Efficient routes to ethyl-2-deoxy-2-phthalimido-1-β-D-thio- galactosamine derivatives via epimerization of the corresponding glucosamine compounds

Article abstract of DOI:10.1081/CAR-200061584

Short synthetic routes to protected ethyl 2-deoxy-2-phthalimido-1-β-D- thio-galactosamine derivatives via epimerization of the corresponding glucosamine compounds are described. Starting from D-glucosamine hydrochloride, the epimerizations were performed

Full text of DOI:10.1081/CAR-200061584

Journal of Carbohydrate Chemistry, 24:297–320, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1081/CAR-200061584
Efficient Routes to Ethyl-2-
Deoxy-2-phthalimido-1-b-D-
thio-galactosamine
Derivatives via
Epimerization of the
Corresponding
Glucosamine Compounds
Markus Hederos and Peter Konradsson
¨
¨
Division of Chemistry, IFM, Linkoping University, Linkoping, Sweden
Short synthetic routes to protected ethyl 2-deoxy-2-phthalimido-1-b-D-thio-galactosa-
mine derivatives via epimerization of the corresponding glucosamine compounds are
described. Starting from D-glucosamine hydrochloride, the epimerizations were
performed by displacement of presynthesized triflates with nitrite anions and by an
oxidation/reduction route. The latter method involved Moffatt oxidation to the
corresponding 4-ketohexoses and subsequent reduction using sodium borohydride/
tetrabutylammonium borohydride, zinc borohydride, or lithium tri-sec-butyl borohy-
dride in THF. The displacement route was found to be the preferred method for
epimerization of 3-O-acyl (benzoyl) derivatives. For glucosamine compounds with 3-O-
etheral- (allyl or benzyl) and 6-O-benzyl protecting groups, the oxidation/reduction
route was the most convenient procedure to achieve corresponding galactosamine
compounds. The produced galactosamine derivatives will be useful building blocks in
the synthesis of antifreeze glycoproteins substances and analogues thereof.
Keywords Galactosamine, Epimerization, Oligosaccharides, Glycosyl donors, Anti-
freeze glycoproteins
Received November 19, 2004; accepted March 18, 2005.
¨
Address correspondence to Peter Konradsson, Division of Chemistry, IFM, Linkoping
¨
University, SE-581 83, Linkoping, Sweden. Tel.: þ 46-13-281728; Fax: þ46-13-281399;
E-mail: petko@ifm.liu.se
297

M. Hederos and P. Konradsson
298
INTRODUCTION
2-N-Acetamido-2-deoxy-D-galactopyranosides are building units found in, for
example, the mucin class of glycopeptides, human blood specific glycoproteins,
and the oligosaccharide portion of glycosphingolipids.[1] Moreover, a-glycosidic
bonds of 2-N-acetamido-2-deoxy-D-galactopyranosides to threonine are present
in antifreeze glycoproteins.[2,3] In 1978 Lemieux presented the azidonitration of
3,4,6-tri-acetyl-D-galactal as a most convenient method to achieve multigrams
of D-galactosamine and 2-deoxy-2-azido-D-galactosyl donors/acceptors, which
is a well-known problem in the synthesis of 2-N-acetamido/2-amino-2-deoxy-
D-galactopyranoside containing compounds.[4] The use of the azido group as a
masked amine is well known and was introduced in the carbohydrate field
by Paulsen and co-workers in 1978.[5–7] During glycosylation with this nonpar-
ticipating azido group at position 2, the a-O-linked glycoside is obtained as the
major product. To form 1,2-trans glycosidic bonds, the use of a participating
neighboring group is necessary. The N-phthalimido group fulfills this
requirement and has been used widely after its introduction in carbohydrate
chemistry in the mid-70s.[8]
Antifreeze glycoproteins (AFGPs) are found in the bloodstream of some fish
species living in subzero environments and inhibit, in a noncolligative manner,
the growth of ice crystals in the blood and thereby allow these organisms to
survive. A typical AFGP consists of a repeating tripeptide (Thr-Ala-Ala),
in which every hydroxyl of the threonine residue is glycosylated with a
b-D-Gal-(1 ! 3)-a-D-GalNAc disaccharide. We are interested in ethyl-2-
deoxy-2-phthalimido-thiogalactosyl donors/acceptors to be used in the syn-
thesis of AFGPs and analogues thereof. The aim of this project was to find
(a) satisfying method(s) for the epimerization of C-4 in ethyl-2-deoxy-2-
phthalimido-thioglucosamine compounds, with acyl- or alkyl-protecting
groups at C-3 and C-6, respectively, to their axial analogues. Thioglycosides
are easily prepared, show stability in a variety of conditions, and can be selec-
tively activated with several thiophilic promoters.[9] Further, for synthetic
flexibility in future and ongoing projects, C-3 was protected with a benzoyl, a
benzyl, or an allylic group, whereas C-6 was protected either with a benzoyl
or a benzyl group. With respect to these protecting groups, we focused on two
different methods for the epimerization, a substitution with inversion (SN2-
type) and an oxidation/reduction route.
In 1974 Lattrell and Lohaus found that when a chiral secondary sulfonate
was treated with sodium nitrite in DMSO, the corresponding alcohol with
inverted stereochemistry was isolated.[10] This was further developed by
Albert et al., showing promising results in carbohydrate chemistry by substi-
tution of trifluoromethanesulfonate (triflate) glucosides with sodium- or tetra-
butylammonium nitrite in DMF or acetonitrile to provide the corresponding
inverted hydroxyl compounds.[11] As a consequence, there are several reports

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
299
using this epimerization method in carbohydrate synthesis.[12–19] To our know-
ledge, there is only one example using this method for employing an ethyl-N-
phthalimido thiogalactosamine compound.[12] Since they only investigated
the epimerization with benzoyl-protecting groups, we decided to examine this
procedure further with our series of N-phthalimido glucosamine derivatives.
The second method was an oxidation/reduction route where the alcohols
were converted to their ketoform via Moffatt oxidation,[20,21] followed by
reduction of the crude ketosugars with sodium borohydride (NaBH4) and a
catalytic amount of tetrabutylammonium borohydride (Bu4NBH4), zinc boro-
hydride (Zn(BH4)2), or lithium tri-sec-butyl borohydride (L-selectridew) in
THF. The factors in controlling the stereoselective reduction of 4-ketohexoses
with NaBH4 were recently summarized in a publication pointing at the charac-
teristic of the vicinal-protecting group as a criterion to predict the formation of
an axial or equatorial hydroxyl group.[22] It was suggested that the presence of
a vicinal equatorial alkoxyl group will favor the formation of an axial hydroxyl
group. Moreover, the protecting groups at C-6 of the 4-keto sugars were stated
to have a minor effect in controlling the stereoselectivity in the reductions.
However, these conclusions were drawn from compounds with rather large
structural differences compared to the 2-deoxy-2-phthalimido-glucosamine
compounds we have synthesized and compared. The only relevant example
we found in the literature is in a paper from Vliegenthart and co-workers,
where the reduction of ethyl 3-O-benzyl-2-deoxy-2-phthalimido-6-O-trityl-b-
D-xylo-thiohexa-pyranoside-4-ulose with Bu4NBH4 formed the galacto and
gluco epimers in a 10:1 ratio.[23] Zn(BH4)2 was chosen as a reagent to investi-
gate the ability of controlling the stereoselectivity in the reductions by chela-
tion of the zinc cation between the carbonyl oxygen and the vicinal donor
substituents. Reduction of a-hydroxy ketones and a-alkoxy ketones have
shown, through chelated transition states, to give the anti products in prefer-
ence where the hydride is delivered from the least sterically hindered face.[24–
26]
On the other hand, L-selectridew is a sterically demanding borohydride
and has been used earlier in carbohydrate chemistry with the purpose of
stereoselective reduction of 4-ketohexoses forming the axial alcohol as major
product.[27–29]
RESULTS AND DISCUSSION
Bearing the cost aspect of galactosamine in mind, our starting point was
thioglycoside 1 (Sch. 2), which can be prepared in multigram scale from
D-glucosamine hydrochloride using standard synthetic methods.[30,31] With
conventional methods, C-3 was protected either with a benzoyl, benzyl, or an
allylic group, whereas C-6 was protected either with a benzoyl or benzyl
group, leading to a series of six ethyl-2-deoxy-2-phtalimido-thioglucosides
available for epimerization (Fig. 1).

