Solvent-free, under air selective synthesis of α-glycosides adopting glycosyl chlorides as donors

Article abstract of DOI:10.1039/d0ob01024c

α-Glycosides are highly relevant synthetic targets due to their abundance in natural oligosaccharides involved in many biological processes. Nevertheless their preparation is hampered by several issues, due to both the strictly anhydrous conditions typically required in glycosylation procedures and the non-trivial achievement of high α-stereoselectivity, one of the major challenges in oligosaccharide synthesis. In this paper we report a novel and efficient approach for the highly stereoselective synthesis of α-glycosides. This is based on the unprecedented solvent-free combination of triethylphosphite, tetrabutylammonium bromide and N,N-diisopropylethylamine for the activation of glycosyl chlorides under air. Despite the relative stability of glycosyl chlorides with respect to more reactive halide donors, the solvent-free procedure allowed a wide set of α-glycosides, including biorelevant fragments, to be obtained in much shorter times compared with similar glycosylation approaches in solution. The presented method features a wide target scope and functional group compatibility, also serving with partially disarmed substrates, and it does not require a high stoichiometric excess of reagents nor the preparation of expensive precursors. The solvent-free glycosylation can be even directly performed from 1-hydroxy sugars without purification of the in situ generated chloride, providing an especially useful opportunity in the case of highly reactive and labile glycosyl donors. This journal is

Full text of DOI:10.1039/d0ob01024c

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Solvent-free, under air selective synthesis of
α-glycosides adopting glycosyl chlorides as
donors†
Cite this: DOI: 10.1039/d0ob01024c
Serena Traboni, * Giulia Vessella,
Emiliano Bedini
and Alfonso Iadonisi*
α-Glycosides are highly relevant synthetic targets due to their abundance in natural oligosaccharides
involved in many biological processes. Nevertheless their preparation is hampered by several issues, due
to both the strictly anhydrous conditions typically required in glycosylation procedures and the non-trivial
achievement of high α-stereoselectivity, one of the major challenges in oligosaccharide synthesis. In this
paper we report a novel and efficient approach for the highly stereoselective synthesis of α-glycosides.
This is based on the unprecedented solvent-free combination of triethylphosphite, tetrabutylammonium
bromide and N,N-diisopropylethylamine for the activation of glycosyl chlorides under air. Despite the
relative stability of glycosyl chlorides with respect to more reactive halide donors, the solvent-free pro-
cedure allowed a wide set of α-glycosides, including biorelevant fragments, to be obtained in much
shorter times compared with similar glycosylation approaches in solution. The presented method features
a wide target scope and functional group compatibility, also serving with partially disarmed substrates,
and it does not require a high stoichiometric excess of reagents nor the preparation of expensive precur-
sors. The solvent-free glycosylation can be even directly performed from 1-hydroxy sugars without purifi-
cation of the in situ generated chloride, providing an especially useful opportunity in the case of highly
reactive and labile glycosyl donors.
Received 18th May 2020,
Accepted 15th June 2020
DOI: 10.1039/d0ob01024c
rsc.li/obc
with suitable groups capable of directing the approach of the
incoming nucleophilic acceptor.3 Installation of these groups
Introduction
Carbohydrates are fundamental molecules involved in many entails extra synthetic steps and the use of expensive functio-
biological processes. This warrants the broad interest of nalizing agents. Other strategies have been designed to encou-
current research towards new carbohydrate-based therapeutics. rage a SN2-like glycosylation pathway favoring 1,2-cis glycoside
To this aim, chemical synthesis is routinely exploited to generation.4 Among these methods, SN2-like α-glycosylations
produce substantial amounts of pure oligosaccharides and can be achieved through the in situ conversion of the donor
development of ever more practical synthetic methods in this into a reactive β-adduct promoted by exogeneous nucleophiles.
field is crucial. Indeed, glycosylation reactions are burdened To this aim, nucleophilic modulators such as phosphinoxides,
by experimental issues due to the application of demanding sulfoxides, thioethers and amides,5 or urea and thiourea
procedures and ensuring a rigorously anhydrous atmosphere. organocatalysts in combination with phosphorus additives6 or
In addition, the achievement of high stereoselectivity is highly a phenanthroline organocatalyst7 have been used. In this
challenging, especially in the synthesis of 1,2-cis glycosides, frame, since the introduction of the halide ion catalyzed glyco-
due to the lack of a reliable strategy providing absolute stereo- sylation,8 the synthesis of several α-glycosides was accom-
control as the neighbouring group participation is exploited plished through the in situ anomerization of benzylated glyco-
for 1,2-trans glycosylations.1 A large number of approaches syl halides promoted by an external halide source (Scheme 1).
have been proposed to address this issue,2 the most effective When involving a β-bromide intermediate, this strategy
one requiring a preliminary functionalization of the donor
Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4,
I-80126 Naples, Italy. E-mail: serena.traboni@unina.it, iadonisi@unina.it
†Electronic supplementary information (ESI) available: Synthesis of glycosyl
donors and acceptors and characterization of the obtained products including
copies of NMR spectra. See DOI: 10.1039/d0ob01024c
Scheme 1 α-Glycosylation approach based on the in situ anomeriza-
tion of glycosyl halides.
