Potent, versatile, and stable: Thiazolyl thioglycosides as glycosyl donors

Article abstract of DOI:10.1002/anie.200454047

Donating with a difference: Thiazolyl (Taz) substituted thioglycosides have been successfully used in the synthesis of both 1,2-trans- and 1,2-cis-glycosides and also have found application in convergent oligosaccharide synthesis. In addition, this study

Full text of DOI:10.1002/anie.200454047

Angewandte
Chemie
Carbohydrate Synthesis
Potent, Versatile, and Stable: Thiazolyl
Thioglycosides as Glycosyl Donors**
Alexei V. Demchenko,* Papapida Pornsuriyasak,
Cristina De Meo, and Nelli N. Malysheva
The majority of biologically important carbohydrates exist as
polysaccharides or glycoconjugates in which monosaccharide
[*] Prof. Dr. A. V. Demchenko, P. Pornsuriyasak, Dr. C. De Meo,
Dr. N. N. Malysheva
Department of Chemistry and Biochemistry
University of Missouri–St. Louis
8001 Natural Bridge Road, St. Louis, MS 63121 (USA)
Fax: (+1)314-516-5342
E-mail: demchenkoa@umsl.edu
[**] This work was supported by the University of Missouri Research
Board and “The Foundation BLANCEFLOR Boncompagni-Ludovisi,
nØe Bildt”.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 3069 –3072
DOI: 10.1002/anie.200454047
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Communications
units are joined by O-glycosidic bonds.[1] The importance of
chemical and/or enzymatic synthesis of complex oligosac-
charides has come to the fore because of the low availability
of these compounds from natural sources. As a result, many
glycosyl donors have been developed and employed in
oligosaccharide synthesis.[2,3] Despite enormous progress, no
general glycosylation method for oligosaccharide synthesis in
solution or on a polymer support has yet emerged.[4] Recently,
we became interested in a class of glycosyl donors with the
Scheme 2. Thiazolyl thioglycosides synthesized. a: R2 =R3 =B z (b-d-
Glc), b: R2 =R3 =B z (b-d-Gal), c: R2 =R3 =B z (a-d-Man),
d: R2 =R3 =Ac (b-d-Glc), e: R2 =R3 =B n (b-d-Glc), f: R2 =Bn, R3 =Ac
(b-d-Glc), g: R2 =R3 =Ac (b-d-Gal), h: R2 =R3 =Ac (a-d-Man),
i: R2 =H,R3 =Ac (b-d-Glc).
=
generic leaving group SCR1 NR2 (substituted thioimidoyl
derivatives). We have already reported the synthesis of S-
benzoxazolyl (SBox) glycosides and their evaluation in
stereoselective 1,2-cis and 1,2-trans glycosylations.[5,6] We
demonstrated that the SBox glycosides provide high stereo-
selectivity and remarkably high yields. The lower stability of
the SBox glycosides toward some
Similarly, derivatives of d-galactose (4b,g) and d-mannose
(4c,h) were obtained. These results are summarized in
Table 1.
extreme reaction conditions (triflic
Table 1: Synthesis of thiazolyl thioglycosides 4a-i.
acid (TfOH) or NaH) in compar-
ison to the corresponding S-alkyl/
aryl glycosides prompted us to con-
tinue the search for suitable leaving
groups of this class. Here, we
describe the synthesis of novel gly-
cosyl donors, the thiazolyl (Taz)
thioglycosides, their application in
stereoselective glycosylations, and
an evaluation of their usefulness in
convergent oligosaccharide synthe-
sis.
