Synthesis of 3-amido-3-deoxy-β-d-talopyranosides: All-cis-substituted pyranosides as lectin inhibitors

Article abstract of DOI:10.1016/j.tet.2011.09.098

3-Deoxy-3-amino-β-d-talopyranosides have been synthesized for the first time. The amines were obtained from galactopyranosides through 2,3-anhydrogulosides that were opened to idosides followed by an oxidation/reductive amination sequence. From the amines, 11 corresponding 3-deoxy-3-arylamido-β-talopyranosides have been synthesized and evaluated as inhibitors against galectin-1, -2, -3, -4C, -4N, -7, -8N and -9N. The synthesized talosamides showed selectivity for Galectin-4C with three of the monosaccharides having dissociation constants at around 100 μM against the lectin, which is more than two orders of magnitude better than methyl β-galactoside and significantly better than the previous best galectin-4C monosaccharide inhibitor.

Full text of DOI:10.1016/j.tet.2011.09.098

Tetrahedron 67 (2011) 9164e9172
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3-amido-3-deoxy-
b- -talopyranosides: all-cis-substituted
D
pyranosides as lectin inhibitors
a
a
b
a,
*
€
Christopher T. Oberg , Ann-Louise Noresson , Hakon Leffler , Ulf J. Nilsson
a Centre for Analysis and Synthesis, Lund University, PO Box 124, SE-22100 Lund, Sweden
Section MIG, Department of Laboratory Medicine, Lund University, Solvegatan 23, SE-22362 Lund, Sweden
b
€
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2011
Received in revised form 29 August 2011
Accepted 20 September 2011
Available online 25 September 2011
3-Deoxy-3-amino-
tained from galactopyranosides through 2,3-anhydrogulosides that were opened to idosides followed by
an oxidation/reductive amination sequence. From the amines, 11 corresponding 3-deoxy-3-arylamido-
talopyranosides have been synthesized and evaluated as inhibitors against galectin-1, -2, -3, -4C, -4N, -7,
-8N and -9N. The synthesized talosamides showed selectivity for Galectin-4C with three of the mono-
b-D-talopyranosides have been synthesized for the first time. The amines were ob-
b-
saccharides having dissociation constants at around 100 mM against the lectin, which is more than two
Keywords:
Talose
Talopyranoside
Talosamide
Galectin
orders of magnitude better than methyl
galectin-4C monosaccharide inhibitor.
b
-galactoside and significantly better than the previous best
Ó 2011 Elsevier Ltd. All rights reserved.
Galectin-4C
1. Introduction
terminal domain) and 8N (N-terminal domain) were discovered to
be talosides. So far, only a limited number of 2OH substituents on
talosides have been synthesized and tested, thus the optimal 2OH
substituent likely still remains to be found.
Taloside-based compounds as lectin inhibitors appear of par-
ticular interest due to the fact that, as far as we know, there are no
mammalian talose-containing glycoconjugates or talose-specific
processing or recognizing proteins. Hence, talose-based com-
pounds may not suffer from some of the poor pharmacological
properties generally associated with carbohydrates. In order to
investigate this hypothesis, we embarked on a project aiming at
talose-based inhibitors of galectins.1 Galectins have been impli-
cated in cancer progression, immunity and inflammation,2e5 and
the underlying molecular mechanisms responsible have in-
creasingly been understood, such as regulation of apoptosis, cell
signalling, intracellular trafficking and cell adhesion.6e14
Taloside based, as opposed to galactoside based, galectin in-
hibitors were envisioned after observation of an extended binding
pocket in the direction an axial 2OH of a bound saccharide (Fig. 1)
would have in X-ray structures of several galectins.15e18 GRID
simulations later corroborated the finding and prompted us to
synthesize a first generation of taloside-based galectin inhibitors.1
Taloside inhibitors turned out to have different specificity than
galactoside inhibitors to the galectin members, and among the
highest-affinity monosaccharide inhibitors against galectin-4C (C-
Fig. 1. Galectin interaction sites close to H2 of bound natural ligand monosaccharide
D-galactose can be targeted by axial C2-functionalities of D-talopyranosides.
In this paper we present the synthesis and biological evaluation
of 3-amido-3-deoxy-talosides. As mentioned, there seem to be no
(or very few) mammalian taloside-processing or recognizing pro-
teins, which may make taloside-based galectin inhibitors more
metabolically resilient ligands. To increase stability further, we now
report on the replacement of the affinity-enhancing 3-O-ester of
the first generation taloside inhibitors with 3-N-amides. As an ad-
ditional benefit, for some galectin members, 3-N-amides confer
increased affinity compared to the corresponding 3-O-esters.19e21
* Corresponding author. Tel.: þ46 46 2228218; fax: þ46 46 2228209; e-mail
address: ulf.nilsson@organic.lu.se (U.J. Nilsson).
Finally, 3-N-b-talosides and consequently 3-N-amido-b-talosides
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.098

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have not been reported in the literature and this class of all-cis
glycosides present challenging synthetic targets.
With key intermediate talo-amine 7 in hand, we were in position
to acylate to form seven selected aromatic amides 10e16 (Table 1).
The choice of amido structure was based on earlier observations that
m- and p-substituted benzamides, together with 2-naphthamides,
are optimal galactose 3-N-amido substituents for galectin-3 in-
hibition.27,28 Hence, a representative panel of these particularly well
galectin-3-binding aromatic 3-N-amide structures was selected for
incorporation into the talose 3-N-amides. Acylation of 7 afforded
protected talo-amides that were subsequently de-benzylidenated to
give 17e23. Four of these (17, 20, 21 and 22) were further saponified
to furnish 24e27.
2. Synthesis
O-Glycosides. One may imagine several routes, both de novo and
carbohydrate based, to obtain 3-N-amido-talosides. After surveying
talose-related literature we settled on carbohydrate-based ap-
proaches. We have previous experience with 3-amido-
sides, and have developed several routes to these targets.22 Thus,
perhaps the most obvious route to 3-amido- -talosides would be
b-galacto-
b
S-Glycosides. Currently, the highest-affinity monosaccharide
galectin inhibitors are in the low micromolar range.29 To reach the
nanomolar range, disaccharide (or higher) saccharides seem to be
needed (for monovalent inhibitors). Thus, to allow for the in-
corporation of 3-amido-3-deoxy-talosides in disaccharides we syn-
thesized one S-glycoside 34 as a talosyl donor. The synthetic strategy
to S-glycoside 34 was essentially the same as for O-glycosides 10e16.
