Tunable activation of glycosyl trichloro- and (N-phenyl)trifluoro- acetimidates with ytterbium(III) triflate: One-pot synthesis of trisaccharides under catalytic conditions

Article abstract of DOI:10.1055/s-2006-932484

A mild promoter such as Yb(OTf)₃ allows selective activation of glycosyl trichloroacetimidate building blocks in the presence of glycosyl (N-phenyl)trifluoroacetimidates with a similar pattern of protecting groups. This selectivity has been exp

Full text of DOI:10.1055/s-2006-932484

LETTER
583
Tunable Activation of Glycosyl Trichloro- and (N-phenyl)trifluoro-
acetimidates with Ytterbium(III) Triflate: One-Pot Synthesis of
Trisaccharides under Catalytic Conditions
One-Pot Synthesis of
T
a
risaccharid
t
es und
t
e
lytic
C
ondi
otions Adinolfi, Alfonso Iadonisi,* Alessandra Ravidà
Dipartimento di Chimica Organica e Biochimica, Università degli Studi di Napoli Federico II, Via Cynthia 4, 80126 Napoli, Italy
Fax +39(081)674393; E-mail: iadonisi@unina.it
Received 6 December 2005
sides) whose selective activation can be tuned by the
proper choice of the experimental conditions.3c,6
Abstract: A mild promoter such as Yb(OTf)3 allows selective acti-
vation of glycosyl trichloroacetimidate building blocks in the pres-
ence of glycosyl (N-phenyl)trifluoroacetimidates with a similar
pattern of protecting groups. This selectivity has been exploited in
the one-pot assembly of two different trisaccharides in good overall
yields. In contrast to other reported procedures, a catalytic amount
of promoter is sufficient to trigger both glycosidation steps of the
sequential process.
The one-pot multiglycosidation procedures are more
commonly accomplished with thioglycosides.7 This is not
surprising if one considers that partially non-protected
thioglycosides, the necessary building blocks for this
purpose, can be routinely prepared. Glycosyl fluorides,
bromides,8 selenides, sulfoxides9 and underivatized
hemiacetals10 have also been used, especially in synthetic
schemes relying on orthogonal activation.4 These men-
tioned methodologies are all based on activation systems
entailing at least a stoichiometric reagent (NIS, triflic
anhydride, phenyl sulfoxide, silver triflate, Cp2HfCl2,
BF3·OEt2, etc). In contrast, use of glycosyl trichloro-
acetimidates11 in multiglycosidation approaches is seri-
ously restricted by the difficult preparation of saccharidic
derivatives equipped with the trichloroacetimidate leav-
ing group at the anomeric position while bearing a free ac-
cepting hydroxyl functionality. Indeed, the installation of
the trichloroacetimidate leaving group is commonly car-
ried out by reacting the sugar hemiacetal with trichloro-
acetonitrile in the presence of a catalytic amount of a base.
Under similar conditions non-anomeric hydroxyl groups
of sugars are also known to react, so that the trichloro-
acetimidate functionality may also be exploited for
protection of non-anomeric alcohols.12 As a matter of fact,
use of glycosyl trichloroacetimidates in multiglycosida-
tion approaches has been limited to the attachment of
fragments at the non-reducing terminus of the targets and
in combination with donors orthogonally activated under
stoichiometric conditions, such as thio- and pentenyl
glycosides.13
Key words: carbohydrates, glycosidations, ytterbium(III) triflate,
solvent effects, stereoselectivity
One of most important recent advances in oligosaccharide
synthesis is represented by the development of synthetic
procedures enabling the construction of multiple glyco-
sidic bonds in a one-pot fashion. These advances were
strongly elicited by the recognition of the dramatic influ-
ence exerted by protecting groups on the reactivity of the
glycosyl donors, an observation that has been elaborated
in the ‘armed’ and ‘disarmed’ concept.1 This tunable reac-
tivity may be exploited in the sequential connection of
several building blocks all bearing an identical leaving
group.2,3 Recently, this approach culminated in the devel-
opment of a computer-assisted planning of oligosaccha-
ride synthesis based on the preliminary assessment of the
relative reactivity for a great number of protected or par-
tially protected thioglycoside donors.2
In an alternative conceptual approach, the one-pot sequen-
tial multiglycosidation process can also take advantage of
an available set of glycosyl donors activated under ortho-
gonal conditions.4 A further option is represented by the
preactivation of a thioglycoside building block (donor)
with a stoichiometric promoter and the subsequent addi-
tion of a partially protected thioglycoside which is intend-
ed to act at this stage as the acceptor, and the iteration of
the sequence until the desired elongation is achieved.5
This approach allows one to circumvent the normal reac-
tivity of the building blocks, i.e. a disarmed thioglycoside
can be selectively activated in the coupling with an armed
thioglycoside. A less common approach contemplates the
use of residues equipped with analogous but differentiated
leaving groups (for example thioaryl and thioethyl glyco-
Recently, Yu and co-workers have introduced glycosyl
(N-phenyl)trifluoracetimidates as a class of analogues of
trichloroacetimidate donors.14 On the other hand, in the
course of our investigation aimed at establishing the de-
velopment of glycosidation procedures relying on mois-
ture stable promoters such as ytterbium(III) triflate,15 we
have realized that the activation of these novel donors is
entailing relatively more forced conditions than their
trichloroacetimidate analogues with a similar protection
pattern. For example, the coupling in nitrile solvents be-
tween the trichloro donor 2 (1.4 equiv) and acceptor 1 (1
equiv) proceeds at –30 °C and requires a very low amount
of catalyst (3%) whereas higher temperatures and
SYNLETT 2006, No. 4, pp 0583–0586
0
2.