M. Hederos and P. Konradsson
300
Figure 1: The C-3 and C-6 protecting groups used on the ethyl 2-deoxy-2-phthalimido-1-b-D-
thio-glucosamine compounds subjected to epimerization.
Conversion of the secondary alcohols to triflates, treating them with nitrite
anion, gave alcohols with inverted stereochemistry as the main products.
Furthermore, all alcohols were oxidized to their corresponding ketoform follow-
ing the procedure described by Moffatt using DCC, pyridine, and trifluoroacetic
acid in DMSO and CH2Cl2. Reduction of the crude ketohexoses were performed
using NaBH4/Bu4BH4, Zn(BH4)2 and L-selectridew for comparison of the
stereoselectivity (Sch. 1).
For the synthesis of the 4-OH derivatives 3 and 4 prepared for epimeriza-
tion, 1 was treated with benzoyl chloride in pyridine to give crystalline 2 in
nearly quantitative yield (99%). Removal of the benzylidene acetal with
ethylene glycol in CH2Cl2/TFA (4:1) and subsequent benzoylation of the
primary alcohol with benzoyl chloride in pyridine afforded compound 3[12] in
Scheme 1: The displacement and the oxidation/reduction route, respectively, used for the
epimerization of the glucosamine compounds: (a) Tf2O, pyridine, CH2Cl2; (b) NaNO2/DMF or
Bu4NNO2/toluene; (c) DCC, TFA, pyridine, DMSO/CH2Cl2 (l:1); (d) NaBH4/Bu4NBH4, Zn(BH4)2,
or L-selectride in THF.

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
301
87% yield for the two steps. Reductive opening of the benzylidene acetal in 2
with sodium cyanoborohydride and HCl saturated diethyl ether in THF gave
compound 4 in good yield (83%).
The 3-O-benzylated compound 5[32] was produced in 84% yield from 1 using
benzyl bromide and sodium hydride in DMF, and treated in a similar fashion as
in the preparation of 3 and 4 to give derivatives 6 and 7[32] in 84% and 90%
yield, respectively. Analogically, the two allylic compounds 9 and 10 were syn-
thesized. The 3-OH position in 1 was treated with allylic bromide and sodium
hydride in DMF to give compound 8[33] in 86% yield, and was used to produce
the two derivatives 9 (84%) and 1033 (82%) following the same protocols as
described above (Sch. 2).
For all the glucosamine compounds, (3, 4, 6, 7, 9, and 10), the conversions
to the corresponding triflates were followed with TLC and proved by the typical
downfield shift of H-4 in 1H NMR (Table 1). The triflates were used directly in
the displacement reactions without further characterization.
The results of the epimerization of the 4-OH derivatives using the
displacement route are presented in Table 2. The 3-O-benzoylated derivatives
Scheme 2: (a) BzCl, pyridine; (b) 1. ethylene glycol, TFA/CH2Cl2 (5:1); 2. BzCl, pyridine; (c)
NaCNBH3, Et2O/HCl, THF; (d) BnBr, NaH, DMF; (e) AllBr, NaH, DMF.

M. Hederos and P. Konradsson
302
Table 1: Selected NMR data for the crude triflates and ketohexoses.
13C NMR (75.4 MHz, CDCl3)
1H NMR (300 MHz, CDCl3)
R1
Bz
R2
Bz
d 5.38 (dd, 1H, J ¼ 9.6, 9.6 Hz, H-4),
5.67 (d, 1H, J ¼ 10.8 Hz, H-1)
d 194.1 (C-4), 81.7 (C-1)
d 194.7 (C-4), 81.4 (C-1)
d 199.6 (C-4), 81.5 (C-1)
d 200.2 (C-4), 81.3 (C-1)
d 199.3 (C-4), 81.7 (C-1)
d 200.5 (C-4), 81.5 (C-1)
Bz
Bn
Bz
d 5.43 (dd, 1H, J ¼ 9.6, 9.6 Hz, H-4),
5.57 (d, 1H, J ¼ 10.8 Hz, H-1)
Bn
Bn
All
All
d 5.15 (dd, 1H, J ¼ 9.3, 9.3 Hz, H-4),
5.30 (d, 1H, J ¼ 10.5 Hz, H-1)
Bn
Bz
d 5.10 (dd, 1H, J ¼ 9.3, 9.3 Hz, H-4),
5.23 (d, 1H, J ¼ 10.4 Hz, H-1)
d 5.07 (dd, 1H, J ¼ 9.3, 9.3 Hz, H-4),
5.35 (d, 1H, J ¼ 10.5 Hz, H-1)
Bn
d 5.02 (dd, 1H, J ¼ 9.6, 9.6 Hz, H-4),
5.28 (d, 1H, J ¼ 10.5 Hz, H-1)
3 and 4 (entries i and ii) were successfully epimerized to their galacto epimers
11[12] and 12 in good yields, 88% and 82%, respectively, using 10 molar eq. of
NaNO2 in DMF at rt. The triflates of 3 and 4 were both totally consumed
during 3 hr at rt. In the former reaction, no byproduct was observed, but in
the latter one, the slightly lower yield of the desired product could be explained
by the observation of the 4-O-benzoylated-3-OH galacto epimer in 5% yield.
On the other hand, the reaction of triflates of the 3-O-benzylated deriva-
tives 6 and 7 (entries iii and v) with NaNO2 in DMF was slower. To obtain
complete consumption of the triflates, the reaction mixture was heated to
358C for 12 hr. Raising the temperature additionally gave lower yields of
products. Galacto epimers 13 and 14 were obtained in 74% and 71% yield,
respectively. The significantly lower yield of the benzylated compounds
compared to their benzoylated analogues encouraged us to optimize the con-
ditions in the displacement route. Using tetrabutylammonium nitrite
(Bu4NNO2) in toluene was found to increase the yield of 13 (82%) and 14
(78%) (entries iv and vi). Still, the reaction rates were similar to the displace-
ment reactions using NaNO2 in DMF.
The 3-O-allylic compounds 9 and 10 showed the same behavior as their
benzylated analogues and needed longer reaction times than the corresponding
benzoylated compounds to achieve complete consumed triflate. The galacto
epimers 15 and 16[33] were produced in 68% and 63% yields, respectively,
using NaNO2 in DMF for 12 hr at 358C (entries vii and ix). Also here,
changing to Bu4NNO2 in toluene increased the yield of the desired products
15 (73%) and 16 (68%) (entries viii and x).

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
303
Table 2: Epimerization using displacement of presynthesized triflates by nitrite
anions
Results
GlcN
compound
Entry
R1
Bz
Bz
Bn
R2
Conditionsa
Product
Yield (%)
i
ii
iii
3
4
6
Bz
Bn
Bz
NaNO2 DMF, rt, 2 hr
NaNO2 DMF, rt, 3 hr
NaNO2 DMF, 358C,
12 hr
11
12
13
88
82
74
iv
v
6
7
Bn
Bn
Bn
All
All
All
All
Bz
Bn
Bn
Bz
(Bu)4NNO2 toluene,
358C, 12 hr
NaNO2 DMF, 358C,
12 hr
(Bu)4NNO2 toluene,
358C, 12 hr
NaNO2 DMF, 358C,
12 hr
(Bu)4NNO2 toluene,
358C, 12 hr
NaNO2 DMF, 358C,
12 hr
(Bu)4NNO2 toluene,
358C, 12 hr
13
14
14
15
15
16
16
82
71
78
68
73
63
68
vi
vii
viii
ix
7
9
9
Bz
10
10
Bn
Bn
x
aAll triflates were treated with 7–10 molar eq. of NaNO2.
To our knowledge there is a limited number of reports in the literature
thoroughly discussing mechanistic aspects of the inversion with nitrite
anions. Binkley has proposed a nitrous acid ester as an intermediate that,
after attack from a second nitrite anion, collapses to the alcohol and N2O3.[15]
To investigate if a nitrous acid ester intermediate could be identified, we
followed the substitution of presynthesized triflate of 3 with NaNO2 in DMF-
d7 in the NMR-tube (see Fig. 2). Interestingly, directly after addition of
NaNO2, a doublet appeared at 6.1 ppm (J ¼ 3.6 Hz) from a new compound.
Moreover, both a doublet and a double doublet at 5.5 ppm (J ¼ 10.2 Hz) and
6.0 ppm (J ¼ 3.6, 11.0 Hz), respectively, were seen and most likely belong to
H-1 and H-3 in this compound. This observation could be the intermediate
nitrous acid ester with respect to the chemical shift and coupling pattern of
the proton at 6.1 ppm. After stirring for 1 hr at 258C, both signals from the
triflate and the intermediate compound had disappeared and the only
observed compound was the galacto epimer (H-3, 5.50 ppm (J ¼ 3.0, 11.1 Hz);
H-1, 5.26 ppm (J ¼ 10.5 Hz)). Whether this is a general reaction pathway for
all the triflates synthesized has not been investigated.

