Synthesis, glycosidation, and hydrolytic stability of novel glycosyl thioimidates

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Synthesis, Glycosidation, and Hydrolytic
Stability of Novel Glycosyl Thioimidates
Archana Ramakrishnan a , Papapida Pornsuriyasak a & Alexei V.
Demchenko a
a Department of Chemistry & Biochemistry , University of Missouri ‐
St. Louis , St. Louis, Missouri, USA
Published online: 16 Aug 2006.
To cite this article: Archana Ramakrishnan , Papapida Pornsuriyasak & Alexei V. Demchenko
(2005) Synthesis, Glycosidation, and Hydrolytic Stability of Novel Glycosyl Thioimidates, Journal of
Carbohydrate Chemistry, 24:4-6, 649-663
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Journal of Carbohydrate Chemistry, 24:649–663, 2005
Copyright # Taylor & Francis, Inc.
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500176387
Synthesis, Glycosidation,
and Hydrolytic Stability of
Novel Glycosyl Thioimidates
Archana Ramakrishnan, Papapida Pornsuriyasak, and
Alexei V. Demchenko
Department of Chemistry & Biochemistry, University of Missouri - St. Louis, St. Louis,
Missouri, USA
INTRODUCTION
Despite significant progress in the area of synthetic carbohydrate chemistry,
the necessity to form a glycosidic bond with complete stereoselectivity
remains to be the main reason chemical O-glycosylation is still ranked
among the most challenging problems of modern synthetic chemistry. The
development of new glycosylation techniques persists to be of paramount
importance for the rapidly developing area of glycosciences. Factors affecting
the stereoselectivity of glycosylation include temperature, pressure, structure,
conformation, solvent, promoter, steric hindrance, or leaving group.[1] While
some of these factors influence the stereoselectivity dramatically, the leaving
group is undoubtedly one of the major players in this respect. As a result, a
number of glycosyl donors have been developed,[2] among which glycosyl
halides,[3] trichloroacetimidates,[4] and alkyl/aryl thioglycosides,[5] though
most commonly used, still have significant drawbacks. For example, thioglyco-
sides are inert under other glycosyl donor activation conditions, and therefore
can fit into various orthogonal and (chemo)selective strategies for complex
oligosaccharide assembly.[6] Unfortunately, only modest stereoselectivity is
Received February 15, 2005; accepted May 24, 2005.
Address correspondence to Alexei V. Demchenko, Department of Chemistry &
Biochemistry, University of Missouri - St. Louis, One University Boulevard, St. Louis,
Missouri 63121-4499, USA. E-mail: demchenkoa@umsl.edu
649

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
650
typically achieved with these stable compounds.[1] Conversely, being rather
unstable glycosyl donors, trichloroacetimidates or halides (especially
iodides)[7] often demonstrate complete stereoselectively in glycosylations.[1]
Unfortunately, these compounds are not sufficiently stable to be used in
block oligosaccharide synthesis via convergent pathways.[6]
Our work on the development of glycosylation methods has resulted in the
discovery of novel glycosyl donors with a generic thioimidoyl leaving group
(SCR1 ¼ NR2, 1, Fig. 1). We have already reported that S-benzoxazolyl (2,
SBox)[8,9] and, especially, S-thiazolinyl (3, STaz)[10] moieties are sufficiently
stable to be used at the anomeric center; also, they can be mildly activated
under a variety of reaction conditions for glycosylation. The high stability
along with accessibility and excellent stereoselectivity make these derivatives
attractive and very promising targets for future studies. Conversely, a fairly
low stability was reported for a number of previously studied thioimidates,
which was the major reason benzothiazolyl,[11] pyridin-2-yl,[12,13] pyrimidin-
2-yl,[12,14] imidazolin-2-yl,[12] and 10-phenyl-1H-tetrazolyl[15] glycosides could
not be applied as building blocks in convergent oligosaccharide syntheses.
We wanted to clarify this disagreement and here we report our studies on
the synthesis, glycosidation, and stability evaluation of a range of cyclic
glycosyl thioimidates structurally related to thioimidates 2 and 3.
RESULTS AND DISCUSSION
The major motivation for these systematic studies was the discovery and
appreciation of the unique properties of the thioimidoyl glycosides. The SBox
and STaz glycosyl donors have several useful features. First, these compounds
can be efficiently synthesized from inexpensive odorless aglycones.[9,10] While
this is a convenient feature for laboratory preparation, it becomes increasingly
important for industrial applications. Second, glycosidation of 2 and 3 allowed
very high stereoselectivity and excellent yields (often over 90%) of glycosida-
tions.[9,10] Third, high stability of the SBox and STaz glycosides toward major
protecting group manipulations and other glycosyl donor activation conditions
makes it possible to use these moieties as a temporary protection of the
anomeric center.[10,16] Lastly, it has been demonstrated that glycosyl thio
Figure 1

Novel Glycosyl Thiomidates
651
Figure 2
imidates not only easily fit into existing glycosylation strategies for complex
oligosaccharide synthesis, but also permit conceptually new strategies, such
as temporary deactivation approach.[17]
However, our knowledge of this promising methodology is not yet complete.
In this respect it seemed essential to extend these studies to a range of five- and
six-membered heterocyclic moieties, structurally related to our first targets,
SBox and STaz glycosides. For this purpose we obtained novel per-acylated
S-oxazolinyl (4), S-oxazinyl (5), S-benzothiazolyl (6), and S-thiazinyl (7) deriva-
tives. It should be noted that per-benzylated S-benzothiazolyl glucosides and
peracetylated S-benzothiazolyl furanosides have been previously synthesized
(Fig. 2).[11,18]
Synthesis of Aglycones
A general procedure to introduce the anomeric moiety (aglycone) involved
the use of anomeric acetates or bromides as suitable starting compounds for
these syntheses. In this context, aglycones 8–11 for the synthesis of 2, 6, 4,
and 3, respectively, are readily available from commercial sources, while tetra-
hydro-1,3-oxazine-2-thione (12)[19] and tetrahydro-1,3-thiazine-2-thione (13)[20]
needed to be synthesized (Fig. 3). For this purpose, a common precursor 3-ami-
nopropanol was used as a starting material. The synthesis of 12 was achieved by
the reaction of 3-aminopropanol with CS2 in the presence of triethylamine in
methanol at 08C followed by the treatment with 30% H2O2.[19] Compound 13
Figure 3