The only difference in route was that tetrabutylammonium nitrite
(QNO2) worked better than hydroxide for opening of oxirane 30 to
through 3-amido-b-galactosides, which we have developed con-
venient routes to.22 However, in our hands, all attempts at epime-
rizing (i.e., LattrelleDax and Mitsonobu reactions) the 2-OH of
3-amido-
merization to talosides have been reported from suitable protected
all-O-galactosides.23,24 Synthesis of the all-cis-substituted
-talo-
b-galactosides failed. Contrary to our amides, 2-OH epi-
b
sides by epimerization of galactose 2-OH proved a more daunting
task than epimerization of 3-OH galactosides or gulosides. The
resulting 1,3-diaxial interactions between 2,4-OH in talose pre-
sumably being a major impediment.25 Instead, we decided on
a route where the 1,3-diaxial relationship of 2-OH and 4-OH was
installed in an intermediate idoside before the equatorial 3-NH2
was installed through a substitution or oxidation/reductive ami-
nation sequence.
idoside 31. Perhapsnotsurprisinggiventhatthetransb-epoxysulfide
30 (i.e., a mustard) was positioned to work against axial external
nucleophilic epoxide opening, thus likely explaining the lowered
tolerance to the combination of heat and basic nucleophiles com-
pared to the corresponding O-methyl glycoside 3 (Scheme 3).
Thus, starting from benzylidene-protected methyl
b-D-gal-
actopyranoside 1 (Scheme 1), selective 3-OH tosylation followed by
base-promoted oxirane formation afforded the 2,3-anhydro gulo-
side 3 in excellent yield. Treatment with KOH under microwave
conditions opened the oxirane 3 selectively at C2 to obtain idoside
4, presumably due to a favourable chair-like transition state. Tol-
uoylation quantitatively gave the 2-OH derivatized idoside 5 as the
only observable isomer, likely explained by the activating effect of
a vicinal cis-oxygen. All attempts at displacing the intermediate 3-
OTf of idoside 5 with azide failed to produce the desired product.
Consequently, we resorted to an oxidation/reductive amination
3. Biological evaluation
Compounds17e27, together with references methyl b-galactoside
29andmethylb
-taloside128, wereevaluatedagainstgalectin-1, -2,-3,
-4C, -4N, -7, -8N, -9N in a fluorescence polarization assay30 (Table 2).
For galectin-1, inhibitors 17 and 18 showed affinity slightly
lower than 1 mM (compared to methyl
b-galactoside 29 at
>10 mM). Most of the inhibitors tested were in the 2e3 mM range.
There was no clear preference with 2-O-toluoylation (17e23) or
without (24e27), indicating that either talosides are not ideal
against galectin-1 or that the 2-OH was not derivatized suitably
here (previous work1 with other 2-OH substituents showed no hits
sequence to obtain 3-amino-3-deoxy-b-taloside 7 for the first time.
NOE-experiment confirmed the talo-configuration.
Scheme 1. Synthesis of 3-amino-taloside 7. Reagents and conditions: (a) TsCl, pyridine (94%). (b) (CH3)3SiOK, DMF (98%). (c) KOH (aq, 5 M), MW (88%). (d) p-toluoyl chloride,
pyridine (quant.). (e) DesseMartin periodinane. (f) NaBH3CN, NH4OAc, trimethyl orthoformate, MeOH, THF (23% over two steps).
Incidentally, the opening of the 2,3-anhydro guloside 3 seems
little investigated. Besides opening with the oxygen nucleophiles
(hydroxide and nitrite) discussed here, nitrogen and halogen nu-
cleophiles were successfully attempted (Scheme 2). Opening with
tetrabutylammonium azide (QN3) under microwave irradiation
improved on the previously reported26 yield of 8 while opening
with bromide to obtain 9 has not been reported to our knowledge.
Other nucleophiles may work and expand the scope of the ring
opening of the 2,3-anhydro guloside 3.
either). Given the close kinship, it is not surprising to see very
similar affinities for galectin-2 as for galectin-1. Six inhibitors
showed greater affinities than 1 mM for galectin-3, the best being
20 at 0.57 mM (compared to methyl b-galactoside 29 at 4.4 mM).
Again, no clear preference was seen with or without 2-O-toluoy-
lation. By far the best matches for these talosamide inhibitors were
found against Gal-4C (C-terminal) with Kd down to ca. 100
compounds 17, 20 and 21, and compounds 18 and 22 in the 200
range. Thus compared to the parent monosaccharide methyl
mM for
mM
b
-
galactoside 29, there is a two order of magnitude improvement in
affinity. It is clear that the axial 2-O-toluoyl contributes beneficially
to overall binding, results that corroborate previous findings for
structurally similar 3-O-esters.1 For galectin-4N (N-terminal), af-
finities of the 2-O-toluoylated compounds 17e23 clustered around
1 mM (compared to methyl b-galactoside 29 at 6.6 mM), while the
free 2-OH compounds 24e27 were decidedly worse. The taloside
scaffold may likely not be ideal for galectin-7 as generally poor
Scheme 2. Ring opening of oxirane 3.

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Table 1
Synthesis of 3-amido-
D
-talopyranosides 10e27
10
11
12
13
14
15
16
R1
R2
CHPh
Toluoyl
CHPh
Toluoyl
CHPh
Toluoyl
CHPh
Toluoyl
CHPh
Toluoyl
CHPh
Toluoyl
CHPh
Toluoyl
R3
17
18
19
20
21
22
23
R1
R2
R3
H
H
H
H
H
H
H
Toluoyl
As above
Toluoyl
As above
Toluoyl
As above
Toluoyl
As above
Toluoyl
As above
Toluoyl
As above
Toluoyl
As above
24
25
26
27
R1
R2
R3
H
H
H
H
H
H
H
H
As above
As above
As above
As above
Scheme 3. Synthesis of 3-amido-thio-taloside 34. Reagents and conditions: (a) TsCl, pyridine (38%). (b) (CH3)3SiOK, DMF (73%). (c) QNO2, DMF (56%). (d) p-Toluoyl chloride, pyridine
(88%). (e) DesseMartin periodinane. (f) i. NaBH3CN, NH4OAc, trimethyl orthoformate, MeOH, THF ii. m-anisoyl chloride, lutidine, DCM (18% from 32).
inhibitors were seen for all talosamides tested. Given the poor af-
finities, any preference for 2-O-toluoylation is hard to discern. For
galectin-8N and -9N, the highest-affinity compounds reached
0.32 mM (27) and 0.94 mM (25), respectively (compared to methyl
may very well be enough to inhibit the cellular functions of intact
galectin-4. Moreover, we believe the talosamides hold promise in
terms of chemical hydrolytic stability as well as the apparent lack of
mammalian talose-recognizing and processing proteins potentially
offering reduced rate of systemic clearance.
b-galactoside 29 at 6.3 and 1.2 mM, respectively). For these galec-
tins, there was a small but clear preference for the free 2-OH
(24e27), an effect seen previously for galectin-8N with structur-
ally similar 3-O-esters.1 Also noted before is the interesting obser-
5. Experimental section
5.1. General methods
vation that galectin-8N in fact prefers methyl
methyl -galactoside (29).
b-taloside (28) over
b
NMR spectra were recorded on a Bruker Avance II 400 MHz
spectrometer at ambient temperature. 1H NMR spectra were
assigned using 2D-methods (COSY and NOESY). Chemical shifts are
given in parts per million downfield from the signal for Me4Si, with
reference to residual CHCl3, DMSO, HDO or CD2HOD. HRMS was
recorded on a Micromass Q-TOF micro spectrometer (ESI) and
a JEOL SX-120 FAB spectrometer. Reactions were monitored by TLC
using aluminium-backed silica gel plates (Merck 60 F254) and vi-
sualized using UV light and by charring with ethanolic H2SO4 (ca.
