Stereoselective synthesis of α-glucosides by neighbouring group participation via an intermediate thiophenium ion

Article abstract of DOI:10.1016/j.tetasy.2009.02.018

The use of a 2-O-(thiophen-2-yl)methyl protecting group allows highly stereoselective α-glucosylation of a trichloroacetimidate donor; increased stereoselectivity, presumably arising from the intramolecular formation of a transient intermediate thiophenium ion, correlates with increased bulk of the glycosyl acceptor.

Full text of DOI:10.1016/j.tetasy.2009.02.018

Tetrahedron: Asymmetry 20 (2009) 773–780
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of a-glucosides by neighbouring group
participation via an intermediate thiophenium ion
Daniel J. Cox a, Antony J. Fairbanks b,
*
a Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
b Department of Chemistry, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of a 2-O-(thiophen-2-yl)methyl protecting group allows highly stereoselective a-glucosylation of
Received 2 February 2009
Accepted 10 February 2009
Available online 9 March 2009
a trichloroacetimidate donor; increased stereoselectivity, presumably arising from the intramolecular
formation of a transient intermediate thiophenium ion, correlates with increased bulk of the glycosyl
acceptor.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor George Fleet on the
occasion of his 65th birthday
1. Introduction
the linking tether is short enough. Originally developed by Hinds-
gaul8 and Stork,9 several IAD approaches10 have subsequently been
The importance of oligosaccharides in a plethora of fundamen-
tal biological processes,1 taken together with their frequently low
natural abundance, a factor which is often compounded by difficul-
ties in isolation and purification, continues to necessitate their to-
tal synthesis by chemical and/or enzymatic means. Whilst the use
of glycosyl transferases and glycosidases has led to vast improve-
ments in the efficiency of synthetic access to certain oligosaccha-
rides, the availability of enzymes that are capable of performing
desired transformation remains a limiting factor in many cases.
Therefore, chemical synthesis currently remains the principal syn-
thetic tool available to the scientific community.2
Oligosaccharide assembly hinges upon the linking of pre-
formed building blocks by glycosylation. As considerable progress
has been made in facilitating the speed of assembly of oligosaccha-
ride structures from these highly functionalised building blocks,3
the issue of control of anomeric stereochemistry during glycosyla-
tion now remains the principal challenge to be addressed. In par-
ticular, although 1,2-trans glycosidic linkages can usually be
synthesised with high levels of stereocontrol by taking advantage
of the classical neighbouring group participation (NGP) of 2-O-acyl
protected glycosyl donors,4 the stereocontrolled synthesis of 1,2-
cis glycosidic linkages is considerably more difficult.5
developed including the use of PMB,11 allyl,12 propargyl13 and
NAP14 protection of the 2-hydroxyl of the glycosyl donor, but none
has yet to find general application.
Intramolecular approaches to glycosylation suffer the disadvan-
tage of being more protracted than intermolecular glycosylation,
necessitating an extra linking step, though one-pot approaches
have been developed.10e Moreover, linking and glycosylation effi-
ciencies tend to decrease when the technique is applied to more
extended donors and acceptors, obviating the utility of the IAD ap-
proach for block synthesis.8c,13b The current situation is therefore
one in which there is still no generally applicable method available
for the formation of all 1,2-cis glycosidic bonds.
The use of new types of neighbouring group participation15 to en-
force the formation of 1,2-cis glycosidic linkages represents an
attractive alternative proposition. In theory, such an approach could
be applied generally to access
-galacto), although perhaps not to synthesise b-1,2-cis glycosides,
such as b-mannosides. Taken to the extreme the use of cyclic b-gly-
cosyl donors also has the potential to effect high levels of -stereo-
a-1,2-cis glycosides (e.g., a-gluco and
a
a
control during glycosylation,16 though the reactivity of such
donors remains an issue that must be addressed. Boons has been
the pioneer of the novel NGP approach, and has recently reported a
highly innovative intermolecular glycosylation process in which
the stereochemical outcome of the reaction could be controlled
by the configuration of a chiral protecting group at the 2-position
of the glycosyl donor.17 For example, gluco donors with an (S)-(phen-
ylthiomethyl)benzyl moiety at the 2-position gave exclusively
Substantial effort has been expended in the search for a general
solution to this problem. One promising approach is the use of
intramolecular aglycon delivery (IAD),6 in which glycosyl donor
and acceptor are temporarily linked via a protecting group at the
2-postion of the donor; subsequent intramolecular glycosylation7
usually then enforces the formation of a 1,2-cis linkage, provided
a
-selectivity due to neighbouring group participation via a cyclic
intermediate sulfonium ion.17b More recently, Boons also reported18
the use of acyclic intermediate sulfonium ions to achieve -glycosyl-
ation of donors that did not posses participating groups at the
a
* Corresponding author. Tel.: +64 33643097; fax: +64 33642110.
E-mail address: antony.fairbanks@canterbury.ac.nz (A.J. Fairbanks).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.018

774
D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
2-position. For example, when either phenylthioethyl ether or
thiophene was added to the reaction mixture high -selectivity
2-azido gluco
intermediate sulfonium ion, but one using the optimum additive
that was identified for sulfonium ion mediated glycosylation with-
out neighbouring group participation.18 The results of a series of
preliminary investigations into the potential use of glycosyl donors
a
was achieved during glycosylation of
trichloroacetimidate.18
a
Although the arguments presented for the potentially wide-
spread utility of the chiral auxiliary approach for the control of
anomeric stereochemistry are compelling, we reasoned that per-
haps chirality was not necessary in the 2-OH protecting group in
bearing a 2-O-(thiophen-2-yl)methyl group for stereoselective a-
glycosylation via putative intermediate thiophenium ions are de-
tailed below.
order to simply achieve good a-selectivity for the formation of a-
2. Results and discussion
1,2-cis glycosides. Indeed it was considered that the inherent steric
and stereoelectronic preferences for a sulfonium ion to exist in the
b-configuration18 would ensure the formation of a trans-decalin
sulfonium ion intermediate without the need for a directing ste-
reocentre in the linking chain.19 We therefore sought to investigate
a ‘halfway-house’ situation following on from the earlier work of
Boons, in which thiophene was appended to the 2-position of the
glycosyl donor so that reaction could proceed via a thiophenium
ion formed intramolecularly (Fig. 1). Such a situation would repre-
sent another variant on neighbouring group participation via an
Commercially available 2-thiophene methanol 1 was converted
into the bromide 2,20 to be used for subsequent alkylation reac-
tions, by treatment with 33% HBr in glacial acetic acid (Scheme
1). Orthoester 321 served as a divergent intermediate allowing ac-
cess to glycosyl donors in which the 2-position was unprotected
for later alkylation with 2. Glycosyl fluoride alcohol 4, synthesised
from 3 as previously described,12c was alkylated by treatment with
2 and sodium hydride in DMF to produce glycosyl fluoride donor 5.
Alternatively treatment of orthoester 3 with aqueous acetic acid
produced a mixture of monoacetates, which were immediately
converted to an anomeric mixture of diacetates 622 by treatment
with acetic anhydride and pyridine. Reaction of 6 with thiophenol
and boron trifluoride etherate (BF3ꢀOEt2) produced the b-thio-
phenyl glycoside 7a,23 from which the 2-O-acetate was removed
by treatment with catalytic methoxide, yielding alcohol 7b.24
Alkylation of 7b with 2, again achieved by treatment with sodium
hydride in DMF, gave the thioglycoside donor 8. Hydrolysis of 8,
mediated by N-iodosuccinimide (NIS) and trifluoroacetic acid
(TFA) yielded hemiacetals 9, which were then converted to the tri-
chloroacetimidate donors 10 by reaction with trichloroacetonitrile
and DBU (Scheme 1).
OBn
O
OBn
O
activation
BnO
BnO
BnO
BnO
X
O
O
S
S
NGP
OBn
O
OBn
BnO
BnO
O
BnO
BnO
S
O
O
OR
With a selection of glycosyl donors 5, 8 and 10 in hand preli-
minary investigations were undertaken into finding suitable acti-
S
ROH
vation conditions using diacetone galactose 11 as
a model
glycosyl acceptor (Table 1). Activation of glycosyl fluoride 5 with
supra-stoichiometric quantities of BF3ꢀOEt2 was investigated at a
Figure 1. Putative a-selective glycosylation process involving neighbouring group
participation (NGP) via an intermediate b-thiophenium ion.