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
652
was obtained by refluxing a mixture of 3-aminopropanol and CS2 in 1M aqueous
KOH.[20] Therefore, obtained derivatives 12 and 13 were then purified by
crystallization.
Synthesis of Glycosyl Thioimidates
Having acquired the aglycone derivatives suitable for introduction at the
anomeric center, we turned our attention to the synthesis of acylated
glycosyl thioimidates. These syntheses were accomplished by slightly
modified experimental procedures in comparison to those previously developed
for the synthesis of SBox and STaz glycosides.[8–10] Thus, per-acetylated thioi-
midoyl derivatives 4–7 were obtained from glucose pentaacetate 14 in the
presence of TMSOTf at room temperature; in this context, SBox and STaz gly-
cosides were obtained in the presence of BF3-Et2O at low temperature. The
synthesis of acetylated thioimidates was also accomplished from acetobromo-
glucose 15[21] by the reaction of a potassium salt of 10–13 in acetone or
MeCN at room temperature. Similarly, benzobromoglucose 16[21] was
employed in the syntheses of perbenzoylated thioimidates. It should be noted
that while the sodium salt was previously found to be advantageous in the syn-
thesis of STaz glycosides 3,[10] better results were obtained with the use of pot-
assium salts in this case. The synthesis of benzoylated thioimidates were
accomplished in the presence of 18-crown-6. The use of the crown ether was
not only found to be essential for the efficient conversion, but also very influen-
tial for the synthesis of the desired S- linked derivatives.
While the results obtained for the synthesis of structurally similar benzox-
azolyl (2) and benzothiazolyl (3) derivatives were very comparable (entries 1–3
vs. 4–6, Table 1), other pairs of the structurally similar derivatives provided
very different results. Overall, the introduction of the sulfur-containing hetero-
cyclic moieties at the anomeric center was significantly more simple and high
yielding than that of their oxygen-containing counterparts. Thus, the synth-
eses of thiazolinyl 3a and thiazinyl 7a from pentaacetate 14 were achieved
in high yields of 91% and 84% (entries 10 and 16), respectively, whereas the
syntheses of oxazolinyl 4a and oxazinyl 5a under similar reaction conditions
failed (entries 7 and 13). Along with these observations, notably higher
yields were obtained in the syntheses of sulfur-containing heterocyclic
anomeric moieties from halides 15 or 16.
Thus, for the synthesis of the sulfur-containing five-membered heterocyclic
anomeric moieties: 3a and 3b was obtained in 53% and 50% yield, respectively
(entries 11 and 12), whereas the synthesis of structurally similar oxygen-con-
taining 4a and 4b was achieved in only 34% and 23%, respectively. Similar cor-
relation, but lower yields, was obtained in the syntheses of the sixmembered
heterocyclic leaving groups (5 and 7, entries 13–19).

Table 1: Synthesis of glycosyl thioimidates 2–7.
Entry
SM
Aglycone
Conditions
Product
Yield
Side products
Ref.
1
2
3
14
15
16
8
8
BF3-Et2O, CH2Cl2, 08C ! rt
K2CO3, acetone, 508C
18-c-6, acetone, rt
2a
2a
2b
79%
96%
99%
[9]
[9]
[9]
8, K salt
4
5
6
14
15
16
9
TMSOTf, CH2Cl2, rt
acetone, rt
18-c-6, acetone, rt
6a
6a
6b
85%
99%
88%
9, K salt
9, K salt
7
8
9
14
15
16
10
10, K salt
10, K salt
TMSOTf, CH2Cl2, rt
MeCN, rt
18-c-6, MeCN, rt
4a
4a
4b
0%
34%
23%
18a (80%)
17a (36%), 18a (24%)
17b (49%)
10
11
12
14
15
16
11
BF3-Et2O, CH2Cl2, 08C ! rt
MeCN, rt
15-c-5, MeCN, rt
3a
3a
3b
91%
53%
50%
[10]
[10]
[10]
11, Na salt
11, Na salt
17a (13%), 18b (11%)
17b (41%)
13
14
15
14
15
16
12
12, K salt
12, K salt
TMSOTf, CH2Cl2, rt
MeCN, rt
18-c-6, MeCN, rt
5a
5a
5b
0%
0%
12%
Complex mixture
17a (58%), 18c (27%)
17b (70%)
16
17
18
19
14
15
16
7a
13
TMSOTf, CH2Cl2, rt
MeCN, rt
18-c-6, MeCN, rt
1. MeONa, 2. BzCl/C5H5 N
7a
7a
7b
7b
84%
22%
18%
72 %
13, K salt
13, K salt
—
17a (54%), 18d (18%)
17b (55%)
SM—starting material

