a), 70.9 (d, C-3a), 71.0 (d, C-3a), 71.2 (d, C-4a), 71.6 (d, C-4a), 72.0 (d,
109.3 [s, (C)CH3], 109.7 [s, (C)CH3], 126.2, 126.3, 126.3, 126.4, 126.6, C-5bꢀ), 75.3 (t, OCH2Ph), 75.4 (t, OCH2Ph), 79.2 (2 × d, C-2bα & C-
126.8, 127.6, 128.3, 128.3, 129.1, 129.2, 129.9, 137.1, 137.3, 140.6, 3bα), 81.1 (d, C-3bꢀ), 81.1 (d, C-2bꢀ), 96.5, 96.5 (2 × d, C-1aα & C-
141.0 (16 × aromatic C), 170.0 [s, C(O)CH3] ppm. HRMS (ESI-TOF):
1aꢀ), 97.4 (d, C-1bα), 104.6 (d, C-1bꢀ), 108.7 [s, (C)CH3], 108.8 [s,
(C)CH3], 109.5 [s, (C)CH3], 109.6 [s, (C)CH3], 126.1, 126.4, 126.7, 126.8,
calcd. for C32H40O12SNa+: 671.2133, found 671.2313 [MNa+].
Eur. J. Org. Chem. 2016, 1520–1532
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
127.0, 127.4, 127.7, 127.7, 127.9, 128.1, 128.5, 128.5, 138.6, 138.7, tography (petroleum ether/EtOAc, 1:2) to afford disaccharide 8a
140.8, 141.1 (16 × aromatic C), 169.7 [s, C(O)CH3], 169.8 [s, C(O)CH3],
171.0 [s, C(O)CH3], 171.0 [s, C(O)CH3] ppm. HRMS (ESI-TOF): calcd.
for C34H44O13SNa+: 715.2395, found 715.2406 [MNa+].
(0.096 g, 85 %) as a colourless oil.
3,4,6-Tri-O-benzyl-α/ꢀ- -glucopyranosyl-(1→6)-1,2:3,4-di-O-iso
propylidene-
-galactopyranose (8b):[6h] A sample of disaccharide
D
D
7f (α/ꢀ ratio 9:1) (0.200 g, 0.254 mmol) was dissolved in freshly
distilled CH2Cl2 (10 mL) under an atmosphere of argon. The reaction
was cooled to 0 °C and TMSI (0.036 mL, 0.254 mmol, 1.0 equiv.) was
added. The reaction was stirred at 0 °C for 30 min, after which time
TLC (toluene/EtOAc, 9:1) indicated the formation of a major product
(Rf = 0.2) and complete consumption of starting material (Rf = 0.4).
The reaction was diluted with CH2Cl2 (20 mL) and washed with
water (20 mL). The aqueous layer was then extracted with CH2Cl2
(2 × 20 mL) and the combined organic extracts were washed with
saturated sodium hydrogen carbonate (20 mL) then brine (20 mL).
The organic phase was dried (MgSO4), filtered, and concentrated in
vacuo. The resulting residue was purified by flash column chroma-
tography (toluene/EtOAc, 6:1) to afford disaccharide 8b[6h] (0.137 g,
78 %) as a colourless oil; δH (400 MHz, CDCl3) [9:1 mixture of α/ꢀ
anomers observed, major α-anomer quoted]: δ = 1.34, 1.35, 1.45,
1.54 (4 × s, 12 H. 4 × CH3), 3.63–3.79 (m, 6 H, 2b-H, 3b-H, 4b-H, 6b-
H, 6′b-H, 6a-H), 3.85 (ddd, J = 9.9, J = 3.0, J = 2.2 Hz, 1 H, 5b-H), 3.91
(m, 1 H, 6′a-H), 3.99–4.01 (m, 1 H, 5a-H), 4.25 (dd, J = 7.9, J = 1.9 Hz,
1 H, 4a-H), 4.34 (dd, J1,2 = 4.9, J2,3 = 2.2 Hz, 1 H, 2a-H), 4.63 (dd,
J2,3 = 2.2, J3,4 = 7.8 Hz, 1 H, 3a-H), 4.49, 4.83 (ABq, J = 10.3 Hz, 2 H,
3,4,6-Tri-O-benzyl-2-O-(thiophen-2-yl)-α/ꢀ-
D-glucopyranosyl-
(1→6)-1,2:3,4-di-O-isopropylidene- -galactopyranose (7f): The
D
general procedure for glycosylation with trichloroacetimidate 6f
(0.12 mmol) and diacetone galactose (0.24 mmol, 2 equiv.) gave
disaccharide 7e as a colourless oil; δH (400 MHz, CDCl3) [9:1 mixture
of α/ꢀ anomers observed]: δ = 1.34 (br. s, 12 H, 2 × CH3α, 2 × CH3ꢀ),
1.46, 1.47, 1.53, 1.55 (4 × s, 12 H, 2 × CH3α, 2 × CH3ꢀ), 3.44 (m, 1 H,
