2,3-Anhydrosugars in glycoside bond synthesis: application to furanosyl azides and C-glycosides

Article abstract of DOI:10.1016/j.tet.2009.06.008

The preparation of 2-deoxy-2-thiotolylfuranosyl azides and C-glycosides from a 2,3-anhydrosugar thioglycoside with the d-lyxo stereochemistry is described. The reaction is performed by treatment of the thioglycoside with a trimethylsilylated nucleophile i

Full text of DOI:10.1016/j.tet.2009.06.008

Tetrahedron 65 (2009) 5916–5921
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
2,3-Anhydrosugars in glycoside bond synthesis: application to furanosyl azides
and C-glycosides
*
Dianjie Hou, Todd L. Lowary
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, Alberta T6G 2G2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2009
Received in revised form 27 May 2009
Accepted 3 June 2009
Available online 10 June 2009
The preparation of 2-deoxy-2-thiotolylfuranosyl azides and C-glycosides from a 2,3-anhydrosugar thio-
glycoside with the D-lyxo stereochemistry is described. The reaction is performed by treatment of the
thioglycoside with a trimethylsilylated nucleophile in the presence of BF3$OEt2. This approach provides
a convenient route to the preparation of the corresponding 2-deoxy-furanosyl azides and C-glycosides. In
contrast, the use of an isomeric substrate, with the 2,3-anhydro-
products in low to modest yield.
D-ribo stereochemistry, gave these
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
sulfur bond is reductively cleaved to generate the 2-deoxy-glyco-
side. This reaction manifold is thus similar to other migration–gly-
cosidation protocols involving thio- or selenoglycosides possessing
leaving groups at C-2.4
Earlier work from our laboratory has reported the use of 2,3-
anhydrosugar thioglycosides (1–4, Fig. 1) for the assembly of 2,3-
anhydrosugar glycosides (e.g., 5)1 and 2-deoxy-glycosides (e.g., 6).2,3
With regard to the latter process, the transformation requires two
steps. First, reaction with an alcohol and a Lewis acid induces the
migration of the thiotolyl group from C-1 to C-2 with concomitant
stereocontrolled glycosidation at C-1 thus generating a 2-deoxy-2-
thiotolyl glycoside (e.g., 7). In the products, the relationship be-
tween the groups at C-1 and C-2 is trans, while the C-3 substituent is
cis to that at the anomeric carbon. In a second step, the carbon–
Due to the success in synthesizing 2-deoxy,2 and 2,6-dideoxy-
sugar3 O-glycosides from 1–4 by reaction with a range of alcohols,
we wanted to determine how other nucleophiles would perform in
these reactions. We describe here studies directed towards the
synthesis of 2-deoxy-2-thiotolylfuranosyl azides and C-glycosides
from 1 and 2.
Glycosyl azides are valuable carbohydrate building blocks, espe-
cially as precursors to glycosylamines.5,6 C-Glycosides, molecules in
which the anomeric oxygen is replaced by a methylene group, have
been used as mimetics of O-glycosides.7,8 These compounds, which
do not contain the acetal linkages present in their O-glycoside par-
ents, are believed to have promising applications as inhibitors of cell-
surface recognition events and glycoside metabolism because of
their greater chemical and enzymatic stability.7,8 Thus, the de-
velopment of new methods for the stereoselective synthesis of gly-
cosyl azides and C-glycosides continues to be of interest.
STol
STol
BzO
O
O
BzO
O
O
O
BzO
BzO
STol
O
O
1
2
3
HO
O
OR
BzO
OR
2. Results and discussion
BzO
O
O
O
BzO
To explore the potential of 1 and 2 in these reactions, we initially
carried out a model study in which 1 was treated with trimethylsilyl
azide (TMSN3) so that optimum reaction conditions could be
established (Table 1). We first treated 1 with TMSN3 and 10 equiv
(by weight) of 4 Å molecular sieves in dichloromethane, conditions
that worked well in the glycosylation of simple alcohols and acti-
vated carbohydrate alcohols.2,3 Unfortunately, none of the desired
product was detected, even after reflux for several hours. It was then
determined that copper(II) triflate2,3 could promote the reaction at
room temperature, but the desired product (8) was obtained only in
STol
X
4
5
6, X = H
7, X = STol
Figure 1. Structures of 2,3-anhydrosugar thioglycosides (1–4) and reaction products
(5–7).
* Corresponding author. Tel.: þ1 780 492 1861; fax: þ1 780 492 7705.