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
654
Although the reaction conditions reported here are optimized to favor the
glycosylation at the softer sulfur atom (S-glycosylation), some of these
coupling reactions were significantly compromised by competitive side
processes. Among those, b-elimination resulting in the formation of a 1,2-
dehydro (glycal) derivative 17a, b and/or N-glycosylation resulting in the for-
mation of a corresponding N-linked derivative (18a–d) were found to be the
most common (Sch. 1). Moreover, 17a or 17b was obtained as a major
product in the syntheses of 4a, 4b, 5a, 5b, 7a, and 7b with the isolated
yields ranging from 36% (entry 8) to 70% (entry 15). Although the correspond-
ing per-acetylated N- linked derivatives (18a–d, see Fig. 4) were only obtained
in the attempted synthesis of 4a from 14 (entry 7) as a major product (18a),
they were often detected in the reaction mixtures.
Glycosidation and Hydrolytic Stability Studies
Glycosidation of perbenzoylated thioimidates 4b, 6b, and 7b were studied
under essentially the same reaction conditions as previously investigated for
the glycosidations of SBox (2b) and STaz (3b) glycosides.[8–10] Although novel
derivatives appear to be somewhat less efficient glycosyl donors than either
2b or 3b, these results are in line with many other glycosylation methods.[2]
Thus, while typical yields for the synthesis of 20[22] in glycosylations of 19[23]
with 2a and 3a were in the range of 94% to 97% (Table 2, entries 1–4), the
yields achieved with either 4b, 6b, or 7b were consistently lower (51% to
81%, entries 5–10). The use of per-acetylated glycosyl donors was found to be
impractical due to a competing process of the 2-O-acetyl moiety migration
from a glycosyl donor to the 6-OH of the glycosyl acceptor 19.[24]
Per-acetylated derivatives 2a, 3a, 4a, 6a, and 7a were studied under acid
hydrolysis conditions (synthesis of 21, Fig. 5). Reaction conditions selected for
Scheme 1

Novel Glycosyl Thiomidates
655
Figure 4
this purpose were essentially the same as those previously reported for the
hydrolysis of S-ethyl or S-phenyl glycosides (22[25] or 23,[26] respectively,
Fig. 5). The first procedure involved hydrolysis in the presence of N-iodosucci-
nimide (2 equiv.) and TfOH (0.1–0.2 equiv). in wet CH2Cl2.[27] Under these
reaction conditions 2a, 22, and 23 were rapidly converted into the hemiacetal
21[28]; these reactions required 15, 2, and 20 min, respectively, whereas the
hydrolysis of 3a, 4a, 6a, and 7a was significantly slower and required 16, 2,
16, and 48 hr, respectively.
The second procedure involved hydrolysis in the presence of N-bromosucci-
nimide (2 equiv.) in aqueous acetone.[29] Under these reaction conditions 22
was hydrolyzed in 5 min, 3a, 7a, and 23 were hydrolyzed in 3 to 5 hr, while
2a and 6a were significantly more resistant: their hydrolysis was sluggish
and the reaction was not completed even in 48 hr. These observations clearly
illustrate that S-ethyl or S-phenyl glycosides are significantly more susceptible
under hydrolytic conditions than their thioimidoyl counterparts. In the long
run, this advantageous feature of thioimidates may become an important
factor in their application as building blocks in convergent oligosaccharide
synthesis.
Table 2: Glycosylation of 19 with per-benzoylated glycosyl donors 2–7: synthesis of 20.
Entry
Donor
Promoter
Time
Yield
Ref
1
2
3
4
5
6
7
8
9
2b
2b
3b
3b
4b
4b
6b
6b
7b
7b
AgOTf
MeOTf
AgOTf
MeOTf
AgOTf
MeOTf
AgOTf
MeOTf
AgOTf
MeOTf
5 min
1 hr
16 hr
2 hr
5 min
3.5 hr
16 hr
2 hr
30 min
16 hr
94%
95%
97%
97%
60%
81%
79%
67%
65%
51%
[9]
[9]
[10]
[10]
10

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
656
Figure 5
CONCLUSIONS
We investigated a number of novel thioimidoyl glycosides, which can be
obtained from anomeric acetates and halides. In case of glycosidation of
somewhat more basic oxygen-containing heterocyclic aglycones, the isolated
yields were compromised due to competing side processes, namely b-elimin-
ation and N-glycosylation. The glycosyl donor properties of these derivatives
were studied in comparison to other glycosyl donors of this class, SBox and
STaz glycosides. Hydrolytic stability studies have clearly demonstrated that
the glycosyl thioimidates are more stable compounds overall than their
S-ethyl and S-phenyl counterparts.
EXPERIMENTAL
General Methods
Column chromatography was performed on silica gel 60 (EM Science, 70–230
mesh); reactions were monitored by TLC on Kieselgel 60 F254 (EM Science). The
compounds were detected by examination under UV light and by charring with
10% sulfuric acid in methanol or KMnO4 solution in EtOH. Solvents were
removed under reduced pressure at ,408C. CH2Cl2, (ClCH2)2, andMeCNweredis-
tilled from CaH2 directly prior to application. MeOH was dried by refluxing with
magnesium methoxide, distilled, and stored under argon. Pyridine was dried by
˚
refluxing with CaH2 and then distilled and stored over molecular sieves (3A). Mole-
˚
cular sieves (3A), used for reactions, were crushed and activated in vacuo at 3908C
during 8 hr in the first instance and then for 2 to 3 hr at 3908C directly prior to appli-
cation. AgOTf (Acros) was coevaporated with toluene (3 ꢀ 10 mL) and dried in
vacuo for 2 to 3 hr directly prior to application. Optical rotations were measured
at Jasco P-1020 polarimeter. UV-VIS spectra were recorded at HP 8452A Diode
Array Spectrophotometer. 1H NMR spectra were recorded at 300 MHz, 13C NMR
spectra were recorded at 75 MHz (Bruker Avance). HRMS determinations were
made with the use of JEOL MStation (JMS-700) Mass Spectrometer.
Preparation of thioimidates 4–7. General procedure for the synthesis of
4a, 5a, 6a, and 7a. Method A. A mixture of 1,2,3,4,6-penta-O-acetyl-b-D-gluco-
pyranose (14, 0.128 mmol), a thiol (9, 10, or 13, 0.192 mmol), and activated

