Activation of glycoyl trihaloacetimidates with acid-washed molecular sieves in the glycosidation reaction

Article abstract of DOI:10.1021/ol027353i

Figure presented Commercially available 4 A acid washed molecular sieves (4 A AW 300 MS) are efficient activators of glycosyl trichloro- and N-phenyltrifluoroacetimidates. These promoters allow glycosidation of primary and secondary saccharidic acceptors to be performed in high yield, under very mild conditions and by an experimentally simple procedure. In addition, the recyclability of such promoters also has been demonstrated.

Full text of DOI:10.1021/ol027353i

ORGANIC
LETTERS
2
003
Vol. 5, No. 7
87-989
Activation of Glycoyl
9
Trihaloacetimidates with Acid-Washed
Molecular Sieves in the Glycosidation
Reaction
Matteo Adinolfi, Gaspare Barone, Alfonso Iadonisi,* and Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica,
UniVersit a` degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli, Italy
iadonisi@unina.it
Received November 26, 2002
ABSTRACT
Commercially available 4 Å acid washed molecular sieves (4 Å AW 300 MS) are efficient activators of glycosyl trichloro- and
N-phenyltrifluoroacetimidates. These promoters allow glycosidation of primary and secondary saccharidic acceptors to be performed in high
yield, under very mild conditions and by an experimentally simple procedure. In addition, the recyclability of such promoters also has been
demonstrated.
In the course of our recent investigations aimed at developing
In both cases, we postulated that ordinary molecular sieves
could interfere with glycosidation due to their ability to act
as proton scavengers. In the case of ytterbium triflate
activation, glycosidations with the disarmed trifluoroace-
timidate donor 1 were efficiently promoted at room temper-
ature with AW 300 MS rather than at 60 °C with ordinary
1
novel moisture-stable activators of glycosyl trichloro- and
2
N-phenyltrifluoroacetimidates, we observed with two dif-
3
4
ferent systems, iodine/triethylsilane and ytterbium triflate,
respectively, the beneficial effect of the use of 4 Å acid-
washed molecular sieves (AW 300 MS) in place of ordinary
molecular sieves. As a matter of fact, in the case of the first
system, the use of these drying reagents allowed glycosida-
tions to be completed in shorter times at room temperature,
while with the lanthanide promoter, reactions could be
effected at much lower temperatures and with a higher yield
4
molecular sieves. This led us to investigate the viable use
of acid-washed molecular sieves as promoters as well as
drying agents. As a matter of fact, we found that only acid-
washed molecular sieves 4 Å AW 300 MS could promote
the coupling between donor 1 (1.3 equiv) and acceptor 5 (1
equiv) (Table 1, entry 1). However, to achieve good yields
within a few hours a higher temperature was required than
5
6
than previously reported, especially with disarmed donors.
when using Yb(OTf)
room temperature).
Acid-washed molecular sieves were also found to activate
3
and AW 300 MS (70 °C instead of
(
1) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
4
5
0, 21-124.
(
2) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405-2407.
(3) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M. Synlett 2002,
disarmed trichloroacetimidate donors 2, 3, and 4 efficiently,
2
69-270.
4) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M. Tetrahedron
Lett. 2002, 43, 5573-5577.
5) Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni, L.; Schiattarella,
M. Tetrahedron Lett. 2001, 42, 5967-5969.
6) Fraser Reid, B.; Udodong, U. E.; Wu, Z.; Ottesson, H.; Merritt, J.
R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927-942.
4
,7
(
and the expected higher reactivity of trichloro- vs. N-
phenyltrifluoroacetimidate donors was evidenced by the
(
(
(7) Nakajima, N.; Saito, M.; Kudo, M.; Ubukata, M. Tetrahedron 2002,
58, 3579-3588.
1
0.1021/ol027353i CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/11/2003