4. Concluding remarks
3-Deoxy-3-amino-b-D-talopyranosides have been synthesized
for the first time from galactopyranosides via 2,3-
anhydrogulosides. The gulosides were opened with hydroxide to
idosides, followed by an oxidation/reductive amination sequence to
give a 3-amino-taloside. From this amine, 11 corresponding 3-
deoxy-3-arylamido-b-D-talopyranosides 17e27 were synthesized
and evaluated as inhibitors against galectin-1, -2, -3, -4C, -4N, -7,
-8N and -9N. The standout result was against galectin-4C with in-
7%). Preparative chromatography was performed using silica gel
ꢀ
(Amicon Matrex 35e70
mm, 60 A) columns. Preparative TLC was
hibition below 100
orders of magnitude improved affinity compared to the parent
monosaccharide methyl -galactoside. These talose C3 amides thus
m
M for these monosaccharides, offering two
performed using glass-backed silica gel plates (200ꢀ200ꢀ1 mm, 60
ꢀ
F254). DMF was distilled and stored over 4 A M.S. Other solvents
b
were dried by storing over activated M.S. Reagents were supplied
improve on the talose O3 esters reported previously in terms of
affinity.1 In analogy with tandem-repeat (two binding sites within
the same polypeptide) galectin-8, where the two CRDs display very
different selectivities but where both need to be present to result in
strong avidity and cell signalling,12,13 inhibiting the galectin-4C CRD
by SigmaeAldrich and used as is.
5.1.1. Methyl 4,6-O-benzylidene-3-O-p-toluenesulfonyl-
anoside (2). Methyl 4,6-O-benzylidene-galactoside
17.7 mmol) was dissolved in pyridine (100 mL) at rt and p-
b-
D
-galactopyr-
(5.00 g,
1

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Table 2
Dissociation constants for compounds 17e29 to galectin-1, -2, -3, -4C, -4N, -7, -8N and -9Na
Compd
Structure
Galectins
1
2
3
4C
4N
7
8N
9N
17
1000ꢁ120
n.a.b
2300ꢁ340
120ꢁ26
1100ꢁ88
>4000
2000ꢁ2901 >4000
18
720ꢁ52
n.a.
2900ꢁ240
260ꢁ23
n.a.
2500ꢁ57
1000ꢁ61
3900ꢁ240
19
2900ꢁ240
2800ꢁ480
1800ꢁ180
670ꢁ61
1000ꢁ230 >4000
3300ꢁ61
>4000
20
1900ꢁ200
1700ꢁ8
570ꢁ110
94ꢁ16
900ꢁ210
>4000
4ꢂ10,000
>4000
21
2400ꢁ160
2600ꢁ590
910ꢁ190
120ꢁ4
1300ꢁ12
>4000
3100ꢁ11
>4000
(continued on next page)

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Table 2 (continued )
Compd
Structure
Galectins
1
2
3
4C
4N
7
8N
9N
22
2400ꢁ340
1700ꢁ180
900ꢁ500
220ꢁ120
1100ꢁ260 2ꢂ10,000
2000ꢁ250
>4000
23
2100ꢁ0
2000ꢁ370
720ꢁ110
620ꢁ110
760ꢁ160
1200ꢁ290
3100ꢁ23
>4000
24
2500ꢁ1100 2700ꢁ150
3000ꢁ280
1700ꢁ210
>4000
>4000
1100ꢁ12
4400ꢁ350
25
1700ꢁ81
1800ꢁ250
860ꢁ150
1100ꢁ99
2500ꢁ65
1400ꢁ380
820ꢁ100
940ꢁ86
26
>4000
4800ꢁ470
2500ꢁ130
2400ꢁ210
>4000
4ꢂ10,000
770ꢁ99
3300ꢁ130

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Table 2 (continued )
Compd
Structure
Galectins
1
2
3
4C
4N
7
8N
9N
27
3300ꢁ170
2000ꢁ29
740ꢁ47
870ꢁ190
4ꢂ10,000
2700ꢁ360
320ꢁ55
2600ꢁ14
281
>10,000
>10,000
10,000ꢁ3600 10,000ꢁ2000 >10,000
>10,000
1500ꢁ500
4600ꢁ100
291
>10,000
13,000ꢁ3000
4400ꢁ800
>10,000
6600ꢁ200 4100ꢁ1700 6300ꢁ1500 1200ꢁ200
a
Dissociation constants (m
M) for compounds 17e29 binding to galectin-1, -2, -3, -4C, -4N, -7, -8N and -9N as measured in a fluorescence polarization assay30 The average
dissociation constants were calculated from 2 to 6 data points that gave 20e80% inhibition.
b
Not available.
toluenesulfonyl chloride (6.09 g, 32.0 mmol) was added in portions
solution of idoside 4 (190 mg, 670 mmol) in pyridine (7 mL) at
0
over 43 h. Unreacted reagent was quenched by addition of excess H2O
and the reaction was concentrated and purified by column chroma-
tography (toluene/acetone 100:10 to 100:20 to 100:30 gradient) to
ꢃC. After 1 h, H2O (excess) was added, the reaction was con-
centrated, and purified by column chromatography (toluene/ac-
etone 100:10) to give toluoate 5 in quantitative yield (270 mg); 1H
give tosylate 231 in 94% yield (7.24 g); 1H NMR (CDCl3)
d
7.85 (d,
NMR (CDCl3)
d
7.93 (d, J¼8.1 Hz, 2H, ArH), 7.49e7.44 (m, 2H, ArH),
J¼8.3 Hz, 2H, ArH), 7.46e7.41 (m, 2H, ArH), 7.37e7.32 (m, 3H, ArH),
7.28 (d, 2H, ArH), 5.38 (s, 1H, CH), 4.60 (dd, J¼9.9, 3.8 Hz, 1H, H3),
4.37e4.32 (m, 2H, H4þH6), 4.24 (d, J¼7.7 Hz,1H, H1), 4.05 (dd, J¼12.5,
1.8 Hz, 1H, H6), 3.98 (dd, J¼9.9, 7.7 Hz, 1H, H2), 3.56 (s, 3H, OCH3), 3.47
(d, J¼1.1 Hz, 1H, H5), 2.42 (s, 3H, CH3).