Novel Glycosyl Thiomidates
657
˚
molecular sieves 3 A (100 mg) in dry CH2Cl2 (1.0 mL) was stirred under an atmos-
phere of argon for 30 min at rt. TMSOTf (0.192 mmol) was then added dropwise
and the reaction mixture was kept for 45 min at rt. After that, additional
amounts of thiol (0.192 mmol) and TMSOTf (0.192 mmol) were added and the
reaction mixture was kept for 1 hr at reflux (458C). Upon completion, the
mixture was diluted with CH2Cl2, the solid was filtered off, and the residue was
washed with CH2Cl2. The combined filtrate (30 mL) was washed with aq. NaOH
(2 ꢀ 15 mL) and water (3 ꢀ 10 mL), and the organic layer was separated, dried,
and concentrated in vacuo. The residue was purified by crystallization from
CH2Cl2/ether/hexane or by column chromatography on silica gel (ethyl acetate/
toluene elution) to afford a corresponding thioimidate.
General procedure for the synthesis of 4a, 5a, 6a, and 7a. Method B.
KOH (4.2 mmol) was added to a solution of 9, 10, or 13 (4.2 mmol) in a distilled
acetone. The reaction mixture was refluxed at 608C for 3 hr, then concentrated
in vacuo and dried to afford the corresponding potassium salts as white solids,
which were sufficiently pure to be used in subsequent applications. A potass-
ium salt (4.5 mmol) was added to a stirred solution of 2,3,4,6-tetra-O-acetyl-
a-D-glucopyranosyl bromide (15, 3.0 mmol) in dry acetone or MeCN (20 mL).
The reaction mixture was stirred under argon for 1 hr at rt. Upon completion,
the mixture was diluted with toluene (20 mL) and washed with water (10 mL),
1% aq. NaOH (10 mL), and water (3 ꢀ 10 mL), and the organic phase was sep-
arated, dried, and concentrated in vacuo. The residue was purified by silica gel
column chromatography (ethyl acetate/hexane elution) to afford a correspond-
ing thioimidate.
4,5-Dihydrooxazol-2-yl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-glucopyrano-
side (4a) was prepared as white crystals from 15 (Method B) in 34% yield.
Analytical data for 4a: Rf ¼ 0.44 (acetone/toluene, 2/3, v/v); m.p. þ126–
1298C (CH2Cl2/ether/hexane); [a]2D4–3.08 (c ¼ 0.3, CHCl3); UV: lmax ¼ 272 nm;
1H NMR: d 5.37 (d, 1H, J1,2 ¼ 10.4 Hz, H-1), 5.24 (dd, 1H, J3,4 ¼ 9.2 Hz, H-3),
5.15 (dd, 1H, J2,3 ¼ 9.2 Hz, H-2), 5.15 (dd, 1H, J4,5 ¼ 9.9 Hz, H-4), 4.40 (m, 2H,
CH2O), 4.29 (dd, 1H, J5,6a ¼ 4.6 Hz, J6a,6b ¼ 12.5 Hz, H-6a), 4.15 (dd, 1H,
J5,6b ¼ 2.2 Hz, H-6b), 3.92 (dd, 2H, CH2 N), 3.85 (m, 1H, H-5), 2.08, 2.06, 2.05,
2.03 (4s, 12H, 4 ꢀ COCH3) ppm; 13C NMR: d 171.03, 170.44, 169.75 (ꢀ2),
163.04, 83.67, 76.85, 74.24, 74.49, 70.13, 68.29, 62.11, 55.15, 21.12 (ꢀ2), 21.00,
20.95 ppm; HR-FAB MS [M þ Na]þ calcd. for C17H23NNaO10S 456.0940, found
456.0947. 2,3,4,6-Tetra-O-acetyl-1-N-(4,5-dihydro-2-thione-oxazol-3-yl)-
b-D-glucopyrano- sylamine (18a) was isolated as a sole product in the
attempt of the synthesis of 4a from 14 (80%, Method A) and as a side
product in the synthesis of 4a from 15 (24%, Method B). Analytical data for
18a: Rf ¼ 0.41 (ethyl acetate/hexane, 1/1, v/v); [a]2D6 þ 26.88 (c ¼ 1.13,
1
CHCl3); UV: lmax ¼ 300 nm; H NMR: d, 5.82 (d, 1H, J1,2 ¼ 9.4 Hz, H-1), 5.43