Precursor
Conditions[a]
Products
Yield [%]
1a
1a
1a
1a
1b
1c
1d
1e
1 f
2a
2b
2c
3
HSTaz, NaH, MeCN, RT
4a, 5a, 6a
4a, 5a, 6a
4a, 5a, 6a
4a, 5a, 6a
4b, 5b, 6b
4c, 5c, 6a
4d, 5d, 6d
4e, 5e, 6e
4 f, 5 f, 6 f
4d, 5d, 6d
4g, 5g, 6g
4h, 5h, 6d
4I, 5I, 6i
49, 0, 41
50, 0, 41
41, 0, 39
60, 0, 20
90, 0, 0
NaSTaz, [15]crown-5, MeCN, RT
KSTaz, [18]crown-6, MeCN, RT
NaSTaz, [15]crown-5, acetone, RT
KSTaz, [18]crown-6, MeCN, RT
KSTaz, [18]crown-6, MeCN, RT
NaSTaz, [15]crown-5, MeCN, RT
NaSTaz, [15]crown-5, acetone, RT
NaSTaz, [15]crown-5, MeCN, RT
HSTaz, BF3·Et2O, 3-Š MS, CH2Cl2, 458C
HSTaz, BF3·Et2O, 3-Š MS, CH2Cl2, 458C
HSTaz, BF3·Et2O, 3-Š MS, CH2Cl2, 458C
HSTaz, ZnCl2, CH2Cl2, RT
70, 0, 0
53, 11, 13
55, 38, 0
46, 28, 21
91, 0, 0
85, 0, 0
70, 0, 0
We reasoned that various syn-
thetic precursors, such as anomeric
78, 0, 0
halides (1a–f, Scheme 1), acetates [a] MS=molecular sieves.
(2a–c), or 1,2-anhydrosugars (3)
Having synthesized a number of thiazolyl thioglycosides
(4a–i), our attention turned to an evaluation of their stability
toward hydrolysis in the presence of acidic thiophilic reagents
(N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS)/
TfOH), common conditions for the thioglycoside hydroly-
sis.[7,8] For these studies per-benzylated 4e was compared
with ethyl per-O-benzyl-1-thio-b-d-glycopyranoside (7,
Scheme 3)[9] and its 1-S-phenyl counterpart, 8.[10] Thus, 4e, 7,
Scheme 1. Precursors for the synthesis of thiazolyl thioglycosides. 1a–
c and 2a–c are derivatives of d-glucose, d-galactose, and d-mannose,
as indicated. Bn=benzyl, Bz=benzoyl.
could serve as suitable precursors for the synthesis of thiazolyl
thioglycosides (4a–i, Scheme 2). 2-Thiazoline-2-thiol (HSTaz)
is an odorless solid, readily available from a variety of
commercial sources; as a matter of fact, it is even cheaper
than commonly used thiophenol. However, the ambiguous
reactivity of HSTaz could lead to the formation of the N-
linked product (5a–i). Also, the relatively high basicity of
HSTaz (pKa = 13.01) and its conjugate base would promote
undesired b elimination, which would result in glycal (1,2-
dehydro derivative) formation (6a,b,d–g,i).
Scheme 3. Stability of STaz versus SEt/SPh toward acidic hydrolysis.
Conditions: a) NIS/TfOH, aqueous dichloromethane (RT, 1 h); b) NBS,
aqueous acetone (RT, 1 h).
or 8 was treated under standardized conditions to afford
hemiacetal 9. We were thrilled to find that 4e appears to be
much more stable than either 7 or 8. For example, treatment
of 4e with NIS/TfOH in aqueous CH2Cl2 (conditions a)
resulted in trace amounts of 9 (< 5%) in 1 h, while hydrolysis
of either 7 or 8 was complete in less than 5 min.
In many cases the side reactions could be significantly
suppressed by varying the reaction conditions. To our delight,
conversion of 2 or 3 allowed formation of the desired S-linked
derivatives with complete stereoselectivity and in high yields.
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Table 2: Synthesis of 1,2-trans-linked disaccharides 16–25.
Also, the thiazolylthio moiety was found to be stable
toward common protective-group manipulations involving
strong bases. For example, conversion of 4d into 4e by
sequential deacetylation (NaOMe/MeOH) and benzylation
(BnBr/NaOH in N,N-dimethylformamide) proceeded in high
overall yield (83%).
Having established the relative stability of the STaz
glycosides, we turned our attention to an investigation of
their glycosyl donor properties. It should be noted that,
although 4d[11] and a number of thiazolyl thiofuranosides[12]
have been reported, to the best of our knowledge this class of
compounds has never been glycosidated. We discovered that
the STaz glycosides could be activated under a range of
reaction conditions, for example, with MeOTf, a common
activator for the glycosidation of thioglycosides, as well as
AgOTf or Cu(OTf)2. It should be highlighted that virtually no
reaction takes place in the presence of NIS/catalytic TfOH,
whereas the reaction is smoothly driven to completion in the
presence of stoichiometric amounts of TfOH.