OBn
S
S
O
(i)
BnO
HO
Br
BnO
O
O
1
2
3
Me
OEt
(iii)
OBn
Ref. 12d
OBn
O
OBn
(ii)
O
O
BnO
BnO
BnO
BnO
BnO
F
F
BnO
OAc
HO
OAc
O
5
4
6
(iv)
S
OBn
O
OBn
OBn
(vii)
(vi)
O
O
BnO
BnO
BnO
BnO
SPh
SPh
BnO
BnO
OR
O
OR
O
7a
7b
R = Ac
R =H
(v)
S
S
9 R = H
10 R = C(NH)CCl3
8
(viii)
Scheme 1. Reagents and conditions: (i) HBr/AcOH, Et2O, 16 h, 85%; (ii) 2, NaH, DMF, 16 h, 74%; (iii) AcOH/H2O, 16 h; then Ac2O, DMAP, pyridine, 16 h, 81%; (iv) PhSH,
BF3ꢀOEt2, CH2Cl2, 6 h, 89%; (v) NaOMe, MeOH/THF, 16 h, 85%; (vi) 2, NaH, DMF, 16 h, 78%; (vii) TFA, NIS, CH2Cl2/H2O, 0 °C, 2 h, 84%; (viii) Cl3CCN, DBU, CH2Cl2, 0 °C, 3 h, 80%.

D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
775
Table 1
Glycosylation of diacetone galactose with donors 5, 8 and 10
OBn
O
OBn
activation
conditions
OH
O
O
BnO
BnO
O
BnO
BnO
X
+
O
O
O
CH2Cl2
O
O
O
O
O
S
O
S
O
5
8
X = F
O
X = SPh
X = OC(NH)CCl3
10
11
12
Entry
Glycosyl donor
Activation conditions
Time (h)
Temp (°C)
Yield of 12 (%)
a
:b Ratioa
a
b
c
d
e
f
g
h
i
5
5
5
8
8
8
10
10
10
1.5 equiv BF3ꢀOEt2
1.5 equiv BF3ꢀOEt2
1.5 equiv BF3ꢀOEt2
0.5
1
1.5
1
0
45
40
36
36
51
48
93
84
71
1:1.25
1:1
2:1
1.5:1
2:1
6:1
1:1.25
9:1
8:1
ꢁ41
ꢁ78
0
ꢁ41
ꢁ78
0
1.5 equiv NIS, 0.5 equiv TMSOTf
1.5 equiv NIS, 0.5 equiv TMSOTf
1.5 equiv NIS, 0.5 equiv TMSOTf
0.1 equiv TMSOTf
2
3.5
0.5
1
0.1 equiv TMSOTf
0.1 equiv TMSOTf
ꢁ41
1.5
ꢁ78
a
Anomeric ratios were determined by integration of appropriate peaks in the 1H NMR spectra.
range of temperatures in dichloromethane (DCM), but in all cases
yields of glycosylation were modest. Moreover, disaccharide 12
was produced as an anomeric mixture of products, and although
In order to confirm that the high a-stereoselectivity observed in
these reactions was actually due to the presence of the thiophene
moiety at the 2-position of the donor, and that it did not simply
represent an inherent stereochemical preference arising from ste-
ric match/mismatch of the donor/acceptor pairs, a series of control
reactions were undertaken using the perbenzylated trichloroace-
timidate 18 as donor (Table 3). Glycosylation of 18 with diacetone
galactose 11 produced disaccharide 1926 as anomeric mixture in
the
at ꢁ78 °C only very modest selectivity was observed in favour of
the desired -anomer 12 :b ratio, 2:1, Table 1, entry c). Atten-
a:b ratio increased with decreased reaction temperature, even
a
a (a
tion turned to the possible use of thioglycoside donor 5. Activation
was achieved by treatment with NIS and trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) in DCM, but again overall yields for
glycosylation were poor, and the formation of numerous by-prod-
ucts indicated the non-orthogonal reactivity profile of the thiogly-
coside and the thiophene moieties. Moreover, anomeric selectivity
favour of the b-anomer (a:b ratio 1:4, Table 3, entry a). This inher-
ent preference for b-selectivity for sterically unhindered acceptors
was confirmed by glycosylation of 18 with methanol, which pro-
duced methyl glycosides 2027 in a 1:8,
a:b ratio (Table 3, entry
was again modest, though at ꢁ78 °C the desired
a
-anomer was fa-
b). Glycosylation with the more hindered secondary carbohydrate
voured ( :b ratio, 6:1, Table 1, entry f). Attention therefore moved
a
acceptors 13 and 14 produced disaccharides 2126 and 22 as mix-
to the potential the use of trichloroacetimidate 10 as the donor.
Activation of 10 in the presence of 11 with a catalytic amount of
TMS triflate at 0 °C in DCM produced disaccharide 12 in an excel-
lent 93% yield, but with low anomeric selectivity actually in favour
tures in which the a-anomer was actually slightly favoured (Table
3, entries c and d), but in both of these cases the observed stereose-
lectivity was a factor of 10 lower than that observed for the corre-
sponding 2-O-(thiophen-2-yl)methyl donor 10, confirming the
of the undesired b-anomer (
a
:b ratio 1:1.25, Table 1, entry g). How-
strong a-stereo-directing effect of the thiophene moiety.
ever, reducing the reaction temperature to ꢁ40 °C had a marked ef-
fect on the stereoselectivity of glycosylation; now disaccharide 12
was produced in good yield (84%) and with high stereoselectivity
3. Conclusions
in favour of the desired
a
-anomer (
a
:b ratio 9:1, Table 1 entry
A series of glycosyl donors possessing a 2-O-(thiophen-2-yl)-
methyl protecting group at the 2-position were synthesised. Acti-
vation of both the glycosyl fluoride and the thioglycoside donors
resulted in low-yielding glycosylation processes, indicating the
incompatibility of thiophene moiety with those particular activa-
tion conditions. However, glycosylation of the trichloroacetimidate
h). Lowering the reaction temperature further (entry i) did not im-
prove either the yield or stereoselectivity, so it was concluded that
ꢁ40 °C represented the optimum temperature for glycosylation of
the trichloroacetimidate 10.
Subsequent investigations focussed on glycosylation of donor 10
with a series of different acceptors at ꢁ40 °C in DCM (Table 2). Gly-
cosylation with methanol as acceptor produced methyl glycoside 15
donor with a series of glycosyl acceptors resulted in highly
tive glycosylation; higher -stereoselectivity being observed with
more hindered carbohydrate acceptors. Based on comparison with
previous work by Boons, it is postulated that this high -selectivity
a-selec-
a
in a good yield but with low stereoselectivity (a:b ratio 1:1.25, Table
2, entry a) indicating that the stereoselectivity of glycosylation was
a
highly dependent on the steric bulk of the glycosyl acceptor. How-
ever with carbohydrate alcohols as acceptors the a-stereoselectivity
results from the intramolecular formation of a transient intermedi-
ate b-thiophenium ion, which then undergoes SN2-like substitution
by the glycosyl acceptor. Although the stereocontrol during these
glycosylation processes is lower than the optimum results reported
by Boons17b using the (S)-(phenylthiomethyl)benzyl moiety at the
2-position, this procedure does not require the synthesis of a chiral
phenyl (phenylsulfanyl)ethyl ester, making such an approach
perhaps more amenable to routine synthetic use. Further
of the process was considerable; glycosylation of the axial 2-hydro-
xyl of the manno acceptor 1325 produced disaccharide 16 with very
high a-selectivity (a:b ratio 30:1, Table 2, entry b), whilst similar
reaction of the manno acceptor 1425 possessing an equatorial sec-
ondary alcohol group produced disaccharide 17 with almost as high
selectivity (a:b ratio 28:1, Table 2, entry c).

776
D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
Table 2
Glycosylation of various glycosyl acceptors with donor 10 at ꢁ40 °C in CH2Cl2 with 0.1 equiv TMSOTf as activator
Entry
Acceptor
Product
Yield
90
a:b Ratio
OBn
O
BnO
BnO
a
MeOH
1.5:1
30:1
28:1
O
OMe
S
15
OBn
O
BnO
BnO
OH
O
O
Ph
O
O
b
55
BnO
O
S
13
OMe
Ph
O
O
O
BnO
16
OMe
OBn
O
BnO
OBn
O
Ph
O
O
BnO
c
54
O
OBn
O
HO
Ph
O
O
O
OMe
14
S
17
OMe
investigations into the use of novel types of neighbouring group
participation for the stereoselective synthesis of -1,2-cis-glyco-
sides are currently in progress and the results will be reported in
calcium hydride, or dried on an alumina column. Anhydrous THF,
DMF, pyridine, methanol and toluene were purchased from Fluka
over molecular sieves. ‘Petrol’ refers to the fraction of light petro-
leum ether boiling in the range of 40–60 °C.
a
due course.