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
658
(dd, 1H, J3,4 ¼ 9.4 Hz, H-3), 5.08 (dd, 1H, J4,5 ¼ 9.4 Hz, H-4), 5.07 (dd, 1H,
J2,3 ¼ 9.5 Hz, H-2), 4.44–4.62 (m, 2H, CH2O), 4.28 (dd, 1H, J5,6a ¼ 4.9 Hz,
J6a,6b ¼ 12.5 Hz, H-6a), 4.11 (dd, 1H, J5,6b ¼ 1.8 Hz, H-6b), 3.77–3.99 (m, 3H,
H-5, CH2 N), 2.03, 2.05, 2.06, 2.09 (4s, 12H, 4 ꢀ COCH3) ppm; 13C NMR: d,
189.44, 170.71, 170.54, 169.90, 169.78, 84.17, 74.61, 72.74, 68.78, 68.18,
67.70, 61.91, 43.06, 20.93, 20.86 (ꢀ2), 20.77 ppm.
5,6-Dihydro-4H-1,3-oxazin-2-yl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-gluco-
pyranoside (5a) could not be obtained by either Method A or B. 2,3,4,6-
Tetra-O-acetyl-1-N-(5,6-dihydro-4H-2-thione-1,3-oxazin-3-yl)-b-D-gluco-
pyranosylamine (18c) was isolated as a colorless film in the attempt of the
synthesis of 5a from 15 (27%, Method B). Analytical data for 18c: Rf ¼ 0.50
(acetone/toluene, 1/3, v/v); [a]2D6 þ.25.78 (c ¼ 1.25, CHCl3); UV: lmax ¼ 300 nm;
1H NMR: d, 6.77 (d, 1H, J1,2 ¼ 9.4Hz, H-1), 5.43 (dd, 1H, J3,4 ¼ 9.6 Hz, H-3),
5.14 (dd, 1H, J2,3 ¼ 9.5 Hz, H-2), 5.05 (dd, 1H, J4,5 ¼ 9.6 Hz, H-4), 4.20–4.37
(m, 3H, H-6a, CH2O), 4.12 (dd, 1H, J5,6b ¼ 1.9 Hz, J6a,6b ¼ 12.5 Hz, H-6b), 3.89–
3.94 (m, 1H, H-5), 3.51 (dd, 2H, CH2N), 2.13–2.16 (m, 2H, CCH2C), 2.02, 2.05,
2.07, 2.09 (4s, 12H, 4 ꢀ COCH3) ppm; 13C NMR: d, 188.57, 170.74, 170.65,
169.90, 169.84, 87.34, 74.55, 72.96, 68.47, 68.25, 68.15, 61.95, 40.46, 21.15,
20.97 (ꢀ2), 20.78 (ꢀ2) ppm; HR-FAB MS [M þ Na]þ calcd for C18H25NNaO10S
470.1097, found 470.1090.
Benzothiazol-2-yl
2,3,4,6-tetra-O-acetyl-1-thio-b-D-glucopyranoside
(6a) was prepared as white crystals from 14 (Method A) or 15 (Method B) in
85% or 99% yield, respectively. Analytical data for 6a: Rf ¼ 0.38 (ethyl
acetate – toluene, 3/7, v/v); m.p. þ121–1248C (CH2Cl2/ether/hexane); [a]D25
1
þ34.78 (c ¼ 1.04, CHCl3); UV: lmax ¼ 276 nm; H NMR: d, 7.40–8.00 (m, 4H,
aromatic), 5.59 (d, 1H, J1,2 ¼ 10.2 Hz, H-1), 5.33 (dd, 1H, J3,4 ¼ 9.2 Hz, H-3),
5.25 (dd, 1H, J2,3 ¼ 9.2 Hz, H-2), 5.19 (dd, 1H, J4,5 ¼ 10.0 Hz, H-4), 4.32 (dd,
1H, J5,6a ¼ 4.9 Hz, J6a,6b ¼ 12.5 Hz, H-6a), 4.19 (dd, 1H, J5,6b ¼ 1.9 Hz, H-6b),
3.94 (m, 1H, H-5), 2.05, 2.05, 2.05, 2.03 (4s, 12H, 4 ꢀ COCH3) ppm; 13C
NMR: d 170.98, 170.47, 169.78, 162.28, 153.11, 136.21, 126.79 (ꢀ2), 125.45,
122.76 (ꢀ2), 121.43 (ꢀ2), 84.41, 74.17, 70.10, 68.50, 62.26, 21.09, 20.97 (ꢀ2)
ppm; HR-FAB MS [M þ Na]þ calcd. for C21H23NNaO9S2 520.0712, found
520.0717.
5,6-Dihydro-4H-1,3-thiazin-2-yl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-gluco-
pyranoside (7a) was prepared as white crystals from 14 (Method A) or 15
(Method B) in 84% or 22% yield, respectively. Analytical data for 7a:
Rf ¼ 0.53 (ethyl acetate-toluene, 3/7, v/v); m.p. þ102–1048C (CH2Cl2/ether/
1
hexane); [a]2D4 þ9.28 (c ¼ 1.03, CHCl3); UV: lmax ¼ 274 nm; H NMR: d, 5.55
(d, 1H, J1,2 ¼ 10.5 Hz, H-1), 5.27 (dd, 1H, J3,4 ¼ 9.2 Hz, H-3), 5.08–5.15
(m, 2H, J2,3 ¼ 9.2 Hz, H-2, 4), 4.27 (dd, 1H, J5,6a ¼ 4.3 Hz, J6a,6b ¼ 12.4 Hz,

Novel Glycosyl Thiomidates
659
H-6a), 4.13 (dd, 1H, J5,6b ¼ 2.2 Hz, H-6b), 3.74–3.84 (m, 3H, H-5, CH2 N), 3.08
(m, 2H, CH2S), 2.08, 2.05, 2.02, 2.02 (4s, 12H, 4 ꢀ COCH3) 1.95 (m, 2H,
CCH2C), ppm; 13C NMR: d, 171.04, 170.49, 169.76 (ꢀ2), 152.59, 81.02, 74.50,
69.49, 68.54, 62.27, 48.98, 30.06, 28.16, 20.86, 20.81, 20.72 (ꢀ2), 20.48 ppm;
HR-FAB MS[M þ Na]þ calcd. for C18H25NNaO9S2 486.0868, found 486.0876.
2,3,4,6-Tetra-O-acetyl-1-N-(5,6-dihydro-4H-2-thione-1,3-thiazin-3-yl)-b-
D-glucopyranosylamine (18d) was isolated as a side product in the syn-
thesis of 7a from 15 (18%, Method B). Analytical data for 18d: Rf ¼ 0.42
(ethyl acetate/hexane, 1/1, v/v); [a]2D6 þ40.68 (c ¼ 1.02, CHCl3); UV:
lmax ¼ 296 nm; 1H NMR: d, 7.08 (d, 1H, J1,2 ¼ 9.3 Hz, H-1), 5.41 (dd, 1H,
J3,4 ¼ 9.5 Hz, H-3), 5.16 (dd, 1H, J2,3 ¼ 9.4 Hz, H-2), 5.10 (dd, 1H, H-4), 4.26
(dd, 1H, J5,6a ¼ 4.9 Hz, J6a,6b ¼ 12.5 Hz, H-6a), 4.13 (dd, 1H, J5,6b ¼ 2.1 Hz,
H-6b), 3.87–3.92 (m, 1H, H-5), 3.41–3.66 (m, 2H, CH2 N), 2.92 (dd, 2H, CH2S),
2.16–2.25 (m, 2H, CCH2C), 2.01, 2.04, 2.05, 2.08 (4s, 12H, 4 ꢀ COCH3) ppm;
13C NMR: d, 197.03, 170.73, 170.43, 169.89, 169.81, 87.74, 74.52, 72.91, 68.77,
68.33, 61.99, 44.29, 31.87, 22.71, 20.96, 20.86, 20.76 (ꢀ2) ppm.
General procedure for the synthesis of 4b, 5b, 6b, and 7b. KOH
(4.2 mmol) was added to a solution of 9, 10, 12, or 13 (4.2 mmol) in a distilled
acetone. The reaction mixture was refluxed at 608C for 3 hr, then concentrated
in vacuo and dried to afford the corresponding potassium salts as white solids,
which were sufficiently pure to be used in subsequent applications. A potass-
ium salt (4.5 mmol) and 18-crown-6 (0.45 mmol) were added to a stirred
solution of 2,3,4,6-tetra-O-benzoyl-a-D-glucopyranosyl bromide (16,
3.0 mmol) in dry acetone or MeCN (20 mL). The reaction mixture was stirred
under argon for 1 hr at rt. Upon completion, the mixture was diluted with
toluene (20 mL) and washed with water (10 mL), 1% aq. NaOH (10 mL), and
water (3 ꢀ 10 mL), and the organic phase was separated, dried, and concen-
trated in vacuo. The residue was purified by silica gel column chromatography
(ethyl acetate/toluene elution) to afford a corresponding thioimidate.
4,5-Dihydrooxazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-b-D-glucopyra-
noside (4b) was obtained as white crystals in 23% yield. Analytical data for
4b: Rf ¼ 0.41 (acetone-toluene, 1/4, v/v); m.p. þ82–848C (CH2Cl2/ether/
1
hexane); [a]2D4 þ48.18 (c ¼ 1.0, CHCl3); UV: lmax ¼ 274 nm; H NMR: d, 7.20–
8.00 (m, 20H, aromatic), 5.93 (dd, 1H, J3,4 ¼ 9.2 Hz, H-3), 5.56–5.69 (m, 3H,
H-1, 3, 4), 4.56 (dd, 1H, J5,6a ¼ 2.8 Hz, J6a,6b ¼ 12.3 Hz, H-6a), 4.43 (dd, 1H,
J5,6b ¼ 5.2 Hz, H-6b), 4.13–4.28 (m, 3H, H-5, CH2O), 3.74 (m, 2H, CH2N)
ppm; 13C NMR: d, 166.00, 165.63, 165.13, 165.06, 162.58, 133.43, 133.24,
133.03, 129.91 (ꢀ2), 129.76 (ꢀ4), 129.66 (ꢀ3), 128.97, 128.64 (ꢀ2), 128.37
(ꢀ2), 128.33 (ꢀ2), 128.25, 128.17 (ꢀ2), 125.24, 85.52, 73.96, 70.23, 69.34,
69.19, 62.93, 54.58, 29.64, 21.39 ppm; HR-FAB MS [M þ Na]þ calcd. for
C37H31NNaO10S 704.1566, found 704.1573.