7.32e7.15 (m, 5H, ArH), 7.04 (d, J¼8.4 Hz, 2H, ArH), 5.56 (s, 1H,
CH), 5.17 (br s, 1H, H2), 4.94 (app. s, 1H, H1), 4.51 (dd, J¼12.5,
1.1 Hz, 1H, H6), 4.31 (br s, 1H, tent. H3), 4.18 (app. d, J¼12.3 Hz, 1H,
H6), 3.97 (app. s, 1H, tent. H4), 3.85 (d, J¼1.5 Hz, 1H, tent. H5),
3.60 (s, 3H, OCH3), 2.38 (s, 3H, CH3).
5.1.2. Methyl
2,3-anhydro-4,6-O-benzylidene-
b
-D
-gulopyranoside
5.1.5. Methyl 3-amino-4,6-O-benzylidene-3-deoxy-2-O-toluoyl-b-D-
(3). Potassium trimethylsilanoate (1.41 g, 11.0 mmol) was added to
a stirred solution of tosylate 2 (3.19 g, 7.30 mmol) in DMF (73 mL) at
rt. After 1.25 h, the reaction was diluted with CH2Cl2 (1.0 L) and
washed with NaHCO3 (satd, aq, 2ꢀ500 mL) and brine (500 mL). The
organic phase was dried over MgSO4 before being concentrated to
talopyranoside (7). DesseMartin periodinane (2.19 g, 5.2 mmol)
was added to a stirred solution of toluoate 5 (1.38 g, 3.44 mmol) in
CH2Cl2 (35 mL) at rt. After 3 h, the reaction was concentrated and
purified by column chromatography (CH2Cl2/MeOH 100:5) to give
crude methyl 4,6-O-benzylidene-2-O-toluoyl-lyxo-b-D-hexopyr-
give epoxide 331 in 98% yield (1.89 g); 1H NMR (CDCl3)
d
7.57e7.51
anosid-3-ulose 6. NaCNBH3 (1.08 g, 17.2 mmol) was added to
a stirred solution of crude 6 (<3.44 mmol) and NH4OAc (10.6 g,
138 mmol) in MeOH/THF (100:70 mL) and CH(OMe)3 (35 mL) under
nitrogen atmosphere and at rt. After 17 h, the reaction was con-
centrated and purified by repeated column chromatography
(CH2Cl2/MeOH 100:5 to 100:10) to give intermediate amine 7 in
(m, 2H, ArH), 7.41e7.35 (m, 3H, ArH), 5.60 (s, 1H, CH), 4.83 (app. s,
1H, H1), 4.35 (app. d, J¼12.6 Hz, 1H, H6), 4.32 (t, J¼1.9 Hz, 1H, H4),
4.10 (dd, J¼12.7, 2.1 Hz, 1H, H6), 3.62 (s, 3H, OCH3), 3.46 (br s, 1H,
H3), 3.32e3.28 (m, 2H, H2þH5).
5.1.3. Methyl 4,6-O-benzylidene-
b-
D-idopyranoside (4). Epoxide 3
23% yield (0.32 g) from toluoate 5; 1H NMR (CDCl3)
d 7.86 (d,
(900 mg, 3.41 mol) was stirred in KOH (5 M, 15 mL) in a microwave
reactor at 140 ꢃC for 30 min. The reaction was concentrated and
purified by column chromatography (CH2Cl2/MeOH 100:5) to give
J¼8.2 Hz, 2H, ArH), 7.63e7.57 (m, 2H, ArH), 7.42e7.33 (m, 3H, ArH),
6.96 (d, J¼7.9 Hz, 2H, ArH), 5.60 (s, 1H, CH), 5.41 (br d, J¼3.0 Hz, 1H,
H2), 4.50 (d, J¼1.1 Hz, 1H, H1), 4.47 (dd, J¼12.5, 1.3 Hz, 1H, H6), 4.18
(dd, J¼12.6, 2.0 Hz, 1H, H6), 4.11 (br d, J¼3.0 Hz, 1H, H4), 3.52 (s, 3H,
OCH3), 3.49 (app. d, J¼1.1 Hz, 1H, H5), 3.35 (t, J¼3.8 Hz, 1H, H3), 2.35
(s, 3H, CH3).
idoside 431 in 88% yield (850 mg); 1H NMR (CD3OD)
d 7.52e7.46 (m,
2H, ArH), 7.39e7.34 (m, 3H, ArH), 5.60 (s, 1H, CH), 4.75 (d, J¼1.1 Hz,
1H, H1), 4.31 (dd, J¼12.6, 1.6 Hz, 1H, H6), 4.18 (dd, J¼12.6, 1.9 Hz, 1H,
H6), 4.01e3.98 (m, 2H, tent. H3H4), 3.83 (app. s, 1H, tent. H2), 3.58
(s, 3H, OCH3), 3.54 (br s, 1H, H5).
5.2. Typical procedure for acylation of amines 10e16
5.1.4. Methyl 4,6-O-benzylidene-2-O-toluoyl-b-D-idopyranoside (5). p-
5.2.1. Methyl 4,6-O-benzylidene-3-deoxy-3-(2-naphthamido)-2-O-
Toluoyl chloride (107 mL, 810 mmol) was added to a stirred
toluoyl-b-D-talopyranoside (15). 2-Naphthoyl chloride (44 mg,

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232 mmol) followed by pyridine (31 mL, 387 mmol) were added
to a stirred solution of the intermediate amine 7 in CH2Cl2 (1 mL)
under nitrogen atmosphere and at rt. After 24 h, the reaction
was concentrated and purified by column chromatography (tol-
uene/acetone100:20) to give amide 15 in 82% yield (31 mg); 1H
H6), 3.64 (app. d, J¼1.2 Hz, 1H, H5), 3.58 (s, 3H, OCH3), 2.39 (s, 3H,
CH3), 2.34 (s, 3H CH3).
5.2.7. Methyl 4,6-O-benzylidene-3-deoxy-3-(3-carboxybenzamido)-
2-O-toluoyl-b-D d 8.41 (t,
-talopyranoside (16). 1H NMR (CDCl3)
NMR (CDCl3)
d
8.09 (d, J¼1.4 Hz, 1H, ArH), 7.98 (d, J¼8.2 Hz, 2H,
J¼1.6 Hz, 1H, ArH, aromatic region obscured by traces of residual
reagent, which was removed after conversion to 23), 8.18 (dt, J¼7.7,
1.3 Hz, 1H, ArH), 7.93 (d, J¼8.3 Hz, 2H, ArH), 7.82e7.73 (m, 1H, ArH),
7.44 (t, J¼7.7 Hz, 1H, ArH), 7.40e7.33 (m, 5H, ArH), 7.00 (d, J¼8.0 Hz,
2H, ArH), 6.91 (d, J¼8.8 Hz, 1H, NH), 5.66 (br d, J¼3.5 Hz, 1H, H2),
5.62 (s, 1H, CH), 4.83 (dt, J¼8.7, 3.8 Hz, 1H, H3), 4.69 (d, J¼1.0 Hz, 1H,
H1), 4.54 (dd, J¼12.6,1.2 Hz,1H, H6), 4.27 (dd, J¼3.8, 0.9 Hz,1H, H4),
4.23 (dd, J¼12.5, 2.0 Hz, 1H, H6), 3.66 (br s, 1H, H5), 3.58 (s, 3H,
OCH3), 2.35 (s, 3H, CH3).