4.2. 2-Bromomethyl thiophene 220
4. Experimental
4.1. General
2-Thiophenemethanol 1 (1.66 ml, 17.5 mmol) was dissolved in
anhydrous ether (50 ml) under an argon atmosphere. The mixture
was cooled to 0 °C and HBr (33% in glacial acetic acid, 4 ml) was
added. The reaction was allowed to warm to room temperature.
After 16 h, TLC (petrol/ethyl acetate, 1:1) indicated the formation
of a single product (Rf 0.9) and complete consumption of starting
material (Rf 0.7). The reaction was diluted with ice and water
(50 ml), and the aqueous layer was extracted with ether
(2 ꢂ 25 ml). The combined organic extracts were washed with cold
saturated sodium bicarbonate solution until neutral pH and then
washed with brine (50 ml). The organic phase was dried (MgSO4),
filtered and concentrated in vacuo to afford 2-bromomethyl-thio-
phene 2 (2.64 g, 85%) as a pale yellow liquid; dH (400 MHz, CDCl3)
4.77 (2H, br s, ArCH2Br), 6.96 (1H, dd, J 5.31 Hz, J 3.54 Hz, Ar-H),
7.13 (1H, d, J 3.54 Hz, Ar-H), 7.34 (1H, d, J 5.31 Hz, Ar-H); dC (CDCl3)
26.8 (t, ArCH2Br), 127.1, 127.2, 128.1 (3 ꢂ d, 3 ꢂ Ar-CH), 140.4 (s,
Ar-C).
Melting points were recorded on a Kofler hot block and are
uncorrected. Proton and carbon nuclear magnetic resonance (dH,
dC) spectra were recorded on Bruker DPX 250 (250 MHz), Bruker
DPX 400 (400 MHz), Bruker DQX 400 (400 MHz), Bruker AVC 500
(500 MHz) or Bruker AMX 500 (500 MHz) spectrometers. All chem-
ical shifts are quoted on the d-scale in ppm using residual solvent
as an internal standard. Low resolution mass spectra were re-
corded on a Micromass Platform 1 spectrometer using electrospray
ionisation in either positive or negative polarity (ES+ or ESꢁ), or
using a VG Micromass spectrometer. High resolution mass spectra
were recorded on a Walters 2790-Micromass LCT electrospray ion-
isation mass spectrometer, using either electrospray ionisation
(NH3, Cl) techniques as stated. m/z values are reported in Daltons
and are followed by their percentage abundance in parentheses.
Optical rotations were measured on a Perkin–Elmer 241 polarime-
ter with a path length of 1 dm. Concentrations are given in g/
100 mL. Microanalyses were performed by the Inorganic Chemistry
Laboratory Elemental Analysis service, Oxford University, UK. Thin
Layer Chromatography (TLC) was carried out on Merck Kieselgel
60F254 pre-coated glass-backed plates. Visualisation of the plates
was achieved using a UV lamp (kmax = 254 or 365 nm), and/or
ammonium molybdate (5% in 2 M sulfuric acid), or sulfuric acid
(5% in ethanol). Flash column chromatography was carried out
using Sorbsil C60 40/60 silica. Dichloromethane was distilled from
4.3. 3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-b-D-
glucopyranosyl fluoride 5
3,4,6-Tri-O-benzyl-b-
0.603 mmol) was dissolved in anhydrous DMF (2.5 ml) and then
slowly added to suspension of sodium hydride (0.600 g,
D
-glucopyranosyl fluoride 412c (0.273 g,
a
0.90 mmol) in anhydrous DMF (2.5 mL) at 0 °C under an argon
atmosphere. 2-Bromomethyl-thiophene 13 (0.214 g, 1.206 mmol)

D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
777
Table 3
81.1 (dd, J2,F 20.8 Hz, C-2), 83.3 (dd, J3,F 11.2 Hz, C-3), 109.8 (dd,
J1,F 215.7 Hz, C-1), 126.3, 126.7, 127.1, 127.8, 127.9, 127.9, 128.0,
128.0, 128.4 (9 ꢂ d, 9 ꢂ Ar-CH), 137.8, 137.8, 138.2, 140.0 (4 ꢂ s,
4 ꢂ Ar-C); m/z (ES+) 571 (M+Na+, 80) 566 (M+NH4þ, 100%). (HRMS
(ES+) Calcd for C32H33FO5SNa (MNa+) 571.6546. Found 571.6544).
(C32H33FO5S requires C, 70.05; H, 6.06. Found: C, 70.08; H, 6.06).
Control glycosylation of acceptors with perbenzylated donor 18 at ꢁ40 °C in CH2Cl2
with 0.1 equiv TMSOTf as activator
OBn
O
BnO
BnO
NH
CCl3
O
BnO
18
4.4. 1,2-O-Acetyl-3,4,6-tri-O-benzyl-a,b-D
-glucopyranoside 622
Entry Acceptor Product
Yield
a:b
Ratio
Orthoester 321 (14.5 g, 27.8 mmol) was dissolved in glacial ace-
tic acid (60% in water, 250 ml) and was stirred at room tempera-
ture. After 16 h, TLC (petrol/ethyl acetate, 1:1) indicated the
formation of a single product (Rf 0.6) and complete consumption
of starting material (Rf 0.9). The reaction mixture was co-evapo-
rated with toluene and subsequently left under high vacuum for
2 h. The crude residue and DMAP (0.34 g, 2.79 mmol) were dis-
solved in anhydrous pyridine (100 ml) and the mixture was cooled
to 0 °C under a nitrogen atmosphere. Acetic anhydride (5.27 ml,
55.8 mmol) was then slowly added. Once addition of acetic anhy-
dride was complete, the reaction was allowed to warm to room
temperature. After 16 h, TLC (petrol/ethyl acetate, 1:1) indicated
the formation of a single product (Rf 0.9) and complete consump-
tion of starting material (Rf 0.6). The reaction was cooled to 0 °C
and quenched with ethanol (75 ml). The reaction mixture was con-
centrated in vacuo. The residue was dissolved in ether (100 ml) and
washed with 1 M HCl (100 ml), then with saturated sodium bicar-
bonate (100 ml) and then with brine (100 ml). The organic phase
was then dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by flash column chromatography (toluene/
ethyl acetate, 8:1) to afford diacetate 622 (12.0 g, 81%) as a pale yel-
OBn
O
BnO
BnO
BnO
O
O
a
11
80
1:4
O
O
O
O
19
OBn
O
BnO
BnO
b
MeOH
87
1:8
BnO
OMe
20
OBn
O
BnO
BnO
BnO
O
O
low oil; dH (400 MHz, CDCl3) [13:1 mixture of a:b anomers ob-
c
13
68
2:1
served, major
a
anomer quoted] 2.00, 2.14 (6H, 2 ꢂ s, 2 ꢂ CH3),
Ph
O
O
0
3.70 (1H, dd, J5,6 1.8 Hz, J6,6 10.9 Hz, H-6), 3.77–3.87 (2H, m, H-4,
BnO
H-60), 3.94 (1H, ddd, J4,5 10.1 Hz, J5,6 1.8 Hz, J5,6 3.3 Hz, H-5), 4.03
0
OMe
(1H, at, J 9.5 Hz, H-3), 4.45 (1H, d, J 11.37, PhCHH0), 4.52–4.67
(3H, m, 1 ꢂ PhCHH0, 2 ꢂ PhCHH0), 4.79, 4.88 (2H, ABq, JAB 11.4,
PhCH2), 4.85 (1H, d, J 10.6, PhCHH0), 5.09 (1H, dd, J1,2 3.6 Hz, J2,3
10.0 Hz, H-2), 6.34 (1H, d, J1,2 3.6 Hz, H-1), 7.17–7.39 (15H, m,
15 ꢂ Ar-H); m/z (ES+) 552 (M+NH4þ, 100%).