Figure 1. Compounds 1-26.
lower temperatures required for glycosidations to be com-
pleted in short times (entries 3-5). Interestingly, use of the
more unusual 2-O-methoxycarbonylated donor 2 yielded
better results than with the usual peracetylated and benzoy-
lated donors 3 and 4. An analogous behavior had been
previously observed in the investigations on the iodine/
triethylsilane promoter.3
This mild activation system proved also effective with
other secondary and primary acceptors (entries 6, 8, 9, and
10). Entries 7 and 8 show the feasible activation of the
trifluoro disarmed donor 1 even at room temperature,
although much longer reaction times are required for the
completion of glycosidations. However, under these condi-
tions remarkably high yields were registered. Interestingly,
Table 1. Glycosidation of Saccharidic Acceptors (1 equiv) with Trichloro- and N-Phenyltrifluoroacetimidate Donors (1.3-1.4 equiv)
under the Activation of 4 Å AW 300 Molecular Sieves
entry
donor
acceptor
product
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dichloroethane
toluene
toluene
toluene
toluene
toluene
temp, °C
time, h
yieldb
88
-
85
68
65
84
91
95
71
82
68
89 (0.8)
90 (1.7)
75 (1.7)
81 (1.6)
73 (1.1)
78 (1.7)
1
2a
3
4
5
6
7
8
9
1
1
2
3
4
1
1
1
1
5
5
5
5
5
6
5
7
8
9
17
8
8
7
7
7
17
10
70
70
rt
rt
40
75
rt
rt
60
60-70
rt
rt
-10
rt
-10
rt
2
7
6
2
3
no reaction
10
12
13
14
10
11
15
16
19
23
23
24
24
25
26
4
24
24
4
3
48
2
1
2
1
3
1
1
1
1
1
1
1
1
0
1
2
3c
1
18
20
20
20
20
21
22
4
5c
6
7d
dichloroethane
-10 to rt
6
a
Ordinary molecular sieves were used. Both the donor and the acceptor were recovered unaltered. b Isolated yields (R/â ratios). c TMSOTf (0.05 equiv)
d
was used as the promoter. 2 equiv of the donor were used.
988
Org. Lett., Vol. 5, No. 7, 2003