ArH), 7.83e7.78 (m, 2H, ArH), 7.72 (d, J¼8.0 Hz, 1H, ArH), 7.68
(dd, J¼8.6, 1.8 Hz, 1H, ArH), 7.64e7.60 (m, 2H, ArH), 7.57e7.36 (m,
5H, ArH), 7.04 (d, J¼7.9 Hz, 2H, ArH), 6.93 (d, J¼8.8 Hz, 1H, NH),
5.69 (dd, J¼3.6, 0.7 Hz, 1H, H2), 5.63 (s, 1H, CH), 4.87 (dt, J¼8.9,
3.9 Hz, 1H, H3), 4.70 (d, J¼1.1 Hz, 1H, H1), 4.55 (dd, J¼12.5, 1.2 Hz,
1H, H6), 4.29 (dd, J¼3.9, 0.8 Hz, 1H, H4), 4.23 (dd, J¼12.6, 2.0 Hz,
1H, H6), 3.66 (app. d, J¼1.1 Hz, 1H, H5), 3.60 (s, 3H, OCH3), 2.40
(s, 3H, CH3).
5 . 2 . 2 . M e t h y l 4 , 6 - O - b e n z y l i d e n e - 3 - d e o x y - 3 - ( 4 -
5.3. Typical procedure for debenzylidenation of amides 17e23
trifluoromethylbenzamido)-2-O-toluoyl-
NMR (CDCl3)
b-D
-talopyranoside (10). 1H
d
7.95 (d, J¼8.2 Hz, 2H, ArH), 7.78e7.70 (m, 2H, ArH),
5.3.1. Methyl 3-deoxy-3-(2-naphthamido)-2-O-toluoyl-b-D-talopyr-
7.63e7.56 (m, 4H, ArH), 7.43e7.33 (m, 3H, ArH), 7.06 (d, J¼7.9 Hz,
2H, ArH), 6.85 (d, J¼8.7 Hz, 1H, NH), 5.64 (d, J¼3.0 Hz, 1H, H2), 5.60
(s, 1H, CH), 4.80 (dt, J¼8.7, 3.8 Hz, 1H, H3), 4.69 (d, J¼1.1 Hz, 1H, H1),
4.55 (dd, J¼12.6,1.2 Hz,1H, H6), 4.26 (dd, J¼3.9, 0.8 Hz,1H, H4), 4.22
(dd, J¼12.6, 2.0 Hz, 1H, H6), 3.66 (app. d, J¼1.1 Hz, 1H, H5), 3.59 (s,
3H, OCH3), 2.40 (s, 3H, CH3).
anoside (22). Benzylidenated 15 (30.8 mg, 55.6 mmol) was stirred
in HOAc (aq, 67%, 2.4 mL) at 70 ꢃC for 17 h before being concen-
trated and purified by column chromatography (CH2Cl2/MeOH
100:5) to give ester 22 in 76% yield (19.6 mg); 1H NMR (CD3OD)
d
8.09 (br s, 1H, ArH), 8.04 (d, J¼2 Hz, ArH), 7.87e7.81 (m, 2H, ArH),
7.73e7.67 (m, 2H, ArH), 7.56e7.46 (m, 2H, ArH), 7.30 (d, J¼8.0 Hz,
2H, ArH), 5.73 (br d, J¼3.9 Hz, 1H, H2), 4.79 (d, J¼1.4 Hz, 1H, H1),
4.56 (t, J¼3.6 Hz, 1H, H3), 3.99e3.89 (m, 3H, H4H6H6), 3.82 (ddd,
J¼6.7, 5.4,1.2 Hz,1H, H5), 3.57 (s, 3H, OCH3), 2.41 (s, 3H, CH3); ESIMS
m/z calcd for [C26H28NO7]þ, 466.1866; found, 466.1858.
5.2.3. Methyl
mido)-2-O-toluoyl-
4,6-O-benzylidene-3-deoxy-3-(4-tert-butylbenza-
-talopyranoside (11). 1H NMR (CDCl3)
7.96
b-
D
d
(d, J¼8.2 Hz, 2H, ArH), 7.64e7.54 (m, 4H, ArH), 7.42e7.34 (m, 5H,
ArH), 7.04 (d, J¼7.9 Hz, 2H, ArH), 6.78 (d, J¼8.9 Hz,1H, NH), 5.63 (dd,
J¼3.6, 0.7 Hz, 1H, H2), 5.60 (s, 1H, CH), 4.82 (dt, J¼8.9, 3.8 Hz, 1H,
H3), 4.67 (d, J¼1.1 Hz, 1H, H1), 4.52 (dd, J¼12.5, 1.2 Hz, 1H, H6),
4.24e4.17 (m, 2H, H4H6), 3.64 (app. d, J¼1.0 Hz, 1H, H5), 3.58 (s, 3H,
OCH3), 2.39 (s, 3H, CH3), 1.29 (s, 9H, tBu).
5.3.2. Methyl 3-deoxy-3-(4-trifluoromethylbenzamido)-2-O-toluoyl-
b
-
D
-talopyranoside (17). 1H NMR (CD3OD)
d
8.01 (d, J¼8.2 Hz, 2H,
ArH), 7.83 (d, J¼8.1 Hz, 2H, ArH), 7.70 (d, J¼8.2 Hz, 2H, ArH), 7.30 (d,
J¼8.0 Hz, 2H, ArH), 5.68 (d, J¼3.7 Hz, 1H, H2), 4.77 (d, J¼1.4 Hz, 1H,
H1), 4.52 (t, J¼3.6 Hz, 1H, H3), 3.97e3.86 (m, 3H, H4H6H6), 3.79
(ddd, J¼6.8, 5.4, 1.3 Hz, 1H, H5), 3.56 (s, 3H, OCH3), 2.42 (s, 3H, CH3);
ESIMS m/z calcd for [C23H25F3NO7]þ, 484.1583; found, 484.1579.
5.2.4. Methyl 4,6-O-benzylidene-3-deoxy-3-(3-methoxybenzamido)-
2-O-toluoyl-b-D d 7.94 (d,
-talopyranoside (12). 1H NMR (CDCl3)
J¼8.2 Hz, 2H, ArH), 7.62e7.57 (m, 2H, ArH), 7.42e7.35 (m, 3H, ArH),
7.26e7.15 (m, 2H, ArH), 7.11 (dt, J¼7.6, 1.0 Hz, 1H, ArH), 7.01 (d,
J¼7.9 Hz, 2H, ArH), 6.99 (ddd, J¼8.3, 2.7, 1.0 Hz, 1H, ArH) 6.78 (d,
J¼8.9 Hz, 1H, NH), 5.63 (dd, J¼3.6, 0.6 Hz, 1H, H2), 5.61 (s, 1H, CH),
4.80 (dt, J¼8.8, 3.9 Hz, 1H, H3), 4.68 (d, J¼1.1 Hz, 1H, H1), 4.53 (dd,
J¼12.6, 1.3 Hz, 1H, H6), 4.24 (dd, J¼4.0, 0.9 Hz, 1H, H4), 4.21 (dd,
J¼12.6, 2.0 Hz, 1H, H6), 3.68 (s, 3H, OCH3), 3.64 (app. d, J¼1.1 Hz, 1H,
H5), 3.58 (s, 3H, OCH3), 2.38 (s, 3H, CH3).
