Stereoselective glycosylations using oxathiane spiroketal glycosyl donors

Article abstract of DOI:10.1016/j.carres.2011.07.020

Novel oxathiane spiroketal donors have been synthesised and activated via an umpolung S-arylation strategy using 1,3,5-trimethoxybenzene and 1,3-dimethoxybenzene. The comparative reactivity of the resulting 2,4,6-trimethoxyphenyl (TMP)- and 2,4-dimethoxyp

Full text of DOI:10.1016/j.carres.2011.07.020

Carbohydrate Research 348 (2012) 6–13
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Stereoselective glycosylations using oxathiane spiroketal glycosyl donors
Martin A. Fascione a, Nicola J. Webb a, Colin A. Kilner a, Stuart L. Warriner a,b, W. Bruce Turnbull a,b,
⇑
a School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
b Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 June 2011
Received in revised form 16 July 2011
Accepted 20 July 2011
Available online 26 July 2011
Novel oxathiane spiroketal donors have been synthesised and activated via an umpolung S-arylation
strategy using 1,3,5-trimethoxybenzene and 1,3-dimethoxybenzene. The comparative reactivity of the
resulting 2,4,6-trimethoxyphenyl (TMP)- and 2,4-dimethoxyphenyl (DMP)-oxathiane spiroketal sulfon-
ium ions is discussed, and their
a-stereoselectivity in glycosylation reactions is compared to the
analogous TMP- and DMP-sulfonium ions derived from an oxathiane glycosyl donor bearing a methyl
ketal group. The results show that the stereoselectivity of the oxathiane glycosyl donors is dependent
on the structure of the ketal group and reactivity can be tuned by varying the substituent on the sulfo-
nium ion.
Keywords:
Glycosylation
Spiroketal
Oxathiane
Ó 2011 Elsevier Ltd. All rights reserved.
a-Glycoside
1. Introduction
ketal sulfonium ions 4 are notable for the formation of glycosides
with complete
a
-stereoselectivity,19,21 the resulting O-2 acyclic
The chemical synthesis of complex oligosaccharides presents
many technical challenges ranging from lengthy reaction sequences
to problematic purification steps.1,2 But such is the biological
importance of carbohydrates3 that solutions for many of these dif-
ficulties are on the horizon, for example, through ‘one-pot’ glycosyl-
ations using orthogonally activated donors4–6 and the advent of
solid-phase automated oligosaccharide synthesis.1,7–10 Despite
these advances, stereocontrol over the formation of the glycosidic
linkage still remains a challenge, particularly in the synthesis of
1,2-cis-glycosides.11–15 Much recent work in this field has focussed
on the study of stabilised glycosyl sulfonium ions and their stereo-
directing ability,16–22 including our recent report of oxathiane ketal-
S-oxide glycosyl donors 1 for stereoselective 1,2-cis glycosylations
(Scheme 1a).19
Attempts to arylate glycosyl oxathianes with benzyne led to the
formation of glycosyl acetates.21 However, oxidation of the oxathi-
ane to give oxathiane ketal-S-oxides 1, and subsequent treatment
with Tf2O, led to the formation of surprisingly stable activated
intermediates that were sufficiently long-lived to undergo electro-
philic aromatic substitution in the presence of 1,3,5-trimethoxy-
benzene (TMB). Therefore, conversion of the previously
nucleophilic sulfide into an electrophilic S(IV) centre facilitated
an ‘umpolung’ approach to S-arylation. The resulting 2,4,6-trime-
thoxyphenyl (TMP)-oxathiane ketal sulfonium ions 2 then afforded
ketal formed in the product 5 occasionally decomposed under
the reaction conditions, diminishing yields in more challenging
glycosylation reactions. Therefore, in an attempt to circumvent this
issue, we set out to design a new oxathiane donor scaffold in which
the axial methoxy group was replaced with an O-substituent con-
strained in a spirocyclic ring (Scheme 1b). It was anticipated that
following glycosylation, spiroketal sulfonium ion 6 would afford
glycosides 7 bearing an O-2 cyclic ketal which would be more sta-
ble than the corresponding O-2 acyclic ketal, but still sufficiently
labile to be removed by Lewis acid catalysed cleavage. To this
end, we present the synthesis and activation of oxathiane spirok-
etal-S-oxides via an umpolung S-arylation strategy, and compare
their
ogous oxathiane ketal sulfonium ions. We also demonstrate that
the stability and -stereoselectivity of oxathiane spiroketal sulfo-
a-stereoselectivities in glycosylation reactions with the anal-
a
nium ions in glycosylation reactions can be modulated by changing
the S-aryl appendage exogenous to the oxathiane ring. Both TMP
and 2,4-dimethoxyphenyl (DMP) sulfonium ions are synthesised,
and their reactivities and
a-stereoselectivities are compared.
2. Results and discussion
The synthesis of the oxathiane spiroketal donor began from
pentaacetate 8, which was activated with a Lewis acid in the
presence of thiourea to afford an intermediate b-glycosyl isothio-
uronium salt.23,24 Thioglycoside 9 was then isolated in 50% yield
following treatment with Et3N and mesylated dihydropyran 17,
which was synthesised from alcohol 16 (Scheme 2).25 Subsequent
deacetylation under Zemplén conditions afforded the unprotected
a-glycosides 3 with complete stereoselectivity following heating at
50 °C. However, although glycosylation reactions with oxathiane
⇑
Corresponding author. Tel.: +44 1133437438; fax: +44 11333436565.
E-mail address: w.b.turnbull@leeds.ac.uk (W.B. Turnbull).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.07.020

M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
7
Scheme 1. (a) Umpolung S-arylation strategy for oxathiane ketal-S-oxide donors 1.
(b) Oxathiane ketal donor scaffold 4 and oxathiane spiroketal donor scaffold 6.
thioglycoside, which was subjected to a regio- and stereoselective
acid-catalysed cyclisation to afford key oxathiane spiroketal scaf-
fold 10 in 60% yield over two steps. Acetylation then furnished
protected spiroketal 11, which was oxidised with m-CPBA to af-
ford sulfoxide 13 in 93% yield with a diastereomeric ratio of
93:7. The equatorial sulfoxide 13-R was unequivocally assigned
as the major diastereomer based on analysis of the geminal cou-
pling constants for the methylene protons adjacent to sulfur.26,27
Benzylation of triol 10 similarly led to the protected oxathiane
12, which was oxidised to sulfoxide 14 as virtually a single diaste-
reomer in 30% yield over two steps. Importantly the structural
integrity of the spiroketal ring was confirmed by X-ray crystallo-
graphic analysis. The X-ray structure of the acetylated axial sulfox-
ide 13-S (Scheme 2) illustrates how the interlocked ring
Scheme 2. Reagents and conditions: (a) (i) BF3ꢁOEt2/SC(NH2)2/CH3CN, (ii) Et3N/17
(50%); (b) (i) NaOMe/MeOH, (ii) p-TSA/CHCl3 (60%); (c) 11 Ac2O/Et3N/DMAP/CH2Cl2
(100%); 12 NaH/BnBr/DMF; (d) 13 m-CPBA/CH2Cl2 (93%, dr 97:3, only the major
diastereomer is shown); 14 m-CPBA/CH2Cl2 (30% from 10, dr 99:1); (e) n-BuLi/
TMEDA/THF/(CH2O)n (47%); (f) Et3N/MsCl/CH2Cl2—the crude product 17 was used
without purification. The crystal structure depicts an ellipsoid probability of 50%.