E-mail address: tlowary@ualberta.ca (T.L. Lowary).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.008

D. Hou, T.L. Lowary / Tetrahedron 65 (2009) 5916–5921
5917
Table 1
Determining the sterochemistry of carbon–carbon bond forma-
tion proved initially challenging. Due to spectral overlap, 1H–1H
coupling constants were not diagnostic and we thus turned to the
measurement of Nuclear Overhauser Effects (NOEs). However,
compared to six-membered rings, five-membered rings are in-
herently flexible and can adopt several twist and envelope confor-
mations.11 Therefore, we considered that the direct determination
of the stereochemistry in 9 and 10 using NOEs would be problem-
atic. To circumvent this problem, 11 and 12 (Fig. 2), derivatives of 9
and 10 that have an isopropylidene protecting group spanning O3
and O5, were synthesized (Scheme 2) to lock the five-membered
ring into a more rigid conformation. Reaction of 9 with sodium
methoxide followed by treatment with dimethoxypropane and
p-toluenesulfonic acid in acetone led to the formation of 11 in 83%
yield over the two steps. The synthesis of 12 was somewhat more
involved. First, the ketone in 10 was reduced to an w1:1 di-
astereomeric mixture of alcohols, the benzoate ester was cleaved
and the product was the converted to the isopropylidene acetal 13 in
62% yield over the three steps. Next, oxidation of the alcohol with
Dess–Martin periodinane gave 12 in 90% yield. The oxidation–re-
duction protocol was necessary because the ketone functionality
interfered with the formation of the isopropylidene acetal.
Optimization of the synthesis of 8 from 1a
HO
N3
BzO
BzO
TMSN3, promotor
CH2Cl2
O
O
O
STol
STol
8
1
Entry
Promoter
Equivb
Temperature
Yield (%)
b/a
ratioc
1
2
3
4 Å MS
Cu(OTf)2
BF3$Et2O
10
1.0
1.0
Reflux
rt
ꢀ78 ꢁ
0
35
91
d
100:0
100:0
C
a
Conditions: thioglycoside 1 (0.29 mmol) and TMSN3 (1.16 mmol) in CH2Cl2
(20 mL).
b
Relative to 1, molecular sieves are by weight.
c
Ratio determined by 1H NMR spectroscopy after chromatography.
low yield. Fortunately, the use of BF3$Et2O at ꢀ78 ꢁC was more
successful, and under these conditions the reaction provided ex-
clusively the
b-linked glycosyl azide in 91% yield. The b-stereo-
chemistry was ascertained from the 3JH1,H2 (1.3 Hz) of the signal for
H-1, which resonated at 5.34 ppm in the 1H NMR spectrum.9
Having identified a suitable promotion protocol, we next in-
vestigated the scope of this approach using nucleophiles that would
produce C-glycosides (Scheme 1). For this we explored two reagents
that have been widely used for the preparation of C-glycosides:
allyltrimethylsilane or trimethyl(1-phenylvinyloxy)silane.10 We
were pleased to find that treatment of 1 with either of these species
and BF3$Et2O at ꢀ78 ꢁC gave the corresponding C-glycosides in
excellent yield. Although both nucleophiles proceeded to give an
excellent yield of the expected C-glycosides, when the same re-
action was attempted with trimethylsilyl cyanide, only de-
composition products were obtained.
CH3
CH3
O
H3C
H3C
H
H
H
H
H
H
O
H
Ph
O
O
O
O
O
H
TolS
STol
11
12
Figure 2. Key NOE interactions present in 11 and 12.
TMS
HO
BzO
.
Rigid bicyclic molecules of this type are more amenable to the
measurement of NOEs, and in the case of 11 and 12 the through-
space interactions shown in Figure 2 were observed. These data
support the structure of the products as shown, and this stereo-
control is also consistent with reactions involving oxygen nucleo-
philes,2,3 in which the glycosidic bond is formed trans to the
thiotolyl group.
Given the successful results with 1, we next explored the poten-
tial for the synthesis of a-linked glycosyl azides and C-glycosides via
glycosidations with thioglycoside 2. Thus, treatment of 2 and tri-
methylsilyl azide and BF3$Et2O at ꢀ78 ꢁC was attempted (Scheme 3).
However, although this reaction gave a single product when 1 was
used as the substrate, with 2 a different result was obtained. Two
BF3 OEt2
O
CH2Cl2
86%
STol
BzO
O
O
9
STol
O
1
TMSO
Ph
HO
.
Ph
BF3 OEt2
BzO
O
CH2Cl2
82%
STol
10
Scheme 1. Synthesis of C-glycosides 9 and 10 from 1.
O
O
H3C
1. NaOCH3, CH3OH
O
9
2. 2,2-dimethoxypropane
p-TsOH, acetone
H3C
STol
2 steps, 83%
11
O
OH
Ph
1. NaBH4, CH3OH
O
Ph
O
Dess-Martin
Periodinane
CH2Cl2
90%
O
H3C
H3C
O
H3C
H3C
O
O
2. NaOCH3, CH3OH
10
3. 2,2-dimethoxypropane
p-TsOH, acetone
STol
STol
3 steps, 62%
12
13
Scheme 2. Synthesis of 11 and 12.