Donor
Acceptor
Promoter
Time
Product
Yield [%]
4a
4a
4a
4a
4a
4a
4b
4b
4c
4c
10
11
12
13
14
15
12
15
12
15
AgOTf
16 h
20 h
16 h
2 h
16
17
18
19
20
21
22
23
24
25
91
99
93
90
82
99
92
84
85
87
MeOTf
NIS/TfOH
AgOTf
MeOTf
Cu(OTf)2
AgOTf
AgOTf
AgOTf
AgOTf
1 h
4 days
40 min
30 min
6 days
6 days
Table 3: AgOTf-promoted synthesis of 1,2-cis-linked disaccharides 26–
36.
Donor
Acceptor
Solvent[a]
Product
Yield [%]
a/b ratio
4e
4e
4e
4e
4e
4e
4e
4e
4 f
4 f
4 f
4 f
4 f
10
10
11
11
12
13
14
15
10
11
12
13
15
DCE
T/D
DCE
T/D
T/D
T/D
T/D
T/D
DCE
DCE
DCE
DCE
DCE
26
26
27
27
28
29
30
31
32
33
34
35
36
96
85
88
97
95
82
76
85
78
88
89
74
70
2.9/1
7.7/1
1.5/1
4.5/1
3.5/1
4.1/1
4.0/1
2.7/1
1.5/1
9.3/1
>19/1
4.8/1
2.7/1
Per-benzoyl derivatives of glucose, galactose, and man-
nose (4a–c) were chosen to perform test reactions for the
synthesis of 1,2-trans-linked disaccharides. Differently pro-
tected glycosyl acceptors 10–15[13–17] were selected for this
purpose (Scheme 4). Disaccharides 16–25 were obtained in
[a] T/D=toluene/dioxane, 1/1 (v/v).
acetylated glycosyl donors or a toluene/dioxane participating
solvent mixture[19] in the presence of Cu(OTf)2 or AgOTf was
found to be especially beneficial.
Additionally, we decided to evaluate the applicability of
the STaz method to chemoselective glycosylation strategies
for convergent oligosaccharide synthesis. We assumed that
STaz glycosides could be activated over O-pentenyl glyco-
sides (with MeOTf, AgOTf, or Cu(OTf)2) or thioglycosides
(with AgOTf or Cu(OTf)2), as found for SBox glycosides.[5,6]
Conversely, it should be possible to activate other glycosyl
donors over STaz glycosides, for example, bromides (with
Koenigs–Knorr or Helferich conditions), trichloroacetimi-
dates (with trimethylsilyl triflate), and even “stable” glycosyl
donors such as S-alkyl/phenyl or O-pentenyl glycosides (with
NIS/cat. TfOH).[2,3] To prove this hypothesis we synthesized
trisaccharide 39 through two conceptually different
approaches: activation of the STaz moiety in 4e over the
SEt moiety in 37a[20] with AgOTf and activation of the SEt
moiety in 7 over the STaz group in 37b with NIS/cat. TfOH
(Scheme 5). The obtained disaccharides 38a and 38b were
coupled with 15 to provide 39, which was isolated in 83 and
69% overall yields over the two-step activation sequence
STaz–SEt–OMe and SEt–STaz–OMe, respectively.
Scheme 4. Glycosyl acceptors 10–15 and disaccharides 16–36 formed
by use of thiazolyl thioglycosides.
the presence of each promoter; representative reactions are
highlighted in Table 2. Complete stereoselectively was ach-
ieved reliably with the assistance of a participating substituent
at the C-2 position.[18]
We also chose to demonstrate that 1,2-cis-glycosides could
be obtained with the use of the STaz glycosides bearing a
nonparticipating substituent at the C-2 position, for example,
4e or 4 f. Although stereoselectivity is average in 1,2-
dichloroethane (DCE), similar to that with the S-alkyl/aryl
glycosides, it is apparent that these results can be significantly
improved by varying common factors that influence the
stereoselectivity at the anomeric center.[4] Some of these
studies are outlined in Table 3. Thus, the use of partially
Based on the presented results, we conclude that the STaz
glycosides can be successfully applied to the synthesis of both
1,2-trans- and 1,2-cis-glycosides. In addition, a fully orthog-
onal character of thiazolylthio and ethylthio moieties has
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CH2Cl2. The combined filtrate (30 mL) was subjected to
aqueous work-up and column chromatography.
