Remarkably efficient activation of glycosyl trichloro- and (N-phenyl)trifluoroacetimidates with bismuth(III) triflate

Article abstract of DOI:10.1016/j.tetlet.2006.02.034

Easily handled and nontoxic Bi(OTf)₃ is a powerful activator for trichloro- and (N-phenyl)trifluoroacetimidate glycosyl donors. This catalyst allows glycosidations to be performed at low temperatures in very short times. Rewarding yields were o

Full text of DOI:10.1016/j.tetlet.2006.02.034

Tetrahedron Letters 47 (2006) 2595–2599
Remarkably efficient activation of glycosyl trichloro- and
(N-phenyl)trifluoroacetimidates with bismuth(III) triflate
*
`
Matteo Adinolfi, Alfonso Iadonisi, Alessandra Ravida and Silvia Valerio
`
Dipartimento di Chimica Organica e Biochimica, Universita degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli, Italy
Received 20 January 2006; revised 1 February 2006; accepted 6 February 2006
Available online 23 February 2006
Abstract—Easily handled and nontoxic Bi(OTf)3 is a powerful activator for trichloro- and (N-phenyl)trifluoroacetimidate glycosyl
donors. This catalyst allows glycosidations to be performed at low temperatures in very short times. Rewarding yields were obtained
from a wide range of donors of varying reactivity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
An impressive progress has been registered over the last
years in oligosaccharide synthesis with the development
of automated procedures1 and the development of a
programmable one-pot approach enabling the construc-
tion of more than one glycosidic bond in a single
synthetic operation.2 Despite these advances, oligosac-
charide synthesis is still presenting a variety of problems
partly related to the inherent structural complexity of
saccharidic molecules with a great number of possible
glycosidic connections. As a matter of fact, there is
not yet a ‘universal’ glycosidation procedure which
serves at best in every possible case of connection. In
addition, the most adopted protocols are experimentally
demanding as strictly anhydrous conditions are neces-
sary for good yields to be attained.3 Furthermore, harsh
acidic agents (TMSOTf, BF3ÆOEt2, triflic anhydride, tri-
flic acid, etc.) are routinely included in the promoter sys-
tems. These agents are either moisture sensitive or highly
hygroscopic, and special caution is thereby necessary for
their handling and storage. A further drawback is repre-
sented by the problems of chemical compatibility occa-
sionally observed in glycosidations conducted in the
presence of acid labile functional groups.
the use of perchloric acid supported on silica gel as an
operationally simpler alternative to conventional pro-
moters.6 Along this line, in the last years we have been
devoting a wide interest toward the development of
alternative glycosidation promoters featuring moisture
stability and Yb(OTf)3 turned out to be a rather versa-
tile promoter in glycosidations conducted with glycosyl
trichloroacetimidates and the recently introduced
(N-phenyl)trifluoroacetimidate7 analogues.8,9 This lan-
thanide salt was found able to activate both ‘armed’
and ‘disarmed’10 donors, and was applied in the con-
struction of biologically interesting oligosaccharide anti-
gene sequences or glycoconjugates.9 The commercial
availability of several metal triflates prompted us to
search for even improved results.11
From a literature survey we have realized that bis-
muth(III) triflate is often serving better than lanthanide
triflates in acid promoted transformations of organic
synthesis,12 and therefore this nontoxic and cheap salt
has been examined as a potential activator of glycosyl
trihaloacetimidates. To the best of our knowledge, the
only reported application of this salt in glycosidation
chemistry concerns its use in combination with
BF3ÆOEt2 (both agents in exceeding stoichiometric
amount) for effecting the activation of sialyl acetates
donors.13
Glycosyl trichloroacetimidates are broadly used glycosyl
donors whose activation is typically accomplished with
catalytic amounts of TMSOTf or BF3ÆOEt2,4 whereas
alternative acidic promoters have occasionally been
used.5 Very recently two independent reports described
In a preliminary screening, a dramatic influence exerted
by the nature of the solvent on the reactivity of this salt
was observed. Armed perbenzylated trifluoroacetimi-
date and trichloroacetimidate 1 and 2 (Table 1) of glu-
cose were smoothly activated in solvent mixtures
*
Corresponding author. Fax: +39 081 674393; e-mail: iadonisi@
unina.it
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.034