Content that the formation of TMP-spiroketal 18 occurred un-
der the reaction conditions, glycosylation of diacetone galactose
19 was then attempted. As anticipated, glycosylation reactions at
room temperature proceeded very slowly, demonstrating the sta-
bility of sulfonium ion 18. Therefore, the glycosylation reaction
was attempted at an elevated temperature of 50 °C (Scheme 3). It
proved convenient to cleave the O-2 cyclic ketal protecting group
with BF3ꢁOEt2 prior to isolation of glycoside product 20, which
configuration benefits from stabilisation by double n(O)?
r
⁄(C–
O) overlap.28–30
With spiroketal-S-oxide 13-R in hand, umpolung S-arylation
using triflic anhydride and TMB was attempted (Fig. 1). Pleasingly,
clean formation of the TMP-sulfonium ion 18 as a single diastereo-
mer was observed by 1H NMR spectroscopy. Assignment of sulfo-
nium ion stereochemistry is tentative in the absence of both
diastereomers of sulfonium ion 18; however, comparison of the
geminal coupling constant for the methylene protons adjacent to
sulfur are consistent with analogous equatorial aryl sulfonium
salts.19 Following activation of sulfoxide 13-R in CD2Cl2, a charac-
teristic ꢀ1.5 ppm downfield shift of the H-1 proton signal oc-
curs,16,19 indicative of the formation of sulfonium ion 18. This is
accompanied by similar downfield shifts for the H-axial and H-
equatorial protons adjacent to the positively charged sulfur, and
the appearance of signals corresponding to the aromatic protons
and methoxy groups associated with the TMP S-appendage.
was obtained in a yield of 38% over two steps (a:b 93:7). By reduc-
ing the temperature to 37 °C, it proved possible to increase the
yield of the glycosylation reaction, affording glycoside 20 in an im-
proved yield of 60%, but without change to the anomeric ratio (
93:7; Table 1, entry 1).
a:b
These conditions were then applied to the glycosylation of the
secondary alcohol, 2-propanol, with acetylated spiroketal 13-R,
which afforded
an improved anomeric ratio of
a
-glycoside 28 in 61% yield, on this occasion with
:b 98:2 (Table 1, entry 2). Glyco-
a
sylation reactions with the benzylated spiroketal 14-R proceeded
at room temperature, which is consistent with the increased reac-

8
M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
Figure 1. Formation of TMP-spiroketal 18, observed by 1H NMR in CD2Cl2.
(1.5 equiv in entries 1–4 vs 2.5 equiv in entry 7, or 5 equiv in entry
OAc
O
8) may be a result of competing intramolecular glycosylation.
However, no conclusive evidence for the formation of any resulting
bicyclic O-glycoside products could be obtained, even prior to the
Lewis acid catalysed cleavage step.
AcO
AcO
OAc
O
O
AcO
AcO
a
HO
S
O
O
O
O
Although still highly a-stereoselective, the spiroketal sulfonium
13-R
O
O
O
OH
O
O
ions 21 were less stereoselective than the corresponding methyl
ketal sulfonium ions 23.19 This difference is intriguing, considering
that both sulfonium ions appear to have comparable reactivity and
that both scaffolds contain a ketal substituent in the oxathiane
20
O
O
O
O
ring. Recently, it has been proposed that the complete a-stereose-
19
lectivity of ketal sulfonium ions 23 may be a direct result of their
inherent stability.33 This theory is based on the assumption that
ketal 23 can exist in either its bicyclic sulfonium ion form, or in a
ring-opened oxacarbenium ion form.18,34–36 In a manifestation of
the Thorpe–Ingold effect,37,38 the ketal group is proposed to stabi-
Scheme 3. Reagents and conditions: (a) (i) Tf2O/TMB/DIPEA/ꢂ30 to ꢂ10 °C, (ii) 19/
C2H4Cl2/ꢂ10 to 50 °C (ii) BF3ꢁOEt2/CH2Cl2.
tivity that is expected on moving from the ‘disarming’ acetyl to the
‘arming’ benzyl ether protecting group.31,32 Thus, glycosylation of
lise the cyclic sulfonium ion, thus promoting an ‘SN2-like’
oselective glycosylation.39–41 However, from a comparison of the
results reported in Table 1, it seems unlikely that the -stereose-
a-stere-
primary alcohol 19 afforded
a-glycoside 27 in 58% yield with an
a
a
:b ratio of 92:8 (Table 1, entry 3), and glycosylation of 2-propanol
lectivity of sulfonium ions 23 results simply from stabilising the
oxathianium ion with a ketal group; instead it would appear that
stereoselectivity may also be influenced by the other substituents
on the oxathiane ring.