the glycosidation outcome was strongly influenced by the
nature of the solvent, the best results being obtained with
toluene or dichloroethane (experiments in more polar solvents
such as dioxane or acetonitrile led to low yields). These
ever, thorough washing of commercial AW 300 MS with
distilled water prior to the drying procedure (overnight
heating at 200 °C under vacuum) did not result in any loss
in efficiency. These results suggest that the activation process
occurs on the surface of the sieves, whose acidic sites could
3
observations confirm that Yb(OTf) is the actual promoter
4
11
in the glycosidation conditions we recently reported, where
ether and nitrile solvents were used in the activation of both
armed and disarmed donors. Under these latter conditions
the activating power of AW 300 MS is negligible and they
essentially act as drying agents devoid of proton scavenging
properties.
favor the approach of the activated donor and the acceptor.
Very interestingly, acid-washed molecular sieves turned out
to be recoverable promoters. The coupling of entry 7 was
performed three times with the same sieves. The yield of
1
the second and third experiment was higher than 80% ( H
1
2
NMR).
The proposed protocol was also successfully tested in the
srereocontrolled synthesis of the disaccharide 19, performed
in a scale of hundreds of milligrams (entry 11).
In conclusion, the activation procedure described here
looks particularly attractive due to the noteworthy simplifica-
1
3
tion of the experimental procedure, the avoidance of more
acidic promoters, and the mildness of the reaction conditions.
Although this activation protocol implies higher reaction
temperatures or longer reaction times than those with more
common acidic promoters (including the recently reported
lanthanide triflates), the resulting yields are often competitive.
In addition, to the best of our knowledge this appears to be
the first report on the use of recoverable activators for
commonly used glycosyl imidate donors.
While the stereoselectivity of glycosidations with disarmed
donors was controlled by the neighboring participation of
their 2-O-protecting groups, in the case of armed donors the
stereoselectivity was not satisfying, although equally good
yields could be achieved with three different perbenzylated
N-phenyltrifluoroacetimidates as shown in entries 12, 14, 16,
and 17. Attempts to overcome this problem by the use of
solvents such as acetonitrile or dioxane, able to direct the
stereoselectivity of the glycosidation in the absence of a
participating group in the donor,4 resulted in low yields,
similarly to disarmed donors. For comparison purposes,
glycosidations in entries 12 and 14, involving an armed
glucosyl donor with a primary and a secondary acceptor,
respectively, were also performed in the same solvent
Acknowledgment. This work was supported by MIUR
,8,9
(Programmi di Ricerca di Interesse Nazionale 2001-2) and
by a grant (to M.S.) from Universit a` Federico II di Napoli
(Progetto Giovani Ricercatori).
Supporting Information Available: 1H and 13C NMR
data for all disaccharides. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
toluene) under the activation of the standard TMSOTf
promoter (entries 13 and 15). In the case of the secondary
acceptor, comparable R:â ratios were observed (entries 14
and 15), while with the primary acceptor a pronounced
difference in the stereoselectivity was found (entries 12 and
OL027353I
(11) For applications of zeolites in organic synthesis see: Holderich,
W.; Hesse, M.; Naumann, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 226-
1
3). However, in no case was a high control of stereoselec-
241.
(12) For recent examples in the use of solid acids as recoverable activators
tivity attained.
of armed sulfoxide donors see: (a) Nagai, H.; Matsumura, S.; Toshima, K.
Tetrahedron Lett. 2000, 41, 10233-10237. (b) Nagai, H.; Kawahara, K.;
Matsumura, S.; Toshima, K. Tetrahedron Lett. 2001, 42, 4159-4162.
Some experiments have been performed to clarify the
reasons for the efficiency of the commercial AW 300 MS
as promoters. First, ordinary 4 Å molecular sieves were found
totally ineffective in promoting glycosidation (entry 2), both
coupling partners being quantitatively recovered. In the
second place, the reactions were reproducible when acid-
washed molecular sieves from two different commercial
batches were used. Furthermore, we have considered the
presence of residual traces of acids (possibly introduced in
the acid-washing procedure) as the actual promoter. How-
(
13) Typical procedure: donor 1 (23.0 mg, 0.042 mmol) and acceptor 5
(
12.1 mg, 0.032 mmol) were dissolved under argon in toluene (1 mL) in
10
the presence of freshly activated acid-washed 4 Å molecular sieves AW
1
MS 300 (600 mg, purchased from Fluka, /8 in. rods). After being stirred
for 30 min at room temperature, the mixture was heated at 70 °C for 2 h,
and then a few drops of triethylamine was added. The mixture was filtered
and concentrated and the residue chromatographed on a short silica gel
column eluted with 7:3 hexane/ethyl acetate to afford disaccharide 10 (21.7
mg, yield 91%). The procedure was upscaled for the synthesis of 19:
acceptor 17 (228 mg, 0.48 mmol) and donor 18 (426 mg, 0.62 mmol) were
azeotroped three times with anhydrous toluene. The mixture was then
dissolved at 0 °C (ice bath) under argon in anhydrous dichloroethane (10
mL) in the presence of 4 Å AW 300 MS (2.4 g). After 30 min the ice bath
was removed, and the mixture was left under stirring for 24 h at room
temperature. An additional aliquot of AW MS (2.4 g) was then added. After
a further 24 h, a few drops of triethylamine was added and the mixture
was filtered and concentrated. Silica gel chromatography of the residue
(eluent 85:15 hexane-AcOEt) yielded 312 mg (68%) of disaccharide 19.
The recovered sieves were dehydrated and reactivated by overnight heating
at 200 °C under vacuum.
(
(
96.
8) Demchenko, A.; Stauch, T.; Boons, G.-J. Synlett 1997, 818-821.
9) Schmidt, R. R.; Behrendt, M. M.; Toepfer, M. W. Synlett 1990, 694-
6
(
10) Reactive furanosyl chloride donors can be activated by ordinary
molecular sieves: (a) Zissis, C.; Glaudemans, C. P. J. Carbohydr. Res. 1976,
0, 292-294. (b) Nilsson, S.; Bengtsson, M.; Norberg, T. J. Carbohydr.
Chem. 1992, 11, 265-285.
5
Org. Lett., Vol. 5, No. 7, 2003
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