5918
D. Hou, T.L. Lowary / Tetrahedron 65 (2009) 5916–5921
products were isolated: the expected monosaccharide azide 14 in
49% yield, as well as disaccharide glycosyl azide 15 in 16% yield.12 In
both cases, the newly formed glycosidic linkages were found to have
When the results described here for the reactions of 2 with
these nucleophiles are considered together with those reported
previously for alcohol nucleophiles2 is clear that its reactivity can
differ markedly from that of 1. In particular, although 1 uniformly
gives clean reactions with O-, C- and N-nucleophiles, under the
same reaction conditions, 2 often gives multiple products or un-
expected byproducts.
the a
-stereochemistry, as ascertained from the 3JH1,H2 magnitudes.
BzO
STol
O
We are unsure as to the origin of this contrasting reactivity. The
obvious structural difference in the products formed from 1 and 2 is
that the oxygen at C-3 is cis, and trans, respectively, to the protected
hydroxylmethyl group at C-4. It could be, therefore, that this bulky
group hinders further reactions with products resulting from 1,
whereas in the case of the products arising from 2, this group is less
sterically encumbered and thus undergoes additional reactions.
Such an explanation could be used to rationalize the results shown
in Scheme 2, but does not readily explain the formation of 16 from 2.
It should also be noted that we explored the possibility of syn-
thesizing glycosyl azides and C-glycoside analogs from the analo-
gous pyranoside systems (e.g., 4, Fig. 1). However, in all cases the
only product formed was hydrolyzed donor.
In summary, it appears that this migration–glycosidation pro-
tocol, while working well for oxygen nucleophiles is of limited
scope with the carbon and nitrogen nucleophiles described here. In
particular, the reactions leading to the glycosyl azides and C-gly-
cosides proceeded in good yield with 1, but were less successful
with 2 and pyranoside analogs.
O
2
TMSN3
BF3 OEt2
CH2Cl2
STol
N3
STol
N3
BzO
BzO
O
O
+
O
HO
14
TolS
BzO
O
OH
15
Scheme 3. Products formed from reaction of 2 and TMSN3 in the presence of BF3$OEt2.
In an earlier study with 2,2 we reported similar oligomerization
byproducts, resulting from further reaction of the hydroxyl group
liberated during the initial glycosylation event. As could be done in
previous cases, the formation of this byproduct could be sup-
pressed by using the nucleophile in excess. In this particular case,
10 equiv of TMSN3 were used together with 0.2 equiv of BF3$Et2O.
Under these conditions, the desired product, 14, was obtained in
86% yield.
3. Experimental section
3.1. General methods
Solvents used in reactions were purified by successive passage
through columns of alumina and copper under argon atmosphere
before use. All reagents used in reactions were purchased from
commercial sources and were used without further purification
unless noted otherwise. All reactions were carried out under
a positive pressure of argon atmosphere and monitored by TLC on
silica gel G-25 UV254 (0.25 mm) unless stated otherwise. Spots were
detected under UV light and/or by charring with a solution of
anisaldehyde in ethanol, acetic acid and H2SO4. Column chroma-
We next investigated the reaction of 2 and allyltrimethylsilane
upon activation with BF3$Et2O at ꢀ78 ꢁC (Scheme 4). An interesting
result was obtained. From the NMR data, it was clear that the
product had a trimethylsilyl group and no alkene moiety. Further
analysis of the data indicated that the product was the bicyclic
compound 16 produced as a 65:35 ratio of isomers. The identifica-
tion of the attachment between C-9 and the silicon was ascertained
by the small chemical shift values for H-9 (dH¼1.03–0.77 ppm) and
C-9 (dC¼27.1, 25.0 ppm). The bond between O-3 and C-8 was de-
termined by the chemical shift of H-8 (dH¼4.16–3.88 ppm) and C-8
tography was performed on Silica Gel 60 (40–60 mm). The ratio
between silica gel and crude product ranged from 100:1 to 20:1
(w/w). 1H NMR and 13C NMR spectra were recorded at 500 MHz and
125 MHz, respectively. 1H NMR chemical shifts are referenced to
TMS (0.0, CDCl3) and 13C NMR chemical shifts are referenced to
CDCl3 (77.23, CDCl3). 1H NMR data were obtained through first or-
der analysis and the peak assignments were made on the basis of
2D-NMR (1H–1H COSY and HMQC) experiments. Optical rotations
were measured at 21ꢂ2 ꢁC at the sodium D line (589 nm) and are in
unit of deg mL(dm g)ꢀ1. ESI-MS spectra were carried out on samples
suspended in THF or CH3OH and added NaCl.
(
dC¼68.2, 65.6 ppm). A possible mechanism for the formation of 16
under these conditions is shown in Scheme 4.
Finally, we attempted the reaction between 2 and trimethyl(1-
phenylvinyloxy)silane. However, under the conditions that had
given C-glycoside 10 in good yield from 1, with 2 the only isolated
product was hydrolyzed donor.