afforded the desired a-glycoside 29 in 57% yield with an a:b ratio
of 96:4 (Table 1, entry 4). Both reactions using the benzylated spi-
roketal 14-R were, therefore, marginally less -stereoselective than
a
the comparable glycosylations using the acetylated spiroketal 13-
R, which is a trend noted previously with oxathiane ether glycosyl
donors.21,33 It was pleasing to note that glycosylation reactions
using spiroketal donors required significantly less glycosyl accep-
tor than analogous reactions. Previously, it was found that the
higher concentrations of acceptor were needed to avoid a compet-
ing glycosylation reaction involving MeOH that can be released
from glycoside products bearing the methyl ketal protecting group
on O-2.19 This side reaction was found to be equally problematic at
either 50 °C or room temperature. However, the increased stability
of the O-2 cyclic ketal protecting group under the reaction condi-
tions successfully avoids comparable side reactions. Although no
quantitative comparison of the stability of the O-2 acyclic and cyc-
lic ketal was performed, analysis of the crude reaction mixtures
following glycosylation reactions using methyl ketal donors re-
vealed significant loss of the O-2 acyclic ketal, while far less cleav-
age of the O-2 cyclic ketal was observed following reactions
employing oxathiane spiroketal donors. The lower yields in reac-
tions using spiroketal donors 13-R and 14-R, compared to the anal-
ogous reactions using the methyl ketal donors 25-R and 26-R
Therefore, our attention turned next to the S-aryl appendage on
the sulfonium ions. 2,6-Dimethoxyphenyl (DMP) sulfonium ions
22 and 24 were prepared to study the effects of removing a meth-
oxy group from the aromatic ring. Activation of the oxathiane
ketal-S-oxide 25-R in the presence of dimethoxybenzene (DMB)
and addition of primary alcohol 19 afforded the desired
ide 20 in 62% yield (Table 1, entry 9). The yield of the desired
coside was lower than in the case of TMB activation (Table 1, entry
7) as a result of concomitant formation of the analogous -methyl
glycoside in 12% yield; nevertheless, both glycosides were still
formed with complete -stereoselectivity. However, when spirok-
etal-S-oxide 13-R was activated in the same fashion, the resulting
DMP-sulfonium ion afforded glycosides with lower -stereoselec-
a-glycos-
a-gly-
a
a
a
tivity than that observed for the TMP-sulfonium ion. For example,
glycosylation of primary alcohol 19 afforded the glycoside 20 in
50% yield with an anomeric ratio of
compared to :b 93:7 for glycosylation using the analogous TMP-
sulfonium ion (Table 1, entry 1). Also the glycosylation of 2-propa-
nol afforded -glycoside 28 in 52% yield with an anomeric ratio of
:b 95:5 (Table 1, entry 6), which was less -stereoselective than
a:b 86:14 (Table 1, entry 5),
a
a
a
a

M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
9
Table 1
Glycosylation reactions with (a) oxathiane spiroketal sulfonium ions 21 and 22 and (b) oxathiane ketal sulfonium ions 23 and 24
Entry
Donor
ArH
ROH
Product
Yielda (%)
a:b
1b
2b
3c
4c
5b
6b
7e
8e
9
13-R
13-R
14-R
14-R
13-R
13-R
25-R
26-R
25-R
TMB
TMB
TMB
TMB
DMB
DMB
TMB
TMB
DMB
19
iPrOH
19
iPrOH
19
20
28
27
29
20
28
20
28
20
60
61
58
57
50
52
85
77
62
93:7
98:2
92:8d
96:4d
86:14
95:5
iPrOH
19f
>98:2g
>98:2g
>98:2g
iPrOHh
19f
a
b
c
Isolated yield over two steps.
Glycosylations were performed in CH2Cl2 at ꢂ30 °C, before being warmed to ꢂ10 °C, followed by ROH (1.5 equiv) addition and stirring for 24 h at 37 °C.
After ROH (1.5 equiv) addition reaction mixture was stirred for 24 h at rt.
Measured by 1H NMR spectroscopy, following purification on Sephadex LH-20 column.
Reproduced from Ref. 19 for comparison.
d
e
f
2.5 equiv of ROH.
g
h
No b-anomer was detected in the 1H NMR spectrum of the crude mixture.
5 equiv the ROH.
the corresponding glycosylation using the TMP-sulfonium ion (
98:2, Table 1, entry 2).
a:b
1 signal at 5.9 ppm compared to the more shielded TMP-sulfonium
ion H-1 signal at 5.75 ppm.
We wondered if the reduction in
a-stereoselectivity on moving
Therefore, the decrease in the a-stereoselectivity of glycosyla-
from TMP-sulfonium ions to DMP-sulfonium ions would be accom-
panied by any differences in reactivity of the spiroketal sulfonium
ions. To this end, the reaction of MeOH with equimolar amounts of
TMP-sulfonium ion 18 and DMP-sulfonium ion 30 was monitored
by 1H NMR spectroscopy in CD2Cl2 (Fig. 2).
tion reactions using the DMP-sulfonium ion 30 compared to the
TMP-sulfonium ion 18 is accompanied by an increase in reactivity
of the sulfonium ion. A similar trend was observed when increas-
ing the reactivity of the sulfonium ions by moving from ester to
benzyl ether protecting groups.33 However, due to the limited
scope of this study, care must be taken not to over interpret this
After 35 h at rt, the H-1 signal of the TMP-spiroketal 18 was 48%
of its original intensity (52% reacted), while the H-1 signal for the
DMP-spiroketal 30 was only 24% of its original intensity (76% re-
acted). The reduction in H-1 signal intensities was also accompa-
nied by the formation of methyl glycosides 31-TMP/DMP,
characterised by an H-1 doublet at ꢀ4.8 ppm. The experiment
demonstrated that DMP-sulfonium ion 30 was approximately 1.5
times as reactive as the TMP-sulfonium ion 18. However, this
experiment also illustrates the high stability of these spiroketal
sulfonium ions as the glycosylation reaction was still not complete
after 93 h at room temperature (4% DMP-spiroketal 30 and 10%
TMP-spiroketal 18 remained). The increased reactivity of the
DMP-sulfonium ion 30 is perhaps unsurprising, as intuition would
suggest that the more electron-donating TMP aromatic group
should stabilise the positively charged sulfonium ion more effec-
tively.18,42 This reactivity difference may also be reflected in the
H-1 proton shifts for the sulfonium ions, as the more reactive
and less stabilised DMP-sulfonium ion 30 has the lowest field H-
correlation between reactivity and a-stereoselectivity.
In conclusion, the synthesis and reactivity of new oxathiane spi-
roketal glycosyl donors have been described. The aryl sulfonium
ions derived from the oxathiane spiroketal-S-oxides 13-R and 14-
R have comparable stability to analogous sulfonium ions derived
from other oxathiane ketal donors, but afford glycosides with low-
er a
-stereoselectivities than those reported previously.19 Stereose-
lectivity could be improved by changing the protecting groups on
the sugar ring (esters vs benzyl ethers) or the S-aryl appendage
(TMP-sulfonium ion vs DMP-sulfonium ion). Although these
changes in stereoselectivity appear to correlate with the stability
of the sulfonium ions, the stabilising effect of an oxygen substitu-
ent on the oxathianium ring is not sufficient to explain the high a-
stereoselectivity of the oxathiane ketal donors.19 The difference in
reactivity between TMP and DMP-sulfonium ions in the spiroketal
series potentially offers a strategy for ‘arming’ or ‘disarming’ oxa-
thiane glycosyl donors without changing protecting groups.

10
M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
sition
a to the axial oxygen and ending at the ketal carbon. Electro-
spray-ionisation (ES+) mass spectra were obtained on a Bruker HCT
Ultra Ion Trap mass spectrometer connected to an Agilent 1200
series HPLC system, and high resolution ES+ were performed on
a Bruker Daltonics MicroTOF mass spectrometer. Infrared spectra
were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer.