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provides high α-selectivity but its scope is restricted to highly spite of their easier handling than their iodinated and bromi-
reactive substrates (e.g. per-O-benzylated fucosyl donors) nated counterparts. Instead, herein we report novel
taking in any case extended reaction times (up to days).8,9
α-glycosylation method based on the efficient activation of gly-
a
A higher efficiency, especially with primary acceptors, could cosyl chlorides under air in the absence of any solvent.
be achieved by adopting more reactive β-iodides10 although Reactions are mediated by a small stoichiometric excess of
with the use of a highly toxic solvent (dry benzene) and high DIPEA as the base and a combination of triethylphosphite
stoichiometric excess of the donor and the halide promoter. In and tetrabutylammonium bromide as promoters, affording
the arsenal of α-glycosylation methods, one-pot dehydrative α-glycosides in short times with high stereoselectivity.
strategies are also appreciated since they rely on the in situ con-
version of 1-hydroxy sugars to reactive halide,11 oxosulfo-
nium12 or oxophosphonium13 donors which are directly
coupled with the nucleophilic acceptor. Nevertheless, reagents
Results and discussion
for the in situ anomeric activation are often sensitive, expen-
sive or non-commercially available; in addition, long reaction
times, use of toxic or high boiling solvents, a high excess of
the acceptor and modest stereoselectivity can be further limit-
ations of these one-pot methods.
In the last few years, we focused our research on the devel-
opment of practical protocols for regioselective derivatization
of carbohydrates14 featuring the possibility to perform reac-
tions under air with high efficiency, including multiple one-
pot functionalizations, under solvent-free conditions. In this
frame, we introduced a solvent-free fast preparation of glycosyl
chlorides based on a PPh3/hexachloroacetone system14f which
spurred us to consider their use in the development of a practi-
cal α-glycosylation procedure. Due to their relatively low reac-
tivity, chlorides are seldom preferred as glycosyl donors, in
Initially, the coupling of galactosyl chloride 1 with acceptor 2,
yielding the α-gal epitope disaccharide 3, was studied as the
model reaction (Table 1).
Inspired by previous solvent-free reactions mediated by
neat liquid amines,14 we firstly employed a slight stoichio-
metric excess of DIPEA as the base, and a sub-stoichiometric
amount of TBAB as an exogeneous halide source, obtaining 3
in 4.5 h in 75% isolated yield, with exclusive α-selectivity. In
an attempt to minimize the generation of hemiacetal 4
and glycal 5 side-products, we extensively tested alternative
bases and nucleophilic additives. In this survey, we also
evaluated some liquid bases supposed to be nucleophilic
enough to act as mild promoters in place of the exogenous
halide ions. Among these, cyclic tertiary amines such as
N-methylmorpholine and N-ethylmorpholine provided dis-
Table 1 Optimization of a solvent-free glycosylation procedure
Entry
Base (equiv.)a
Additive (equiv.)a
Temperature, time
Isolated yield of 3 (α/β)b
1
2
3
4
5
6
7
8
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
TBAB (0.6)
TBAB (1.2)
TBAI (1.2)
LiI (1.5)
LiI (1.5)
LiI (0.1)
LiI (0.1)
—
80 °C, 4.5 h
100 °C, 2.5 h
100 °C, 2.5 h
100 °C, 1 h
60 °C, 3 h
70 °C, 4 h
90 °C, 5.5 h
80 °C, 7 h
90 to 120 °C, 12 h
120 °C, 5 h
100 °C, 6 hd
100 to 130 °C, 8 hd
100 °C, 3 h
90 °C, 5 h
90 °C, 5 h
90 °C, 6 h
90 °C, 7 h
90 °C, 2 h
90 °C, 7 h
90 °C, 7.5 h
75% (only α)
75% (only α)
60% (only α)
<15% (2.5 : 1)
20% (2.5 : 1)
49% (2.5 : 1)
50% (2.5 : 1)
52% (3.5 : 1)
62% (3.2 : 1)
85% (3 : 1)
—
DIPEA (3.5)
TEA (7.5)c
9
N-Methylmorpholine (7.5)c
N-Ethylmorpholine (5)
Imidazole (3.5)
Imidazole (3.5)
DIPEA (3.5)
—
—
—
10
11
12
13
14
15
16
17
18
19
20
TBAB (1.2)
HMPA (1)
(PhS)2 (1)
(PhSe)2 (1)
PPh3 (1)
PBu3 (1)
PBr3 (1)
—
53% (4.5 : 1)
54% (3 : 1)
65% (3 : 1)
73% (7.2 : 1)
70% (6.7 : 1)
—
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
DIPEA (3.5)
P(OEt)3 (1)
P(OEt)3 (0.7) + TBAB (0.3)
87% (7 : 1)
89% (only α)
a Equivalents refer to the glycosyl acceptor. b The α/β ratio in parenthesis refers to the isolated product. c 3.5 equivalents were initially added, fol-
lowed by the addition of further 2 equivalent aliquots after 3 h and 5 h, respectively. d TLC analysis displayed quantitative consumption of the
chloride after 1 h.