21
OBn
O
BnO
BnO
OBn
O
d
14
60
3:1
Ph
O
BnO
O
4.5. Phenyl 2-O-acetyl-3-4-6-tri-O-benzyl-1-thio-b-D-
O
glucopyranoside 7a23
22
OMe
Diacetate 6 (4.06 g, 7.59 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (80 ml) under a nitrogen atmosphere. Thiophenol
(1.16 ml, 11.4 mmol) was added and the mixture was then cooled
to 0 °C. Boron trifluoride diethyl etherate (1.40 ml, 9.90 mmol) was
added dropwise to the mixture. Once addition of the boron trifluor-
ide diethyl etherate was complete, the mixture was allowed to
warm to room temperature. After 6 h, TLC (petrol/ethyl acetate,
7:3) indicated the formation of a single product (Rf 0.8) and com-
plete consumption of starting material (Rf 0.7). The reaction was
diluted with CH2Cl2 (250 ml) and washed with saturated sodium
bicarbonate (100 ml), then with water (100 ml) and then with
brine (100 ml). The organic phase was dried (MgSO4), filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography (petrol/ethyl acetate, 9:1) to afford thioglycoside
7a (3.97 g, 89%) as a white crystalline solid; mp 112–113 °C (meth-
was then added slowly as a solution in anhydrous DMF (2.5 ml).
Once the addition of the 2-bromomethyl thiophene solution was
complete, the reaction was allowed to warm to room temperature.
After 16 h, TLC (petrol/ethyl acetate, 4:1) indicated the formation
of a single product (Rf 0.6) and complete consumption of starting
material (Rf 0.3). The reaction was quenched with methanol
(5 ml) and concentrated in vacuo. The resulting residue was dis-
solved in ether (25 ml), washed with water (50 ml), and the aque-
ous layer extracted with ether (2 ꢂ 25 ml). The combined organic
extracts were washed with brine (50 ml), dried (MgSO4), filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (petrol/ethyl acetate, 15:1) to afford fluoride
5 (0.244 g, 74%) as a pale yellow oil; ½a D25
¼ þ9:7 (c 1.0 in CHCl3);
ꢃ
anol); ½a 2D3
ꢃ
¼ þ9:4 (c 1.1 in CHCl3) [Lit. mp 113 °C; ½a D20
¼ þ10 (c
ꢃ
dH (400 MHz, CDCl3) 3.50–3.75 (6H, m, H-2, H-3, H-4, H-5, H-6,
H-60), 4.52, 4.80 (2H, ABq, JAB 10.9 Hz, ArCH2), 4.54, 4.62 (2H,
ABq, JAB 12.1 Hz, ArCH2), 4.76, 4.95 (2H, ABq, JAB 11.1 Hz, ArCH2),
4.86, 5.03 (2H, ABq, JAB 11.9 Hz, ArCH2), 5.24 (1H, dd, J1,2 6.6 Hz,
J1,F 52.6 Hz, H-1), 6.98 (1H, dd, J 5.1 Hz, J 3.3 Hz, Ar-H), 7.03 (1H,
d, J 3.3 Hz, Ar-H), 7.12–7.14 (2H, m, 2 ꢂ Ar-H), 7.25–7.35 (14H,
m, 14 ꢂ Ar-H); dC (100 MHz, CDCl3) 68.3 (t, C-6), 68.5, 73.6, 75.1,
75.6 (4 ꢂ t, 4 ꢂ ArCH2), 74.8 (dd, J5,F 4.8 Hz, C-5), 76.8 (d, C-4),
1.0 in CHCl3)]23; dH (400 MHz, CDCl3) 2.01 (3H, s, CH3), 3.54–3.58
(1H, m, H-5), 3.71–3.73 (2H, m, H-3, H-4), 3.77 (1H, dd, J5,6
0
0
0
4.9 Hz, J6,6 11.0 Hz, H-6), 3.84 (1H, dd, J5,6 1.8 Hz, J6,6 11.0 Hz, H-
60), 4.59 (1H, d, J 10.1 Hz, PhCHH0), 4.63 (1H, d, J1,2 9.5 Hz, H-1),
4.64–4.72 (3H, m, 3 ꢂ PhCHH0), 4.81–4.84 (2H, m, 2 ꢂ PhCHH0),
5.03 (1H, at, J 9.5 Hz, H-2), 7.18–7.35 (18H, m, 18 ꢂ Ar-H), 7.45–

778
D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
7.53 (2H, m, 2 ꢂ Ar-H); m/z (ES+) 607 (M+Na+, 60) 602 (M+NH4
,
were added, and the mixture was stirred vigorously. After 2 h,
TLC (toluene/ethyl acetate, 9:1) indicated the formation of a single
major product (Rf 0.1) and complete consumption of starting mate-
rial (Rf 0.8). The reaction was quenched with triethylamine
(0.5 mL) and then with sodium thiosulfate (5 ml of a 10% solution).
The reaction mixture was diluted with CH2Cl2 (15 ml), washed
with saturated sodium bicarbonate (30 ml), and the aqueous layer
was extracted with CH2Cl2 (2 ꢂ 15 ml). The organic phase was
dried (MgSO4), filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (petrol/ethyl ace-
tate, 1:1) to afford hemiacetals 9 (0.724 g, 84%) as a clear oil: mmax
þ
100%).
4.6. Phenyl 3,4,6-tri-O-benzyl-1-thio-b-D
-glucopyranoside 7b24
A solution of sodium (0.23 g) in methanol (10 ml) was added to
a stirred solution of thioglycoside 7a (1.50 g, 2.57 mmol) in meth-
anol/THF (20 ml, 1:1). After 16 h, TLC (petrol/ethyl acetate, 7:3)
indicated the formation of a single product (Rf 0.7) and complete
consumption of starting material (Rf 0.8). Amberlite 120 (H+) resin
was added, and the mixture was stirred for 15 min until pH neu-
tral. The reaction was filtered and concentrated in vacuo. The res-
idue was purified by flash column chromatography (petrol/ethyl
acetate, 5:1) to afford alcohol 7b (1.18 g, 85%) as a white crystalline
(KBr) 3510 (br, OH) cmꢁ1; dH (400 MHz, CDCl3) [2:1 mixture of
anomers observed] 3.43 (0.5H, at, J 8.47, H-2b), 3.53–3.72 (7H, m,
a:b
H-2
4.09 (1.5H, m, H-5
a, H-3a, H-4a, H-6a
, H-60a, H-3b, H-4b, H-6b, H-60b), 4.98–
solid; mp 72–73 °C (ethanol); ½a D23
ꢃ
¼ ꢁ9:7 (c 1.0 in CHCl3) [Lit. mp
a
, H-5b), 4.48–4.62 (4.5H, m, 3 ꢂ ArCHH0a
,
71–73 °C; ½a 2D0
ꢃ
¼ ꢁ11:5 (c 1.4 in CHCl3)]24; dH (400 MHz, CDCl3)
3 ꢂ ArCHH0b), 4.70 (0.5H, d, J1,2 7.83, H-1b), 4.78–5.02 (7H, m,
5 ꢂ ArCHH0a, 4 ꢂ ArCHH0b), 5.13–5.16 (0.5H, m, ArCHH0b), 5.19
2.45 (1H, d, JOH,2 2.0 Hz, OH), 3.49–3.58 (2H, m, H-2, H-5), 3.60–
0
3.66 (2H, m, H-3, H-4), 3.76 (1H, dd, J5,6 4.4 Hz, J6,6 11.0 Hz, H-6),
(1H, br s, H-1
a
), 6.95–7.04 (2H, m, 3 ꢂ Ar-H), 7.13–7.19 (3H, m,
3.82 (1H, dd, J5,6 1.8 Hz, J6,6 11.0 Hz, H-60), 4.53 (1H, d, J1,2
9.6 Hz, H-1), 4.56–4.66 (3H, m, 3 ꢂ PhCHH0), 4.84–4.95 (3H, m,
3 ꢂ PhCHH0), 7.21–7.39 (18H, m, 18 ꢂ Ar-H), 7.58–7.61 (2H, m,
2 ꢂ Ar-H); m/z (ES+) 565 (M+Na+, 90) 560 (M+NH4þ, 100%).
3 ꢂ Ar-H), 7.25–7.39 (22H, m, 21 ꢂ Ar-H); dC (100 MHz, CDCl3)
67.7, 68.7 (2 ꢂ t, C-6 C-6b), 68.8, 73.5, 75.1, 75.8 (4 ꢂ t,
4 ꢂ ArCH2), 70.2 (d, C-5 /b), 74.6, 77.8, 77.8, 79.5 (4 ꢂ d, C-3 , C-
3b, C-4 , C-4b), 81.8, (d, C-5 /b), 82.7 (d, C-2 ), 84.4 (d, C-2b),
91.4 (d, C-1 ), 97.4 (d, C-1 b), 126.0, 126.4, 126.7, 126.8, 126.8,
0
0
a,
a
a
a
a
a
a
4.7. Phenyl 3,4,6-tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-1-
thio-b-D-glucopyranoside 8
127.1, 127.7, 127.7, 127.8, 127.8, 127.9, 128.0, 128.0, 128.1,
128.4, 128.4 (16 ꢂ d, 16 ꢂ Ar-CH), 137.7, 137.8, 138.2, 138.7,
140.6 (5 ꢂ s, 5 ꢂ Ar-C); m/z (ES+) 564 (M+NH4þ, 100%). (HRMS
(ES+) Calcd for C32H34O6SNa (MNa+) 569.1968. Found 569.1964).