All synthesized compounds have adequate 1H and
13C NMR spectroscopy data and high-resolution MS data
(see the Supporting Information).
Received: February 18, 2004 [Z54047]
Keywords: carbohydrates · chemoselectivity ·
.
Scheme 5. Selective activation of STaz over SEt and vice versa. Tf=trifluoromethanesulfonyl.
glycosides · glycosylation
been discovered. These derivatives fulfill major requirements
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toward protecting group manipulations, mild activation con-
ditions, orthogonality toward other glycosyl donors, and good
stereoselectivity. Many other synthetic strategies can be
developed with these unique glycosyl donors, further evalua-
tion of which is underway in our laboratory.
[6] A. V. Demchenko, M. N. Kamat, C. De Meo, Synlett 2003, 1287 –
1290.
[7] M. S. Motawia, J. Marcussen, B. L. Moeller, J. Carbohydr. Chem.
1995, 14, 1279 – 1294.
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[18] A. F. Bochkov, G. E. Zaikov, Chemistry of the O-glycosidic
bond: formation and cleavage, Pergamon, 1979.
[19] A. Demchenko, T. Stauch, G. J. Boons, Synlett 1997, 818 – 820.
[20] P. J. Garegg, I. Kvarnstrom, A. Niklasson, G. Niklasson, S. C. T.
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Experimental Section
Preparation of the STaz glycosides:
Method Afrom glycosyl halides: [15]Crown-5 (or [18]crown-6,
0.6 mmol) and NaSTaz (or KSTaz, 6.0 mmol) were added to a stirred
solution of a glycosyl halide (1a–f, 3.0 mmol) in acetone (or MeCN,
4 mL) under argon. The reaction mixture was stirred for 1 h at RT.
The mixture was then diluted with toluene (30 mL) and washed with
1% aqueous NaOH (15 mL) and water (3 ” 10 mL). The organic
phase was separated, dried, and concentrated. The residue was
purified by column chromatography on silica gel (ethyl acetate/
hexane gradient elution) to afford the STaz glycoside (4a–d).
Method B from glycosyl acetates: Asolution of a glycosyl acetate
(2a–c, 0.128 mmol), HSTaz (0.256 mmol), and activated 3-Š molec-
ular sieves (100 mg) in CH2Cl2 (1.0 mL) was stirred under argon for
30 min at RT. BF3·Et2O (0.256 mmol) was added dropwise and the
reaction mixture was left for 45 min at RT. Additional portions of
HSTaz (0.256 mmol) and BF3·Et2O (0.256 mmol) were added and the
reaction mixture was left for 1 h under reflux conditions (458C).
Upon completion, the STaz glycoside (4d,g, or h) was isolated and
purified as described in Method A.
Method C from Briglꢀs anhydride 3: HSTaz (0.347 mmol) and
ZnCl2 (0.0087 mmol) were added to
a stirred solution of 3
(0.174 mmol) in anhydrous CH2Cl2. The reaction mixture was stirred
for 10 min at RT. Et3N was then added dropwise until a neutral
pH value was reached. The mixture was subjected to aqueous work-
up and column chromatography to afford 4i.
Method D from thioglycosides: The solution of 37a (0.128 mmol)
and 3-Š molecular sieves (70 mg) in CH2Cl2 (2 mL) was stirred under
argon for 1 h. Afreshly prepared solution of Br in CH2Cl2 (1.2 mL,
2
1/165 (v/v)) was then added and the reaction mixture was left for
5 min at RT. The CH2Cl2 was then evaporated off under reduced
pressure at RT. The crude residue was treated with NaSTaz
(0.51 mmol) in dry MeCN (1 mL) under an argon atmosphere for
2 h at RT. The mixture was then diluted with toluene, the solid was
filtered-off, and 37b was isolated and purified as described in
Method A.
Preparation of di- and trisaccharides:
Typical AgOTf-promoted glycosylation procedure: A mixture
the glycosyl donor (0.11 mmol), glycosyl acceptor (0.10 mmol), and 3-
Š molecular sieves (200 mg) in CH2Cl2 (2 mL) was stirred under
argon for 1.5 h. Freshly conditioned AgOTf (0.22 mmol) was added
and the reaction mixture was stirred for 1–2 h at RT, then diluted with
CH2Cl2. The solid was filtered off and the residue was washed with
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