Direct and stereoselective synthesis of 2-acetamido-2-deoxy-β-D- glycopyranosides by using the phosphite method

Article abstract of DOI:10.1002/anie.200461988

(Chemical Equation Presented) Avoiding the intermediate: The β-selective glycosidation of 2-acetamido-2-deoxyglycosyl diethyl phosphites promoted by bis(trifluoromethanesulfonyl)imide (Tf₂NH) proceeds in a direct manner and does not afford an o

Full text of DOI:10.1002/anie.200461988

Angewandte
Chemie
b-Selective Glycosidation
Direct and Stereoselective Synthesis of
2-Acetamido-2-deoxy-b-d-glycopyranosides by
Using the Phosphite Method**
Ryoichi Arihara, Seiichi Nakamura, and
Shunichi Hashimoto*
2-Acetamido-2-deoxy-d-glycopyranosides occur as common
and important structural units in oligosaccharides and glyco-
conjugates, such as glycolipids, glycoproteins, proteoglycans,
and peptidoglycans, and are associated with a wide range of
biological processes.[1] Whereas 2-acetamido-2-deoxy-a-d-
galactopyranose residues are linked through a glycoside
bond to the side-chain hydroxy groups of serine and
threonine, the majority of 2-acetamido-2-deoxy-d-glycopyr-
anosides are found as b-linked glycosides.
The most general and extensively developed strategy for
the synthesis of 1,2-trans-b-glycosides of 2-amino-2-deoxysu-
gars utilizes donors containing a participating group as the
amino-protecting functionality, which is replaced by an acetyl
group after the glycosidation event.[2,3] 2-Azido-2-deoxygly-
cosyl donors have also been used for this purpose.[4,5] Clearly,
a direct glycosidation method by using donors with the
natural N-acetyl function would constitute an ideal procedure
in terms of efficiency and practicality. In practice, however,
the reaction of these donors, 1, generally leads to the
predominant formation of oxazoline derivatives 3 through
neighboring-group participation and the subsequent abstrac-
tion of a proton from the NH group (Scheme 1).[6,7] Although
oxazolines can react with acceptor alcohols in the presence of
Brønsted or Lewis acids to afford 2-acetamido-2-deoxy-b-
glycosides 4 via oxazolinium ion intermediates 2 or 5 (that is,
oxazoline method[8]), the harsh reaction conditions required
for this conversion have precluded its wide application in the
synthesis of complex oligosaccharides. As part of a program
to extend the recently developed glycosidation method that
capitalizes on diethyl phosphite as a leaving group,[9,10] we
wish to report the stereoselective synthesis of 2-acetamido-2-
deoxy-b-glycosides by a direct glycosidation that does not
proceed via an oxazolinium ion intermediate.
At the outset of this study, we explored the trimethylsilyl
trifluoromethanesulfonate (TMSOTf) promoted glycosida-
tion of 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-a-d-glucopyr-
[*] R. Arihara, Dr. S. Nakamura, Prof. Dr. S. Hashimoto
Graduate School of Pharmaceutical Sciences
Hokkaido University
Sapporo 060–0812 (Japan)
Fax: (+81)11-706-3236
E-mail: hsmt@pharm.hokudai.ac.jp
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) “Exploitation of Multi-Element Cyclic
Molecules” from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. We thank H. Matsumoto, A.
Maeda, S. Oka, and M. Kiuchi of the Center for Instrumental
Analysis, Hokkaido University, for technical assistance with MS and
elemental analysis.
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DOI: 10.1002/anie.200461988
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Communications
reaction revealed a trend for the yield of disaccharide 8 to
increase with descending temperature (entries 1–3). The
temperature limit for a smooth reaction was À608C, at
which disaccharide 8 was produced in 36% yield (entry 3).[12]
A number of other promoters were then examined for the
reaction of diethyl phosphite 6 and alcohol 7. Among a
variety of Lewis acids that were screened (entries 3–6),
[13]
Hf(OTf)4
proved to be superior to TMSOTf; however,
disaccharide 8 was still obtained in only 66% yield (entry 6).