M. Hederos and P. Konradsson
304
Figure 2: 1H NMR spectra from the substitution of presynthesized triflate of 3 using NaNO2
in DMF-d7. (a) T ¼ 0, synthesized triflate of compound 3; (b) T ¼ 1.5 min, mixture of starting
compound and the suggested intermediate nitrous acid ester; (c) T ¼ 1 hr, only galacto
epimer 11 is observed after collapse of the intermediate compound. For further information
see text.
To summarize the epimerization via the displacement route there is a
correlation between the yield/reaction rates and the choice of protecting
group in position 3. The 3-O-benzoylated- and the 3-O-allyl derivatives gave
the highest and lowest yield, respectively, of their inverted analogues. These
results indicate the displacement route to be better for glucosamine compounds
with electron-withdrawing acyl protecting groups at position 3. Moreover as a
“trend,” a benzoyl group is better in position 6 than the benzyl group.
As the alternative route, the 4-OH position was subjected to an oxidation/
reduction inversion. The glucosamine compounds were oxidized using DCC,
pyridine, and TFA in CH2Cl2 and DMSO (1:1) and used directly in the
reduction step. We found the ketosugars forming the corresponding gem-
diols to a varied extent when purified on silica gel column, which has been
reported earlier in the oxidation of similar structures.[34,35] Therefore, the
crude ketohexoses were subjected to reduction immediately after identification
1
by H and 13C NMR (Table 1). Fortunately, the oxidation was complete using
1.5 eq. of DCC, and after workup, the insoluble impurities as dicyclohexylurea
could be filtered off following the original procedure with minor modifi-
cations.[20,21] Due to the poor solubility of NaBH4 in THF, a catalytic amount
of Bu4NBH4 was used in the reductions. The results from the reduction of
the 4-ketohexoses are summarized in Table 3.
In the reduction of the ketohexose formed from 3,6-di-O-benzoylated 3
(entry i, Table 3) with NaBH4/Bu4NBH4, the galacto/gluco epimers 11 and 3
were formed in a 1:2 ratio in 81% total yield. There were no problems in separ-
ating galactosamine derivative 11 from the corresponding glucosamine

Table 3: Epimerization of the glucosamine compounds via the oxidation/reduction route.
Resultsb
R3
GlcN
Compound
Entry
R1
Bz
Bz
Bz
Bz
Bz
Bz
Bn
Bn
Bn
R2
Bz
Bz
Bz
Bn
Bn
Bn
Bz
Bz
Bz
Reducing agenta
NaBH4/(Bu)4NBH4
L-selectridew
Zn(BH4)2
Products
R1
R2
R4
Yield (%)
i
3
3
3
4
4
4
6
6
6
11
3
11
17
11
3
12
4
12
18
12
4
13
6
13
19
13
6
H
OH
H
H
H
OH
H
OH
H
OH
H
OH
OBz
OH
H
OH
H
OH
OBz
OH
H
OH
H
OH
OBz
OH
H
27
54
20
49
11
71
11
67
39
43
4
76
62c
15c
58
20
37c
44c
ii
H
Bz
iii
iv
v
NaBH4/(Bu)4NBH4
L-selectridew
Zn(BH4)2
H
Bn
H
vi
vii
viii
ix
H
OH
H
OH
H
NaBH4/(Bu)4NBH4
L-selectridew
Zn(BH4)2
Bn
OH
H
H
OH
(continued)

Table 3: Continued.
Resultsb
R3
GlcN
Compound
Entry
R1
R2
Reducing agenta
Products
R1
R2
R4
Yield (%)
x
7
Bn
Bn
NaBH4/(Bu)4NBH4
14
7
14
14
7
15
9
15
20
15
9
16
10
16
16
10
H
OH
H
H
OH
H
OH
H
H
H
OH
H
OH
H
OH
OH
H
OH
H
OH
OBz
OH
H
OH
H
OH
OH
H
66c
11c
80c
50c
33c
61c
12c
50
xi
xii
7
7
Bn
Bn
Bn
Bn
L-selectridew
Zn(BH4)2
xiii
xiv
xv
9
9
All
All
All
All
Bz
Bz
Bz
Bn
NaBH4/(Bu)4NBH4
L-selectridew
Zn(BH4)2
All
OH
20
9
53c
26c
66c
9c
xvi
10
NaBH4/(Bu)4NBH4
OH
H
H
xvii
xviii
10
10
All
All
Bn
Bn
L-selectridew
Zn(BH4)2
83
60c
15c
OH
a The reductions were performed at 2108C for NaBH4/(Bu)4NBH4 and L-selectridew and at 08C for Zn(BH4)2, all in THF.
b Unless otherwise stated, R1 and R2 are identical to the groups presented in corresponding row.
c The epimers were not separated; the ratio was determined from 1H NMR (300 MHz).

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
307
compound 3. Reduction with L-selectridew produced only the galacto isomer,
but unfortunately, the benzoyl group at C-3 partly migrated to the axial
hydroxyl, leading to the formation of 11 (20%) and the 4-O-benzoylated
analogue 17 in 49% yield (entry ii). Using Zn(BH4)2 as the reducing agent
obstructed the desired stereoselectivity leading to galacto/gluco epimers 11
and 3 being formed in a 1:6.5 relationship (entry iii).
In the reduction of oxidized 4 with NaBH4/Bu4NBH4, the galacto epimer
12 was observed in 11% yield together with regenerated starting compound
4 (67%) (entry iv). When reduction was performed with L-selectridew (entry
v), the benzoyl-migrated compound 18 (43%) was found as the major product,
together with the compound 12 in 39% yield. Zn(BH4)2 reduction of 3-O-
benzoyl-6-O-benzylated ketohexose gave almost gluco epimer 4 (76%) (entry
vi). It should be noted, that, no gluco epimer was observed using L-selectridew
for either of the oxidized 3-O-benzoylated compounds 3 and 4.
For the 3-O-benzylated ketohexoses formed from compounds 6 and 7, the
stereoselectivity in the reduction with NaBH4/Bu4NBH4 favored the formation
of 13 and 14 with axial hydroxyl groups (entries vii and x). The best ratio of
galacto/gluco epimer was observed for the 6-O-benzylated derivative 7 (6:1,
77%) (entry x). Unfortunately, it was impossible to separate the product from
the starting material in both reductions using silica gel chromatography. The
ratio between the isomers was determined from 1H NMR experiments.
Changing to L-selectridew gave only the galacto epimer, but as described
above, the reaction conditions enabled the 6-O-benzoyl group to migrate to
the axial hydroxyl group on C-4. Derivative 13 was isolated in 58% yield
together with the migrated analogue 19 in 20% yield (entry viii). On the
other hand, when oxidized compound 7 was treated with L-selectridew, the
only product was the corresponding galactosamine compound 14 in 80% yield
(entry xi). The reductions with Zn(BH4)2 gave remarkable changes in stereo-
selectivity compared to using NaBH4/Bu4NBH4. For 3-O-benzyl-6-O-benzoyl
ketohexose produced from 6, the ratio of galacto/gluco epimer changed from
4:1 to 0.8:1 (entries vii and ix). The stereoselectivity of the corresponding
reaction of 3,6-di-O-benzyl derivative 7 with Zn(BH4)2 was nearly leveled out
(entry xii).
Further, the oxidized 3-O-allyl protected derivatives 9 and 10 showed
favored formation of their axial analogues 15 and 16, respectively, when
treated with NaBH4/Bu4NBH4. Also here the 6-O-benzylated derivative 10
gave the highest ratio (7.3:1) of axial alcohol compared to the 6-O-benzoyl
compound 9 (5:1), and likewise, the separation between the two sets of
epimers failed (entries xvi and xiii). Reduction of ketohexose of 9 with
L-selectridew gave the desired galactosamine derivative 15 in 50% yield
together with the 4-O-benzoylated compound 20 in 20% yield (entry xiv). In
the reduction of oxidized 10 with L-selectridew, the result was satisfying; the
epimer 16 with an axial hydroxyl group was found in 83% total yield for