0
3.
2
0
0
6
Advanced online publication: 20.02.2006
DOI: 10.1055/s-2006-932484; Art ID: G39305ST
© Georg Thieme Verlag Stuttgart · New York

584
M. Adinolfi et al.
LETTER
amounts of promoter (10%) are needed with the fluori- readily accessible 2,3,4-tri-O-benzyl glucopyranose18 was
nated donor 3 (Scheme 1).
reacted with (N-phenyl)trifluoroacetimidoyl chloride in
the presence of a slight excess of K2CO3 in acetone to
yield the desired derivative 5 in a satisfying isolated yield
(Scheme 2).19
O
OH
O
O
OH
O
NPh
CF3
O
OH
O
O
a
BnO
BnO
1
BnO
BnO
OH
O
+
+
OBn
NPh
CF3
OBn
OBn
O
OBn
5
O
BnO
BnO
BnO
BnO
O
Scheme 2 Reagents and conditions: a) (N-phenyl)trifluoro-
acetimidoyl chloride (2 equiv), K2CO3 (1.1 equiv), acetone, r.t., 66%
yield.
BnO
OBn
O
NH
Cl3C
3
2
NPh
OBn
O
b
OH
O
a
BnO
BnO
BnO
BnO
O
CF3
+
O
BnO
BnO
BnO
BnO
O
O
OBn
O
O
NH
O
Cl3C
5
2
OBn
O
O
a
4
OBn
O
Scheme 1 Reagents and conditions: a) Yb(OTf)3 (0.03 equiv),
MeCN–t-BuCN 19:1, –30 °C, 1 h, 86% yield, a:b 9:8; b) Yb(OTf)3
(0.10 equiv), MeCN–t-BuCN 6:1, from –25 °C to r.t., 5 h, 95% yield,
a:b >10.
BnO
BnO
NPh
O
O
BnO
BnO
BnO
O
CF3
OBn
O
In both these experiments the lanthanide salt was added as
a solution in pivalonitrile, the beneficial effect of such a
cosolvent on both rate and b-selectivity having been re-
cently disclosed.16 This different behavior suggested the
feasible development of a one-pot multiglycosidation
procedure based on: i) selective activation of a trichloro-
acetimidate donor in the presence of a (N-phenyl)trifluo-
OH
O
O
b
O
O
O
1
OBn
O
BnO
BnO
O
O
BnO
BnO
O
O
O
roacetimidate derivative bearing
a free hydroxyl
BnO
O
functionality (acting as the acceptor in the first glycosida-
tion step), and ii) the subsequent addition of a further new
acceptor and the adjustment of the conditions to achieve
the activation of the less-reactive trifluoroacetimidate
leaving group. For the accomplishment of this scheme the
OBn
6
O
Scheme 3 Reagents and conditions: a) MeCN, Yb(OTf)3 (0.03 equiv)
in t-BuCN, –30 °C, 30 min; b) 1 in MeCN, Yb(OTf)3 (0.07 equiv) in
synthetic access to a partially protected glycosyl (N- t-BuCN, from –30 °C to r.t., 5 h.
phenyl)trifluoroacetimidate is necessary. In contrast to
trichloroacetimidates, these derivatives appear less
The successful access to this building block prompted us
difficult to be prepared. Indeed, the installation of (N-
phenyl)trifluoroacetimidate group entails a substitution
reaction with (N-phenyl)trifluoroacetimidoyl chloride in
the presence of a stoichiometric amount of a mild base
(for instance K2CO3). Use of one equivalent of the base
should allow the selective functionalization of the hemi-
acetal hydroxyl group in the presence of a second alcohol-
ic function owing to the higher acidity of the former.