Our interest was then directed to the use of promoters with
Brønsted acidity.[10b,14] We found that the coupling of donor 6
with 7 in CH2Cl2 in the presence of TfOH proceeded even at
À788C to give disaccharide 8 in 75% yield (entry 7). It is
interesting to note that the sulfonic acids with greater
Brønsted acidity[15] resulted in higher yields of 8 (entries 7–
Scheme 1. Glycosidation of 2-acetamido-2-deoxyglycosyl donors. Ac=
acetyl, LA=Lewis acid, LG=leaving group.
[16]
9). The use of HClO4 prepared from tBuBr and AgClO4
anosyl diethyl phosphite (6)[11] with 6-O-unprotected glyco-
side 7 (1.1 equiv; Table 1). An initial experiment revealed
that the donor 6 was completely consumed within 5 min at
08C, thereby affording a mixture of disaccharide 8 and
oxazoline 9 in the ratio of 0.3:1 (Table 1, entry 1). To our
surprise, an examination of the temperature profile of the
also promoted the reaction at À788C, but a significantly
longer time was required to reach completion (entry 10).
Finally, we were gratified to find that a simple change in the
counterion in super Brønsted acids from trifluoromethane-
sulfonate (triflate) to bis(trifluoromethanesulfonyl)imide
(triflimide)[17] dramatically enhanced the reaction rate, with-
out compromising product yield. Although the reason for this
difference in reactivity is currently unclear, the use of Tf2NH
provided disaccharide
8 rapidly (1 h) in 73% yield
Table 1: Effect of temperature and promoter on the glycosidation of 6
with 7.[a]
(entry 11).[18] Eventually, the use of 2 equivalents of acceptor
alcohol 7 led to an additional increase in the yield (84%) of 8
(entry 12). When the reaction was carried out using 2 equiv-
alents of donor 6, disaccharide 8 was obtained in comparable
(93%) yield (entry 13).
With the reaction conditions optimized, we then explored
the glycosidation of 6 and 10–12[11] for both the d-gluco and d-
galacto series with a range of acceptor alcohols with different
reactivities (Scheme 2, Table 2). The examples highlighted in
Table 2 deserve some comments. In all cases, ÀTf2NH-
promoted glycosidations in CH2Cl2 at À788C were found to
offer a facile, efficient, and stereoselective route to 1,2-trans-
b-linked glycosides. Under these conditions, secondary as well
Entry
Promoter
T [8C]
t [h]
8:9[b]
Yield of 8 [%]
1[c,d]
2[c,d]
3[c,d]
4
5
6
TMSOTf
TMSOTf
TMSOTf
BF3·OEt2
Sn(OTf)2
Hf(OTf)4
TfOH
0
À23
À60
À60
À60
À60
À78
À78
À78
À78
À78
À78
À78
0.1
0.1
0.5
4
1
1
5
1
1
12
1
0.3:1
0.4:1
0.7:1
2.0:1
1.6:1
2.9:1
4.2:1
1.8:1
0.8:1
2.2:1
4.1:1
7.8:1
–
18
24
36
39
46
66
75
51
38
59
73
84
93
7
8
9
10
TsOH
MsOH
HClO4[e]
Tf2NH
Tf2NH
Tf2NH
11[d]
12[d,f]
13[g]
1
1
[a] The reaction was carried out on a 0.1 mmol scale with 1.1 equivalents
of acceptor 7 and 1.5 equivalents of promoter in the presence of
pulverized 4-ꢀ molecular sieves (4-ꢀ MS) in CH2Cl2, unless otherwise
noted. Ts=p-toluenesulfonyl, MS=methanesulfonyl. [b] The ratio was
determined by 500-MHz 1H NMR spectroscopic analysis of the crude
mixture. [c] The reaction was performed in the absence of 4-ꢀ MS.