M. Hederos and P. Konradsson
308
the oxidation/reduction route (entry xvii). As in all former reactions with
Zn(BH4)2, the selectivity for formation of galacto epimer were turned to
preferred formation of gluco isomer compared to the reductions using
NaBH4/Bu4NBH4. For the 3-O-allylic-6-O-benzoyl compound, the ratio of
galacto/gluco epimer was changed from 5:1 to 2:1 (entries xiii and xv),
whereas the corresponding 6-O-benzylated derivative changed from 7.3:1 to
4:1 (entries xvi and xviii).
In conclusion, the oxidation/reduction route is a most convenient epimer-
ization method with L-selectridew as a reducing agent, when no benzoyl-
protecting groups are used, due to their migratory aptitude during these
conditions. No glucosamine derivatives were obtained in the reductions using
L-selectridew. The stereoselectivity in the reductions with NaBH4/Bu4NBH4
gave a favored galacto/gluco epimer ratio for the 3-O-etheral (allyl or benzyl)
derivatives compared to the 3-O-benzoylated compounds. Interestingly, for
the 3-O-etheral compounds, a 6-O-benzylic group enhanced the formation of
the galacto epimer, whereas for the 3-O-benzoylic derivatives, a 6-O-benzoyl-
protecting group favored the formation of axial alcohol.
CONCLUSIONS
The displacement route via the triflate using NaNO2 in DMF was most
convenient for the 3-O-benzoylated species 3 and 4 with respect to yield and
reaction times. Using alkoxy groups in position 3 gave both acceptable and
similar yields of inverted epimers 13–16 (74–63%). Improvements were
found using Bu4NNO2 in toluene (82–68%), but still the epimerizations
required longer reaction times and higher temperatures than the
3-O-benzoylated derivatives. The influence of the chemical character of the
C-6 protecting group is risky to state as the differences in yield are small.
The stereoselectivity in the reductions of oxidized acylated compounds 3
and 4 with NaBH4/Bu4NBH4 were not satisfying and, using L-selectridew,
gave partial acyl migrations to the formed axial hydroxyl. Thus, to obtain
derivatives 11 and 12, the preferred method is the displacement route. For
the benzylated compounds 6 and 7, the stereoselectivity using NaBH4/
Bu4NBH4 was much better, but unfortunately, the galacto/gluco epimers
could not easily be separated. For 3,6-di-O-benzylated 7, this would not be a
problem as changing the reducing agent to L-selectridew produced the
galacto epimer 14 in good yield (80%). On the other hand, the best way to
epimerize C-4 in 6 ! 13 would be to use the displacement route. Of note is
that a benzylated C-6 gave higher stereoselectivity to produce axial hydroxyl
(ratio 6:1 for 14/7 compared to 4:1 for 13/6; see Table 2 entries ix and vii).
This relationship was also found for the two 3-O-allylic species 9 and 10
(ratio 7.3:1 for 16/10 compared to 5:1 for 15/9, entries xvi and xiii). The dia-
stereocourse of the reduction of oxidized 3-O-benzoyl derivatives was shown

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
309
to be the opposite. Here, the benzylated C-6 compound 4 gave a diminished
stereoselectivity toward axial galacto epimer (ratio 1:2 for 11/3 compared to
1:6 for 12/4, entries i and iv). As mentioned above, the epimers were not
possible to separate. Naturally, choosing between the epimerization methods,
the displacement route is preferred for 9 ! 15 and the oxidation/reduction
using L-selectridew for the conversion of 10 ! 16. To summarize the reductions
of synthesized 4-ketohexoses with Zn(BH4)2, the galacto/gluco ratio was in all
cases disfavored compared with the reductions using NaBH4/Bu4NBH4,
revealing Zn(BH4)2 not to be a good choice as a reducing agent in the
oxidation/reduction route.
Efficient synthetic protocols for ethyl-2-deoxy-2-phtalimido-thiogalactosyl
acceptors/donors have been worked out using the ability to prepare crystalline
thioglycoside 1 in a large amount from D-glucosamine hydrochloride. These
results will be undertaken in future projects involving oligosaccharide syn-
thesis, for example, the synthesis of antifreeze glycoprotein derivatives.
EXPERIMENTAL
General Methods
Organic extracts were dried over MgSO4, filtered, and concentrated in
vacuo below 408C. NMR spectra were recorded on a Varian Mercury 300
(1H 300 MHz and 13C 75.4 MHz) instrument at 258C in CDCl3/MeOH 99:1
(1H, for deuteration of alcohol protons) or in 100% CDCl3 (13C). Chemical
shifts are given in ppm relative to TMS (d ¼ 0.00) for 1H and to CDCl3
(d ¼ 77.0), for 13C, respectively. Signals were assigned by using DEPT, 2D
(COSY and HMQC), and homonuclear decoupled experiments. TLC was
performed on silica gel F254 (E. Merck) with detection by UV light (254 nm)
and/or by charring with ethanol/sulfuric acid/p-anisaldehyde/acetic acid
(90:3:2:1) followed by heating at 2508C. Silica gel MERCK 60(0.040–0.063 mm)
was used for flash chromatography (FC). Optical measurements were
recorded at rt with a Perkin-Elmer 241 polarimeter. Melting points were
recorded with an uncorrected Gallenkamp melting point apparatus. MALDI-
TOF mass spectra were recorded with a Voyager-DE STR Biospectrometry
Workstation, in positive mode, using a a-cyano-4-hydroxycinnamic acid matrix
and the dimer (m/z 379.0930) as internal standard. IR spectra were recorded
(KBr pellets) on a Perkin-Elmer SPECTRUM 1000 FT-IR Spectrometer.
Triflate Formation
To a solution of alcohol (0.70 mmol) and pyridine (1.40 mmol) in dry CH2Cl2
(5 mL) was added Tf2O (0.90 mmol) at 258C. The solution was allowed to reach
rt during 1 hr, diluted with CH2Cl2, and washed sequentially with 0.1 M aq.

M. Hederos and P. Konradsson
310
hydrochloric acid and aq. NaHCO3 (sat.). The organic phase was dried, filtered,
and concentrated to give the crude triflate.
Displacement of Triflates with Nitrite Anions
A. NaNO2/DMF
To a solution of triflate (0.70 mmol) in DMF (4 mL), NaNO2 (7 mmol) was
added. When the triflate was consumed according to TLC, the mixture was
diluted with CH2Cl2, washed with water, dried, filtered, and concentrated
followed by purification with FC.
B. Bu4NNO2/toluene
To a solution of triflate (0.70 mmol) in toluene (4 mL), Bu4NNO2 (4.9 mmol)
was added. When the triflate was consumed according to TLC, the mixture was
concentrated followed by purification with FC.
Oxidation to 4-Ketohexose
DCC (1.05 mmol) was added to a solution of alcohol (0.70 mmol), pyridine
(0.74 mmol), and TFA (0.39 mmol) in CH2Cl2/DMSO (4 mL, 1:1). The mixture
was stirred overnight and diluted with CH2Cl2, filtered through zelite, and
washed twice with water. The organic phase was dried, filtered, and concen-
trated. The crude ketosugar was dissolved in Et2O (15 mL), insoluble materials
were filtered off, and concentration of the filtrate gave crude ketohexose.
Reduction of 4-ketohexoses with Hydrides
A. NaBH4/Bu4NBH4
To a solution of the obtained ketosugar (0.70 mmol) in THF (6 mL) was
added NaBH4 (0.70 mmol) and n-Bu4NBH4 (0.14 mmol) at 2108C. After
10 min the solution was diluted with CH2Cl2, washed twice with aq. NaHCO3
(sat.), dried, filtered, and concentrated, and the obtained residue was subjected
to FC.
B. L-selectridew
To the crude ketohexose (0.70 mmol) dissolved in THF (6 mL) at 2108C,
L-selectridew (0.80 mmol, 1 M in THF) was added. The solution was stirred
for 10 min, diluted with CH2Cl2, poured into a separatory funnel, and
washed sequentially with 0.1 M aq. hydrochloric acid and aq. NaHCO3 (sat.).
The organic phase was dried, filtered, and concentrated, and the obtained
residue was subjected to FC.
C. Zn(BH4)2
To the crude ketohexose (0.70 mmol) dissolved in THF (6 mL) at 08C,
[26]
Zn(BH4)2
(1.40 mmol, 0.35 M in Et2O) was added. The solution was
stirred for 30 min, diluted with CH2Cl2, poured into a separatory funnel,
and washed sequential with aq. NaHCO3 (sat.). The organic phase was
dried, filtered, and concentrated, and the obtained residue was purified by
silica FC.