STol
BzO
BzO
STol
O
O
TMS
BF3 OEt2
3.2. 5-O-Benzoyl-2-deoxy-2-p-thiotolyl-b-D-xylofuranosyl
azide (8)
O
O
F3B
CH2Cl2
Compound 11a (100 mg, 0.29 mmol) and trimethylsilyl azide
2
(0.16 mL, 1.22 mmol) were dissolved in CH2Cl2 (20 mL) and the
Si(CH3)3
solution was cooled to ꢀ78 ꢁC. At this temperature BF3$Et2O (42
mL,
STol
BzO
O
0.29 mmol) was added. After stirring at this temperature for 1 h,
the reaction mixture was allowed to warm to rt. Triethylamine
(0.3 mL) was used to neutralize the reaction. The solution was
subsequently concentrated to yield a crude oil that was purified by
chromatography (4:1 hexane–EtOAc) to give 8 (103 mg, 91%) as
O
8
9Si(CH3)3
16
a colorless oil: Rf 0.55 (2:1 hexane–EtOAc); [
a
]
ꢀ68.3 (c 0.4,
D
CH2Cl2); 1H NMR (500 MHz, CDCl3, dH) 8.10–8.05 (m, 2H, Ar), 7.61–
Scheme 4. Product formed from reaction between 2 and allyltrimethylsilane in the
presence of BF3$OEt2.
7.56 (m, 1H, Ar), 7.49–7.43 (m, 2H, Ar), 7.36–7.31 (m, 2H, Ar), 7.18–

D. Hou, T.L. Lowary / Tetrahedron 65 (2009) 5916–5921
5919
7.13 (m, 2H, Ar), 5.34 (d, 1H, J1,2¼1.3 Hz, H-1), 4.82 (dd, 1H,
J5a,5b¼11.9 Hz, J4,5a¼5.5 Hz, H-5a), 4.64–4.62 (m, 1H, H-4), 4.51 (dd,
1H, J5a,5b¼11.9 Hz, J4,5b¼6.1 Hz, H-5b), 4.28 (br d, 1H, J3,4¼3.3 Hz, H-
3), 3.67 (dd, 1H, J1,2¼J2,3¼1.3 Hz, H-2), 3.10 (br, 1H, OH), 2.35 (s, 3H,
tolyl CH3); 13C NMR (125 MHz, CDCl3, dC) 166.8 (C]O), 138.4 (Ar),
133.3 (Ar), 132.1 (2ꢃAr), 130.3 (2ꢃAr), 129.8 (2ꢃAr), 129.6 (Ar),
128.7 (Ar),128.5 (2ꢃAr), 95.0 (C-1), 81.6 (C-4), 75.5 (C-3), 63.1 (C-5),
58.7 (C-2), 21.1 (tolyl CH3). HRMS (ESI) calcd (MþNa)þ
C19H19N3O4S: 408.0989. Found: 408.0992.
was neutralized with triethylamine (1 mL) and concentrated. The
crude product was purified by chromatography (6:1 hexane–
EtOAc) to give 11 (55 mg, 83%) as a colorless oil: Rf 0.82 (3:1 hex-
ane–EtOAc); [
a]
ꢀ53.3 (c 0.4, CH2Cl2); 1H NMR (500 MHz, CDCl3,
D
dH) 7.30–7.25 (m, 2H, Ar), 7.16–7.10 (m, 2H, Ar), 5.85 (dddd, 1H,
J2,3trans¼17.2 Hz, J2,3cis¼10.2 Hz, J1a,2¼6.9 Hz, J1b,2¼6.9 Hz, –CH]),
5.17–5.06 (m, 2H, ]CH2), 4.22 (d, 1H, J3,4¼2.8 Hz, H-3), 4.06 (dd,1H,
J5a,5b¼13.1 Hz, J4,5a¼3.4 Hz, H-5a), 3.98 (dd, 1H, J5a,5b¼13.1 Hz,
J4,5b¼2.5 Hz, H-5b), 3.89–3.81 (m, 2H, H-1, H-4), 3.39 (d, 1H,
J1,2¼4.9 Hz, H-2), 2.60–2.45 (m, 2H, H-7a, H-7b), 2.33 (s, 3H, tolyl
CH3), 1.39 (s, 3H, C(CH3)2), 1.35 (s, 3H, C(CH3)2); 13C NMR (125 MHz,
CDCl3, dC) 136.9 (Ar), 134.2 (–CH]), 131.0 (Ar), 130.6 (2ꢃAr), 129.9
(2ꢃAr), 117.4 (]CH2), 98.2 (C(CH3)2), 83.3 (C-1), 76.7 (C-3), 73.1 (C-
4), 60.7 (C-5), 55.4 (C-2), 39.6 (C-7), 28.4 (C(CH3)2), 21.3 (tolyl CH3),
19.6 (C(CH3)2). HRMS (ESI) calcd (MþNa) C18H24O3S: 343.1338.
Found: 343.1336.
3.3. 3-(5-O-Benzoyl-2-deoxy-2-p-thiotolyl-b-D-
xylofuranosyl)-1-propene (9)
Compound 11a (100 mg, 0.29 mmol) and allyltrimethylsilane
(0.18 mL, 1.16 mmol) were reacted with BF3$Et2O (42 L,
m
0.29 mmol) in CH2Cl2 (20 mL) as described for the synthesis of 8.