Melting points were obtained on a Reichert hot-stage apparatus
and are uncorrected. Optical rotations were measured at the so-
dium D-line with an Optical Activity AA-1000 polarimeter. [a]
D
values are given in units of 10ꢂ1 deg cm2 gꢂ1. Analytical T.L.C was
performed on Silica Gel 60-F254 (E. Merck) with detection by fluo-
rescence and/or charring following immersion in a 5% H2SO4/
MeOH solution, unless otherwise stated.
3.2. (3,4-Dihydro-2H-pyran-6-yl)methanol (16)25
Commercially available 3,4-dihydro-2H-pyran (15) (13.3 mL,
145.45 mmol) and TMEDA (24.1 mL, 160 mmol) were stirred and
cooled to 0 °C. n-BuLi (100 mL, 160 mmol) was added slowly, and
the flask was cooled for a further 45 min and then left for 20 h
overnight at room temperature. The colour of the solution changed
from a pale yellow to a burnt orange with a precipitate. Upon addi-
tion of tetrahydrofuran (100 mL) the precipitate dissolved to give
an orange solution. The reaction mixture was cooled to 0 °C, and
paraformaldehyde (9.6 g, 320 mmol) was added portionwise
(ꢃ1 g per addition) over 1 h. The reaction mixture was held at
0 °C for 1 h and left to warm to room temperature slowly, and then
stirred for a further 20 h. The reaction was quenched with aq NH4Cl
(100 mL) and then diluted with Et2O (60 mL). The organic phase
was poured over a solution of CuSO4ꢁ5H2O (100 mL) and stirred
for 30 min. The ether was then decanted and washed with satd
aq NaHCO3 (2 ꢄ 100 mL), dried (MgSO4) and concentrated to afford
3,4-dihydro-2H-pyran-6-(1-hydroxymethyl) (16) (7.85 g, 47%), as
a yellow oil; Rf 0.4 (1:1 (v/v) hexane–EtOAc); 1H NMR (500 MHz,
C6D6): dH 4.59 (t, 1H, J 3.8 Hz, RC@CHCH2CH2CH2), 3.88 (s, 2H,
CH2OH), 3.67 (t, 2H, J 5.1 Hz, RC@CHCH2CH2CH2), 1.71 (dd, 2H, J
6.4,
J 4.0 Hz, RC@CHCH2CH2CH2), 1.38 (q, 2H, 6.0, J 5.1 Hz,
RC@CHCH2CH2CH2); 13C NMR (75 MHz, C6D6): dC 154.7
(RC@CHCH2CH2CH2), 97.1 (RC@CHCH2CH2CH2), 66.7 (CH2OH),
63.6 (RC@CHCH2CH2CH2), 23.3 (RC@CHCH2CH2CH2), 20.8
(RC@CHCH2CH2CH2).
Figure 2. 1H NMR stackplot illustrating relative reactivities of TMP-sulfonium ion
18 and DMP-sulfonium ion 30 in CD2Cl2 at room temperature.
3. Experimental
3.3. (3,4-Dihydro-2H-pyran-6-yl)-methyl 2,3,4,6-tetra-O-acetyl-
1-thio-b-D-glucopyranoside (9)
3.1. General methods
Thiourea (1.35 g, 19.3 mmol) was added to
a solution of
All solvents were dried prior to use, according to standard
methods.43 Trifluoromethanesulfonic anhydride (Tf2O) was dis-
tilled under a N2(g) atmosphere. Boron trifluoride diethyl etherate
(BF3ꢁOEt2) was distilled over calcium hydride, and all other com-
mercially available reagents were used as received. Where appro-
priate, anhydrous quality material was purchased. All solvents
used for flash chromatography were GPR grade, except hexane
and EtOAc, when HPLC grade was used. All concentrations were
performed in vacuo, unless otherwise stated. All reactions were
performed in oven-dried glassware under a N2(g) atmosphere, un-
less otherwise stated. 1H NMR spectra were recorded at 500 MHz
on a Bruker Avance 500 instrument or at 300 MHz on a Bruker
Avance 300 instrument. 13C NMR spectra were recorded at
75 MHz on a Bruker Avance 300 instrument. Chemical shifts are gi-
ven in parts per million downfield from tetramethylsilane. The fol-
lowing abbreviations are used in 1H NMR analysis: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, dd = double dou-
blet, dt = double triplet, td = triple doublet, ddd = double double
doublet. In 1H NMR and 13C NMR of the oxathiane spiroketals,
the spiroketal ring is labelled ‘a’ through to ‘e’ starting from the po-
1,2,3,4,6-penta-O-acetyl-b- -glucopyranose (8) (6.83 g, 17.5 mmol)
D
in MeCN (60 mL) and heated to 85 °C. BF3ꢁOEt2 (4.66 mL,
36.8 mmol) was then added, and the reaction mixture was stirred
for 2 h at 85 °C. The solution was then cooled to room temperature
and degassed before addition of Et3N (7.62 mL, 54.3 mmol). Simul-
taneously, methanesulfonyl chloride (4.47 mL, 57.8 mmol) was
added to a separate solution of (3,4-dihydro-2H-pyran-6-yl)meth-
anol (16) (6.0 g, 52.5 mmol) and Et3N (14.75 mL, 105 mmol) in
CH2Cl2 (100 mL) at 0 °C before stirring for 10 min. This solution
was then added to the reaction mixture, which was left to stir at
room temperature for 18 h. The reaction mixture was then concen-
trated and redissolved in EtOAc (150 mL), washed with aq NaCl
(3 ꢄ 50 mL), dried and concentrated. The crude oil was purified
by flash column chromatography (silica gel; 2:1 (v/v) hexane–
EtOAc) to afford (3,4-dihydro-2H-pyran-6-yl)methyl 2,3,4,6-tetra-
O-acetyl-1-thio-b-D-glucopyranoside (9) (4.0 g, 50% yield) as an or-
ange oil; Rf 0.19 (2:1 (v/v) hexane–EtOAc); ½a D21
ꢅ
18.9 (c 0.7, CHCl3);
FTIR (m
max/cmꢂ1) 1671 (C@C), 1750 (C@O); 1H NMR (500 MHz,
CDCl3): dH 5.23 (t, 1H, J2,3 9.4 Hz, J3,4 9.4 Hz, H-3), 5.09 (dd, 1H,
J1,2 10.3 Hz, J2,3 9.4 Hz, H-2), 5.04 (t, 1H, J3,4 9.4 Hz, J4,5 9.4 Hz, H-

M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
11
4), 4.69 (t, 1H, J 3.4 Hz, RC@CHCH2CH2CH2), 4.63 (d, 1H, J1,2 10.3 Hz,
(d, 1H, JSCHeq,SCHax 13.7 Hz, SCHax), 2.08 (s, 3H, C(O)CH3), 2.06 (s,
3H, C(O)CH3), 2.03 (s, 3H, C(O)CH3), 1.56 (m, 6H, H-b, H-b0, H-c,
H-c0, H-d, H-d0); 13C NMR (75 MHz, CDCl3): dC 171.2, 170.6, 169.9
(C(O)CH3), 93.1 (C-e), 77.2 (C-1), 76.2 (C-5), 73.4 (C-4), 72.0 (C-2),
68.8 (C-3), 62.4 (C-6), 61.6 (C-a), 37.6 (SCH2), 34.5 (C-d), 25.1 (C-
b), 21.2 (C(O)CH3), 21.1 (C(O)CH3), 21.0 (C(O)CH3), 19.0 (C-c); HRE-
SIMS: found [M+Na]+ 441.1190 C18H26NaO9S requires 441.1195.