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
311
Ethyl-4,6-O-benzylidene-3-O-benzoyl-2-deoxy-2-phthalimido-1-thio-
b-D-glucopyranoside (2). To an ice-cold solution of thioglucoside 1[30] (5.00 g,
11.30 mmol) in pyridine (25 mL), benzoylchloride (1.90 mL, 16.35 mmol) was
added dropwise. After 1 hr the solution was diluted with CH2Cl2, washed
with water, and concentrated. The crude product was dissolved in CH2Cl2
and washed with 1 M aq. hydrochloride acid, aq. NaHCO3 (sat.), dried,
filtered, and concentrated. FC (toluene/EtOAc 10:1 ! 4:1) gave 2 (6.120 g,
11.23 mmol, 99%) as a white foam. Rf 0.56 (toluene/EtOAc 6:1); [a]D ¼ þ 48
(c 1.0, CHCl3); m.p. 1028C (from MeOH); IR nmax cm21 530, 646, 701, 712,
762, 874, 994, 1069, 1097, 1261, 1385, 1451, 1468, 1601, 1717, 1777, 2870,
1
1929, 1973, 3034, 3063; H NMR d 1.22 (3H, t, J ¼ 7.4 Hz, CH3CH2), 2.62–
2.81 (2H, m, CH3CH2), 3.83–3.97 (3H, m, H-4,5,6a), 4.46 (1H, dd, J ¼ 9.1,
10.2, Hz, H-6b), 4.56 (1H, t, J ¼ 10.1 Hz, H-2), 5.57 (1H, s, PhCH-), 5.65 (1H,
d, J ¼ 10.1 Hz, H-1) 6.22 (1H, t, J ¼ 10.1 Hz, H-3), 7.26–7.88 (14H, Ph); 13C
NMR d 14.9 (CH3CH2), 24.5 (CH3CH2), 54.2 (C-2), 68.7 (C-6), 70.7 (C-5), 70.9
(C-4), 79.7 (C-1), 81.9 (C-3), 101.6 (PhCH), 123.7 (Ph), 126.2 (Ph), 128.2–
129.8 (Ph), 130.1 (Ph), 130.5 (Ph), 131.2 (Ph), 131.6 (Ph), 133.1 (Ph), 133.6
(Ph), 134.1 (Ph), 134.3 (Ph), 134.5 (Ph), 136.8 (Ph), 165.6 (PhCOO), 167.3
(PhCON), 167.8 (PhCON); Anal. Calcd for C30H27NO7S: C, 66.04; H, 4.99.
Found: C, 66.27; H, 5.04. MALDI-TOF calcd for C30H27NO7S: [M þ Na]þ
568.1. Found: [M þ Na]þ 568.1.
Ethyl-3,6-di-O-benzoyl-2-deoxy-2-phtalimido-1-thio-b-D-glucopyrano
side (3). Compound 2 (1.24 g, 2.28 mmol) and ethylene glycol (3.5 mL) were
stirred in CH2Cl2/TFA (5:1, 24 mL). After 1 hr, the mixture was diluted
with CH2Cl2, washed with aq. NaHCO3 (sat.), dried, filtered, and concen-
trated. The residue was dissolved in pyridine (10 mL) and cooled to 08C,
whereupon benzoyl chloride (0.41 mL, 3.53 mmol) was added. After 2 hr the
mixture was diluted with toluene and washed with 1 M aq. H2SO4 and aq.
NaHCO3 (sat.), dried, filtered, and concentrated. FC (toluene/EtOAc
10:1 ! 3:1) gave 3 (1.10 g, 1.98 mmol, 87%) as a white solid. Rf 0.36
(toluene/EtOAc 4:1); IR nmax cm21 531, 650, 713, 872, 968, 1027, 1085,
1118, 1180, 1271, 1285, 1321, 1375, 1390, 1450, 1601, 1698, 1722, 1780,
2870, 2885, 2930, 2948, 2964, 2976, 3064; 1H spectrum was identical to
that previously published.[12] 13C NMR d 14.9 (CH3CH2), 24.3 (CH3CH2),
53.7 (C-2), 64.0 (C-6), 69.9 (C-4), 74.7 (C-3), 78.2 (C-5), 81.0 (C-1), 123.4
(Ph), 128.0–129.6 (Ph), 131.0–134.2 (Ph), 166.6 (PhCOO), 166.7(PhCOO),
167.3 (PhCON), 167.9 (PhCON); MALDI-TOF calcd for C30H27NO8S:
[M þ Na]þ 584.1. Found: [M þ Na]þ 584.1.
Ethyl-3-O-benzoyl-6-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-gluco-
pyranoside (4). Sodium cyanoborohydride (NaCNBH3) (4.15 g, 65.99 mmol)
˚
was added at rt to a solution of 2 (4.00 g, 7.33 mmol) and 3 A molecular sieves

M. Hederos and P. Konradsson
312
in dry THF (50 mL). Under vigorous stirring the mixture was treated with HCl
in diethyl ether until gas evolution ceased. The mixture was stirred for 2 hr,
filtered through a pad of celite, and concentrated. FC (toluene/EtOAc
10:1 ! 4:1) gave 4 (3.33 g, 6.08 mmol, 83%) as a white amorphous solid. Rf
0.39 (toluene/EtOAc 4:1); [a]D þ 91 (c 1.1, CHCl3); IR nmax cm21 3087, 3030,
2966, 2927, 2869, 1776, 1717, 1601, 1496, 1451, 1386, 1270, 1199, 1178, 1070,
1
1026, 968, 875, 713, 650, 530; H NMR d 1.23 (t, 3H, J ¼ 7.5 Hz, CH3CH2),
2.60–2.77 (m, 2H, CH3CH2), 3.82 (ddd, 1H, J ¼ 3.3, 4.5, 8.1, Hz, H-5), 3.87–
3.89 (m, 2H, H-6ab), 3.93 (dd, 1H, J ¼ 8.1, 8.7 Hz, H-4), 4.52 (dd, 1H, J ¼
10.2, 10.5 Hz, H-2), 4.61 (d, 1H, J ¼ 12.0 Hz, CH2Ph), 4.66 (d, 1H,
J ¼ 12.0 Hz, CH2Ph), 5.53 (d, 1H, J ¼ 10.5 Hz, H-1), 5.93 (dd, 1H, J ¼ 8.7,
10.2 Hz, H-3), 7.29–7.86 (m, 14H, Ph); 13C NMR d 14.8 (CH3CH2), 24.1
(CH3CH2), 53.6 (C-2), 69.8 (C-6), 70.6 (C-4), 73.5 (CH2Ph), 74.8 (C-3), 79.0
(C-5), 80.8 (C-1), 123.4 (Ph), 127.5 (Ph), 128.2 (Ph), 128.8 (Ph), 129.6 (Ph),
130.9 (Ph), 131.3 (Ph), 133.2 (Ph), 134.0 (Ph), 134.1 (Ph), 137.8 (Ph), 166.5
(PhCOO), 167.3 (PhCON), 167.8 (PhCON). Anal. Calcd for C30H29NO7S: C,
65.80; H, 5.34. Found: C, 65.67; H, 5.42. MALDI-TOF calcd for C30H29NO7S:
[M þ Na]þ 570.2. Found: [M þ Na]þ 570.2.
Ethyl-6-O-benzoyl-3-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-gluco-
pyranoside (6). Compound 6 (2.615 g, 4.78 mmol, 84%) was synthesized
following the same procedure as for 3, using 5 (3.00 g, 5.69 mmol), ethylene
glycol (4.0 mL), CH2Cl2/TFA (5:1, 30 mL), benzoyl chloride (0.92 mL,
7.97 mmol), and pyridine (10 mL). FC (toluene/EtOAc 6:1 ! 3:1) gave 6 as a
white solid. Rf 0.32 (toluene/EtOAc 4:1) [a]D þ 26 (c 2.0, CHCl3); IR
nmax cm21 3087, 3064, 3028, 2958, 2940, 2924, 2882, 1782, 1716, 1602, 1583,
1495, 1452, 1386, 1319, 1288, 1180, 1119, 1086, 1061, 976, 965, 873, 751, 719,
651, 532; 1H NMR d 1.17 (t, 3H, J ¼ 7.4 Hz, CH3CH2), 2.53–2.74 (m, 2H,
CH3CH2), 3.69 (dd, 1H, J ¼ 8.0, 9.9 Hz, H-4), 3.78 (ddd, 1H, J ¼ 2.1, 4.0,
9.9 Hz, H-5), 4.23 (dd, 1H, J ¼ 9.9, 10.2 Hz, H-2), 4.31 (dd, 1H, J ¼ 8.0,
10.2 Hz, H-3), 4.55 (d, 1H, J ¼ 12.1 Hz, CH2Ph), 4.59 (dd, 1H, J ¼ 2.1 12.2 Hz,
H-6a), 4.75 (d, 1H, J ¼ 12.1 Hz, CH2Ph), 4.78 (dd, 1H, J ¼ 4.0, 12.2 Hz, H-6b),
5.32 (d, 1H, J ¼ 9.9 Hz, H-1) 6.95–8.10 (m, 14H, Ph); 13C NMR d 14.9
(CH3CH2), 24.0 (CH3CH2), 54.5 (C-2), 63.8 (C-6), 71.8 (C-4), 74.6 (CH2Ph),
78.1 (C-5), 79.5 (C-3), 81.2 (C-1), 123.2 (Ph), 123.4 (Ph), 127.4 (Ph), 127.8–
129.7 (Ph), 131.4 (Ph), 133.2 (Ph), 133.8 (Ph), 137.8 (Ph), 167.1 (PhCOO),
167.4 (PhCON), 168.0 (PhCON); Anal. Calcd for C30H29NO7S: C, 65.80; H,
5.34. Found: C, 65.76; H, 5.44. MALDI-TOF calcd for C30H29NO7S: [M þ Na]þ
570.2. Found: [M þ Na]þ 570.2.
Ethyl-3-O-allyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-1-thio-b-D-
glucopyranoside (8). A solution of 130 (3.00 g, 6.80 mmol) and allylbromide
(1.20 mL, 13.60 mmol) in DMF (25 mL) was added dropwise to NaH (544 mg,