(C32H34O6S requires C, 70.31; H, 6.27. Found: C, 70.50; H, 6.25).
Alcohol 7b (0.244 g, 0.45 mmol) was dissolved in anhydrous
DMF (5 ml) and then slowly added to a suspension of sodium hy-
dride (0.600 g, 0.90 mmol) in anhydrous DMF (5 mL) at 0 °C under
an argon atmosphere. 2-Bromomethyl thiophene
2
(0.119 g,
4.9. O-(3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-a/b-D-
0.67 mmol) was then added slowly as a solution in anhydrous
DMF (5 ml). Once the addition of the 2-bromomethyl-thiophene
solution was complete, the reaction was allowed to warm to room
temperature. After 16 h, TLC (toluene/ethyl acetate, 9:1) indicated
the formation of a single product (Rf 0.8) and complete consump-
tion of starting material (Rf 0.6). The reaction was quenched with
methanol (5 ml) and concentrated in vacuo. The resulting residue
was dissolved in ether (100 ml), washed with water (100 ml),
and the aqueous layer was extracted with ether (2 ꢂ 100 ml). The
combined organic extracts were washed with brine (100 ml), dried
(MgSO4), filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (toluene/ethyl acetate, 12:1)
to afford thioglycoside donor 8 (0.223 g, 78%) as a white crystalline
glucopyranosyl) trichloroacetimidate 10
Hemiacetals 9 (0.700 g, 1.28 mmol) was dissolved in freshly dis-
tilled CH2Cl2 (8 ml) at 0 °C under an argon atmosphere. DBU
(0.078 ml, 0.51 mmol) was added followed by trichloroacetonitrile
(1.31 ml, 12.8 mmol). After 5 h, TLC (petrol/ethyl acetate, 4:1, with
1% added triethylamine) indicated the formation of a single prod-
uct (Rf 0.4) and complete consumption of starting material (Rf
0.1). The reaction was concentrated in vacuo and the resulting res-
idue was purified by flash column chromatography (petrol/ethyl
acetate, 7:1, with 1% added triethylamine) to afford trichloroace-
timidates 10 (0.710 g, 80%) as a pale yellow oil; mmax (KBr) 3345
(w, NH), 1659 (s, C@N) cmꢁ1; dH (400 MHz, CDCl3) [15:1 mixture
solid; mp 84–85 °C (petrol/ethyl acetate); ½a D25
ꢃ
¼ ꢁ2:0 (c 1.05 in
of a:b anomers observed, major a anomer quoted] 3.67–3.70
CHCl3); dH (400 MHz, CDCl3) 3.49–3.54 (2H, m, H-2, H-5), 3.66
(1H, at, J 9.35, H-4), 3.70–3.75 (2H, m, H-3, H-6), 3.80 (1H, dd,
(1H, m, H-5), 3.76–3.83 (3H, m, H-2, H-6, H-60), 3.98–4.07 (2H,
m, H-3, H-4), 4.49, 4.63 (2H, ABq, JAB 12.0 Hz, ArCH2), 4.54, 4.87
(2H, ABq, JAB 10.6 Hz, ArCH2), 4.83, 5.00 (2H, ABq, JAB 10.8 Hz,
ArCH2), 4.85, 4.93 (2H, ABq, JAB 12.1 Hz, ArCH2), 6.52 (1H, d, J1,2
3.4 Hz, H-1), 6.97 (1H, dd, J 5.1, J 3.4 Ar-H), 7.00 (1H, m, Ar-H),
7.15–7.17 (2H, m, 2 ꢂ Ar-H), 7.27–7.38 (14H, m, 14 ꢂ Ar-H), 8.61
(1H, br s, NH); dC (100 MHz, CDCl3) 68.0 (t, C-6), 73.1 (d, C-4),
73.5, 73.6, 75.0, 75.4 (4 ꢂ t, 4 ꢂ ArCH2), 78.8 (d, C-2), 81.3 (d, C-
5), 84.4 (d, C-3), 94.4 (s, OC(NH)CCl3), 97.6 (d, C-1), 126.2, 126.6,
126.9, 127.7, 127.8, 127.9, 128.0, 128.1, 128.1, 128.4, 128.4, 128.6
(12 ꢂ d, 12 ꢂ Ar-CH), 137.8, 138.0, 138.6, 140.5, (4 ꢂ s, 4 ꢂ Ar-C),
163.6 (s, C@NH); m/z (ES+) 709 (M+NH4þ, 100%). (HRMS (ES+) Calcd
for C34H34Cl3NO6SNa (MNa+) 714.0501. Found 714.0504).
J5,6 1.9 Hz, J6,6 10.7 Hz, H-60), 4.56, 4.63 (2H, ABq, JAB 11.9 Hz,
ArCH2), 4.60, 4.84 (2H, ABq, JAB 11.3 Hz, ArCH2), 4.65 (1H, d, J1,2
9.6 Hz, H-1) 4.87, 4.97 (2H, ABq, JAB 10.7 Hz, ArCH2), 4.93, 5.03
(2H, ABq, JAB 11.0 Hz, ArCH2), 6.98 (1H, dd, J 5.05 Hz, J 3.28 Hz,
Ar-H), 7.02 (1H, m, Ar-H), 7.19–7.36 (21H, m, 21 ꢂ Ar-H); dC
(100 MHz, CDCl3) 69.0 (t, C-6), 69.5, 73.4, 75.1, 76.0 (4 ꢂ t,
4 ꢂ ArCH2), 77.7 (d, C-4), 79.1 (d, C-2), 80.5 (d, C-5), 86.6 (d, C-3),
87.5 (d, C-1), 126.2, 126.7, 126.9, 127.5, 127.6, 127.7, 127.8,
127.8, 127.9, 127.9, 128.4, 128.4, 128.5, 128.9, 132.0 (15 ꢂ d,
15 ꢂ Ar-CH), 133.7, 138.0, 138.2, 138.4, 140.3 (5 ꢂ s, 5 ꢂ Ar-C);
m/z (ES+) 656 (M+NH4þ, 100%). (HRMS (ES+) Calcd for C38H38O5S2-
Na (MNa+) 661.2053. Found 661.2049). (C38H38O5S2 requires C,
71.44; H, 6.00. Found: C, 71.46; H, 6.05).
0
0
4.10. General procedure for glycosylation with donors 10 and
18
4.8. 3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-a/b-D-
glucopyranose 9
A solution of either donor 10 or donor 18 (120 mmol) and the
glycosyl acceptor (240 mmol, 2 equiv) in freshly distilled CH2Cl2
(1 mL) were added to a flame-dried round-bottomed flask contain-
ing activated 3 Å molecular sieves (0.100 g) under argon. The reac-
tion mixture was cooled to ꢁ40 °C and stirred for 10 min, before
Thioglycoside 8 (1.00 g, 1.57 mmol) was dissolved in CH2Cl2/
H2O (16.5 mL, 10:1), and the mixture was cooled to 0 °C. N-Iodo-
succinimide (0.352 g, 1.57 mmol) and TFA (0.12 ml, 1.57 mmol)

D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
779
TMSOTf (0.012 mmol) was added. The reaction was monitored by
TLC, and after the donor was consumed the reaction was quenched
by the addition of saturated sodium bicarbonate solution and was
filtered through CeliteÒ. The mixture was then diluted with CH2Cl2,
washed with saturated sodium bicarbonate solution, and the aque-
ous layer was re-extracted with CH2Cl2. The combined organic ex-
tracts were then washed with brine, dried (MgSO4), filtered and
concentrated in vacuo and the resulting residue was purified by
flash column chromatography.