0
0
H-1), 4.25 (dd, 1H, J5,6 5.1 Hz, J6,6 11.9 Hz, H-6), 4.14 (dd, 1H, J5,6
5.1 Hz, J6,6 11.9 Hz, H-60), 4.03 (m, 2H, RC@CHCH2CH2CH2), 3.67
(m, 1H, H-5), 3.33 (d, 1H, J 13.6 Hz, SCH2), 3.13 (d, 1H, J 13.6 Hz,
0
0
SCH2 ), 2.08 (s, 3H, C(O)CH3), 2.05 (s, 3H, C(O)CH3), 2.02 (s, 3H,
C(O)CH3), 2.01 (s, 3H, C(O)CH3), 2.07 (dd, 2H, J 3.4 Hz, J 5.1 Hz,
RC@CHCH2CH2CH2), 1.82 (dd, 2H,
J
5.1,
J
6.0 Hz, RC@
CHCH2CH2CH2); 13C NMR (75 MHz, CDCl3): dC 171.0, 170.7, 169.8
(C(O)CH3), 149.9 (RC@CHCH2CH2CH2), 99.7 (RC@CHCH2CH2CH2),
82.8 (C-1), 76.1 (C-5), 74.4 (C-4), 70.4 (C-2), 68.7 (C-3), 66.9
(RC@CHCH2CH2CH2), 62.6 (C-6), 33.6 (SCH2), 22.4 (RC@
CHCH2CH2CH2), 22.4 (C(O)CH3), 21.4 (C(O)CH3), 20.9 (C(O)CH3),
20.7 (C(O)CH3), 19.5 (RC@CHCH2CH2CH2); HRESIMS: Found
3.6. (6S)-1,7-Dioxa-(3,4,6-tri-O-acetyl-1,2-dideoxy-b-D-
glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]undecane (R/S)-S-oxide
(13)
A solution of m-CPBA (250 mg, 1.26 mmol) in CH2Cl2 (1 mL) was
added to a solution of (6S)-1,7-dioxa-(3,4,6-tri-O-acetyl-1,2-dide-
[M+H]+ 461.1476 C20H29O10
S
requires 461.1481, [M+Na]+
483.1295 C20H29NaO10S requires 483.1301.
oxy-b-
D
-glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]undecane
(11)
(500 mg, 1.20 mmol) in CH2Cl2 (12 mL) and stirred for 10 min at
ꢂ78 °C. The reaction was then quenched with aq NaHCO3
(25 mL) and diluted with CH2Cl2 (50 mL), and the organic phase
was separated and concentrated to afford a crude syrup. The crude
syrup was then purified by flash column chromatography (silica
gel; 98:2 (v/v) CH2Cl2–MeOH) to afford (6S)-1,7-dioxa-(3,4,6-tri-
3.4. (6S)-1,7-Dioxa-4-thia-(1,2-dideoxy-b-
b]-spiro[6.6]undecane (10)
D-glucopyranoso)[1,2-
A solution of NaOMe (380 mg, 6.95 mmol) in anhydrous MeOH
(10 mL) was added to a solution of 3,4-dihydro-2H-pyran-6-yl)-
methyl 2,3,4,6-tetra-O-acetyl-1-thio-b-
D
-glucopyranoside (9) (4.0
O-acetyl-1,2-dideoxy-b-D-glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]
g, 8.69 mmol) in anhydrous MeOH (100 mL) and stirred overnight.
The reaction mixture was then neutralised with Amberlite IRC H+
resin and concentrated to leave a crude oil. The resulting oil was
redissolved in chloroform (50 mL) and acidified with p-TSA
(800 mg, 4.37 mmol) and left to stir for 45 min. The reaction mix-
ture was then neutralised with Et3N and concentrated to afford a
crude oil. The crude oil was purified by flash chromatography (sil-
ica gel; 9:1 (v/v) CH2Cl2–MeOH) to afford (6S)-1,7-dioxa-4-thia-
undecane (R/S)-S-oxide (13) (480 g, 93%, dr: 97:3) as an amorphous
solid; Rf 0.66 (9:1 (v/v) CH2Cl2–MeOH); ½a D21
ꢅ
+6.5 (c 0.4, CHCl3);
-glucopy-
(6S)-1,7-dioxa-4-thia-(3,4,6-tri-O-acetyl-1,2-dideoxy-b-
D
ranoso)[1,2-b]-spiro[6.6]undecane (R)-S-oxide (13-R): FTIR (mmax
/
cmꢂ1) 1740 (C@O), 2940 (C–H); 1H NMR (500 MHz, CDCl3): dH
5.23 (dd, 1H, J2,3 9.4 Hz, J3,4 9.4 Hz, H-3), 5.14 (dd, 1H, J3,4 9.4 Hz,
0
J4,5 9.4 Hz, H-4), 4.35 (dd, 1H, J5,6 4.4, J6,6 12.6 Hz, H-6), 4.22
(d, 1H, J1,2 10.2 Hz, H-1), 4.19 (dd, 1H, J5,6 2.4, J6,6 12.6 Hz, H-60),
3.81 (m, 1H, H-5), 3.72 (dd, 1H, J1,2 10.2 Hz, J2,3 9.4 Hz, H-2), 3.68–
3.65 (m, 1H, H-a), 3.54 (d, 1H, JSCHeq,SCHax 12.6 Hz, SCHeq), 3.50–
3.46 (m, 1H, H-a0), 2.77 (d, 1H, JSCHeq,SCHax 12.6 Hz, SCHax), 2.08
(s, 3H, C(O)CH3), 2.06 (s, 3H, C(O)CH3), 2.05 (s, 3H, C(O)CH3), 1.58
(m, 6H, H-b, H-b0, H-c, H-c0, H-d, H-d0); 13C NMR (75 MHz, CDCl3):
dC 171.2, 170.7, 169.9 (C(O)CH3), 98.6 (C-e), 95.9 (C-1), 77.4 (C-3),
73.3 (C-5), 67.9 (C-4), 67.5 (C-2), 61.9 (C-6), 60.2 (SCH2), 33.9 (C-
b), 24.5 (C-d), 24.5 (C(O)CH3), 21.1 (C(O)CH3), 21.1 (C(O)CH3),
18.7 (C-c), 60.2 (C-a); HRESIMS: found [M+Na]+ 457.1139
0
0
(1,2-dideoxy-b-
(1.5 g, 60%) as a colourless foam; Rf 0.24 (9:1 (v/v) CH2Cl2–MeOH);
+19.0 (c 2, CHCl3); FTIR (
max/cmꢂ1) 3391 (OH), 2941 (C–H);
1H NMR (500 MHz, CDCl3): dH 4.39 (d, 1H, J1,2 8.5 Hz, H-1), 3.93
D-glucopyranoso)[1,2-b]-spiro[6.6]undecane (10)
½
a 2D1
ꢅ
m
0
0
0
(dd, 1H, J5,6 1 Hz, J6,6 12.8 Hz, H-6), 3.81 (dd, 1H, J5,6 1 Hz, J6,6
12.8 Hz, H-60), 3.76 (m, 2H, H-a, H-a0), 3.74 (m, 1H, H-4), 3.69
(dd, 1H, J1,2 8.5 Hz, J2,3 9.4 Hz, H-2), 3.59 (dd, 1H, J2,3 9.4 Hz, J3,4