[d] The reaction was performed with 1.1 equivalents of promoter.
[e] Prepared from tBuBr and AgClO4. See ref. [16]. [f] The reaction was
carried out by using 2.0 equivalents of 7. [g] Donor/acceptor/Tf2NH
molar ratio=2.0:1.0:2.2. Bn=benzyl.
Scheme 2. Glycosyl donors and acceptor alcohols used for the
reactions described in Table 2.
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Table 2: Glycosidation of 6, 10–12.[a]
present reaction does not proceed via the intermediacy of an
oxazolinium ion. In this context, it is interesting to note that
Crich and Sun identified an anomeric mixture of glycosyl
triflates as intermediates in the sulfoxide glycosidation
reaction of Kahne et al.[23] when a participating acetyl group
was present on the oxygen atom at position 2.[24,25] Based on
this remarkable observation, a proposed reaction mechanism
is outlined in Scheme 4. Diethyl phosphite 21 is activated by
Entry
Donor
Acceptor
t [h]
Yield [%][b]
1[c]
2
3
4
5
6
6
6
6
6
10
10
10
11
12
12
13
15
17
18
19
7
14
16
7
1
1
1
1
1
1
1
1
80 (83)
89 (92)
79 (78)
57 (44)
65 (64)
83 (87)
81 (79)
74 (71)
70 (72)
67 (70)
59 (59)
6
7[d]
8[c]
9
24
24
24
10
11
15
17
[a] Donor/acceptor/Tf2NH molar ratio=1.0:2.0:1.1 unless otherwise
noted. [b] Yields in parentheses were obtained when a donor/acceptor/
Tf2NH molar ratio of 2.0:1.0:2.2 was used. [c] The reaction was carried
out by using 1.5 equivalents of acceptor alcohol or, for the results in
parentheses, 1.5 equivalents of donor. [d] The reaction was carried out by
using 1.1 equivalents of acceptor alcohol or, for the results in
parentheses, 1.1 equivalents of donor.
as primary alcohols could be employed and b-glycosides were
obtained in good to high yields. It is also noteworthy that the
alcohols bearing acid-sensitive acetal or epoxy groups could
be safely glycosylated (entries 2–4, 10, and 11). The O-acetyl
protective groups in 11 and 12 lowered the reactivities of
these compounds relative to those with the fully benzylated
donors 6 and 10 in a consistent and general trend,[19] but the b-
glycosides were still produced in moderate to good yields
(entries 9–11).[20]
To gain an insight into the mechanism of this glycosidation
reaction, further experiments were performed to determine
whether the glycosidation proceeded via an oxazolinium ion
intermediate. The reaction of oxazoline 9 with 7 did not occur
under the optimized conditions described above
(Scheme 3).[21,22] This result, together with the finding that a
prolonged reaction time (20 h) had no effect on the yield of
disaccharide 8 in the reaction of 6 with 7, suggests that the
Scheme 4. Plausible mechanism of the glycosidation of 2-acetamido-2-
deoxyglycosyl diethyl phosphites.
protonation of the phosphorus atom[26] and the phosphite
group cleaves to produce an equilibrium mixture of a- and b-
glycosyl triflimide intermediates 23 and 24. An SN2-like
displacement by the acceptor alcohol at the anomeric carbon
atom of the a-glycosyl triflimide 23 affords b-glycoside 4 via
intermediate 25. On the other hand, the b-glycosyl triflimide
24 undergoes an intramolecular attack by the acetamido
group, thereby generating the oxazolinium ion 26,[27] from
which the oxazoline 3 is formed by the elimination of a proton
from the NH group.