5.3.3. Methyl 3-deoxy-3-(4-tert-butylbenzamido)-2-O-toluoyl-
talopyranoside (18). 1H NMR (CD3OD)
b-D-
d
8.02 (d, J¼8.2 Hz, 2H, ArH),
7.59 (d, J¼8.7 Hz, 2H, ArH), 7.42 (d, J¼8.6 Hz, 2H, ArH), 7.30 (d,
J¼8.0 Hz, 2H, ArH), 5.66 (br d, J¼3.4 Hz, 1H, H2), 4.77 (d, J¼1.3 Hz,
1H, H1), 4.50 (t, J¼3.6 Hz, 1H, H3), 3.96e3.86 (m, 3H, H4H6H6), 3.78
(br t, J¼5.5 Hz, 1H, H5), 3.56 (s, 3H, OCH3), 2.42 (s, 3H, CH3), 1.30 (s,
t
9H, Bu); ESIMS m/z calcd for [C26H33NO7Na]þ, 494.2155; found,
494.2161.
5.2.5. Methyl 4,6-O-benzylidene-3-deoxy-3-(4-nitrobenzamido)-2-
O-toluoyl-
b
-
D
-talopyranoside (13). 1H NMR (CDCl3)
d
8.19 (d,
5.3.4. Methyl
3-deoxy-3-(3-methoxybenzamido)-2-O-toluoyl-
b-D-
J¼8.9 Hz, 2H, ArH, aromatic region obscured by traces of residual
reagent, which was removed after conversion to 20), 7.96 (d,
J¼8.2 Hz, 2H, ArH), 7.77 (d, J¼8.9 Hz, 2H, ArH), 7.60e7.55 (m, 2H,
ArH), 7.41e7.32 (m, 3H, ArH), 7.07 (d, J¼7.9 Hz, 2H, ArH), 6.91 (d,
J¼8.6 Hz, 1H, NH), 5.64 (br d, J¼3.5 Hz, 1H, H2), 5.60 (s, 1H, CH), 4.79
(dt, J¼8.5, 3.8 Hz, 1H, H3), 4.69 (d, J¼1.1 Hz, 1H, H1), 4.54 (dd,
J¼12.6, 1.1 Hz, 1H, H6), 4.27 (dd, J¼3.8, 0.7 Hz, 1H, H4), 4.23 (dd,
J¼12.6, 2.0 Hz, 1H, H6), 3.66 (app. d, J¼1.0 Hz, 1H, H5), 3.59 (s, 3H,
OCH3), 2.40 (s, 3H, CH3).
talopyranoside (19). 1H NMR (CD3OD)
d
8.03 (d, J¼8.2 Hz, 2H, ArH),
7.33e7.13 (m, 5H, ArH), 7.04e7.00 (m, 1H, ArH), 5.67 (d, J¼3.7 Hz,
1H, H2), 4.77 (d, J¼1.4 Hz, 1H, H1), 4.49 (t, J¼3.6 Hz, 1H, H3),
3.96e3.86 (m, 3H, H4H6H6), 3.79 (ddd, J¼1.2, 5.4, 6.6 Hz, 1H, H5),
3.67 (s, 3H, OCH3), 3.56 (s, 3H, OCH3), 2.42 (s, 3H, CH3); ESIMS m/z
calcd for [C23H28NO8]þ, 446.1815; found, 446.1805.
5.3.5. Methyl 3-deoxy-3-(4-nitrobenzamido)-2-O-toluoyl-
b
-D-talo-
pyranoside (20). 1H NMR (CD3OD)
d
8.22 (d, J¼9.0 Hz, 2H, ArH), 8.00
(d, J¼8.2 Hz, 2H, ArH), 7.86 (d, J¼9.0 Hz, 2H, ArH), 7.29 (d, J¼8.0 Hz,
2H, ArH), 5.69 (d, J¼3.6 Hz, 1H, H2), 4.77 (d, J¼1.3 Hz, 1H, H1), 4.53
(t, J¼3.6 Hz, 1H, H3), 3.96e3.86 (m, 3H, H4H6H6), 3.80 (ddd, J¼1.2,
5.5, 6.7 Hz, 1H, H5), 3.56 (s, 3H, OCH3), 2.40 (s, 3H, CH3); ESIMS m/z
calcd for [C22H24N2O9Na]þ, 483.1380; found, 483.1368.
5.2.6. Methyl 4,6-O-benzylidene-3-deoxy-3-(4-methylbenzamido)-2-
O-toluoyl-b-D d 7.95 (d,
-talopyranoside (14). 1H NMR (CDCl3)
J¼8.2 Hz, 2H, ArH, aromatic region obscured by traces of residual
reagent, which was removed after conversion to 21), 7.62e7.57 (m,
2H, ArH), 7.52 (d, J¼8.2 Hz, 2H, ArH), 7.42e7.35 (m, 3H, ArH), 7.15 (d,
J¼7.9 Hz, 2H, ArH), 7.03 (d, J¼7.9 Hz, 2H, ArH), 6.76 (d, J¼8.9 Hz, 1H,
NH), 5.63 (d, J¼3.6, 0.7 Hz, 1H, H2), 5.60 (s, 1H, CH), 4.80 (dt, J¼8.9,
3.8 Hz, 1H, H3), 4.67 (d, J¼1.1 Hz, 1H, H1), 4.52 (dd, J¼12.6, 1.3 Hz,
1H, H6), 4.24 (dd, J¼3.9, 0.9 Hz, 1H, H4), 4.21 (dd, J¼12.6, 2.0 Hz, 1H,
5.3.6. Methyl 3-deoxy-3-(4-methylbenzamido)-2-O-toluoyl-
lopyranoside (21). 1H NMR (CD3OD)
7.54 (d, J¼8.2 Hz, 2H, ArH), 7.29 (d, J¼7.9 Hz, 2H, ArH), 7.17 (d,
J¼7.9 Hz, 2H, ArH), 5.66 (br d, J¼3.7 Hz, 1H, H2), 4.76 (d, J¼1.4 Hz,
b-D-ta-
d
8.01 (d, J¼8.2 Hz, 2H, ArH),

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C.T. Oberg et al. / Tetrahedron 67 (2011) 9164e9172
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1H, H1), 4.49 (t, J¼3.6 Hz, 1H, H3), 3.96e3.86 (m, 3H, H4H6H6), 3.80
(ddd, J¼1.2, 5.4, 6.8 Hz, 1H, H5), 3.55 (s, 3H, OCH3), 2.41 (s, 3H, CH3),
2.34 (s, 3H, CH3); ESIMS m/z calcd for [C23H28NO7]þ, 430.1866;
found, 430.1860.