9.4 Hz, H-3), 3.48 (m, 1H, H-5), 2.94 (d, 1H, JSCHeq,SCHax 13.6 Hz,
SCHeq), 2.67 (d, 1H, JSCHeq,SCHax 13.6 Hz, SCHax), 1.81 (m, 2H, H-b,
H-b0), 1.65 (m, 2H, H-c, H-c0), 1.53 (m, 2H, H-d, H-d0); 13C NMR
(75 MHz, CDCl3): dC 98.6 (C-e), 80.6 (C-1), 75.9 (C-5), 75.8 (C-4),
73.8 (C-2), 70.9 (C-3), 62.6 (C-6), 61.7 (C-a), 37.7 (SCH2), 34.6 (C-
d), 25.1 (C-b), 19.2 (C-c); HRESIMS: found [M+Na]+ 315.0873
C18H26NaO10S requires 457.1144; (6S)-1,7-dioxa-(3,4,6-tri-O-acet-
yl-1,2-dideoxy-b- -glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]unde-
D
cane (S)-S-oxide (13-S): mp: 194.0–196.1 °C (from hexane–EtOAc):
1H NMR (500 MHz, CDCl3): dH 5.36 (dd, 1H, J2,3 9.6 Hz, J3,4 9.6 Hz,
H-3), 5.16 (dd, 1H, J3,4 9.0 Hz, J4,5 9.0 Hz, H-4), 4.27 (dd, 1H, J5,6
C12H20NaO6S requires 315.0878.
0
6.4, J6,6 13.7 Hz, H-6), 4.09 (d, 1H, J1,2 9.9 Hz, H-1), 4.27 (dd, 1H,
J5,6 6.4, J6,6 13.7 Hz, H-60), 3.89 (m, 1H, H-5), 4.72 (dd, 1H, J1,2
9.9 Hz, J2,3 9.6 Hz, H-2), 3.68–3.65 (m, 1H, H-a), 3.50–3.46 (m, 1H,
H-a0), 3.26 (d, 1H, JSCHeq,SCHax 14.9 Hz, SCHeq), 2.44 (d, 1H,
JSCHeq,SCHax 14.9 Hz, SCHax), 2.08 (s, 3H, C(O)CH3), 2.06 (s, 3H,
C(O)CH3), 2.05 (s, 3H, C(O)CH3), 1.80 (m, 6H, H-b, H-b0, H-c, H-c0,
H-d, H-d0).
0
0
3.5. (6S)-1,7-Dioxa-(3,4,6-tri-O-acetyl-1,2-dideoxy-b-
glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]undecane (11)
D
-
Et3N (1.18 mL, 8.48 mmol), Ac2O (810
DMAP (5 mg, 0.05 mmol), were added to a solution of (6S)-1,7-
dioxa-4-thia-(1,2-dideoxy-b- -glucopyranoso)[1,2-b]-spiro[6.6]
lL, 8.48 mmol) and
D
undecane (10) (0.75 g, 2.57 mmol) in CH2Cl2 (50 mL). The reaction
mixture was left to stir for 1 h, then it was quenched with aq NaH-
CO3 (25 mL). The organic layer was separated, dried (MgSO4) and
concentrated to leave a crude solid. The crude solid was purified
by flash column chromatography (silica gel; 1:1 (v/v) hexane–
EtOAc) to afford (6S)-1,7-dioxa-3,4,6-tri-O-acetyl-1,2-dideoxy-b-
3.7. (6S)-1,7-Dioxa-(3,4,6-tri-O-benzyl-1,2-dideoxy-b-D-
glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]undecane (R)-S-oxide
(14-R)
NaH (60% dispersion in oil, 107 mg, 4.45 mmol) was added in
D
-glucopyranoso)-4-thia-([1,2-b]-spiro[6.6]undecane (11) (1.07 g,
portions to a stirred solution of (6S)-1,7-dioxa-(1,2-dideoxy-b-D-
100%) as colourless plates mp: 159.0–160.3 °C (from methanol);
glucopyranoso)-4-thia-[1,2-b]-spiro[6.6]undecane (10) (420 mg,
1.48 mmol) in N,N-dimethylformamide (10 mL) at 0 °C, and the
mixture was stirred for 30 min while H2(g) evolved. Benzyl bro-
Rf 0.27 (2:1 (v/v) hexane–EtOAc); ½a D21
ꢅ
+16.9 (c 2.6, CHCl3); FTIR
(m
max/cmꢂ1) 1747 (C@O), 2946 (C–H); 1H NMR (400 MHz, CDCl3):
dH 5.14 (dd, 1H, J2,3 9.3 Hz, J3,4 9.3 Hz, H-3), 5.12 (dd, 1H, J3,4
mide (616 lL, 5.18 mmol) was then added dropwise at 0 °C, and
9.3 Hz, J4,5 9.3 Hz, H-4), 4.40 (d, 1H, J1,2 9.3 Hz, H-1), 4.22 (dd, 1H,
the reaction mixture stirred for a further 3 h. The reaction mixture
was quenched with MeOH (10 mL) and concentrated. The crude so-
lid was then redissolved in CH2Cl2 (20 mL) and washed with aq
NaCl (2 ꢄ 20 mL), dried (MgSO4) and concentrated to leave a crude
J5,6 4.6, J6,6 12.3 Hz, H-6), 4.13 (dd, 1H, J5,6 2.3, J6,6 12.3 Hz, H-60),
3.91 (dd, 1H, J1,2 9.3 Hz, J2,3 9.3 Hz, H-2), 3.75 (m, 1H, H-5), 3.65
(m, 2H, H-a, H-a0), 2.95 (d, 1H, JSCHeq,SCHax 13.7 Hz, SCHeq), 2.66
0
0
0

12
M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
benzylated spiroketal 12. The crude benzylated spiroketal 12 was
redissolved in CH2Cl2 (5 mL) and cooled to ꢂ78 °C, and a solution
of m-CPBA (350 mg, 1.73 mmol) in CH2Cl2 (5 mL) was slowly added
over 5 min. The reaction mixture was stirred for 30 min at ꢂ78 °C
and then quenched with aq NaHCO3 (10 mL) and diluted with
CH2Cl2 (10 mL). The organic phase was then separated, washed
with aq NaCl (2 ꢄ 10 mL), dried (MgSO4) and concentrated to leave
a crude colourless solid. The crude solid was purified by flash col-
umn chromatography (silica; 1:1 (v/v) hexane–EtOAc) to afford
(20) as a colourless oil (18 mg, 60%,
Analytical data were identical to those reported previously.