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
313
13.60 mmol, 60% dispersion in oil) at 08C and stirred for 2 hr. Ac2O (5 mL)
was added and the mixture was stirred for an additional 2 hr, quenched
with MeOH, and diluted with toluene. The organic phase was washed with
water, dried, filtered, and concentrated. FC (toluene/EtOAc 8:1) gave 8
(2.81 g, 5.84 mmol, 86%) as a white solid. Rf 0.63 (toluene/EtOAc 4:1); IR
nmax cm21 3083, 3068, 3055, 3035, 3007, 2978, 2964, 2938, 2924, 2871,
2853, 1774, 1717, 1610, 1468, 1455, 1392, 1293, 1258, 1106, 1060, 1012,
1
982, 961, 917, 877, 770, 722, 701, 647, 541, 531; H spectrum was identical
to that previously published.[33] 13C NMR
d 14.8 (CH3CH2), 24.0
(CH3CH2), 54.8 (C-2), 68.6 (C-6), 70.5 (C-5), 73.2 (CHCH2O), 76.0 (C-3),
81.9 (C-1), 82.6 (C-4), 101.2 (PhCH), 117.0 (CH255CH), 123.2 (Ph), 123.7
(Ph) 126.0 (Ph), 128.2 (Ph), 128.9 (Ph), 131.5 (Ph), 131.6 (Ph), 134.2 (Ph),
134.3 (Ph), 137.2 (CH255CH), 167.4 (PhCON), 168.2 (PhCON); MALDI-
TOF calcd far C26H27NO6S: [M þ Na]þ 504.2. Found: [M þ Na]þ 504.2.
Ethyl-3-O-allyl-6-O-benzoyl-2-deoxy-2-phthalimido-1-thio-b-D-glucopyr-
anoside (9). Compound 9 (1.68 g, 4.73 mmol, 84%) was synthesized according
to the method of 6, using 8 (2.00 g, 4.02 mmol), ethylene glycol (4.0 mL),
CH2Cl2/TFA (5:1, 30 mL), benzoyl chloride (0.65 mL, 5.63 mmol), and
pyridine (12 mL). FC (toluene/EtOAc 10:1 ! 4:1) gave 9 as a white solid. Rf
0.29 (toluene/EtOAc 4:1) [a]D þ 2 (c 2.0, CHCl3); IR nmax cm21 3063, 2963,
2927, 2871, 1776, 1714, 1601, 1468, 1452, 1388, 1315, 1275, 1197, 1177, 1070,
1
1026, 873, 718, 650, 530; H NMR d 1.18 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 2.54–
2.75 (m, 2H, CH3CH2), 3.64 (dd, 1H, J ¼ 8.4, 9.9 Hz, H-4), 3.78 (ddd, 1H,
J ¼ 2.1, 4.5, 9.9 Hz, H-5), 3.98 (dddd, 1H, J ¼ 1.5, 1.5, 6.0, 12.6 Hz, CHCH2O),
4.16–4.25 (m, 3H, H-2,3, CHCH2O), 4.60 (dd, 1H, J ¼ 2.1, 12.0 Hz, H-6a),
4.73 (dd, 1H, J ¼ 4.5, 12.0 Hz, H-6b), 4.85–5.07 (m, 2H, CH255CH), 5.35
(d, 1H, J ¼ 9.9 Hz, H-1), 5.54–5.67 (m, 1H, CH2 ¼ CH), 7.43–8.08 (m, 9H,
Ph); 13C NMR d 14.9 (CH3CH2), 24.0 (CH3CH2), 54.6 (C-2), 63.8 (C-6), 71.3
(C-4), 73.5 (CHCH2O), 78.2 (C-5), 79.9 (C-3), 81.3 (C-1), 117.3 (CH255CH),
123.2 (Ph), 123.7 (Ph), 128.3 (Ph), 129.8 (Ph), 131.5 (Ph), 133.2 (Ph), 134.2
(Ph and CH255CH), 134.3 (Ph), 167.1 (PhCOO), 167.5 (PhCON), 168.4
(PhCON); Anal. Calcd for C26H27NO7S: C, 62.76; H, 5.47. Found: C, 62.55; H,
5.35. MALDI-TOF calcd for C26H27NO7S: [M þ Na]þ 520.1. Found: [M þ Na]þ
520.1.
Ethyl-3-O-allyl-6-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-glucopyr-
anoside (10). Compound 10 (1.56 g, 3.24 mmol, 82%) was synthesized follow-
ing the same procedure as for 4, using 8 (1.90 g, 3.95 mmol), NaCNBH3
˚
(2.48 g, 39.5 mmol), 3 A molecular sieves, and HCl/Et2O in dry THF (25 mL)
at 08C. FC (toluene/EtOAc 6:1 ! 1:1) gave 10 as a colorless syrup. Rf 0.30
(toluene/EtOAc 4:1); IR nmax cm21 3086, 3064, 3028, 2926, 2870, 1775, 1716,
1612, 1468, 1453, 1389, 1292, 1266, 1197, 1088, 968, 874, 721, 699, 651, 531;

M. Hederos and P. Konradsson
314
1H spectrum was identical to that previously published.[33] 13C NMR d 14.8
(CH3CH2), 23.9 (CH3CH2), 54.5 (C-2), 70.1 (C-6), 72.4 (C-4), 73.2 (OCH2CH),
73.6 (CH2Ph), 78.7 (C-5), 79.9 (C-3), 81.0 (C-1), 117.0 (CH255CH), 123.1 (Ph),
123.6 (Ph), 127.6 (Ph), 128.3 (Ph), 131.4 (Ph), 131.5 (Ph), 134.1 (Ph), 134.3
(Ph), 137.7 (CH255CH), 167.6 (PhCON), 168.4 (PhCON). MALDI-TOF calcd
for C26H29NO6S: [M þ Na]þ 506.2. Found: [M þ Na]þ 506.2.
Ethyl-3,6-di-O-benzoyl-2-deoxy-2-phthalimido-1-thio-b-D-galactopyr-
anoside (11). 11: Rf 0.44 (toluene/EtOAc 4:1); IR nmax cm21 3089, 3032, 2971,
2960, 2922, 2910, 1765, 1720, 1600, 1467, 1452, 1390, 1344, 1316, 1265, 1157,
1
1114, 1071, 1025, 989, 924, 721, 709, 623, 531; H spectrum was identical to
that previously published.[12] 13C NMR d 14.9 (CH3CH2), 24.2 (CH3CH2),
50.0 (C-2), 63.3 (C-6), 66.8 (C-4), 71.8 (C-3), 76.1 (C-5), 81.3 (C-1), 123.4
(Ph), 123.5 (Ph), 125.2 (Ph), 128.1–129.7 (Ph), 131.1 (Ph), 131.5 (Ph), 133.1
(Ph), 133.3 (Ph), 134.1 (Ph), 135.0 (Ph), 135.1 (Ph), 137.7 (Ph), 165.3
(PhCOO), 166.4 (PhCOO), 167.5 (PhCON), 168.1 (PhCON). MALDI-TOF
calcd for C30H27NO8S: [M þ Na]þ 584.1. Found: [M þ Na]þ 584.1.
Ethyl-3-O-benzoyl-6-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-galac-
topyranoside (12). 12: Rf 0.49 (toluene/EtOAc 4:1) [a]D þ 82 (c 1.1, CHCl3);
IR nmax cm21 3087, 3062, 3030, 2961, 2927, 2869, 1774, 1716, 1601, 1496,
1468, 1452, 1386, 1315, 1269, 1152, 1111, 1070, 1026, 993, 876, 714, 699, 625,
530; 1H NMR d 1.24 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 2.64–2.85 (m, 2H,
CH3CH2), 3.82 (dd, 1H, J ¼ 5.1, 10.2 Hz, H-6a), 3.87 (dd, 1H, J ¼ 5.1,
10.2 Hz, H-6b), 3.99 (ddd, 1H, J ¼ 0.9, 5.1, 5.1 Hz, H-5), 4.45 (dd, 1H, J ¼ 0.9,
3.0 Hz, H-4), 4.59 (d, 1H, J ¼ 12.0 Hz, CH2Ph), 4.63 (d, 1H, J ¼ 12.0 Hz,
CH2Ph), 4.95 (dd, 1H, J ¼ 10.5, 10.5 Hz, H-2), 5.52 (d, 1H, J ¼ 10.5 Hz, H-1),
5.88 (dd, 1H, J ¼ 3.0, 10.5 Hz, H-3), 7.16–8.18 (m, 14H, Ph); 13C NMR d 14.8
(CH3CH2 23.7 (CH3CH2), 49.8 (C-2), 67.4 (C-4), 69.5 (C-6), 72.0 (C-3), 73.4
(CH2Ph), 76.8 (C-5), 80.9 (C-1), 123.2 (Ph), 123.3 (Ph), 127.5–130.2 (Ph),
131.0 (Ph), 131.3 (Ph), 133.0 (Ph), 133.9 (Ph), 134.0 (Ph), 134.4 (Ph), 137.5
(Ph), 165.2 (PhCOO), 167.4 (PhCON), 168.0 (PhCON); Anal. Calcd for
C30H29NO7S: C, 65.80; H, 5.34. Found: C, 65.87; H, 5.46. MALDI-TOF calcd
for C30H29NO7S: [M þ Na]þ 570.2. Found: [M þ Na]þ 570.2.
Ethyl-6-O-benzoyl-3-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-galac-
topyranoside (13). 13: Rf 0.33 (toluene/EtOAc 4:1) [a]D þ 80 (c 1.0, CHCl3);
IR nmax cm21 3087, 3062, 3030, 2963, 2927, 2871, 1772, 1713, 1602, 1496,
1468, 1452, 1388, 1315, 1278, 1154, 1117, 1067, 1027, 899, 751, 718, 701, 631,
530; 1H NMR d 1.17 (t, 3H, J ¼ 7.6 Hz, CH3CH2), 2.54–2.76 (m, 2H,
CH3CH2), 4.00 (ddd, 1H, J ¼ 0.9, 5.4, 5.4 Hz, H-5), 4.18 (dd, 1H, J ¼ 0.9,
3.3 Hz, H-4), 4.34 (dd, 1H, J ¼ 3.3, 10.4 Hz, H-3), 4.38 (dd, 1H, J ¼ 10.4,
10.4 Hz, H-2), 4.53–4.70 (m, 4H, H-6ab, CH2Ph), 5.27 (d, 1H, J ¼ 10.4 Hz,