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crete yields but poor stereoselectivity and required harsher cedure was then assessed to obtain several α-glycosidic bonds
reaction conditions (see Table 1, entries 9 and 10). Therefore, (Table 2).
optimization experiments proceeded by evaluating the use of
α-1,6-Linked disaccharides 6 and 7 were efficiently accessed
neat DIPEA in combination with nucleophilic additives from a per-O-benzylated glucosyl chloride donor, in both cases
alternative to halide ions. Hemiacetal 4 was still identified as with a high stereoselectivity in comparison with typical glyco-
the main byproduct together with traces of glycal 5 when sylations of reactive primary alcohols. Per-O-benzylated man-
either oxygenated or chalcogen nucleophiles such as hexa- nosyl chloride was also efficiently activated in the construction
methylphosphoramide, phenyl disulphide and phenyl disele- of α-linked di-mannosides 8 and 9, key structural elements in
nide (see Table 1, entries 13–15) were used as glycosylation natural high-mannose glycans. α-1,4-Linked disaccharide 10,
promoters. Phosphorus(III) nucleophiles proved to be particu- also occurring in highly relevant structures (e.g. globo-series
larly efficient promoters in the solvent-free glycosylation glycans), was easily obtained with high α-selectivity albeit in a
mediated by neat DIPEA and an especially good result in lower yield, likely due to the poor reactivity of the axial O-
terms of yield and stereoselectivity was achieved with triethyl- 4 hydroxyl group of galactose acceptors. The method was
phosphite (Table 1, entry 19) which is, to the best of our found to be also compatible with benzylidene protected accep-
knowledge, an unprecedented α-glycosylation promoter. tors, as demonstrated by the synthesis of α-1,3-linked disac-
Indeed, triethylphosphite had been previously used in glyco- charides 11, 12 and 13 in high yields. Furthermore, the feas-
sylations essentially as a quenching reagent to prevent ible synthesis of disaccharides 14, 15 and 16 highlighted that
decomposition of the glycosylation product.15 An optimized the efficiency of the solvent-free procedure was not affected by
yield of 89% with exclusive α-selectivity could be eventually the replacement of benzyl ethers with much more disarming
obtained upon combining P(OEt)3 with a catalytic amount of protecting groups such as benzoyl esters on either the donor
TBAB (Table 1, entry 20). The scope of this optimized pro- or the acceptor. Another significant result supporting the wide
Table 2 Solvent-free synthesis of α-glycosides from glycosyl chlorides promoted by P(OEt)3/TBAB/DIPEA under aira
a Obtained products, reaction times and isolated yields (the α/β ratio reported in parentheses also refers to the isolated product).
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Table 3 Optimization of a one-pot chlorination/glycosylation solvent-free procedure from 1-hydroxy sugars
Entry 1st step conditions (equiv.)a
2nd step conditions (equiv.)b
Product, isolated yield (α/β)c
1
PPh3 (1.5), (CCl3)2CO (1.5), 70 °C,
45 min
No glycosylation reaction
2
PPh3 (1.5), CCl4 (1.5), 70 °C, 1 h
2, P(OEt)3 (0.7), TBAB (0.3), DIPEA (3.5), 90 °C,
4.5 h
3
4
PPh3 (1.5), CCl3CN (1.5), 70 °C, 2h
PPh3 (1.5), CCl3CN (1.5), 70 °C, 2h
2, P(OEt)3 (0.7), TBAB (0.3), DIPEA (3.5), 90 °C, 5 h
3, 60% (6.6 : 1)
5
PPh3 (1.5), CCl3CN (1.5), 70 °C, 2 h
18, P(OEt)3 (0.7), TBAB (0.15), DIPEA (3.5), 90 °C,
5 h
19, 75% (6 : 1)
a Equivalents refer to the hemiacetal substrate. b Equivalents refer to the glycosyl acceptor. c The α/β ratio in parentheses refers to the isolated
product.