Table 1. Bi(OTf)3 promoted glycosidations with donors devoid of participating groupsa
Entry
Donor
Acceptor
Solvent
% Bi(OTf)3
5b
T (ꢁC)
Product
Yield (%) (a:b)
OH
O
O
O
BnO
BnO
BnO
BnO
O
O
PhCH3/DME 2:1
ꢀ70 to ꢀ50
97 (1.8)
BnO
BnO
1
BnO
O
BnO
O
O
O
O
NPh
1
12
F3C
O
O
O
19
O
BnO
BnO
O
BnO
2
12
PhCH3/DME 2:1
1.5b
ꢀ70 to ꢀ50
19
97 (1.2)
BnO
O
2
NH
Cl3C
O
Ph
O
O
O
Ph
AcO
O
BnO
BnO
O
O
5b
ꢀ50 to ꢀ30
ꢀ70
86 (6.0)
77 (4.0)
O
3
4
1
2
AcO
PhCH3/DME 2:1
PhCH3/DME 2:1
OCH3
BnO
HO
BnO
13
OCH3
20
13
1.5b
20
OAc
O
AcO
NPh
CF3
OAc
O
AcO
AcO
15
AcO
H3C
O
OAc
OBn
O
H3C
O
5
DCM/dioxane/Et2O 4:1:1
5c
ꢀ50
75 (>10)
OBn
O
HO
OBn
OAc
BnO
OBn
3
BnO
21
OAc
OAc
O
AcO
AcO
AcO
AcO
NHAlloc
CO2Me
O
HO
6
Dioxane/PhCH3/DME 3:1:1
10c
ꢀ10
72 (5.5)
NHAlloc
CO2Me
O
N3
N3
O
22
16
NPh
4
F3C
a General conditions: acceptor (1 equiv), donor (1.2–1.4 equiv) (entries 1–5). For entry 6: acceptor (1.3 equiv), donor (1.0 equiv).
b The promoter was added as a solution in dioxane (10–20 mg/mL).
c The promoter was added as a solution in the reaction solvent mixture.

M. Adinolfi et al. / Tetrahedron Letters 47 (2006) 2595–2599
2597
containing toluene, 1,2-dimethoxyethane and dioxane,
previously found to provide a remarkable a-selectivity
under Yb(OTf)3 activation (Table 1, entries 1–4).8c
azido galactose derivative 4 (entries 5 and 6). Improved
a-stereoselectivity was reached in the case of the fucos-
ylation.9a As for entry 6, it should be noted that the cou-
pling of 4, when performed under Yb(OTf)3 activation,
took several days at room temperature for a comparable
overall yield to be achieved.14
Notably, reactions took very short times (less than
45 min) and could be performed in higher yields at sen-
sibly lower temperatures as well as with a lower catalytic
amount than in the case of the lanthanide activation.8c
a-Stereoselectivity was found to be lower but similarly
influenced by both the nature of the donor leaving group
and the reactivity of the acceptor hydroxyl group. Good
results were obtained also with fucosyl donor 3 and the
In contrast, reactions in nitrile solvents, usefully
adopted with armed donors for b-selective Yb(OTf)3
promoted glycosidations8b,9b gave disappointing results
under Bi(OTf)3 activation due to their extreme sluggish-
ness. This result might be ascribed to the ability of
Table 2. Bi(OTf)3 promoted glycosidations with donors equipped with participating groupsa
b
Entry Donor
Acceptor
% Bi(OTf)3
T (ꢁC)
Product
Yield (%)
87
AcO
AcO
O
O
Ph
Ph
O
O
O
O
O
1
5
ꢀ30 to rt
BnO
AcO
BnO
AcO
AcO
HO
O
O
O
OCH3
AcO
OCH3
AcO
NH
NH
5
OAc
Cl3C
O
14
23
O
BzO
Ph
O
O
BzO
BnO
BzO
BzO
BzO
2
14
5
ꢀ30 to rt
90
BzO
O
O
OCH3
O
6
BzO
OBz
Cl3C
24
O
Ph
AcO
AcO
MeO2CO
MeO2CO
O
O
O
BnO
AcO
AcO
MeO2CO
MeO2CO
3
4
5
14
14
5
10
10
ꢀ30 to rt
85
88
79
O
O
OCH3
O
7
NH
Cl3C
O
25
AcO
AcO
MeO2CO
0
0
25
MeO2CO
O
NPh
8
F3C
O
O
O
O
HO
Ph
O
Ph
AcO
AcO
MeO2CO
O
O
O
8
BnO
BnO
OCH3
OCH3
OCO2Me
17
26
O
Ph
OBn
O
BnO
BnO
O
BnO
O
BnO
O
O
6
17
5
ꢀ30 to rt BnO
BnO
OCH3
91
MeO2CO
O
MeO2CO
NPh
c
9
F3C
27
OCO2Me
O
BnO
BnO
OCO2Me
O
BnO
OBn
O
BnO
HO
OBn
OBn
O
BnO
BnO
BnO
7
8
BnO
8
ꢀ20
ꢀ10
92
88
O
O
28
BnO
OAll
NPh
10
18
F3C
OAll
AcO
O
Ph
O
O
AcO
AcO
AcO
O
AcO
O
AcO
O
17
10
PhtN
O
BnO
PhtN
29
NPh
OCH3
11
F3C
a General conditions: acceptor (1 equiv), donor (1.2–1.4 equiv), DCE.
b The promoter was added as a solution in dioxane (10–20 mg/mL).
c 1.6 equiv of donor were used.