In conclusion, we have demonstrated herein that Tf2NH-
promoted glycosidations of 2-acetamido-2-deoxyglycopyra-
nosyl diethyl phosphites with a variety of acceptor alcohols in
CH2Cl2 at À788C give 1,2-trans-b-linked glycosides in good to
high yields with perfect stereoselectivity. This protocol
represents the first example of the direct glycosidation of 2-
acetamido-2-deoxyglycosyl donors that does not proceed via
an oxazolinium ion intermediate. Spectroscopic investigations
to support the proposed mechanism, as well as further studies
aimed at expanding the synthetic utility of this protocol, are in
progress.
Experimental Section
A representative procedure for glycosidation of 2-acetamido-2-
deoxyglycopyranosyl diethyl phosphite (entry 12 in Table 1): A 1m
solution of Tf2NH in EtCN (0.11 mL, 0.11 mmol) was added to a
Scheme 3. Glycosidation of oxazoline 9 with 7 did not proceed via an
oxazolinium ion intermediate 20 under the optimized conditions.
mixture of donor 6 (61.2 mg, 0.1 mmol), acceptor 7 (92.9 mg,
0.2 mmol), and pulverized 4-ꢀ molecular sieves (61.2 mg) in
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Communications
CH2Cl2 (1 mL) at À788C. After stirring at this temperature for 1 h,
H.-S. Byun, S. Wang, R. Bittman, Tetrahedron Lett. 1994, 35,
505 – 508; c) J. Sun, X. Han, B. Yu, Carbohydr. Res. 2003, 338,
827 – 833; d) I. Carvalho, S. L. Scheuerl, K. P. R. Kartha, R. A.
Field, Carbohydr. Res. 2003, 338, 1039 – 1043.
the reaction was quenched by addition of Et3N (0.15 mL), and the
whole mixture was partitioned between EtOAc and saturated
aqueous NaHCO3. The organic extract was washed with brine and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude products, whose ratio was determined to be 7.8:1
by 500-MHz 1H NMR spectroscopic analysis. For easy purification, a
solution of the crude mixture in EtOAc (12 mL) and CH2Cl2 (2 mL)
was vigorously stirred with 10% aqueous HCl (2 mL) for 10 min,
during which time the oxazoline 9 was completely hydrolyzed to form
the corresponding glycopyranose. The whole mixture was extracted
with EtOAc, and the organic extract was washed successively with
saturated aqueous NaHCO3 and brine, then dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo followed by flash column
chromatography (silica gel, toluene/acetone 7:1) afforded disacchar-
ide 8 (77.2 mg, 84%) as a white solid.
[7] Lubineau and co-workers reported that the Sn(OTf)2-mediated
glycosidation of 2-acetamido-2-deoxy-a-d-glucosyl chloride with
a range of alcohols afforded b-glycosides in good yields. They
suggested that the corresponding oxazoline is not an intermedi-
ate in the reaction since the rate and yield of the glycosidations
were considerably lowered when the oxazoline was used as a
starting donor: A. Lubineau, J. Le Gallic, A. Malleron, Tetrahe-
dron Lett. 1987, 28, 5041 – 5044. However, our experiments
revealed that the glucosyl chloride was quantitatively converted
into the oxazoline within 30 min under the reported conditions
and the desired disaccharide was formed at the expense of the
oxazoline. We speculate that hydrogen chloride generated in situ
would act as a promoter for oxazoline activation.
[8] a) S. E. Zurabyan, T. P. Volosyuk, A. J. Khorlin, Carbohydr. Res.
1969, 9, 215 – 220; b) S. E. Zurabyan, T. S. Antonenko, A. Y.
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Beppu, S. Nakabayashi, Carbohydr. Res. 1981, 93, C6 – C9; f) M.
Kiso, L. Anderson, Carbohydr. Res. 1985, 136, 309 – 323; g) V.
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[9] The effectiveness of glycosyl phosphites as glycosyl donors was
originally demonstrated by the Wong and Schmidt groups in
1992: a) H. Kondo, Y. Ichikawa, C.-H. Wong, J. Am. Chem. Soc.