4.82, 5.19 (2H, ABq, JAB 11.4 Hz, PhCH2), 4.84 (1H, s, H-1a), 5.63
(1H, s, PhCH), 6.83 (1H, d, J 3.8 Hz, Ar-CH), 6.93 (1H, d, J 3.5 Hz,
Ar-CH), 7.13–7.15 (2H, m, 2 ꢂ Ar-CH), 7.24–7.53 (24H, m,
24 ꢂ Ar-CH); selected 1H NMR data for the b-anomer: 5.60
(0.03H, s, PhCH); dC (100 MHz, CDCl3) 55.0 (q, OCH3), 63.9 (d, C-
5a), 68.6, 69.1, 69.1, 71.0, 73.4, 75.2, 75.9 (7 ꢂ t, C-6a, C-6b,
5 ꢂ ArCH2), 73.7, 74.9, 75.7, 77.4, 78.3, 81.2, 84.4 (7 ꢂ d, C-2a, C-
3a, C-4a, C-2b, C-3b, C-4b, C-5b), 99.8 (d, C-1b), 101.6 (d, PhCH),
102.8 (d, C-1a), 126.1, 127.4, 127.7, 127.7, 127.9, 127.9, 128.0,
128.1, 128.2, 128.4, 128.4, 128.5, 128.9, 129.6 (14 ꢂ d, 14 ꢂ Ar-
4.11. 3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-
a/b-
D-
CH), 137.6, 137.8, 137.9, 138.4, 142.3 (5 ꢂ s, 5 ꢂ Ar-C); m/z (ES+)
glucopyranosyl-(16)-1:2,3:4-di-O-isopropylidene-
D
-
918 (M+NH4
,
100%). (HRMS (ES+) Calcd for C53H56O11S1Na
þ
galactopyranoside 12
(MNa+) 923.3436. Found 923.3434).
Rf 0.4 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [1:1
mixture of
:b anomers observed] 1.34 (12H, br s, 2 ꢂ CH3
2 ꢂ CH3b), 1.46, 1.47, 1.53, 1.55 (12H, 4 ꢂ s, 2 ꢂ CH3 , 2 ꢂ CH3b),
3.44 (1H, m, H-5bb), 3.50 (1H, at, J 8.4 Hz, H-2bb), 3.59–3.86
(10H, m, H-2a , H-5a , H-2ab, H-5ab, H-2b , H-5b , H-6b
, H-60ba
4.14. 3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-a/b-D-
glucopyranosyl-(13)-methyl-2-O-benzyl-4,6-O-benzylidene-
D-mannopyranoside 17
a
a
,
a-
a
a
a
a
a
a
,
Rf 0.57 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [28:1
mixture of :b anomers observed, data for the major -anomer
H-6bb, H-60 b), 3.99 (1H, at, J 9.4 Hz, H-4bb), 4.04–4.65 (12H, m,
a
a
H-3a
H-4b
5.00 (1H, d, J1,2 4.3 Hz, H-1b
(1H, d, J1,2 5.1 Hz, H-1a
) 6.95–7.38 (36H, m, 36 ꢂ Ar-CH); dC
(100 MHz, CDCl3) 66.3, 66.9 (2 ꢂ t, C-6a , C-6ab), 68.3, 68.7,
(2 ꢂ t, C-6b , C-6bb), 70.0, 73.5, 75.1, 75.8 (4 ꢂ t, 4 ꢂ 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 ꢂ d, C-2a-C-5a /b, C-2b-C-5b /b), 95.4 (d, C-1ab), 96.3 (d, C-
1a ), 97.0 (d, C-1b ), 104.4 (d, C-1bb), 125.9, 126.0, 126.5, 126.6,
a
, H-4baa, H-6a
a
, H-60aa, H-3ab, H-4ab, H-6ab, H-60 b, H-3b
a,
quoted] 3.36 (3H, s, OCH3), 3.47 (1H, m, H-2b), 3.52–3.69 (4H,
m, H-3b, H-4b, H-5b, H-6b), 3.79–3.99 (4H, m, H-3a, H-5a, H-6a,
H-60 ), 4.26 (1H, m, H-60 ), 4.39 (2H, m, H-2a, H-4a), 4.47, 4.61
a
a
, H-1ab, H-3ab), 4.74–5.31 (16H, m, 8 ꢂ PhCH2
a
, 8 ꢂ PhCH2b),
a
), 5.54 (1H, d, J1,2 5.1 Hz, H-1ab), 5.60
b
a
a
(2H, ABq, JAB 11.9 Hz, PhCH2), 4.52, 4.59 (2H, ABq, JAB 11.6 Hz,
PhCH2), 4.57 (1H, d, J1,2 1.3 Hz, H-1b), 4.58, 4.78 (2H, ABq, JAB
10.6 Hz, PhCH2), 4.72, 4.95 (2H, ABq, JAB 11.1 Hz, PhCH2), 4.74
(1H, br s, H-1a), 4.75, 4.90 (2H, ABq, JAB 10.9 Hz, PhCH2), 5.58
(1H, s, PhCH), 6.76 (1H, d, J 3.8 Hz, Ar-CH), 6.79 (1H, d, J 3.5 Hz,
Ar-CH), 7.15–7.48 (26H, m, 26 ꢂ Ar-CH); selected 1H NMR data
for the b-anomer: 3.37 (0.04H, s, OCH3), 5.61 (0.04H, s, PhCH);
dC (100 MHz, CDCl3) 54.9 (q, OCH3), 64.0 (d, C-5a), 65.6, 68.6,
68.9, 73.5, 73.8, 75.0, 75.6 (7 ꢂ t, C-6a, C-6b, 5 ꢂ ArCH2), 70.9,
73.0, 75.2, 77.3, 78.8, 81.2, 84.8 (7 ꢂ d, C-2a, C-3a, C-4a, C-2b, C-
3b, C-4b, C-5b), 99.8 (d, C-1b), 101.3 (d, C-1a), 102.5 (d, PhCH),
126.0, 126.3, 126.4, 126.4, 127.5, 127.6, 127.7, 127.7, 127.8,
127.9, 127.9, 128.0, 128.2, 128.2, 128.3, 128.3, 128.3, 128.4,
128.4, 128.5, 129.0, 129.2, 129.3, 129.4 (24 ꢂ d, 24 ꢂ Ar-CH),
137.4, 138.0, 138.5, 138.6, 142.7 (5 ꢂ s, 5 ꢂ Ar-C); m/z (ES+) 918
(M+NH4þ, 100%). (HRMS (ES+) Calcd for C53H56O11S1Na (MNa+)
923.3436. Found 923.3431).
a
a
a
a
a
a
127.2, 127.6, 127.6, 127.7, 127.7, 127.9, 127.9, 128.1, 128.2, 128.4
(14 ꢂ d, 14 ꢂ Ar-CH), 137.9, 138.1, 138.3, 138.7, 138.9, 140.9,
141.2 (7 ꢂ s, 7 ꢂ Ar-C); m/z (ES+) 806 (M+NH4þ, 100%). (HRMS
(ES+) Calcd for C44H52O11S1Na (MNa+) 811.3123. Found 811.3118).
4.12. Methyl 3,4,6-tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-
-glucopyranoside 15
a/b-
D
Rf 0.6 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [1.5:1
mixture of :b anomers observed] 3.38–3.50 (3.33H, m, H-2 , H-
2b, H-5 , H-5b), 3.60 (5H, br s, OCH3), 3.61–3.65 (3.33H, m, H-
, H-3b, H-4 , H-4b), 3.68–3.78 (3.33H, m, H-6
, H-6b, H-60a
H-60b), 4.29 (0.66H, d, J1,2 7.8 Hz, H-1b), 4.31 (1H, d, J1,2 3.0 Hz,
H-1 8 ꢂ Ar-CHb), 6.75
), 4.51–4.98 (13.33H, m, 8 ꢂ Ar-CH
(1.66H, m, Ar-CH , Ar-CHb), 6.91 (1.66H, m, Ar-CH , Ar-CHb),
7.15–7.17 (3.33H, m, 2 ꢂ Ar-CH 2 ꢂ Ar-CHb), 7.28–7.37
(23.33H, m, 14 ꢂ Ar-CH , 14 ꢂ Ar-CHb); dC (100 MHz, CDCl3) 57.1
a
a
a
3a
a
a
,
4.15. 2,3,4,6-Tetra-O-benzyl-
a/b-D-glucopyranosyl-(16)-1:2,3:4-
a
a
,
di-O-isopropylidene-
D
-galactopyranoside 1926
a
a
a
,
Rf 0.3 (petrol/ethyl acetate, 4:1); dH (400 MHz, CDCl3) [1:4 mix-
ture of
:b anomers observed] 1.32, 1.46, 1.51, 1.54 (15H, 4 ꢂ br s,
4 ꢂ CH3 , 4 ꢂ CH3b), 3.42–3.49 (2.5H, m, H-2b , H-5b , H-2bb, H-
, H-4b , H-6b , H-
a
a
(q, OCH3), 68.8 (t, C-6), 73.5, 75.1, 75.3, 75.8 (4 ꢂ t, 4 ꢂ ArCH2),
74.9 (d, C-5), 77.8 (d, C-3), 81.9 (d, C-2), 84.4 (d, C-4), 104.5 (d,
C-1), 126.8, 127.6, 127.6, 127.7, 127.8, 127.9, 128.0, 128.4, 128.4,
129.3 (10 ꢂ d, 10 ꢂ Ar-CH), 138.0, 138.1, 138.5, 142.9 (4 ꢂ s,
4 ꢂ Ar-C); m/z (ES+) 578 (M+NH4þ, 100%). (HRMS (ES+) Calcd for
C33H36O6S1Na (MNa+) 583.2125. Found 583.2119).