Purification of the crude product by chromatography (4:1 hex-
ane–EtOAc) give 9 (97 mg, 86%) as a colorless oil: Rf 0.65 (2:1
3.6. 2-(3,5-O-Isopropylidene-2-deoxy-2-p-thiocresyl-b-D-
xylofuranosyl)-acetophenone (12)
hexane–EtOAc); [
a
]
ꢀ69.1 (c 0.2, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3, dH) 8.07–8.02 (m, 2H, Ar), 7.60–7.56 (m, 1H, Ar), 7.47–7.41
(m, 2H, Ar), 7.35–7.31 (m, 2H, Ar), 7.15–7.10 (m, 2H, Ar), 5.91–5.83
(m, 1H, –CH]), 5.16–5.09 (m, 2H, ]CH2), 4.76 (dd, 1H,
J5a,5b¼11.7 Hz, J4,5a¼5.8 Hz, H-5a), 4.41 (dd, 1H, J5a,5b¼11.7 Hz,
J4,5b¼5.0 Hz, H-5b), 4.23–4.17 (m, 2H, H-3, H-4), 3.81 (ddd, 1H,
J1,7a¼11.7 Hz, J1,2¼J1,7b¼6.1 Hz, H-1), 3.36 (dd, 1H, J1,2¼6.1 Hz,
J2,3¼2.2 Hz, H-2), 2.8 (br, 1H, OH), 2.56–2.41 (m, 2H, H-7a, H-7b),
2.33 (s, 3H, tolyl CH3); 13C NMR (125 MHz, CDCl3, dC) 167.0 (C]O),
137.3 (Ar), 133.7 (Ar), 133.3 (–CH]), 131.3 (2ꢃAr), 130.6 (Ar), 130.0
(2ꢃAr), 129.8 (2ꢃAr), 129.6 (Ar), 128.4 (2ꢃAr), 118.1 (]CH2), 82.4
(C-1), 78.9 (C-4), 78.1 (C-3), 62.7 (C-5), 56.9 (C-2), 38.7 (C-7), 21.1
(tolyl CH3). HRMS (ESI) calcd (MþNa)þ C22H24O4S: 407.1288.
Found: 407.1286.
Compound 13 (40 mg, 0.10 mmol) was dissolved in CH2Cl2
(10 mL) containing Dess–Martin periodinane (64 mg, 0.15 mmol) at
rt. The reaction mixture was stirred at rt for 2 h before it was
quenched by the addition satd aq NaHCO3 soln and Na2S2O3 soln.
The aqueous layer was extracted with CH2Cl2 (2ꢃ10 mL). The
combined organic layer was dried with Na2SO4, filtered and con-
centrated. The crude product was purified by chromatography (6:1
hexane–EtOAc) to give 12 (36 mg, 90%) as a colorless oil: Rf 0.75
(2:1 hexane–EtOAc); [
a
]
D
ꢀ9.5 (c 0.4, CH2Cl2); 1H NMR (500 MHz,
CDCl3, dH) 8.01–7.95 (m, 2H, Ar), 7.59–7.53 (m,1H, Ar), 7.48–7.42 (m,
2H, Ar), 7.33–7.28 (m, 2H, Ar), 7.14–7.09 (m, 2H, Ar), 4.51 (ddd, 1H,
J1,7a¼7.4 Hz, J1,7b¼5.4 Hz, J1,2¼3.9 Hz, H-1), 4.26 (dd, 1H, J3,4¼2.7 Hz,
J2,3¼0.9 Hz, H-3), 4.07 (dd, 1H, J5a,5b¼13.4 Hz, J4,5a¼3.4 Hz, H-5a),
4.02–3.96 (m, 2H, H-4, H-5b), 3.66 (dd, 1H, J7a,7b¼16.6 Hz,
J1,7a¼7.4 Hz, H-7a), 3.53 (br d, 1H, J1,2¼3.9 Hz, H-2), 3.30 (dd, 1H,
J7a,7b¼16.6 Hz, J1,7b¼5.4 Hz, H-7b), 2.32 (s, 3H, tolyl CH3), 1.41 (s, 3H,
C(CH3)2), 1.37 (s, 3H, C(CH3)2); 13C NMR (125 MHz, CDCl3, dC) 197.7
(C]O), 137.1 (Ar), 136.9 (Ar), 133.1 (Ar), 130.9 (2ꢃAr), 130.7 (Ar),
129.9 (2ꢃAr), 128.5 (2ꢃAr), 128.4 (2ꢃAr), 98.1 (C(CH3)2), 79.9 (C-1),
76.2 (C-3), 73.1 (C-4), 60.8 (C-5), 56.7 (C-2), 45.0 (C-7), 28.9
(C(CH3)2), 21.2 (tolyl CH3), 19.5 (C(CH3)2). HRMS (ESI) calcd
(MþNa)þ C23H26O4S: 421.1444. Found: 421.1446.