was added to a stirred solution of tosylate 29 (0.53 g, 1.03 mmol) in
DMF (5 mL) at rt. After 1 h, the reaction was diluted with DCM
(100 mL) and washed with NaHCO3 (satd, aq, 2ꢀ100 mL) and brine
(100 mL). The organic phase was dried over MgSO4 before being
concentrated and purified by column chromatography (toluene/
acetone 100:10) to give epoxide 30 in 73% yield (256 mg); 1H NMR
5.3.7. Methyl 3-deoxy-3-(3-carboxybenzamido)-2-O-toluoyl-
b-D-ta-
lopyranoside (23). 1H NMR (CD3OD)
d
8.33 (s, 1H, ArH), 8.11 (d,
(CDCl3) d 7.76e7.72 (m, 2H, ArH), 7.60e7.56 (m, 2H, ArH), 7.46e7.41
J¼7.8 Hz, 1H, ArH), 8.01 (d, J¼8.2 Hz, 2H, ArH), 7.83 (d, J¼7.8 Hz, 1H,
ArH), 7.46 (t, J¼7.8 Hz, 1H, ArH), 7.28 (d, J¼8.0 Hz, 2H, ArH), 5.69 (br
d, J¼3.6 Hz, 1H, H2), 4.77 (d, J¼1.3 Hz, 1H, H1), 4.52 (t, J¼3 Hz, 1H,
H3), 3.96e3.86 (m, 3H, H4H6H6), 3.79 (br t, J¼6.7 Hz, 1H, H5), 3.56
(s, 3H, OCH3), 2.41 (s, 3H, CH3); ESIMS m/z calcd for [C23H26NO9]þ,
460.1608; found, 460.1595.
(m, 3H, ArH), 7.25e7.15 (m, 3H, ArH), 5.60 (s, 1H, CH), 5.20 (app. s,
1H, H1), 4.41 (br d, J¼12.0 Hz,1H, H6), 4.32 (t, J¼1.7 Hz,1H, H4), 4.08
(dd, J¼12.7, 2.0 Hz, 1H, H6), 3.53 (d, J¼3.8 Hz, 1H, H2), 3.44 (d,
J¼1.6 Hz, 1H, H5), 3.33 (br s, 1H, H3).
5.4.7. Phenyl 4,6-O-benzylidene-1-thio-b-D-idopyranoside (31).
Epoxide 30 (100 mg, 292 mmol) and QNO2 (421 mg, 1.46 mmol) in
DMF (3 mL) were stirred in a microwave reactor at 120 ꢃC for
30þ20 min. The reaction was concentrated and purified by column
chromatography (toluene/acetone 100:10) to give idoside 31 in 56%
5.4. Typical procedure for deacylation of amides 24e27
5.4.1. Methyl 3-deoxy-3-(2-naphthamido)-b-D-talopyranoside (27).
NaOMe(1M, 20mL)wasaddedtoastirredsolutionofester22(9.0mg,
19.3 mmol) in MeOH (1 mL) at rt. After 1.5 h, the reaction was con-
centrated and purified by column chromatography (CH2Cl2/MeOH
100:5 to 100:20 gradient) to give amide 27 in 94% yield (6.3 mg); 1H
yield (58.5 mg); 1H NMR (CDCl3)
d 7.53e7.45 (m, 4H, ArH), 7.37e7.22
(m, 6H, ArH), 5.45 (s, 1H, CH), 5.29 (app. s, 1H, H1), 4.35 (dd, J¼12.6,
1.2 Hz,1H, H6), 4.14 (t, J¼2.8 Hz,1H, H3), 3.99 (dd, J¼12.6, 1.8 Hz,1H,
H6), 3.97 (br d, J¼3.0 Hz, 1H, H4), 3.83e3.66 (m, 3H, H2H5OH).
NMR(CD3OD)d8.46(s,1H,ArH),8.03e7.91 (m, 4H, ArH), 7.64e7.55 (m,
2H, ArH), 4.55 (d, J¼0.8 Hz,1H, H1), 4.26 (t, J¼3.1 Hz,1H, H3), 3.98(brd,
J¼2.9 Hz, 1H, H2), 3.93 (br d, J¼3.1 Hz, 1H, H4), 3.85e3.81 (m, 2H,
H6H6), 3.68 (ddd, J¼1.0, 5.6, 6.7 Hz,1H, H5), 3.62 (s, 3H, OCH3); ESIMS
m/z calcd for [C18H22NO6]þ, 348.1447; found, 348.1451.
5.4.8. Phenyl 4,6-O-benzylidene-2-O-toluoyl-1-thio-b-D-idopyrano-
side (32). p-Toluoyl chloride (25 mL, 186 mmol) was added to a stir-
red solution of idoside 31 (58 mg, 161 mmol) in pyridine (2 mL) at rt.
After 30 min, H2O (ꢀs) was added, the reactionwas concentrated and
purified bycolumn chromatography (toluene/acetone 100:10) to give
5.4.2. Methyl 3-deoxy-3-(4-trifluoromethylbenzamido)-
b
-
D
-talopyr-
toluoate 32 in 88% yield (68 mg); 1H NMR (CDCl3)
d
7.99 (d, J¼8.2 Hz,
anoside (24). 1H NMR (CD3OD)
d
8.06 (d, J¼8.1 Hz, 2H, ArH), 7.81 (d,
2H, ArH), 7.62e7.53 (m, 2H ArH), 7.44e7.40 (m, 2H, ArH), 7.32e7.23
(m, 5H, ArH), 7.18e7.09 (m, 4H, ArH), 5.50 (s,1H, CH), 5.46 (d, J¼1.5 Hz,
1H, H1), 5.26 (br s, 1H, H2), 4.49 (br d, J¼12.6 Hz, 1H, H6), 4.34 (t,
J¼2.6 Hz,1H, H3), 4.11 (dd, J¼12.6, 1.9 Hz, 1H, H6), 3.97 (app. s,1H, H4),
3.85 (app. d, J¼1.2 Hz, 1H, H5), 2.41 (s, 3H, CH3).
J¼8.2 Hz, 2H, ArH), 4.53 (d, J¼0.9 Hz,1H, H1), 4.21 (t, J¼3.1 Hz,1H, H3),
3.94 (br d, J¼2.8 Hz, 1H, H2), 3.89 (br d, J¼3.0 Hz, 1H, H4), 3.85e3.79
(m, 2H, H6H6), 3.65 (br t, J¼6.7 Hz,1H, H5), 3.61 (s, 3H, OCH3); ESIMS
m/z calcd for [C15H19F3NO6]þ, 366.1164; found, 366.1154.