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
315
H-1), 6.96–8.08 (m, 14H, Ph); 13C NMR d 14.9 (CH3CH2), 24.0 (CH3CH2), 50.9
(C-2), 63.8 (C-6), 65.7 (C-4), 71.4 (CH2Ph), 75.5 (C-5), 76.0 (C-3), 81.2 (C-1),
123.2 (Ph), 123.5 (Ph), 127.8–129.9 (Ph), 131.5 (Ph), 133.1 (Ph), 133.8 (Ph),
133.9 (Ph), 137.0 (Ph), 166.3 (PhCOO), 167.6 (PhCON), 168.1 (PhCON);
Anal. Calcd for C30H29NO7S: C, 65.80; H, 5.34. Found: C, 65.66; H, 5.61.
MALDI-TOF calcd for C30H29NO7S: [M þ Na]þ 570.2. Found: [M þ Na]þ 570.2.
Ethyl-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-galactopyrano-
side (14). 14: Rf 0.33 (toluene/EtOAc 4:1) [a]D þ 62 (c 1.0, CHCl3); m.p. 1178C
(from EtOH); IR nmax cm21 3085, 3063, 3028, 2971, 2917, 2869, 1771, 1709,
1616, 1495, 1453, 1387, 1366, 1264, 1201, 1154, 1088, 1063, 993, 895, 875,
1
832, 749, 720, 700, 630, 529; H NMR d 1.17 (t, 3H, J ¼ 7.4 Hz, CH3CH2),
2.55–2.77 (m, 2H, CH3CH2), 3.76–3.86 (m, 3H, H-5,6ab), 4.21 (d, 1H, J ¼
3.3 Hz, H-4), 4.27 (dd, 1H, J ¼ 3.3, 10.4 Hz, H-3), 4.31 (dd, 1H, J ¼ 10.4,
10.4 Hz, H-2), 4.54 (d, 1H, J ¼ 10.7 Hz, CH2Ph), 4.59–4.65 (m, 3H, CH2Ph),
5.23 (d, 1H, J ¼ 10.4 Hz, H-1), 6.92–7.86 (m, 14H, Ph); 13C NMR d 14.8
(CH3CH2), 23.6 (CH3CH2), 50.9 (C-2), 65.7 (C-4), 69.1 (C-6), 71.1 (CH2Ph),
73.6 (CH2Ph), 75.6 (C-3), 77.1 (C-5), 81.0 (C-1), 123.1 (Ph), 123.4 (Ph), 127.6–
128.3 (Ph), 131.5 (Ph), 131.6 (Ph), 133.7 (Ph), 133.9 (Ph), 137.1 (Ph), 137.9
(Ph), 167.6 (PhCON), 168.1 (PhCON); Anal. Calcd for C30H31NO6S: C, 67.52;
H, 5.86. Found: C, 67.31; H, 5.74. MALDI-TOF calcd for C30H31NO6S:
[M þ Na]þ 556.2. Found: [M þ Na]þ 556.2.
Ethyl-3-O-allyl-6-O-benzoyl-2-deoxy-2-phthalimido-1-thio-b-D-galacto-
pyranoside (15). 15: Rf 0.27 (toluene/EtOAc 4:1); [a]D þ 51 (c 0.7, CHCl3); IR
nmax cm21 3063, 2965, 2927, 2871, 1773, 1712, 1602, 1468, 1451, 1388, 1315,
1
1277, 1194, 1175, 1118, 1087, 1068, 1027, 990, 774, 715, 621, 530; H NMR
d 1.18 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 2.57–2.77 (m, 2H, CH3CH2), 3.89 (dddd,
1H, J ¼ 1.5, 1.5, 6.0, 12.9 Hz, CHCH2O), 4.00–4.11 (m, 2H, H-5, CHCH2O),
4.19 (d, 1H, J ¼ 3.3 Hz, H-4), 4.31 (dd, 1H, J ¼ 3.3, 10.4 Hz, H-3), 4.58 (dd,
1H, J ¼ 10.4, 10.4 Hz, H-2), 4.61 (dd, 1H, J ¼ 6.1, 11.5 Hz, H-6a), 4.69 (dd,
1H, J ¼ 5.2, 11.5 Hz, H-6b), 4.96–5.14 (m, 2H, CH2 ¼ CH), 5.30 (d, 1H,
J ¼ 10.4 Hz, H-1), 5.57–5.70 (m, 1H, CH2 ¼ CH), 7.14–8.08 (m, 9H, Ph); 13C
NMR d 14.9 (CH3CH2), 24.1 (CH3CH2), 51.0 (C-2), 63.9 (C-6), 66.0 (C-4), 70.5
(CHCH2O), 75.7 (C-3), 76.1 (C-5), 81.3 (C-1), 118.1 (CH255CH), 123.2 (Ph),
123.7 (Ph), 128.3 (Ph), 129.7 (Ph) 129.9 (Ph), 131.6 (Ph), 131.7 (Ph), 133.1
(Ph), 133.6 (CH ¼ CH2), 134.1 (Ph), 166.4 (PhCOO), 167.6 (PhCON), 168.6
(PhCON); Anal. Calcd for C26H27NO7S: C, 62.76; H, 5.47. Found: C, 62.51; H,
5.32. MALDI-TOF calcd for C26H27NO7S: [M þ Na]þ 520.1. Found: [M þ Na]þ
520.1.
Ethyl-3-O-allyl-6-O-benzyl-2-deoxy-2-phtalimido-1-thio-b-D-galacto-
pyranoside (16). 16: Rf 0.31 (toluene/EtOAc 4:1); IR nmax cm21 3074, 3062,