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
660
5,6-Dihydro-4H-1,3-oxazin-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-b-D-glu-
copyranoside (5b) was obtained as a colorless film in 12% yield. Analytical
data for 5b: Rf ¼ 0.40 (acetone-toluene,/9, v/v); [a]2D5 þ25.18 (c ¼ 0.25,
1
CHCl3); UV: lmax ¼ 274 nm; H NMR: d, 7.10–8.00 (m, 20H, aromatic), 5.90
(dd, 1H, J2,3 ¼ 8.7 Hz, H-2), 5.55–5.64 (m, 3H, H-1, 3, 4), 4.54 (dd, 1H,
J5,6a ¼ 2.9 Hz, J6a,6b ¼ 12.2 Hz, H-6a), 4.40 (dd, 1H, J5,6b ¼ 5.3 Hz, H-6b),
4.04–4.21 (m, 3H, H-5, CH2O), 3.33 (m, 2H, CH2N), 1.76 (m, 2H, CCH2C)
ppm; 13C NMR: d, 166.30, 165.91, 165.41, 165.34, 133.72, 133.53, 133.32,
130.22, 130.07 (ꢀ2), 130.05 (ꢀ4), 130.01 (ꢀ3), 129.96, 129.94 (ꢀ2), 129.01
(ꢀ2), 128.93 (ꢀ2), 128.71, 128.66, 128.62 (ꢀ2), 128.54, 87.74, 83.81, 75.05,
70.49 (ꢀ2), 69.94, 63.22, 54.88, 29.93 ppm; HR-FAB MS [M þ Na]þ calcd. for
C37H31NNaO10S 704.1566, found 704.1573.
Benzothiazol-2-yl 2,3,4,6-tetra-O-benzoyl-1-thio-b-D-glucopyranoside
(6b) was obtained as cream crystals in 88% yield. Analytical data for 6b:
Rf ¼ 0.49 (ethyl acetate-hexanes, 2/3, v/v); m.p. þ212–2148C (CH2Cl2/
1
ether/hexane); [a]D25 þ58.68 (c ¼ 1.03, CH2Cl2); UV: lmax ¼ 276 nm; H NMR:
d, 7.20–8.10 (m, 24H, aromatic), 6.08 (dd, 1H, J3,4 ¼ 9.4 Hz, H-3), 5.95
(d, 1H, J1,2 ¼ 10.2 Hz, H-1), 5.71–5.79 (m, 2H, J2,3 ¼ 9.4 Hz, H-2, 4), 4.71 (dd,
1H, J5,6a ¼ 2.1 Hz, J6a,6b ¼ 11.8 Hz, H-6a), 4.42–4.55 (m, 2H, H-5, 6b) ppm;
13C NMR: d, 166.49, 166.11, 165.66, 165.62, 62.57, 153.05, 134.00, 133.95
(ꢀ2), 133.77 (ꢀ2), 133.49 (ꢀ2), 130.38 (ꢀ2), 130.31 (ꢀ2), 130.18 (ꢀ2), 130.02,
129.04 (ꢀ2), 129.02 (ꢀ2), 128.98 (ꢀ3), 128.89 (ꢀ2), 128.79 (ꢀ2), 128.75,
126.67, 125.21, 122.64, 121.36, 84.62, 74.30, 70.81, 69.76, 63.64 ppm; HR-
FAB MS [M þ Na]þ calcd. for C41H31NNaO9S2 768.1338, found 768.1323.
5,6-Dihydro-4H-1,3-thiazin-2-yl 2,3,4,6-tetra -O-benzoyl-1-thio-b-D-glu-
copyranoside (7b) was prepared from 16 in 18% yield. Alternatively it was
prepared from 7a as follows: 0.1 N solution of NaOMe in MeOH was added
dropwise until pH 9 to the solution of 7a (0.4 g, 0.863 mmol) in MeOH
(20 mL). The reaction mixture was kept for 3 hr at rt and then neutralized
(pH 7) by the addition of Dowex (Hþ). The resin was filtered off, washed with
MeOH (5 ꢀ 5 mL), and the combined filtrate (35 mL) was concentrated in
vacuo and dried. The stirring solution of the residual white solid (0.27 g,
0.914 mmol) in pyridine (16 mL) was cooled to 08C and benzoyl chloride
(1.05 mL, 9.146 mmol) was added dropwise. The temperature was allowed to
gradually increase and the reaction mixture was left stirring for 16 h at rt.
Upon completion, the reaction was quenched by slow dropwise addition of
MeOH (5 mL), concentrated in vacuo and then coevaporated with toluene
(3 ꢀ 10 mL). The residue was then diluted with CH2Cl2 (35 mL) and washed
with water (20 mL); the combined filtrate was then washed with NaHCO3
(20 mL), water (20 mL), 1 N aqueous HCl (20 mL), and water (3 ꢀ 20 mL);
and the organic layer was separated, dried, and concentrated in vacuo. The