5bꢀ-H), 3.50 (app. t, J = 8.4 Hz, 1 H, 2bꢀ-H), 3.59–3.86 (m, 10 H, 2aα-
H, 5aα-H, 2aꢀ-H, 5aꢀ-H, 2bα-H, 5bα-H, 6bα-H, 6′bα-H, 6bꢀ-H, 6′bꢀ-H),
3.99 (app. t, J = 9.4 Hz, 1 H, 4bꢀ-H), 4.04–4.65 (m, 12 H, 3aα-H, 4aα-
H, 6aα-H, 6′aα-H, 3aꢀ-H, 4aꢀ-H, 6aꢀ-H, 6′aꢀ-H, 3bα-H, 4bα-H, 1aꢀ-H,
3aꢀ-H), 4.74–5.31 (m, 16 H, 8 × PhCH2α, 8 × PhCH2ꢀ), 5.00 (d, J1,2
4.3 Hz, 1 H, 1bα-H), 5.54 (d, J1,2 = 5.1 Hz, 1 H, 1aꢀ-H), 5.60 (d, J1,2
=
=
5.1 Hz, 1 H, 1aα-H) 6.95–7.38 (m, 36 H, 36 × Ar-CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 66.3, 66.9 (2 × t, C-6aα, C-6aꢀ), 68.3, 68.7, (2 ×
t, C-6bα, C-6bꢀ), 70.0, 73.5, 75.1, 75.8 (4 × t, 4 × ArCH2), 65.7, 67.4,
70.2, 70.5, 70.7, 70.9, 71.5, 74.7, 77.5, 79.3, 81.2, 81.9, 84.3 (13 × d,
C-2a-C-5aα/ꢀ, C-2b-C-5bα/ꢀ), 95.4 (d, C-1aꢀ), 96.3 (d, C-1aα), 97.0 (d,
C-1bα), 104.4 (d, C-1bꢀ), 125.9, 126.0, 126.5, 126.6, 127.2, 127.6,
127.6, 127.7, 127.7, 127.9, 127.9, 128.1, 128.2, 128.4 (14 × d, 14 × Ar-
CH), 137.9, 138.1, 138.3, 138.7, 138.9, 140.9, 141.2 (7 × s, 7 × Ar-
C) ppm. m/z (ES+) 806 (M + NH4+, 100 %). HRMS (ES+) Calcd. for
C44H52O11S1Na [MNa+] 811.3123, found 811.3118.
PhCH2), 4.50, 4.64 (ABq, J = 11.7 Hz, 2 H, PhCH2), 4.93 (d, J1,2
=
3.2 Hz, 1 H, 1b-H), 4.82, 4.98 (ABq, J = 10.7 Hz, 2 H, PhCH2), 5.53 (d,
J1,2 = 4.9 Hz, 1 H, 1a-H), 7.12–7.41 (m, 15 H, 15 × Ar-H) ppm. m/z
(ES+) 715 (M + Na+, 100 %).
α/ꢀ-
D
-Glucopyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-α-D-
galactopyranose (8a):[21] Method 1: NH3(l) was condensed into a
round-bottomed flask containing a stirrer bar at –100 °C. A sample
of disaccharide 7f (α/ꢀ ratio 9:1) (0.200 g, 0.254 mmol) was added
to the reaction as a solution in THF (10 mL). Small pieces of sodium
were then added over the period of 1 h until the blue colour of
the solution persisted. The reaction was quenched by addition of
ammonium chloride and then warmed to temperature. The reaction
was then diluted with EtOAc (20 mL), washed with water (20 mL),
and the aqueous layer extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered and the solvent removed in vacuo. The resulting
residue was purified by flash column chromatography (petroleum
ether/EtOAc, 1:2) to afford disaccharide 8a[21] (0.070 g, 62 %) as a
colourless oil; δH (400 MHz, CDCl3) [9:1 mixture of α/ꢀ anomers
observed, major α-anomer quoted]: δ = 1.30, 1.32, 1.41, 1.52 (4 × s,
12 H, 4 × CH3), 3.53–3.76 (m, 5 H, 2b-H, 3b-H, 4b-H, 5a-H, 6a-H), 3.69
(dd, J6,6′ = 10.8, J5,6 = 5.2 Hz, 1 H, 6b-H), 3.80 (m, 1 H, 6′b-H), 3.84–
Acknowledgments
The authors gratefully acknowledge the Engineering and Physi-
cal Sciences Research Council (EPSRC) (DTA award to D. J. C.)
and the Biomolecular Interaction Centre at the University of
Canterbury for financial support.
Keywords: Protecting groups · Neighbouring group
participation · Glycosylation · Diastereoselectivity
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Received: January 18, 2016
Published Online: February 17, 2016
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