5.4.3. Methyl
3-deoxy-3-(4-nitrobenzamido)-
b
-
D
-talopyranoside
5.4.9. Phenyl
4,6-O-benzylidene-2-O-toluoyl-1-thio-lyxo-b-D-hex-
(25). 1H NMR (CD3OD)
d
8.35 (d, J¼9.0 Hz, 2H, ArH), 8.09 (d,
opyranosid-3-ulose (33). DesseMartin periodinane (93 mg,
219 mmol) was added to a stirred solution of toluoate 32 (68 mg,
146 mmol) in DCM (2 mL) at rt. After 2 h, the reaction was con-
centrated and purified by column chromatography (toluene/ace-
tone 100:10 to 100:20 gradient) to give crude ketone 33.
J¼9.0 Hz, 2H, ArH), 4.53 (d, J¼1.0 Hz, 1H, H1), 4.21 (t, J¼3.0 Hz, 1H,
H3), 3.95 (br d, J¼2.9 Hz, 1H, H2), 3.89 (br d, J¼3.1 Hz, 1H, H4),
3.85e3.79 (m, 2H, H6H6), 3.66 (ddd, J¼1.0, 5.7, 6.7 Hz, 1H, H5), 3.61
(s, 3H, OCH3); ESIMS m/z calcd for [C14H18N2O8Na]þ, 365.0961;
found, 365.0963.
5 . 4 . 1 0 . P h e n y l 4 , 6 - O - b e n z y l i d e n e - 3 - d e o x y - 3 - ( 3 -
5.4.4. Methyl 3-deoxy-3-(4-methylbenzamido)-
b
-
D
-talopyranoside
methoxybenzamido)-2-O-toluoyl-1-thio-b-D-talopyranoside
(26). 1H NMR (CD3OD)
d
7.78 (d, J¼8.2 Hz, 2H, ArH), 7.31 (d,
(34). NaCNBH3 (61 mg, 973 mmol) was added to a stirred solution
of crude ketone 33 (<146 mmol) and NH4OAc (600 mg, 7.78 mmol)
in MeOH/THF (1:1, 10 mL) and CH(OMe)3 (2 mL) under nitrogen
atmosphere and at rt. After 19 h, more NaCNBH3 (61 mg, 973 mmol)
was added. After another 3 h, the reaction was concentrated and re-
dissolved in DCM (100 mL) before being washed with NaHCO3
(satd, aq, 75 mL) and brine (2ꢀ75 mL). The aqueous phases were
extracted with DCM (50 mL) and the pooled organic phases were
dried over MgSO4 before being concentrated and purified by col-
umn chromatography (DCM/MeOH 100:5 to 100:10) to give in-
termediate amine. m-Anisoyl chloride (23 mL, 162 mmol) followed
by lutidine (26 mL, 227 mmol) were immediately added to a stirred
solution of the intermediate amine in DCM (1 mL) under nitrogen
atmosphere and at rt. After 16 h, more m-anisoyl chloride (23 mL,
162 mmol) and lutidine (26 mL, 227 mmol) were added and the
reaction stirred another hour before being concentrated and puri-
fied by column chromatography (toluene/acetone 100:10 to 100:20
gradient) to give amide 34 in 18% yield (16 mg) from toluoate 32; 1H
J¼7.9 Hz, 2H, ArH), 4.52 (d, J¼0.9 Hz, 1H, H1), 4.18 (t, J¼3.1 Hz, 1H,
H3), 3.92 (br d, J¼2.9 Hz, 1H, H2), 3.86 (br d, J¼3.1 Hz, 1H, H4),
3.83e3.79 (m, 2H, H6H6), 3.64 (br t, J¼1 Hz, 1H, H5), 3.60 (s, 3H,
OCH3), 2.41 (s 3H, CH3); ESIMS m/z calcd for [C15H22NO6]þ,
312.1447; found, 312.1461.
5.4.5. Phenyl 4,6-O-benzylidene-3-O-p-toluenesulfonyl-1-thio-b-D-
galactopyranoside (29). Phenyl 4,6-O-benzylidene-1-thio-galacto-
side 28 (1.00 g, 2.77 mmol) was dissolved in pyridine (15 mL) at rt
and p-toluenesulfonyl chloride (1.59 g, 8.32 mmol) was added in
portions over 24 h. Unreacted reagent was quenched by addition of
excess H2O and the reaction was concentrated and purified by col-
umn chromatography (toluene/acetone 100:5 to 100:10 to 100:15
gradient) to give tosylate 29 in 38% yield (0.53 g); 1H NMR (CDCl3)
d
7.80 (d, J¼8.3 Hz, 2H, ArH), 7.66e7.62 (m, 2H, ArH), 7.39e7.19 (m,
5H, ArH), 5.36 (s, 1H, CH), 4.61 (dd, J¼9.5, 3.5 Hz, 1H, H3), 4.52 (d,
J¼9.4 Hz,1H, H1), 4.40e4.34 (m, 2H, H4þH6), 4.00 (dd, J¼12.4,1.6 Hz,
1H, H6), 3.92 (ddd, J¼9.4, 9.4, 2.5 Hz, 1H, H2), 3.56 (app. d, J¼1.1 Hz,
1H, H5), 2.42 (s, 3H, CH3), 2.29 (d, J¼2.6 Hz, 1H, OH).
NMR (CDCl3)
d
8.00 (d, J¼8.2 Hz, 2H, ArH), 7.61e7.55 (m, 4H, ArH),
7.42e7.14 (m, 9H, ArH), 7.09 (d, J¼7.8 Hz, 2H, ArH), 6.99 (ddd, J¼8.2,
2.6, 1.2 Hz, 1H, ArH), 6.79 (d, J¼7.8 Hz, 1H, NH), 5.86 (dd, J¼3.6,
0.9 Hz, 1H, H2), 5.57 (s, 1H, CH), 5.11 (d, J¼1.3 Hz, 1H, H1), 4.79 (dt,
J¼7.8, 3.8 Hz, 1H, H3), 4.53 (dd, J¼12.6, 1.2 Hz, 1H, H6), 4.25 (br d,
5.4.6. Phenyl
2,3-anhydro-4,6-O-benzylidene-1-thio-b-D-gulopyr-
anoside (30). Potassium trimethylsilanoate (198 mg, 1.54 mmol)

€
9172
C.T. Oberg et al. / Tetrahedron 67 (2011) 9164e9172
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H5þOCH3), 2.41 (s, 3H, CH3).
Acknowledgements
We thank Lund University, the Swedish Research Council, the
programs ‘Glycoconjugates in Biological Systems’ (GLIBS) and
‘Chemistry for Life Sciences’ sponsored by the Swedish Strategic
Research Foundation, the Royal Physiographic Society in Lund, and
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the foundation ‘Olle Engkvist Byggmastare’ for financial support.
ꢁ
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