M. Hederos and P. Konradsson
316
3049, 2956, 2926, 2869, 1773, 1712, 1613, 1468, 1453, 1387, 1265, 1146, 1097,
1061, 991, 924, 721, 700, 621, 530; 1H spectrum was identical to that previously
published.[33] 13C NMR d 14.8 (CH3CH2), 23.7 (CH3CH2), 51.0 (C-2), 65.9 (C-4),
69.2 (C-6), 70.3 (CHCH2O), 73.6 (CH2Ph), 75.8 (C-3), 77.2 (C-5), 81.2 (C-1),
117.9 (CH255CH), 123.1 (Ph), 123.7 (Ph), 127.7–129.0 (Ph), 131.6 (Ph), 131.7
(Ph), 133.8 (CH55CH2), 134.0 (Ph), 134.1 (Ph), 138.0 (Ph), 167.7 (PhCON),
168.6 (PhCON). MALDI-TOF calcd for C26H29NO6S: [M þ Na]þ 506.2. Found:
[M þ Na]þ 506.2.
Ethyl-4,6-di-O-benzoyl-2-deoxy-2-phthalimido-l-thio-b-D-galactopyra-
noside (17). 17: Rf 0.28 (toluene/EtOAc 4:1); [a]D þ50 (c 1.0, CHCl3); IR nmax
cm21 3063, 3033, 2966, 2929, 2872, 1774, 1715, 1602, 1584, 1492, 1469, 1452,
1389, 1316, 1273, 1195, 1177, 1115, 1070, 1051, 1026, 907, 869, 803, 758, 711,
622, 579, 531; 1H NMR d 1.23 (t, 3H, J ¼ 7.5 Hz, CH3CH2), 2.62–2.82 (m,
2H, CH3CH2), 4.28 (dd, 1H, J ¼ 6.0, 7.2 Hz, H-5), 4.40 (dd, 1H, J ¼ 6.0,
11.4 Hz, H-6a), 4.57 (dd, 1H, J ¼ 7.2, 11.4 Hz, H-6b), 4.58 (dd, 1H, J ¼ 10.5,
10.5 Hz, H-2), 4.81 (dd, 1H, J ¼ 3.6, 10.5 Hz, H-3), 5.48 (d, 1H, J ¼ 10.5 Hz,
H-1), 5.77 (d, 1H, J ¼ 3.6 Hz, H-4), 7.39–7.63 (m, 6H, Ph), 7.66–7.72
(m, 2H, Ph), 7.78–7.83 (m, 2H, Ph), 7.99–8.03 (m, 2H, Ph), 8.11–8.16
(m, 2H, Ph); 3C NMR d 15.0 (CH3CH2), 24.5 (CH3CH2), 53.3 (C-2),
62.8 (C-6), 68.6 (C-3), 70.8 (C-4), 75.3 (C-5), 81.9 (C-1), 123.3 (Ph), 123.7
(Ph), 128.3–130.1 (Ph), 131.6 (Ph), 131.7 (Ph), 133.2 (Ph), 133.6 (Ph), 134.1
(Ph), 166.1 77 (PhCOO), 166.7 (PhCOO), 168.0 (PhCON), 168.4 (PhCON);
Anal. Calcd for C30H27NO8S: C, 64.16; H, 4.85. Found: C, 63.97; H, 4.84.
MALDI-TOF calcd for C30H27NO8S: [M þ Na]þ 584.1. Found: [M þ Na]þ
584.1.
Ethyl-4-O-benzoyl-6-O-benzyl-2-deoxy-2-phthalimido-l-thio-b-D-galacto-
pyranoside (18). 18: Rf 0.28 (toluene/EtOAc 4:1); [a]D þ 49 (c 1.0, CHCl3);
IR nmax cm21 3063, 3031, 2966, 2927, 2870, 1772, 1714, 1602, 1584, 1496,
1468, 1452, 1389, 1314, 1272, 1196, 1177, 1110, 1070, 1049, 1026, 907, 869,
794, 718, 700, 668, 623, 578, 531; 1H NMR d 1.23 (t, 3H, J ¼ 7.4 Hz,
CH3CH2), 2.63–2.83 (m, 2H, CH3CH2), 3.60 (dd, 1H, J ¼ 6.7, 9.8 Hz, H-6a),
3.67 (dd, 1H, J ¼ 6.2, 9.8 Hz, H-6b), 4.10 (dd, 1H, J ¼ 6.2, 6.7 Hz, H-5),
4.42 (d, 1H, J ¼ 11.8 Hz, CH2Ph), 4.52 (d, 1H, J ¼ 11.8 Hz, CH2Ph), 4.53
(dd, 1H, J ¼ 10.7, 10.7 Hz, H-2), 4.78 (dd, 1H, J ¼ 3.6, 10.7 Hz, H-3),
5.42 (d, 1H, J ¼ 10.7 Hz, H-1), 5.71 (d, 1H, J ¼ 3.6 Hz, H-4), 7.18–7.27
(m, 5H, Ph), 7.44–7.49 (m, 2H, Ph), 7.57–7.62 (m, 1H, Ph), 7.67–7.71
(m, 2H, Ph), 7.78–7.84 (m, 2H, Ph), 8.0–8.12 (m, 2H, Ph); 13C NMR d 14.9
(CH3CH2), 24.2 (CH3CH2), 53.3 (C-2), 68.3 (C-6), 68.5 (C-3), 71.1 (C-4), 73.5
(CH2Ph), 76.6 (C-5), 81.6 (C-1), 123.2 (Ph), 123.6 (Ph), 127.6–130.0 (Ph),
131.6 (Ph), 131.7 (Ph), 133.4 (Ph), 134.1 (Ph), 137.6 (Ph), 166.8 (PhCOO),
168.1 (PhCON), 168.4 (PhCON); Anal. Calcd for C30H29NO7S: C, 65.80; H,

Routes to Ethyl-2-deoxy-2-phthalimido-1-b-D-thio-galactosamine
317
5.34. Found: C, 65.62; H, 5.28. MALDI-TOF calcd for C30H29NO7S: [M þ Na]þ
570.2. Found: [M þ Na]þ 570.2.
Ethyl-4-O-benzoyl-3-O-benzyl-2-deoxy-2-phthalimido-1-thio-b-D-galacto-
pyranoside (19). 19: Rf 0.18 (toluene/EtOAc 4:1); [a]D þ 109 (c 1.0, CHCl3);
IR nmax cm21, 3063, 3031, 2965, 2929, 2873, 1773, 1714, 1602, 1496, 1468,
1453, 1389, 1273, 1314, 1273, 1177, 1113, 1088, 1068, 1026, 908, 870, 720,
629, 530; 1H NMR d 1.22 (t, 3H, J ¼ 7.4 Hz, CH3CH2), 2.63–2.82 (m, 2H,
CH3CH2), 3.61 (m, 1H, H-6a), 3.82 (m, 1H, H-6b), 3.95 (dd, 1 H, J ¼ 6.9,
6.9 Hz, H-5), 4.33 (d, 1 H, J ¼ 12.4 Hz, CH2Ph), 4.50 (dd, I H, J ¼ 3.3,
10.4 Hz, H-3), 4.71 (t, 1H, J ¼ 10.4 Hz, H-2), 5.37 (d, 1H, J ¼ 10.4 Hz, H-1),
5.79 (d, 1H, J ¼ 3.3 Hz, H-4), 6.91–7.06 (m, 5H, Ph), 7.49–7.86 (m, 7H,
Ph), 8.14–8.16 (m, 2H, Ph); 13C NMR d 14.9 (CH3CH2), 24.0 (CH3CH2),
51.8 (C-2), 61.0 (C-6), 67.2 (C-4), 71.0 (CH2Ph), 74.0 (C-3), 77.9 (C-5), 81.7
(C-1), 123.3 (Ph), 123.6 (Ph), 127.7–130.1 (Ph), 131.7 (2C, Ph), 133.6 (Ph),
133.9 (Ph), 134.0 (Ph), 137.2 (Ph), 167.1 (PhCOO), 167.6 (PhCON), 168.0
(PhCON); Anal. Calcd for C30H29NO7S: C, 65.80; H, 5.34. Found: C, 65.90;
H, 5.39. MALDI-TOF calcd for C30H29NO7S: [M þ Na]þ 570.2. Found:
[M þ Na]þ 570.2.
Ethyl-4-O-benzoyl-3-O-allyl-2-deoxy-2-phthalimido-l-thio-b-D-galacto-
pyranoside (20). 20: Rf 0.17 (toluene/EtOAc 4:1); [a]D þ 108 (c 1.0, CHCl3); IR
nmax cm21 3068, 2972, 2934, 2879, 1769, 1714, 1601, 1468, 1454, 1393, 1350,
1316, 1273, 1194, 1179, 1109, 1089, 1063, 1028, 933, 917, 870, 796, 759, 724,
1
715, 668, 619, 530; H NMR d 1.24 (t, 1H, J ¼ 7.4 Hz, CH3CH2), 2.62–2.84
(m, 2H, CH3CH2), 3.59–3.64 (m, 1H, H-6a), 3.76–3.92 (m, 2H, H-6b,
CHCH2O), 3.95–4.06 (m, 2H, H-5, CHCH2O), 4.55 (dd, 1H, J ¼ 3.0, 10.4 Hz,
H-3), 4.73 (dd, 1H, J ¼ 10.4, 10.4 Hz, H-2), 4.91–5.08 (m, 2H, CH255CH),
5.41 (d, 1H, J ¼ 10.4 Hz, H-1), 5.48–5.61 (m, 1H, CH255CH), 5.74 (d, 1H,
J ¼ 3.0 Hz, H-4), 7.47–8.15 (m, 14H, Ph); 13C NMR d 14.9 (CH3CH2), 24.0
(CH3CH2), 51.8 (C-2), 61.0 (C-6), 67.4 (C-4), 70.2 (CHCH2O), 74.2 (C-3), 77.9
(C-5), 81.8 (C-1), 117.8 (CH255CH), 123.2 (Ph), 123.7 (Ph), 128.6 (Ph), 130.1
(Ph), 131.7 (2C, Ph), 133.6 (Ph), 133.7 (CH55CH2), 134.2 (Ph), 168.5
(PhCOO), 167.6 (PhCON), 168.5 (PhCON); Anal. Calcd for C26H27NO7S: C,
62.76; H, 5.47. Found: C, 62.60; H, 5.41. MALDI-TOF calcd for C26H27NO7S:
[M þ Na]þ 520.1. Found: [M þ Na]þ 520.1.
ACKNOWLEDGMENTS
We would like to thank the Swedish Research Council and the Swedish
Foundation for Strategical Research through the Biomimetic Materials
Science program for financial support.

M. Hederos and P. Konradsson
318
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