a:b 93:7) (Table 1, entry 1).
3.8.2. Isopropyl 3,4,6-tri-O-acetyl-a-D-glucopyranoside (28)
(Table 1, entry 2)
Isopropyl 3,4,6-tri-O-acetyl-
a-
D-glucopyranoside (28) as a col-
ourless syrup (22 mg, 61%,
a:b 98:2); Rf 0.38 (1:1 (v/v) hexane–
EtOAc); ½a 2D1
ꢅ
ꢂ56 (c 0.2, CHCl3); FTIR (
m
max/cmꢂ1): 1738 (C@O);
1H NMR (500 MHz, CDCl3): dH 5.21 (dd, 1H, J2,3 9.7 Hz, J3,4 9.7 Hz,
H-3), 5.01 (d, 1H, J1,2 3.8 Hz, H-1), 5.00 (dd, 1H, J4,5 9.9 Hz, J3,4
(6S)-1,7-dioxa-(3,4,6-tri-O-benzyl-1,2-dideoxy-b-D-glucopyranos-
o)-4-thia-[1,2-b]-spiro[6.6]undecane (R)-S-oxide (14-R) (243 mg,
30%, dr: 99:1) as a colourless syrup; Rf 0.19 (1:1 (v/v) EtOAc–hex-
0
9.7 Hz, H-4), 4.26 (dd, 1H, J6,6 12.4 Hz, J5,6 4.9 Hz, H-6), 4.09 (dd,
0
0
0
1H, J6,6 12.4 Hz, J5,6 2.0 Hz, H-6 ), 4.05–4.03 (m, 2H, H-5, CH(CH3)2),
3.65 (ddd, 1H, J1,2 3.8 Hz, J2,3 9.7 Hz, J2,OH-2 11.5 Hz, H-2), 2.08 (s,
3H, C(O)CH3), 2.03 (s, 3H, C(O)CH3), 2.03 (s, 3H, C(O)CH3), 1.96
(d, 1H, J2,2-OH 11.5 Hz, 2-OH), 1.22 (s, 3H, CH3), 1.20 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): dC 170.0 (C(O)CH3), 97.3 (C-1), 74.0,
72.1, 71.1, 68.5 (C-2, C-3, C-4, C-5), 62.5 (C-6), 30.1 (CH(CH3)2),
23.6, 22.3 (CH3); HRESIMS: found [M+Na]+ 371.1323, C15H24NaO9
requires 373.1313.
ane); ½a 2D1
ꢅ
+1.3 (c 1.5, CHCl3); FTIR (m
max/cmꢂ1) 2944 (C–H), 1099,
1051 (S@O); 1H NMR (500 MHz, CDCl3): dH 7.35–7.14 (m, 15H,
ArH), 5.02 (d, 1H, J 10.3 Hz, OCH2Ph), 4.82 (d, 2H, J 10.3 Hz, J
10.3 Hz, OCH2Ph), 4.66 (d, 1H, J 12.0 Hz, OCH2Ph), 4.58 (d, 1H, J
10.3 Hz, OCH2Ph), 4.52 (d, 1H, J 12.0 Hz, OCH2Ph), 4.11 (d, 1H, J1,2
9.4 Hz, H-1), 3.87–3.83 (m, 3H, H-3, H-a, H-a0), 3.78–3.71 (m, 2H,
H-5, H-6), 3.66 (dd, 1H, J1,2 9.4 Hz, J2,3 9.4 Hz, H-2), 3.60 (dd, 1H,
J5,6 5.1 Hz, J6,6 11.1 Hz, H-60), 3.57–3.53 (m, 2H, H-4, SCHeq),
2.75 (d, 1H, JSCHeq,SCHax 12.0 Hz, SCHax), 1.83–1.76 (m, 2H, H-d, H-
c), 1.68–1.58 (m, 3H, H-b, H-c0, H-d0), 1.47 (d, 1H, J 12.8 Hz, H-
b0); 13C NMR (75 MHz, CDCl3): dC 138.2, 137.9, 128.5, 128.4,
128.4, 128.0, 127.9, 127.8, 127.7 (ArC), 98.1 (C-e), 95.8 (C-1), 83.6
(C-2), 80.3 (C-4), 76.6 (C-3), 75.8, 75.5, 73.7 (OCH2Ph), 70.3 (C-5),
67.9 (C-a), 60.9 (C-6), 59.6 (SCH2), 33.8 (C-d), 24.0 (C-b), 18.4 (C-
c); HRESIMS: found [M+Na]+ 601.2238, C33H38NaO7S requires
601.2230.
0
0
3.8.3. 3,4,6-Tri-O-benzyl-
O-isopropylidene-
-galactopyranose (27)19 (Table 1, entry 3)
3,4,6-Tri-O-benzyl- -glucopyranosyl-(1?6)-1,2:3,4-di-O-iso-
-galactopyranose (27) as colourless syrup
:b 92:8); Rf 0.77 (1:1 (v/v) hexane–EtOAc). Analyti-
a-D-glucopyranosyl-(1?6)-1,2:3,4-di-
a
-D
a
-D
propylidene-
(28 mg, 58%,
a
a
-
D
a
cal data were identical to those reported previously.