2598
M. Adinolfi et al. / Tetrahedron Letters 47 (2006) 2595–2599
2. Zhang, Z.; Ollman, I. R.; Ye, X.-S.; Wischnat, R.; Baasov,
trivalent bismuth to form complexes committing several
nitrile molecules.15
T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734–755.
3. (a) Ernst, B.; Hart, G. W.; Sinay, P. In Carbohydrates in
¨
Chemistry and Biology; Wiley-Wch, 2000; Vol. 1; (b)
Boons, G.-J. Tetrahedron 1996, 52, 1021–1095.
4. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21–123.
Activation of disarmed donors was even more sensitive
to the reaction solvents and the best results were
obtained in mixtures of 1,2-dichloroethane and dioxane.
The efficacy of the promoter was tested on donors
derived from glucose (5–8), galactose (9), mannose (10)
and glucosamine (11) as shown in Table 2.
5. For some examples: (a) Nicolaou, K. C.; Daines, R. A.;
Ogawa, Y.; Chakraborty, T. K. J. Am. Chem. Soc. 1988,
110, 4705–4969; (b) Wei, G.; Gu, G.; Du, Y. J. Carbohydr.
Chem. 1993, 22, 385–393; (c) Castro-Palomino, J. C.;
Schmidt, R. R. Tetrahedron Lett. 1995, 36, 5343–5346; (d)
Liao, W.; Lu, D. Carbohydr. Res. 1997, 300, 347–349; (e)
Bartek, J.; Muller, R.; Kosma, P. Carbohydr. Res. 1998,
308, 259–273.
6. (a) Mukhopadhayay, B.; Maurer, S. V.; Rudolph, N.; van
Well, R. M.; Russell, D. A.; Field, R. A. J. Org. Chem.
2005, 70, 9059–9062; (b) Du, Y.; Wei, G.; Cheng, S.; Hua,
Y.; Linhardt, R. J. Tetrahedron Lett. 2006, 47, 307–310.
7. Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405–2407.
8. (a) Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni, L.;
Schiattarella, M. Tetrahedron Lett. 2001, 42, 5967–5969;
(b) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella,
M. Tetrahedron Lett. 2002, 43, 5573–5577; (c) Adinolfi,
Excellent yields were obtained with trichloroacetimi-
dates 5 and 6, protected with conventional acetyl and
benzoyl groups which are prone to give orthoester cou-
pling products.3 As a matter of fact, TLC analysis of the
mixture of entry 2 displayed the fast consumption at low
temperature of both donor and acceptor and the pre-
ponderant generation of an initial intermediate which
was converted, upon warming to room temperature, to
the desired b-linked disaccharide. This evidence strongly
suggests that an orthoester intermediate might be ini-
tially formed as the preponderant coupling product that
subsequently rearranges to the corresponding 1,2-trans
glycoside.
`
M.; Iadonisi, A.; Ravida, A.; Schiattarella, M. Tetra-
hedron Lett. 2004, 45, 4485–4488.
`
9. (a) Adinolfi, M.; Iadonisi, A.; Ravida, A.; Schiattarella,
Also the disarmed donors reacted smoothly and in high
yields (generally less than 30 min were sufficient and in
no case reactions were worked-up after more than 3 h).
M. Synlett 2004, 275–278; (b) Adinolfi, M.; Iadonisi, A.;
Ravida, A.; Schiattarella, M. J. Org. Chem. 2005, 70,
5316–5319; (c) Adinolfi, M.; Galletti, P.; Giacomini, D.;
`
`
Iadonisi, A.; Quintavalla, A.; Ravida, A. Eur. J. Org.
Chem. 2006, 69–73.
In contrast to lanthanide triflates,16 Bi(OTf)3 cannot be
completely dried12 and therefore it was simply coevapo-
rated with dry toluene prior to its use. The observed
results demonstrate that the residual amounts of water
contained in the salt were not detrimental to the achieve-
ment of high coupling yields.
10. Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-
Reid, B. J. Am. Chem. Soc. 1988, 110, 5583–5584.
11. For a very recent review on the use of metal triflates in
carbohydrate chemistry: Kulkarni, S. S.; Hung, H.-C.
Lett. Org. Chem. 2005, 670–677.
12. For a recent review on Bi(OTf)3 in organic synthesis:
Gaspard-Houghmane, H.; Le Roux, C. Eur. J. Org. Chem.
2004, 2517–2532.
In conclusion, Bi(OTf)3 has been found to act as a pow-
erful activator for trichloro- and (N-phenyl)trifluoroace-
timidate glycosyl donors. Glycosidations are efficiently
conducted at low temperature and in very short times,17
comparably with the standard protocols involving strong
Lewis or protic acids as activators. In addition, use of
Bi(OTf)3 appears at least advantageous in that the stor-
age and the handling of this nontoxic agent does not
entail special precautions. The activation protocol was
successfully applied to a variety of both armed and dis-
armed donors from a wide range of saccharidic precur-
sors. Use of this promoter is now being investigated
with other glycosidation approaches as well as in the
assemblage of more complex oligosaccharide sequences.
13. Ikeda, K.; Torisawa, Y.; Nishi, T.; Minamikawa, J.;
Tanaka, K.; Sato, M. Bioorg. Med. Chem. 2003, 11, 3073–
3076.
14. Unpublished results.
15. For an example: Wiley, G. R.; Collins, H.; Drew, M. G. B.
J. Chem. Soc., Dalton Trans. 1991, 961–965.
16. Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.;
Liu, G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J.
J.; Bown, P. S.; Miller, J. L. J. Org. Chem. 1987, 52, 1017–
1021.
17. Typical procedure:
A mixture of donor 8 (58 mg,
0.105 mmol) and acceptor 17 (32 mg, 0.086 mmol) was
coevaporated three times with anhydrous toluene and then
kept for 30 min under vacuum. The mixture of donor and
acceptor was dissolved at 0 ꢁC under argon in anhydrous
1,2-dichloroethane (1.2 mL) in the presence of activated
Acknowledgements
˚
4 A acid washed molecular sieves (AW 300 MS). Bis-
muth(III) triflate was also coevaporated three times with
anhydrous toluene and dissolved in dioxane (20 mg/mL)
in the presence of activated 4 A molecular sieves (ultra-
This research was supported by MIUR (PRIN 2004–5)
and Regione Campania. NMR and MS facilities of
CIMCF (Centro Interdipartimentale di Metodologie
˚
sonication favours solubilization). An aliquot of this
solution (280 lL, 8.5 lmol of promoter) was added at
0 ꢁC to the mixture of the donor and the acceptor. After
10 min TLC analysis displayed complete consumption of
the donor. A few drops of pyridine were added and the
mixture was filtered on a short plug of silica gel. The
resulting crude product was then chromatographed on a
silica gel column eluted with hexane/ethyl acetate mixtures
to yield disaccharide 26 (48 mg, yield 79%). Spectroscopic
`
Chimico Fisiche dell’Universita ‘Federico II’ di Napoli)
are acknowledged.
References and notes
1. Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science
2001, 291, 1523–1527.