3.4. 2-(5-O-Benzoyl-2-deoxy-2-p-thiotolyl-b-D-
xylofuranosyl)-acetophenone (10)
Compound 11a (100 mg, 0.29 mmol) and trimethyl(1-phenyl-
vinyloxy)silane (0.25 mL, 1.22 mmol) were reacted with BF3$Et2O
(42 mL, 0.29 mmol) in CH2Cl2 (20 mL) as described for the synthesis
of 8. Purification of the crude product by chromatography (4:1
hexane–EtOAc) gave 10 (111 mg, 82%) as a colorless oil: Rf 0.67 (2:1
hexane–EtOAc); [
a
]
ꢀ55.8 (c 0.1, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3, dH) 8.07–8.02 (m, 2H, Ar), 7.96–7.92 (m, 2H, Ar), 7.60–7.54
(m, 2H, Ar), 7.48–7.40 (m, 4H, Ar), 7.36–7.32 (m, 2H, Ar), 7.14–7.09
(m, 2H, Ar), 4.78 (dd, 1H, J5a,5b¼11.8 Hz, J4,5a¼5.3 Hz, H-5a), 4.45
(dd, 1H, J5a,5b¼11.8 Hz, J4,5b¼5.5 Hz, H-5b), 4.30–4.23 (m, 3H, H-1,
H-3, H-4), 4.18 (br, 1H, OH), 3.67 (dd, 1H, J2,3¼5.6 Hz, J1,2¼1.0 Hz, H-
2), 3.50 (dd, 1H, J7a,7b¼17.5 Hz, J1,7a¼5.6 Hz, H-7a), 3.43 (dd, 1H,
J7a,7b¼17.5 Hz, J1,7b¼5.5 Hz, H-7b), 2.32 (s, 3H, tolyl CH3); 13C NMR
(125 MHz, CDCl3, dC) 197.9 (C]O), 166.9 (C]O), 137.3 (Ar), 136.8
(Ar), 133.5 (Ar), 133.2 (Ar), 131.1 (2ꢃAr), 130.6 (Ar), 130.0 (2ꢃAr),
129.8 (2ꢃAr), 129.7 (Ar), 128.6 (2ꢃAr), 128.4 (2ꢃAr), 128.2 (2ꢃAr),
79.6 (C-1), 79.4 (C-3), 78.3 (C-4), 63.0 (C-5), 57.0 (C-2), 41.9 (C-7),
21.1 (tolyl CH3). HRMS (ESI) calcd (MþNa)þ C27H26O5S: 485.1393.
Found: 485.1394.
3.7. 2-(3,5-O-Isopropylidene-2-deoxy-2-p-thiocresyl-
xylofuranosyl)-1-(R/S)-phenyl ethanol (13)
b-D-
To a solution of compound 10 (100 mg, 0.22 mmol) in CH3OH
(10 mL) was added NaBH4 (33 mg, 1.08 mmol) at rt. After 30 min,
the reaction was quenched by the addition of satd aq NH4Cl soln
(10 mL). The aqueous layer was extracted with CH2Cl2 (2ꢃ15 mL).
The combined organic layer was dried with Na2SO4, filtered and
concentrated. The resulting oil was dissolved in 1:1 CH2Cl2–CH3OH
(20 mL). To this solution was added 1 M NaOCH3 in CH3OH (0.3 mL).
After stirring for 4 h at rt, the reaction mixture was neutralized with
Amberlite IR-120 Hþ resin, filtered, and concentrated. The oily
residue was dissolved in acetone (10 mL) at rt. To this solution was
3.5. 1-(3,5-O-Isopropylidene-2-deoxy-2-p-thiocresyl-
a-
D-
added 2,2-dimethoxypropane (40 mL, 0.33 mmol) and p-TsOH
xylofuranosyl)-3-propene (11)
(3.8 mg, 0.02 mmol). After stirring for 2 h at rt, the reaction mixture
was neutralized with triethylamine (3 mL) and concentrated. The
crude product was purified by chromatography (4:1 hexane–
EtOAc) to give 13 (55 mg, 62%) over three steps as a colorless oil: Rf
0.56 (2:1 hexane–EtOAc); 1H NMR (500 MHz, CDCl3, dH) 7.40–7.31
(m, 4H, Ar), 7.29–7.23 (m, 3H, Ar), 7.15–7.10 (m, 2H, Ar), 5.09 (dt,
0.54H, J8R,7R¼9.2 Hz, J8R,OH¼3.3 Hz, H-20R), 4.99 (dt, 0.46H,
J8S,7S¼9.5 Hz, J8S,OH¼2.0 Hz, H-8S), 4.26 (d, 0.54H, J3R,4R¼2.7 Hz, H-
3R), 4.24 (d, 0.46H, J3S,4S¼2.8 Hz, H-3S), 4.13–3.99 (m, 3H, H-1R, H-
To a solution of compound 9 (80 mg, 0.21 mmol) in 1:1, CH2Cl2–
CH3OH (20 mL) was added 1 M NaOCH3 in CH3OH (0.21 mL). After
stirring for 2 h at rt, the reaction mixture was neutralized with
Amberlite IR-120 Hþ resin, filtered, and concentrated. The resulting
oil was dissolved in acetone (10 mL) at rt. To this solution was
added 2,2-dimethoxypropane (39