a
a
a
5bb), 3.57–3.85 (7.5H, m, H-2a
a
, H-4a
a
, H-5a
a
a
a
60ba, H-2ab, H-4ab, H-5ab, H-4bb, H-6bb, H-60 b), 3.99 (0.25H, at, J
b
9.2 Hz, H-3b
a
), 4.02–4.11 (1.5H, m, H-3bb, H-6a
a
, H-60aa), 4.17
(1H, dd, J5,6 3.5 Hz, J6,6 10.8 Hz, H-6ab), 4.25 (1H, m, H-60 b),
0
a
4.31–4.37 (1.25H, m, H-3a
1bb), 4.49–5.07 (10H, 4 ꢂ PhCH2
J1,2 2.4 Hz, H-1b ), 5.53 (1H, d, J1,2 5.1 Hz, H-1a
5.1 Hz, H-1ab), 7.12–7.15 (2.5H, m, 2 ꢂ Ar-CH
a
, H-3ab), 4.46 (1H, d, J1,2 7.9 Hz, H-
, 4 ꢂ PhCH2b), 4.58 (0.25H, d,
), 5.57 (1H, d, J1,2
2 ꢂ Ar-CHb),
a
4.13. 3,4,6-Tri-O-benzyl-2-O-(thiophen-2-ylmethyl)-
glucopyranosyl-(12)-methyl-3-O-benzyl-4,6-O-benzylidene-
-mannopyranoside 16
a
/b-
D
-
a
a
a-
a,
D
7.24–7.39 (20H, m, 16 ꢂ Ar-CH , 16 ꢂ Ar-CHb), 7.41–7.44 (2.5H,
a
m, 2 ꢂ Ar-CH
a
, 2 ꢂ Ar-CHb); m/z (ES+) 800 (M+NH4þ, 100%).
Rf 0.6 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [30:1
mixture of :b anomers observed, data for the major -anomer
a
a
4.16. Methyl 2,3,4,6-tetra-O-benzyl-a/b-D
-glucopyranoside 2027
quoted] 3.38 (3H, br s, OCH3), 3.50 (1H, m, H-5b), 3.54–3.63 (3H,
m, H-2b, H-3b, H-4b), 3.68–3.71 (2H, m, H-6b, H-60 ), 3.80–3.83
Rf 0.4 (petrol/ethyl acetate, 7:1); dH (400 MHz, CDCl3) [1:8 mix-
ture of :b anomers observed, data for the major b-anomer quoted]
b
(2H, m, H-5a, H-6a), 3.96 (1H, dd, J2,3 3.5 Hz, J3,4 9.9 Hz, H-3a),
a
4.15 (1H, m, H-4a), 4.24 (1H, m, H-2a), 4.33 (1H, m, H-60 ), 4.45,
3.42–3.48 (2H, m, H-2, H-5), 3.55 (3H, s, OCH3), 3.60–3.71 (3H, m,
a
H-3, H-4, H-6), 3.76 (1H, dd, J5,6 2.1 Hz, J6,6 10.9 Hz, H-60), 4.32 (1H,
0
4.51 (2H, ABq, JAB 12.1 Hz, PhCH2), 4.47, 4.75 (2H, ABq, JAB
11.1 Hz, PhCH2), 4.48 (1H, d, J1,2 4.0 Hz, H-1b), 4.67, 4.85 (2H,
ABq, JAB 12.6 Hz, PhCH2), 4.80, 4.97 (2H, ABq, JAB 10.9 Hz, PhCH2),
d, J1,2 7.5 Hz, H-1), 4.53, 4.80 (2H, ABq, JAB 11.3 Hz, PhCH2), 4.56,
4.63 (2H, ABq, JAB 12.3 Hz, PhCH2), 4.72, 4.82 (2H, ABq, JAB

780
D. J. Cox, A. J. Fairbanks / Tetrahedron: Asymmetry 20 (2009) 773–780
10.9 Hz, PhCH2), 4.92, 4.93 (2H, ABq, JAB 10.9 Hz, PhCH2), 7.14–7.17
(2H, m, 2 ꢂ PhCH), 7.24–7.36 (18H, m, 18 ꢂ PhCH); m/z (ES+) 554
(M+NH4þ, 100%).
References
1. Varki, A. Glycobiology 1993, 3, 97–130.
2. Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357–2364.
3. (a) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523–1527;
(b) Sears, P.; Wong, C.-H. Science 2001, 291, 2344–2350.
4. Wulff, G.; Röhle, G. Angew. Chem., Int. Ed. Engl. 1974, 13, 157–170; . Angew.
Chem. 1974, 86, 173–187.
4.17. 2,3,4,6-Tetra-O-benzyl-
a/b-
D
-glucopyranosyl-(12)-methyl-
3-O-benzyl-4,6-O-benzylidene-
a-D
-mannopyranoside 2126
5. Demchenko, A. V. Curr. Org. Chem. 2003, 7, 35–79.
6. Fairbanks, A. J. Synlett 2003, 1945–1958.
Rf 0.6 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [2:1
mixture of :b anomers observed] 3.29 (4.5H, br s, OCH3 , OCH3b),
3.57 (1H, dd, J1,2 3.8 Hz, J2,3 9.6 Hz, H-2b ), 3.60–3.70 (2H, m, H-
7. For a review of intramolecular glycosylation see: Jung, K.-H.; Müller, M.;
Schmidt, R. R. Chem. Rev. 2000, 100, 4423–4442.
8. (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 9377–9379; (b) Barresi,
F.; Hindsgaul, O. Synlett 1992, 759–760; (c) Barresi, F.; Hindsgaul, O. Can. J.
Chem. 1994, 72, 1447–1465.
a
a
a
5ba
, H-2bb, H-5bb), 3.72–3.80 (4H, m, H-4b
a
a
,
H-6b
, H-3bb, H-4bb,
a, ,
H-60ba
H-6bb, H-60 b), 3.83–3.88 (3.5H, m, H-3a
a, H-5a
b
9. (a) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992, 114, 1087–1088; (b) Stork, G.; La
Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247–248.
H-5ab), 4.00–4.04 (3H, m, H-2aa, H-6aa, H-2ab, H-6ab), 4.20–4.23
(3H, m, H-4a
a
, H-60aa, H-4ab, H-60 b), 4.27–4.31 (1.5H, m, H-3a
a,
a
10. (a) Bols, M. J. Chem. Soc., Chem. Commun. 1992, 913–914; (b) Bols, M. J. Chem.
Soc., Chem. Commun. 1993, 791–792; (c) Bols, M. Tetrahedron 1993, 44, 10049–
10060; (d) Bols, M.; Hansen, H. C. Chem. Lett. 1994, 1049–1052; (e) Ennis, S. C.;
Fairbanks, A. J.; Tennant-Eyles, R. J.; Yeates, H. S. Synlett 1999, 1387–1390; (f)
Ennis, S. C.; Fairbanks, A. J.; Slinn, C. A.; Tennant-Eyles, R. J.; Yeates, H. S.
Tetrahedron 2001, 57, 4221–4230; (g) Chayajarus, K.; Chambers, D. J.; Chughtai,
M. J.; Fairbanks, A. J. Org. Lett. 2004, 6, 3797–3800.
11. (a) Lergenmüller, M.; Nukada, T.; Kuramochi, K.; Dan, A.; Ogawa, T.; Ito, Y. Eur.
J. Org. Chem. 1999, 1367–1376; (b) Dan, A.; Lergenmüller, M.; Amano, M.;
Nakahara, Y.; Ogawa, T.; Ito, Y. Chem. Eur. J. 1998, 4, 2182–2190; (c) Ito, Y.;
Ohnishi, Y.; Ogawa, T.; Nakahara, Y. Synlett 1998, 1102–1104; (d) Dan, A.; Ito,
Y.; Ogawa, T. J. Org. Chem. 1995, 60, 4680–4681; (e) Dan, A.; Ito, Y.; Ogawa, T.