1992, 114, 8748 – 8750; b) T. J. Martin, R. R. Schmidt, Tetrahe-
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[10] a) S. Hashimoto, K. Umeo, A. Sano, N. Watanabe, M. Nakajima,
S. Ikegami, Tetrahedron Lett. 1995, 36, 2251 – 2254; b) H.
Tanaka, H. Sakamoto, A. Sano, S. Nakamura, M. Nakajima, S.
Hashimoto, Chem. Commun. 1999, 1259 – 1260, and references
therein. See also: http://www.glycoforum.gr.jp/science/word/gly-
cotechnology/GT-A01E.html.
[11] 2-Acetamido-2-deoxy-d-glycopyranosyl diethyl phosphites were
readily prepared from the corresponding glycopyranoses by
using a previously reported procedure[10a] (ClP(OEt)2, Et3N,
CH2Cl2, 08C).
[12] With the lone exception of THF, where oxazoline 9 was
exclusively produced, the product ratio (8:9 = 0.7:1) was nearly
the same in the other solvents tested (EtCN/CH2Cl2 (1:1) and
toluene/CH2Cl2 (1:1)), although the low solubility of donor 6 in
EtCN and toluene precluded a direct comparison.
[13] I. Azumaya, M. Kotani, S. Ikegami, Synlett 2004, 959 – 962.
[14] a) H. Kondo, S. Aoki, Y. Ichikawa, R. L. Halcomb, H. Ritzen, C.-
H. Wong, J. Org. Chem. 1994, 59, 864 – 877; b) H. Sakamoto, S.
Nakamura, T. Tsuda, S. Hashimoto, Tetrahedron Lett. 2000, 41,
7691 – 7695.
[15] The pKa values for TfOH, TsOH, and MsOH are À14, À6.5, and
À2.6, respectively: a) F. G. Bordwell, Acc. Chem. Res. 1988, 21,
456 – 463; b) E. N. Krylov, O. G. Tokareva, Russ. J. Gen. Chem.
1997, 67, 1 – 4; c) http://www.chem.wisc.edu/areas/reich/pkata-
ble/ka-water.gif.
Received: September 14, 2004
Revised: December 6, 2004
Published online: March 3, 2005
Keywords: glycosidation · glycosides · neighboring-group
.
effects · phosphites · synthetic methods
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[18] The TMSNTf2-promoted glycosidation of 6 with 7 proceeded at
À608C to give 8 in 35% yield (reaction time 1 h, 8/9 = 0.7:1).
[19] a) B. Fraser-Reid, Z. Wu, C. W. Andrews, E. Skowronski, J. P.
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[20] The limitation of the present method was encountered with
unreactive acceptor alcohols, such as 4- or 2-O-unprotected
glucosides.
[21] 1H NMR spectral data (400 MHz) clearly revealed that oxazo-
line 9 was protonated upon treatment with Tf2NH in CD2Cl2 at
À788C to form oxazolinium ion 20 (9, d = 5.91 (d, J = 7.2 Hz,
H1), 4.20 (m, H2), 1.95 ppm (s, CH3); 20, d = 6.63 (d, J = 8.0 Hz,
H1), 4.51 (m, H2), 2.39 ppm (s, CH3)).
[22] The reaction of glycosyl diethyl phosphites with alcohols is
accompanied by the formation of HP(O)(OEt)2. However, the
addition of HP(O)(OEt)2 was not effective for the Tf2NH-
promoted reaction of oxazoline
9 with alcohol 7, which
proceeded at temperatures above approximately 58C.
[23] a) D. Kahne, S. Walker, Y. Cheng, D. Van Engen, J. Am. Chem.
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1378.
[27] A b-oriented anomeric leaving group of a 2-acetamido-2-
deoxyglycosyl donor is known to be readily eliminated to form
the corresponding oxazoline derivative: a) R. U. Lemieux, H.
Driguez, J. Am. Chem. Soc. 1975, 97, 4063 – 4069; b) G.
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