(4 mg, 0.02 mmol). After stirring for 2 h at rt, the reaction mixture
mL, 0.32 mmol) and p-TsOH

5920
D. Hou, T.L. Lowary / Tetrahedron 65 (2009) 5916–5921
1S, H-5R, H-5S), 3.94–3.92 (m, 0.54H, H-4R), 3.86–3.84 (m, 0.46H,
H-4S), 3.64 (d, 0.54H, JOH,8S¼2.0 Hz, OH), 3.53–3.50 (m, 1H, H-2R, H-
2S), 3.32 (d, 0.46H, JOH,8R¼3.3 Hz, OH), 2.35 (s, 1.62H, tolyl CH3), 2.34
(s, 1.38H, tolyl CH3), 2.28–2.00 (m, 2H, H-7R, H-7S), 1.42–1.38 (m,
6H, C(CH3)2); 13C NMR (125 MHz, CDCl3, dC) 144.4 (Ar), 144.3 (Ar),
137.3 (Ar), 137.2 (Ar), 130.9 (Ar), 130.75 (Ar), 130.7 (Ar), 130.5 (Ar),
130.0 (Ar), 128.4 (Ar), 128.3 (Ar), 127.3 (Ar), 127.1 (Ar), 125.8 (Ar),
125.7 (Ar), 98.44 (C(CH3)2), 98.38 (C(CH3)2), 83.3(C-1R), 82.1 (C-1S),
76.5 (C-3R), 76.4 (C-3S), 73.5 (C-4R), 73.2 (C-4S), 72.7 (C-8S), 70.8
(C-8R), 60.6 (C-5R), 60.4 (C-5S), 56.5 (C-2R), 55.8 (C-2S), 44.3 (C-7R),
42.8 (C-7S), 28.51(C(CH3)2), 28.46 (C(CH3)2), 21.1 (tolyl CH3), 19.5
(C(CH3)2), 19.4 (C(CH3)2). HRMS (ESI) calcd (MþNa)þ C23H28O4S:
423.1601. Found: 423.1601.
5), 58.2 (C-20), 57.3 (C-2), 21.12 (tolyl CH3), 21.07 (tolyl CH3). HRMS
(ESI) calcd (MþNa)þ C38H37N3O8S2: 750.1914. Found: 750.1918.
3.10. (1R,5R,7R,8R)-7-Benzoyloxymethyl-8-(thiotolyl)-3-(R/S)-
((trimethylsilyl)methyl)-2,6-dioxabicyclo[3.2.1]octane (16)
Compound 21a (100 mg, 0.29 mmol) and allyltrimethylsilane
(0.18 mL, 1.16 mmol) were dissolved in CH2Cl2 (20 mL) and the
solution was cooled to ꢀ78 ꢁC. At this temperature BF3$Et2O
(42 mL, 0.29 mmol) was added. After stirring at this temperature
for 1 h, the reaction mixture was warmed to rt. Triethylamine
(0.3 mL) was used to neutralize the reaction. The solution was
subsequently concentrated to yield a crude oil that was purified
by chromatography (8:1 hexane–EtOAc) to give 16 (74 mg, 66%)
as a 65:35 ratio of isomers as a colorless oil: Rf 0.90 (2:1 hexane–
EtOAc); 1H NMR (500 MHz, CDCl3, dH) 8.10–8.07 (m, 2H, Ar), 7.59–
7.54 (m, 1H, Ar), 7.46–7.42 (m, 2H, Ar), 7.38–7.34 (m, 2H, Ar),
7.16–7.12 (m, 2H, Ar), 4.88–4.57 (m, 1H, H-5aR, H-5aS), 4.74–4.64
(m, 2H, H-5bR, H-5bS, H-4R, H-4S), 4.58–4.53 (m, 1H, H-1R, H-1S),
4.40–4.33 (m, 1H, H-3S, H-3R), 4.16–4.08 (m, 0.65H, H-8S), 3.96–
3.88 (m, 0.35H, H-8R), 3.86 (br s, 0.35H, H-2R), 3.50 (br s, 0.65H,
H-2S), 2.34–2.25 (m, 3.35H, tolyl CH3, H-7aR), 2.06 (ddd, 0.65H,
J7aS,7bS¼13.4 Hz, J7aS,1¼J7aS,8S¼4.6 Hz, H-7aS), 1.88 (ddd, 0.35H,
J7bR,7aR¼14.8 Hz, J7bR,1¼J7bR,8R¼9.2 Hz, H-7bR), 1.48 (ddd, 0.65H,
J7bS,7aS¼13.4 Hz, J7bS,1¼J7bS,8S¼10.7 Hz, H-7bS), 1.03 (dd, 0.35H,
J9aR,9bR¼14.2 Hz, J9aR,8R¼6.5 Hz, H-9aR), 0.95 (dd, 0.65H,
J9aS,9bS¼14.2 Hz, J9aS,8S¼6.3 Hz, H-9aS), 0.83–0.77 (m, 1H, H-9bR,
H-9bS), 0.04–0.01 (m, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3,
dC) 166.2 (C]O), 137.6 (Ar), 133.01 (Ar), 132.96 (Ar), 132.0 (Ar),
131.8 (Ar), 130.07 (Ar), 130.05 (Ar), 129.8 (Ar), 128.32 (Ar), 128.29
(Ar), 84.3 (C-1R), 80.12 (C-1S), 80.06 (C-3S), 79.6 (C-4S), 78.7 (C-
3R), 78.3 (C-4R), 68.2 (C-8S), 66.5 (C-5S), 66.0 (C-5R), 65.6 (C-8R),
56.0 (C-2S), 50.5 (C-2R), 43.5 (C-7S), 42.7 (C-7R), 27.1 (C-9R), 25.0
(C-9S), 21.07 (tolyl CH3), 21.06 (tolyl CH3), ꢀ0.78 (Si(CH3)3), ꢀ0.82
(Si(CH3)3). HRMS (ESI) calcd (MþNa)þ C25H32O4SiS: 479.1683.