Novel Glycosyl Thiomidates
661
residue was purified by silica gel column chromatography (ethyl acetate/
toluene) followed by crystallization from CH2Cl2/ether/hexane to afford 7b
as cream crystals in 72% yield. Analytical data for 7b: Rf ¼ 0.49 (acetone-
toluene,1/9, v/v); m.p. þ93–958C (CH2Cl2/ether/hexane); [a]2D5 þ78.68
(c ¼ 1.03, CHCl3); UV: lmax ¼ 276 nm; 1H NMR: d, 7.10–8.00 (m, 20H,
aromatic), 5.93 (dd, 1H, J3,4 ¼ 9.4 Hz, H-3), 5.85 (d, H, J1,2 ¼ 10.4 Hz, H-1),
5.53–5.65 (m, 2H, J2,3 ¼ 9.4 Hz, H-2, 4), 4.56 (dd, 1H, J5,6a ¼ 4.6 Hz,
J6a,6b ¼ 12.2 Hz, H-6a), 4.41 (dd, 1H, J5,6b ¼ 5.6 Hz, H-6b), 4.20 (m, 1H, H-5)
ppm; 13C NMR: d, 166.52, 166.18, 165.62, 152.89, 134.07, 133.95, 133.87,
133.68, 130.64 (ꢀ2), 130.48 (ꢀ3), 130.46 (ꢀ3), 130.37 (ꢀ2), 129.69, 129.45,
129.05 (ꢀ2), 128.94 (ꢀ3), 128.72 (ꢀ4), 81.26, 76.85, 20 74.72, 70.37,
69.99, 63.69, 48.94, 28.07, 20.67 ppm; HR-FAB MS [M þ Na]þ calcd. for
C38H33NNaO9S2 734.1494, found 734.1481.
Synthesis of the disaccharide 20. General AgOTf-promoted glycosyla-
tion procedure. A mixture a glycosyl donor (0.11 mmol), 19 (0.10 mmol), and
˚
freshly activated molecular sieves (3A, 200 mg) in (ClCH2)2 (2 mL) was stirred
under an atmosphere of argon for 1.5 hr. Freshly conditioned AgOTf
(0.22 mmol) was added and the reaction mixture was stirred for 5 min to
16 hr (see Table 2) at rt, then diluted with CH2Cl2; the solid was filtered off
and the residue was washed with CH2Cl2. The combined filtrate (30 mL) was
washed with 20% aq. NaHCO3 (15 mL) and water (3 ꢀ 10 mL), and the
organic phase was separated, dried, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (ethyl acetate-hexane
gradient elution) to afford 20, analytical data for which were essentially the
same as those previously reported.[22]
General MeOTf-promoted glycosylation procedure. A mixture the
glycosyl donor (0.11 mmol), 19 (0.10 mmol), and freshly activated molecular
˚
sieves (3A, 200 mg) in (ClCH2)2 (2 mL) was stirred under an atmosphere of
argon for 1.5 hr. MeOTf (0.22 mmol) was added and the reaction mixture was
stirred for 1 to 16 h (see Table 2) at rt, then diluted with CH2Cl2; the solid
was filtered off and the residue was washed with CH2Cl2. The combined
filtrate (30 mL) was washed with 20% aq. NaHCO3 (15 mL) and water
(3 ꢀ 10 mL), and the organic phase was separated, dried with MgSO4, and con-
centrated in vacuo. The residue was purified by silica gel column chromato-
graphy (ethyl acetate-hexane gradient elution).
Comparative hydrolytic stability studies. Synthesis of 21. General
NIS/TfOH-promoted leaving group hydrolysis. A mixture of 2a, 3a, 4a,
6a, 7a, 22, or 23 (0.10 mmol), N-iodosuccinimide (0.20 mmol), and TfOH
(0.01–0.02 mmol) in CH2Cl2-water (95/5 v/v, 2.5 mL) was stirred for 2 to
48 h. The reaction mixture was then diluted with CH2Cl2 (25 mL) and