Actually, in a recent report Yu and co-workers have
attained this kind of selective functionalization on a di-
saccharide substrate.17 However, in that example the non-
anomeric hydroxyl was barely accessible so that the high
selectivity observed may be ascribed to steric crowding.
To demonstrate the generality of this selectivity the
to test the ‘one-pot’ synthesis of the model trisaccharide 6
(Scheme 3). Initial mixing of 2 (1.4 equiv) and 5 (1 equiv)
in acetonitrile at –30 °C in the presence of a low amount
of Yb(OTf)3 (0.03 equiv) led to the consumption of the
more reactive compound 2 in less than one hour (TLC).
Then acceptor 1 (1.4 equiv) was added together with a
further amount of lanthanide triflate (0.07 equiv) and the
mixture was allowed to slowly warm to room tempera-
ture. The desired trisaccharide was thus obtained in 55%
yield slightly contaminated by anomeric by-products
containing a-glycosidic bonds.20
To demonstrate the applicability of the approach also in
ether solvents, generally adopted for obtaining the prefer-
ential generation of a-glycosides in the absence of a
Synlett 2006, No. 4, 583–586 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Trisaccharides under Catalytic Conditions
585
participating effect on the donor, the protocol was exam- In this case the one-pot synthesis was performed in a
ined for the synthesis of the mannan trisaccharide 7 solvent mixture containing dioxane and diethyl ether to
(Scheme 5) representing the protected form of an impor- maximize the a-selectivity of the Yb(OTf)3-promoted
tant epitope of mannans from Saccharomyces cerevisi- glycosidation steps as suggested by our previous observa-
ae.21 To this aim, trifluoroacetimidate derivative 8, with tions.15 The initial coupling between 8 (1 equiv) and 9 (1.4
the free 3-OH, was readily prepared according to the se- equiv) was performed at –10 °C under the agency of cata-
quence illustrated in Scheme 4. Known allyl 3-O-allyl- lytic Yb(OTf)3 (0.03 equiv, Scheme 5). After one hour,
2,3,6-tri-O-benzyl-a-mannopyranoside22 was submitted acceptor 10 (1.4 equiv) was added to the mixture together
to a sequence of double deallylation and regioselective with an additional amount of promoter (0.07 equiv) and
anomeric installation of the trifluoroacetimidate group the temperature was allowed to rise. Chromatographic
that afforded the desired building block 8.19
purification of the mixture afforded 7 as the only detect-
able trisaccharide in a good 40% overall yield.23
OBn
O
OBn
O
BnO
BnO
AllO
BnO
BnO
HO
It should be noted that this result is comparable with the
overall glycosidation yields reported in a recent synthesis
of the analogous sequence by a conventional stepwise
approach,24 and with the results obtained in the one-pot
synthesis of similar mannan sequences.4d On the other
hand, to the best of our knowledge, the here-reported
syntheses are representing the first examples of one-pot
preparation of trisaccharides under catalytic activation (an
overall 10% amount of promoter is sufficient for both
glycosidation steps).
a
OAll
OH
b
OBn
O
BnO
BnO
HO
O
8
NPh
F3C
In conclusion, we have reported that the different reactiv-
ity of glycosyl trichloro- and (N-phenyl)trifluoroacetim-
idates can be suitably exploited for the one-pot assembly
of trisaccharides without using the stoichiometric activa-
tion of the donors. In addition, a good stereocontrol was
achieved without resorting to donors equipped with ‘dis-
arming’ participating groups. In perspective, the inclusion
of electronically disarmed building blocks in the proposed
approach would offer a further element of flexibility,
which can be useful for the one-pot assembly of even
longer sequences.
Scheme 4 Reagents and conditions: a) PdCl2 (cat.) in MeOH, filtra-
tion; b) (N-phenyl)trifluoroacetimidoyl chloride (2 equiv), K2CO3
(1.1 equiv), acetone, r.t.; 38% yield over two steps.
OBn
O
BnO
BnO
BnO
OBn
O
BnO
BnO
HO
+
O
O
NH
NPh
Cl3C
9
8
F3C
a
OBn
BnO
BnO
BnO
Acknowledgment
O
OBn
This research was supported by MIUR (PRIN 2004-5) and Regione
Campania. NMR and MS facilities of CIMCF (Centro Interdiparti-
mentale di Metodologie Chimico Fisiche dell’Università ‘Federico
II’ di Napoli) are acknowledged.