M. Adinolfi et al. / Tetrahedron Letters 47 (2006) 2595–2599
2599
data of 26: 1H NMR (400 MHz, CDCl3): d 7.30–7.60
(aromatic protons), 5.52 (1H, s), 5.03 (1H, t,
J2,3 = J3,4 = 10.0 Hz, H-40), 5.00–4.90 (2H, overlapped
signals, H-20 and H-30), 4.85 (1H, d, Jgem = 11.2 Hz,
–OCHaHbPh), 4.48 (1H, d, –OCHaHbPh), 4.45 (1H,
J1,2 = 3.6 Hz, H-1), 4.22 (1H, d, J1,2 = 8.0 Hz, H-10),
4.20 (1H, dd, J5,6eq = 2.8 Hz, J6ax,6eq = 10.0 Hz, H-6eq),
4.11 (1H, J5,6a = 4.4 Hz, J6a,6b = 12.0 Hz, H-6a0), 3.93
(1H, J5,6b = 2.4 Hz, H-6b0), 3.85–3.75 (2H, overlapped
signals, H-3 and H-5), 3.77 and 3.76 (6H, 2 · s, 2 ·
–OCO2CH3), 3.72 (1H, t, J5,6ax = J5,6eq = 10.0 Hz,
H-6ax), 3.56 (1H, J3,4 = J4,5 = 10.0 Hz, H-4), 3.52–3.49
(2H, overlapped signals, H-2 and H-50), 3.34 (3H, s, 1-
OCH3), 2.01 and 1.98 (6H, 2 · s, 2 · –COCH3). 13C NMR
(50 MHz, CDCl3): d 170.7 and 169.4 (–COCH3), 155.1 and
154.9 (–OCO2CH3), 138.0 and 137.2 (aromatic C), 129.0–
126.0 (aromatic CH), 101.2 (benzylidene acetal CH), 100.5
(C-10), 98.7 (C-1), 55.3 (–OCH3), 20.7 and 20.6 (–COCH3).
Other signals at d 79.7, 79.6, 75.4, 74.2, 71.4, 68.9, 68.3,
62.2, 61.9.