A. Ramakrishnan, P. Pornsuriyasak, and A. V. Demchenko
662
washed with 20% aq. NaHSO3 (15 mL), and water (3 ꢀ 10 mL), and the organic
phase was separated, dried, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (ethyl acetate-hexane gradient
elution) to afford 21, analytical data for which was essentially the same as
those previously reported.[28]
General NBS-promoted leaving group hydrolysis. A mixture of 2a, 3a,
4a, 6a, 7a, 22, or 23 (0.10 mmol) and N-bromosuccinimide (0.20 mmol) in
acetone-water (9/1 v/v, 2.5 mL) was stirred for 5 min to 48 hr. The reaction
mixture was then diluted with CH2Cl2 (25 mL) and washed with 20% aq.
NaHCO3 (15 mL) and water (3 ꢀ 10 mL), and the organic phase was separated,
dried, and concentrated in vacuo. The residue was purified by silica gel column
chromatography (ethyl acetate- hexane gradient elution) to afford 21.
ACKNOWLEDGMENTS
The authors thank the University of Missouri - St. Louis for financial support
and NSF for grants to purchase the NMR spectrometer (CHE-9974801) and the
mass spectrometer (CHE-9708640) used in this work. We also thank Dr. R. E.
K. Winter and Mr. J. Kramer for HRMS determinations.
REFERENCES
[1] Demchenko, A.V. Curr. Org. Chem. 2003, 7, 35–79.
[2] (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531; (b) Davis, B.G.J.
Chem. Soc. Perkin Trans. 2000, 1, 2137–2160.
[3] (a) Nitz, M.; Bundle, D.R. Glycoscience: Chemistry and Chemical Biology; Fraser-
Reid, B., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin - Heidelberg - New York,
2001; Vol. 2, 1497–1542; (b) Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977,
34, 243–283.
[4] Schmidt, R.R.; Jung, K.H. Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G.W., Sinay, P., Eds.; Wiley-VCH: Weinheim, New York, 2000; Vol. 1, 5–59.
[5] (a) Garegg, P.J. Adv. Carbohydr. Chem. Biochem. 1997, 52, 179–205;
(b) Oscarson, S. In Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G.W., Sinay, P., Eds.; Wiley-VCH: Weinheim, New York, 2000; Vol. 1, 93–116.
[6] (a) Demchenko, A.V. Lett. Org. Chem. 2005, in press; (b) Boons, G.J. Tetrahedron
1996, 52, 1095–1121.
[7] (a) Gervay, J.; Nguyen, T.N.; Hadd, M.J. Carbohydr. Res. 1997, 300, 119–125;
(b) Gervay, J.; Hadd, M.J. J. Org. Chem. 1997, 62, 6961–6967.
[8] Demchenko, A.V.; Malysheva, N.N.; De Meo, C. Org. Lett. 2003, 5, 455–458.
[9] Demchenko, A.V.; Kamat, M.N.; De Meo, C. Synlett 2003, 1287–1290.
[10] Demchenko, A.V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N.N. Angew. Chem.
Int. Ed. 2004, 43, 3069–3072.
[11] Mukaiyama, T.; Nakatsuka, T.; Shoda, S.I. Chem. Lett. 1979, 487–490.

Novel Glycosyl Thiomidates
663
[12] Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80, c17–c22.
[13] (a) Woodward, R.B.; Logusch, E.; Nambiar, K.P.; Sakan, K.; Ward, D.E.; Au-
Yeung, B.W.; Balaram, P.; Browne, L.J.; Card, P.J.; Chen, C.H. J. Am. Chem. Soc.
1981, 103, 3213–3217; (b) Reddy, G.V.; Kulkarni, V.R.; Mereyala, H.B. Tetrahedron
Lett. 1989, 30, 4283–4286.
[14] Chen, Q.; Kong, F. Carbohydr. Res. 1995, 272, 149–157.
[15] Tsuboyama, K.; Takeda, K.; Torii, K.; Ebihara, M.; Shimizu, J.; Suzuki, A.; Sato, N.;
Furuhata, K.; Ogura, H. Chem. Pharm. Bull. 1990, 38, 636–638.
[16] Pornsuriyasak, P.; Demchenko, A.V. Tetrahedron: Asymmetry 2005, 16, 433–439.
[17] Pornsuriyasak, P.; Gangadharmath, U.B.; Rath, N.P.; Demchenko, A.V. Org. Lett.
2004, 6, 4515–4518.
[18] (a) Ferrieres, V.; Blanchard, S.; Fischer, D.; Plusquellec, D. Bioorg. Med. Chem.
Lett. 2002, 12, 3515–3518; (b) Euzen, R.; Ferrie res, V.; Plusquellec, D. J. Org.
Chem. 2005, 70, 847–855.
[19] Li, G.; Ohtani, T. Heterocycles 1997, 45, 2471–2474.
[20] Owen, T.C. J. Chem. Soc. C 1967, 1373–1376.
[21] Lemieux, R.U. In Methods in Carbohydrate Chemistry; Whistler, R.L.,
Wolform, M.L., Eds.; Academic Press Inc.: New York and London, 1963; Vol. 2,
226–228.
[22] Fukase, K.; Hasuoka, A.; Kinoshita, I.; Aoki, Y.; Kusumoto, S. Tetrahedron 1995,
51, 4923–4932.
[23] Byramova, N.E.; Ovchinnikov, M.V.; Backinowsky, L.V.; Kochetkov, N.K. Carbo-
hydr. Res. 1983, 124, C8–C11.
[24] (a) Betaneli, V.I.; Kryazhevskikh, I.A.; Ott, A.Y.; Kochetkov, N.K. Bioorg. Khim.
1989, 15, 217–230; (b) Tsvetkov, Y.E.; Kitov, P.I.; Backinowsky, L.V.;
Kochetkov, N.K. Bioorg. Khim. 1990, 16, 98–104.
[25] Contour, M.O.; Defaye, J.; Little, M.; Wong, E. Carbohydr. Res. 1989, 193,
283–287.
[26] Ferrier, R.J.; Furneaux, R.H. Methods in Carbohydrate Chemistry; Whistler, R.L.,
BeMiller, J.N., Eds.; Academic Press: New York - London, 1980; Vol. 8, 251–253.
[27] Duynstee, H.I.; de Koning, M.C.; Ovaa, H.; van der Marel, G.A.; van Boom, J.H.
Eur. J. Org. Chem. 1999, 2623–2632.
[28] Mikamo, M. Carbohydr. Res. 1989, 191, 150–153.
[29] Motawia, M.S.; Marcussen, J.; Moeller, B.L. J. Carbohydr. Chem. 1995, 14,
1279–1294.