OBn
O
BnO
O
O
NPh
F3C
References and Notes
OH
O
BnO
BnO
BnO
(1) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B. J. Am. Chem. Soc. 1988, 110, 5583.
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10
OAll
OBn
O
BnO
BnO
BnO
OBn
OBn
O
BnO
O
BnO
BnO
O
O
7
BnO
OAll
Scheme 5 Reagents and conditions: a) 4:1 toluene–Et2O, Yb(OTf)3
(0.03 equiv) in dioxane, –10 °C, 1 h; b) 10 in 4:1 toluene–Et2O,
Yb(OTf)3 (0.07 equiv) in dioxane from –10 °C to r.t., 3 h.
(3) (a) Ley, S. V.; Priepke, H. W. M. Angew. Chem., Int. Ed.
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Synlett 2006, No. 4, 583–586 © Thieme Stuttgart · New York

586
M. Adinolfi et al.
LETTER
1998, 51. (c) Fridman, M.; Solomon, D.; Yogev, S.; Baasov,
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CDCl3): d = 7.50–6.80 (aromatic protons), 6.42 (1 H, br s, H-
1), 4.95–4.55 (benzyl CH2), 4.08 (1 H, td, J2,3 = 3.3 Hz,
(4) (a) Grice, P.; Ley, S. V.; Pietuszka, J.; Priepke, H. W. M.;
Walther, E. P. E. Synlett 1995, 781. (b) Cheung, M.-K.;
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Lett. 2004, 33, 10. (i) Tanaka, H.; Adachi, M.; Takahashi, T.
Tetrahedron Lett. 2004, 45, 1433.
J3,OH = J3,4 = 9.3 Hz, H-3), 4.00–3.70 (5 H), 2.45 (d, 3-OH).
13C NMR (50 MHz, CDCl3): d = 143.4, 138.1, 138.0, 137.1,
128.7–127.5, 124.4, 120.6, 119.4, 94.7 (C-1), 76.0, 75.6,
75.1, 73.8, 73.4, 72.8, 71.3, 68.6.
(20) Procedure for the One-Pot Synthesis of 6.
Trichloroacetimidate 2 (38 mg, 56 mmol) and trifluoro-
acetimidate 5 (25 mg, 40 mmol) were co-evaporated three
times in anhyd toluene and then, after the addition of freshly
activated acid-washed molecular sieves, dissolved in MeCN
(0.5 mL). The mixture was cooled at –30 °C and then a
solution of Yb(OTf)3 (0.7 mg, 1.2 mmol) in pivalonitrile (30
mL) was added. After consumption of the trichloro-
acetimidate donor (1 h), a solution of acceptor 1 (13 mg, 56
mmol) in MeCN (0.9 mL) and a further aliquot of Yb(OTf)3
(1.6 mg, 2.8 mmol) in pivalonitrile (70 mL) were added and
the mixture was allowed to warm spontaneously to r.t. A few
drops of pyridine were added and the mixture was filtered on
a short pad of silica gel. The residue was chromatographed
on a silica gel column eluted with PE–EtOAc mixtures to
yield trisaccharide 6 (27 mg, 55% yield) slightly
(5) Huang, X.; Huang, H.; Wang, H.; Ye, X.-S. Angew. Chem.
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contaminated by minor amounts of anomers.
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Spectroscopic data of 6: 1H NMR (400 MHz, CDCl3): d =
7.40–7.22 (aromatic protons), 5.75 (1 H, d, J1,2 = 4.8 Hz, H-
1 Gal), 5.10–4.40 (16 H), 4.43 and 4.41 (2 H, 2 × d, J1,2 = 7.2
Hz, 2 × H-1 Glc), 4.28 (1 H, dd, J2,3 = 2.4 Hz, H-2 Gal),
4.25–3.40 (15 H), 1.50, 1.38, 1.30, 1.22 (12 H, 4 × s,
acetonides CH3). 13C NMR (50 MHz, CDCl3): d = 138.7,
138.6, 138.5, 138.2, 128.3–127.7, 109.3, 108.5, 104.4,
104.0, 96.3, 84.8, 84.5, 81.8, 81.5, 78.0, 77.8, 77.3, 77.1,
76.5, 75.7, 75.6, 75.0, 74.8, 74.7, 74.6, 74.2, 73.5, 71.3, 70.7,
70.5, 70.0, 68.9, 68.6, 67.4, 26.1, 25.9, 25.0, 24.4.
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Barnes, R. M. R. Carbohydr. Polym. 1996, 30, 243.