3.8.4. Isopropyl 3,4,6-tri-O-benzyl-a-D
-glucopyranoside (29)19
(Table 1, entry 4)
Isopropyl 3,4,6-tri-O-benzyl-
ourless oil (27 mg, 57%, :b 94:6); Rf 0.70 (1:1 (v/v) hexane–
3.8. General procedure for glycosylation reactions with
oxathiane spiroketal-S-oxides
a-D-glucopyranoside (29) as a col-
a
EtOAc). Analytical data were identical to those reported previously.
Tf2O (1.1 equiv) was added to a solution of oxathiane spirok-
etal-S-oxide 13-R or 14-R (1 equiv), 1,3,5-trimethoxybenzene
(1.1 equiv) or 1,3-dimethoxybenzene (1.1 equiv), DIPEA (1.2 equiv)
and 4 Å molecular sieves in CH2Cl2 or C2H4Cl2 (initial donor con-
centration 0.26 M), cooled to ꢂ30 °C. The reaction mixture was
warmed to room temperature over 10 min and then DIPEA
3.8.5. From 2,4-dimethoxyphenyl (DMP)-oxathiane spiroketal
sulfonium ion (28): 3,4,6-tri-O-acetyl-
(1?6)-1,2:3,4-di-O-isopropylidene-a-D
a
-
D
-glucopyranosyl-
-galactopyranose (20)19
(Table 1, entry 5)
3,4,6-Tri-O-acetyl-
propylidene- -galactopyranose (20) as a colourless oil (19 mg,
50%, :b 86:14). Analytical data were identical to those reported
a-D-glucopyranosyl-(1?6)-1,2:3,4-di-O-iso-
(1.3 equiv), followed by
a solution of the glycosyl acceptor
a-D
(1.5 equiv) in CH2Cl2 or C2H4Cl2 (final donor concentration
0.11 M) was added, and the reaction mixture was stirred for 24 h
at 37 °C or 50 °C (when using donor 13-R), or room temperature
(when using donor 14-R). The reaction mixture was then diluted
with CH2Cl2 (5 mL), washed with 1 M HCl (2 ꢄ 5 mL), aq NaHCO3
(2 ꢄ 5 mL) and aq NaCl (2 ꢄ 5 mL), dried (MgSO4) and concen-
trated to afford the crude product. The crude product was then
redissolved in CH2Cl2 (1 mL) and cat. BF3ꢁOEt2 and MeOH
(1.5 equiv) were added. After stirring for 30 min at room tempera-
ture the reaction mixture was diluted with CH2Cl2 (5 mL), washed
with aq NaCl (5 mL), dried (MgSO4) and concentrated to afford the
crude O-2 unprotected glycoside. The crude glycoside was purified
by size-exclusion chromatography (Sephadex LH-20 resin; eluted
with MeOH (50 mL/h)) to afford the desired O-2 unprotected
glycoside.
a
previously.
3.8.6. Isopropyl 3,4,6-tri-O-acetyl-a-D-glucopyranoside (28)
(Table 1, entry 6)
Isopropyl 3,4,6-tri-O-acetyl-
a-
D-glucopyranoside (28) as a col-
ourless syrup (13 mg, 52%,
tion 3.8.2.
a:b 95:5). For analytical data see Sec-
3.9. 3,4,6-Tri-O-acetyl-
a-D-glucopyranosyl-(1?6)-1,2:3,4-di-O-
isopropylidene-
a-D
-galactopyranose (20)19 (Table 1, entry 9)
Tf2O (20
oxy-2-(S)-phenyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-b-
oso)[1,2-e]-1,4-oxathiane (R)-S-oxide (25-R) (50 mg, 0.106 mmol),
DTBMP (87 mg, 0.425 mmol), 1,3-dimethoxybenzene (15 L,
0.117 mmol) and 4 Å molecular sieves (50 mg) in C2H4Cl2
(400
L) at ꢂ30 °C. The reaction mixture was warmed to ꢂ10 °C
over 10 min, then a solution of 1,2:3,4-di-O-isopropylidene-
galactopyranose (19) (69 mg, 0.265 mmol) in C2H4Cl2 (100
lL, 0.117 mmol) was added to a solution of 2-meth-
D-glucopyran-
l
3.8.1. From 2,4,6-trimethoxyphenyl (TMP)-oxathiane spiroketal
sulfonium ions (21): 3,4,6-tri-O-acetyl-
(1?6)-1,2:3,4-di-O-isopropylidene-
-galactopyranose (20)19
Reaction time: 24 h at 50 °C gave 3,4,6-tri-O-acetyl- -gluco-
pyranosyl-(1?6)-1,2:3,4-di-O-isopropylidene- -galactopyranose
(20) as a colourless oil (49 mg, 38%, :b 93:7); Rf 0.25 (1:1 (v/v)
a-
D-glucopyranosyl-
l
a
-D
a-D-
lL)
a-
D
a-
D
was added. The reaction mixture was then heated at 50 °C for
2 h, allowed to cool and diluted with CH2Cl2 (10 mL), washed with
1 M HCl (3 ꢄ 10 mL), aq NaHCO3 (2 ꢄ 10 mL) and aq NaCl
(2 ꢄ 10 mL) and concentrated to afford a crude oil. The crude oil
was dissolved in DCM (1 mL), and a cat. amount of BF3ꢁOEt2 and
MeOH (0.163 mmol) were added. After stirring for 30 min at room
a
hexane–EtOAc). Analytical data were identical to those reported
previously.19
Reaction time: 24 h at 37 °C gave 3,4,6-tri-O-acetyl-
a-D-gluco-
pyranosyl-(1?6)-1,2:3,4-di-O-isopropylidene- -galactopyranose
a-D

M. A. Fascione et al. / Carbohydrate Research 348 (2012) 6–13
13
temperature the reaction mixture was diluted with CH2Cl2 (5 mL)
References
washed with aq NaCl (5 mL), dried (MgSO4) and concentrated to af-
ford a crude yellow oil. The crude oil was purified by size-exclusion
chromatography (Sephadex LH-20 resin; eluted with MeOH
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Acknowledgements
This work was supported by The Royal Society (UF051621/
UF090025), EPSRC (EP/G043302/1) and the University of Leeds.
WBT is the recipient of a Royal Society University Research
Fellowship.
Supplementary data
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Crystallographic data, excluding structure factors, have been
deposited with the Cambridge Crystallographic Data Centre as sup-
plementary publication with CCDC No. 805132. Copies of the data
can be obtained free of charge on application with the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax +44 1223 336
033; e-mail: deposit@ccdc.cam.ac.uk). Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.carres.2011.07.020.