Found: 479.1682.
3.8. 5-O-Benzoyl-2-deoxy-2-p-thiotolyl-a-D-arabino-
furanosyl azide (14)
Compound 21a (100 mg, 0.29 mmol) and trimethylsilyl azide
(0.38 mL, 2.91 mmol) were dissolved in CH2Cl2 (20 mL) and cooled to
ꢀ78 ꢁC. At this temperature BF3$Et2O (9
mL, 0.06 mmol) was added.
After stirring at this temperature for 1 h, the reaction mixture was
warmed to room temperature. Triethylamine (0.3 mL) was used to
neutralize the reaction and the solution was subsequently concen-
trated to a crude oil that was purified by chromatography (4:1 hex-
ane–EtOAc) to give compound 14 (97 mg, 86%) as a colorless oil: Rf
0.55 (2:1 hexane–EtOAc); [
a
]
þ25.9 (c 0.5, CH2Cl2); 1H NMR
D
(500 MHz, CDCl3, dH) 8.08–8.05 (m, 2H, Ar), 7.62–7.57 (m, 1H, Ar),
7.48–7.44 (m, 2H, Ar), 7.36–7.40 (m, 2H, Ar), 7.14–7.11 (m, 2H, Ar), 5.42
(d, 1H, J1,2¼3.2 Hz, H-1), 4.58–4.55 (m, 2H, 2ꢃH-5), 4.38 (ddd, 1H,
J3,4¼5.9 Hz, J4,5a¼4.4 Hz, J4,5b¼4.4 Hz, H-4), 4.09 (ddd, 1H,
J3,OH¼6.1 Hz, J3,4¼5.9 Hz, J2,3¼5.7 Hz, H-3), 3.43 (dd, 1H, J2,3¼5.7 Hz,
J1,2¼3.2 Hz, H-2), 2.52 (d,1H, JOH,3¼6.1 Hz, OH), 2.33 (s, 3H, tolyl CH3);
13C NMR (125 MHz, CDCl3, dC) 166.6 (C]O), 138.4 (Ar), 133.3 (Ar),
132.6 (2ꢃAr), 130.2 (2ꢃAr), 129.9 (2ꢃAr), 129.5 (Ar), 128.6 (Ar), 128.4
(2ꢃAr), 95.8 (C-1), 83.2 (C-4), 76.5 (C-3), 63.6 (C-5), 58.8 (C-2), 21.1
(tolyl CH3). HRMS (ESI) calcd (MþNa)þ C19H19N3O4S: 408.0989.
Found: 408.0988.
Acknowledgements
3.9. 5-O-Benzoyl-2-deoxy-2-p-thiotolyl-3-O-(5-O-benzoyl-2-
deoxy-2-p-thiotolyl-
arabinofuranosyl azide (15)
a-D-arabino-furanosyl)-a-D-
This work was supported by the Natural Sciences and Engi-
neering Research Council of Canada, and The Alberta Ingenuity
Centre for Carbohydrate Science.
Compound 21a (100 mg, 0.29 mmol) and trimethylsilyl azide
(0.16 mL, 1.22 mmol) were dissolved in CH2Cl2 (20 mL) and cooled
Supplementary data
to ꢀ78 ꢁC. At this temperature BF3$Et2O (42
mL, 0.29 mmol) was
added. After stirring at this temperature for 1 h, the reaction mix-
ture was warmed to room temperature. Triethylamine (0.3 mL) was
used to neutralize the reaction. The solution was subsequently
concentrated to a crude oil that was purified by chromatography
(6:1 hexane–EtOAc) to give 14 (55 mg, 49%) and 15 (34 mg, 16%)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.008.
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(Ar), 133.19 (Ar), 133.16 (Ar), 132.2 (2ꢃAr), 131.6 (2ꢃAr), 130.3
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