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Paulsen, B. S.; Wold, J. K.; Broker, M.; Barnes, R. M. R.;
Hounsell, E. F. Glycoconjugate J. 1998, 15, 815.
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Communication at 13th European Carbohydrate
Symposium, Bratislava, Slovakia, August 22-26, 2005,
abstract OP 48.
(22) Ogawa, T.; Yamamoto, H. Carbohydr. Res. 1985, 137, 79.
(23) Procedure for the One-Pot Synthesis of 7.
Trichloroacetimidate 9 (58 mg, 85 mmol) and trifluoro-
acetimidate 8 (37 mg, 60 mmol) were coevaporated three
times in anhyd toluene and then, after the addition of freshly
activated acid washed molecular sieves, dissolved in 4:1
toluene–Et2O (0.5 mL). The mixture was cooled at
(17) Sun, J.; Han, X.; Yu, B. Synlett 2005, 437.
(18) This compound was readily accessed by Zemplen
deacetylation of the corresponding 1,6-di-O-acetylated
precursor obtained as described in: Lam, S. N.; Gevay-
Hague, J. Carbohydr. Res. 2002, 337, 1953.
–10 °C and then a solution of Yb(OTf)3 (1.2 mg, 1.7 mmol)
in dioxane (100 mL) was added. After consumption of the
trichloroacetimidate donor (ca. 30 min), a solution of
acceptor 10 (41 mg, 84 mmol) in 4:1 toluene–Et2O (1.2 mL)
and a further aliquot of Yb(OTf)3 (2.8 mg, 4.0 mmol) in
dioxane (230 mL) were added and the mixture was allowed
to warm spontaneously to r.t. After ca. 3 h, a few drops of
pyridine were added and the mixture was filtered on a short
pad of silica gel. The residue was chromatographed on a
silica gel column eluted with PE–EtOAc mixtures to yield
trisaccharide 7 (34 mg, 40% yield) as an oil.
(19) Procedure for the Synthesis of Glycosyl (N-Phenyl)tri-
fluoroacetimidates from Diols.
(N-Phenyl)trifluoroacetimidoyl chloride (55 mL, 0.45
mmol) was added at r.t. to a mixture of 2,3,4-tri-O-benzyl-
glucopyranose (100 mg, 0.22 mmol) and K2CO3 (37 mg,
0.26 mmol) in acetone (2 mL). After ca. 2 h, a few drops of
pyridine were added and the mixture was filtered on a short
pad of neutral alumina (eluent: CH2Cl2). The residue was
chromatographed on neutral aluminum oxide I (eluent: PE–
EtOAc from 85:15 to 7:3) to yield 5 (91 mg, yield 66%) as
an oil. An analogous procedure was adopted for the
synthesis of 8 (38% over two steps).
Spectroscopic data of 7: 1H NMR (400 MHz, CDCl3): d =
7.40–6.90 (aromatic protons), 5.83 (1H, m, -CH2CH=CH2),
5.25–5.22 (2 H, H-1 and -CH2CH=CHtrans), 5.20 (1 H, d,
J1,2 = 1.2 Hz, H-1), 5.13 (1 H, br d, J1,2 = 10.4 Hz,
-CH2CH=CHcis), 4.97 (1 H, d, J1,2 = 1.2 Hz, H-1), 4.90–4.30
(20 H), 4.21 (1 H, dd, J2,3 = 3.2 Hz, J3,4 = 8.4 Hz, H-3), 4.15–
3.55 (19 H). 13C NMR (50 MHz, CDCl3): d = 138.9, 138.6,
138.5, 138.4, 138.3, 13.9, 128.3–127.0, 117.1, 99.5, 99.4,
98.2, 80.1, 79.9, 75.5, 75.3, 75.2, 75.0, 74.8, 73.3, 72.6, 72.3,
72.1, 71.8, 69.4, 68.9, 67.8.
Spectroscopic data of 5 (b-anomer): 1H NMR (300 MHz,
CDCl3): d = 7.60–6.80 (aromatic protons), 5.75 (1 H, br s, H-
1), 5.00–4.40 (benzyl CH2), 4.00–3.20 (6 H). 13C NMR (50
MHz, CDCl3): d = 143.3, 138.3, 137.8, 137.6, 129.3–127.8,
126.2, 124.4, 120.6, 119.3, 97.0 (C-1), 84.3, 81.0, 76.7, 76.0,
75.6, 75.2, 75.1, 61.4.
(24) Carpenter, C.; Nepogodiev, S. A. Eur. J. Org. Chem. 2005,
3286.
Synlett 2006, No. 4, 583–586 © Thieme Stuttgart · New York