Tetrahedron Lett. 1995, 36, 7487–7490; (f) Ito, Y.; Ogawa, T. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1765–1767; . Angew. Chem. 1994, 106, 1843–1845.
12. (a) Seward, C. M. P.; Cumpstey, I.; Aloui, M.; Ennis, S. C.; Redgrave, A. J.;
Fairbanks, A. J. Chem. Commun. 2000, 1409–1410; (b) Aloui, M.; Chambers, D.;
Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J.; Seward, C. M. P. Chem. Eur. J. 2002,
8, 2608–2621; (c) Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J. Org. Lett. 2001, 3,
2371–2374; (d) Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J. Monatsh. Chem.
2002, 133, 449–466; (e) Cumpstey, I.; Fairbanks, A. J.; Redgrave, A. J.
Tetrahedron 2004, 60, 9061–9074; (f) Cumpstey, I.; Chayajarus, K.; Fairbanks,
A. J.; Redgrave, A. J.; Seward, C. M. P. Tetrahedron: Asymmetry 2004, 15, 3207–
3221; (g) Attolino, E.; Cumpstey, I.; Fairbanks, A. J. Carbohydr. Res. 2006, 341,
1608–1618.
H-3ab), 4.37–5.04 (15.5H, H-1a
4.52 (0.5H, s, H-1ab), 4.72 (1H, d, J1,2 1.8 Hz, H-1a
PhCH ), 5.58 (1H, d, J1,2 3.8 Hz, H-1b ), 5.65 (0.5H, s, PhCHb),
7.13–7.19 (6H, m, 4 ꢂ Ar-CH , 4 ꢂ Ar-CHb), 7.24–7.51 (39H, m,
26 ꢂ Ar-CH , 26 ꢂ Ar-CHb); dC (100 MHz, CDCl3) [data for the ma-
jor -anomer quoted] 54.8 (q, OCH3), 64.3 (d, C-5a), 68.7, 68.8
a,
10 ꢂ PhCH2
a,
10 ꢂ PhCH2b),
a
), 5.50 (1H, s,
a
a
a
a
a
(2 ꢂ t, C-6a, C-6b), 71.4, 73.5, 73.9, 75.2, 75.6 (5 ꢂ t, 5 ꢂ ArCH2),
70.7, 74.6, 76.7, 77.5, 79.2, 81.4 (6 ꢂ d, C-2a, C-3a, C-4a, C-3b, C-
4b, C-5b), 79.8 (d, C-2b), 97.4 (d, C-1b), 101.1 (d, C-1a), 101.3 (d,
PhCH), 126.0, 127.4, 127.5, 127.6, 127.7, 127.9, 127.9, 128.0,
128.0, 128.2, 128.2, 128.3, 128.3, 128.4, 128.8 (15 ꢂ d, 15 ꢂ Ar-
CH), 137.8, 138.9, 138.2, 138.4, 139.0 (5 ꢂ s, 5 ꢂ Ar-C); m/z (ES+)
þ
912 (M+NH4
,
100%). (HRMS (ES+) Calcd for C44H52O11S1Na
(MNa+) 917.3871. Found 917.3870).
4.18. 2,3,4,6-Tetra-O-benzyl-
a/b-
D-glucopyranosyl-(13)-methyl-
2-O-benzyl-4,6-O-benzylidene-
a-D-mannopyranoside 22
13. (a) Attolino, E.; Fairbanks, A. J. Tetrahedron Lett. 2007, 48, 3061–3064; (b)
Attolino, E.; Rising, T. W. D. F.; Heidecke, C. D.; Fairbanks, A. J. Tetrahedron:
Asymmetry 2007, 18, 1721–1734.
14. (a) Lee, Y. J.; Ishiwata, A.; Ito, Y. J. Am. Chem. Soc. 2008, 130, 6330–6331; (b)
Ishiwata, A.; Lee, Y. J.; Ito, Y. Eur. J. Org. Chem. 2008, 4250–4263.
15. Esters are not the only protecting groups that participate during glycosylation
reactions. For example see: Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V.
Angew. Chem., Int. Ed. 2005, 44, 7123–7126.
16. Slattegard, R.; Gammon, D. W.; Oscarson, S. Carbohydr. Res. 2007, 342, 1943–
1946.
17. (a) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed. 2005, 44, 947–949; (b)
Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. J. Am. Chem. Soc. 2005, 127, 12090–
12097.
Rf 0.63 (toluene/ethyl acetate, 9:1); dH (400 MHz, CDCl3) [3:1
mixture of :b anomers observed] 3.33 (1H, s, OCH3b), 3.34 (3H,
s, OCH3 ), 3.52 (1.33H, m, H-2b
H-5b , H-6b
(5.33H, m, H-4b
a
a
a
, H-2bb), 3.56–3.71 (4.33H, m,
a
a
, H-60ba, H-4bb, H-5bb, H-6bb, H-60 b), 3.80–3.90
b
a, H-2a
a
, H-5a
a
, H-6a
a, H-3bb, H-2ab, H-5ab, H-
6ab), 4.00 (1H, at, J 9.2 Hz, H-3ba), 4.23–4.39 (4H, m, H-3aa, H-
4a
a
, H-60 b, H-3ab, H-4a
a
, H-60 b), 4.43–4.99 (13.33H, 10 ꢂ PhCH2
a,
a
a
10 ꢂ PhCH2b), 4.59 (0.33H, d, J1,2 7.8 Hz, H-1bb), 4.70 (0.33H, d, J1,2
1.8 Hz, H-1ab), 4.72 (1H, d, J1,2 1.8 Hz, H-1a
5.54 (1H, d, J1,2 3.8 Hz, H-1b ), 5.56 (0.33H, s, PhCHb), 6.98–7.01
(1.33H, m, Ar-CH
, Ar-CHb), 7.13–7.48 (38.66H, m, 29 ꢂ Ar-CH
29 ꢂ Ar-CHb); dC (100 MHz, CDCl3) [data for the major -anomer
a), 5.47 (1H, s, PhCHa),
a
18. Park, J.; Kawatkar, S.; Kim, J. H.; Boons, G. J. Org. Lett. 2007, 9, 1959–1962.
19. Boons has already reported a case where the participating group at the 2-
a
a,
position of the donor was an achiral O–(CH2)2SPh moiety, and an 8:1
selectivity was observed. See Ref. 17b.
a:b
a
quoted] 54.9 (q, OCH3), 63.9 (d, C-5a), 68.7, 69.0 (2 ꢂ t, C-6a, C-
6b), 73.4, 73.5, 73.9, 75.0, 75.5 (5 ꢂ t, 5 ꢂ ArCH2), 70.9, 72.8, 77.3,
77.4, 78.9 (5 ꢂ d, C-2a, C-3a, C-4a, C-4b, C-5b), 79.7 (d, C-2b), 81.4
(d, C-3b), 96.9 (d, C-1b), 100.0 (d, C-1a), 102.4 (d, PhCH), 126.3,
126.4, 127.2, 127.5, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0,
128.1, 128.2, 128.3, 128.3, 128.3, 128.5, 129.3 (17 ꢂ d, 17 ꢂ Ar-
20. Campaigne, E. E.; Tullar, B. F. Org. Synth. 1953, 33, 96–98.
21. Lichtentaler, F. W.; Schneider-Adams, T. J. Org. Chem. 1994, 59, 6728–6734.
22. Agnihotri, G.; Tiwari, P.; Misra, A. K. J. Carbohydr. Chem. 2006, 25, 491–498.
23. de Pouilly, P.; Chenede, A.; Mallet, J.-M.; Sinaÿ, P. Bull. Chem. Soc. Fr. 1993, 256–
265.
24. Gordon, D. M.; Danishefsky, S. J. Carbohydr. Res. 1990, 206, 361–366.
25. Liptak, A.; Czegeny, I.; Harangi, J.; Nanasi, P. Carbohydr. Res. 1970, 73, 327–
CH), 137.4, 138.0, 138.3, 138.5, 138.7 (5 ꢂ s, 5 ꢂ Ar-C); m/z (ES+)
331.
26. Kim, K. S.; Fulse, D. B.; Baek, J. Y.; Lee, B.-Y.; Jeon, H. B. J. Am. Chem. Soc. 2008,
þ
912 (M+NH4
,
100%). (HRMS (ES+) Calcd for C44H52O11S1Na
130, 8537–8547.
(MNa+) 917.3871. Found 917.3868).
27. Vankayalapati, H.; Singh, G.; Tranoy, I. Tetrahedron: Asymmetry 2001, 2, 1373–
1381.
Acknowledgement
The authors gratefully acknowledge the EPSRC (DTA award to
D.J.C.) for financial support.