applicability of the procedure in oligosaccharide synthesis was
the efficient assembly of trisaccharide 17 using per-O-benzy- formed in the absence of solvent have been seldom described
lated maltosyl chloride as a disaccharide donor. in the literature and only in a few cases addressed for the con-
It is worth underlining that glycosylation reactions per-
In order to increase further the simplicity of our struction of glycosidic linkages connecting saccharide resi-
α-glycosylation approach, we also investigated a one-pot glyco- dues. Most of the glycosylation procedures claimed as solvent-
sylation protocol entailing in situ anomeric chlorination of free are indeed targeted towards obtaining simple alkyl glyco-
1-hydroxy sugars. This variation was initially explored for the sides and typically involve a large stoichiometric excess of the
synthesis of 3. To this aim, solvent-free chlorination of com- acceptor and in some cases the assistance of microwave
mercial hemiacetal 4 was first performed, followed by the irradiation.17 Particularly noteworthy in this context are
addition of acceptor 2, P(OEt)3, TBAB and DIPEA to the crude mechanochemical approaches enabling solvent-free glycosyla-
chlorination mixture. A screening of chlorinating agents for tions in a ball mill; such methods have been reported with
the first step evidenced the best performance of the PPh3/ both glycosyl bromide donors for the synthesis of β-alkyl/aryl
CCl3CN combination (see Table 3).
glycosides18 and with armed thioglycoside donors, in this
In the following experiments for the synthesis of glycoside latter case also coupled with some primary saccharide
19, further optimization was achieved by halving the amount acceptors.19
of TBAB, due to minimization of side-product 5 (compare
Some mechanistic hypotheses for the α-glycosylation reac-
entries 4 and 5 in Table 3). Subsequently we also demonstrated tion presented here are summarized in Scheme 2. Reasonably,
the useful applicability of the optimized one-pot procedure in the main reaction pathway involves a glycosyl β-phosphonium
the synthesis of α-fucosides; these are relevant but challenging (or bromide) intermediate then undergoing SN2-like glycosyla-
targets in oligosaccharide synthesis, due to the high instability tion (Scheme 2, pathway A). However, the appreciable minimiz-
of fucosyl donors,16 often not even purifiable by chromato- ation of the hydrolysis side-process (with consequent optimiz-
graphy. As shown in Table 4, using commercial tri-O-benzyl-L- ation of the glycosylation yield) observed in the presence of
fucose 20 as the hemiacetal precursor, an efficient glycosyla- P(OEt)3 as the promoter may suggest its possible involvement
tion could be achieved with different acceptors.
in some alternative, minor mechanisms; for example, P(OEt)3
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Table 4 α-Fucoside synthesis via the one-pot anomeric chlorination/glycosylation procedurea
a Obtained products, reaction times (of the glycosylation step) and isolated yields (the α/β ratio reported in parentheses also refers to the isolated
product). b Equivalents of PPh3 and CCl3CN refer to the hemiacetal substrate, while equivalents of P(OEt)3, TBAB, DIPEA and the glycosyl hemia-
cetal refer to the glycosyl acceptor.
Scheme 2 Proposed mechanistic pathways for TBAB/P(OEt)3-promoted glycosylation.
may act as a mild drying agent and/or recycle the hemiacetal under air and solvent-free conditions. In the presented
side product at high reaction temperature20 by generation of a method, glycosyl chlorides are activated by an unprecedented
transient glycosyl phosphite donor, and then activated21 to combination of P(OEt)3 and TBAB in the presence of a slight
afford the glycoside (Scheme 2, pathway B). These processes stoichiometric excess of neat DIPEA at 90 °C. α-Glycosides are
could be likely catalyzed by the in situ generated DIPEAH+ thus quickly obtained under air with high yields and stereo-
ions, according to our recent findings on the use of selectivity from variously protected donors and acceptors
ammonium species in solvent-free acid catalyzed reactions.14h including poorly reactive precursors. The solvent-free strategy
In an attempt to support this hypothesis, cholestanol 18 (1 is also applicable in a one-pot version, enabling direct glycosy-
equiv.) and hemiacetal 4 (1.5 equiv.) were reacted for 7 h at lation of 1-hydroxy sugars without isolation of the transient
90 °C in a pre-generated mixture of DIPEA and DIPEAH+Cl, and eventually labile glycosyl chloride. In light of the many
obtained by rapid methanolysis of trimethylsilyl chloride in advantages in terms of efficiency, experimental simplicity and
the presence of DIPEA as the base. No reaction was observed cheapness with respect to current glycosylation protocols, we
in the absence of P(OEt)3; instead, the same experiment per- expect that the proposed method might have a large impact in
formed in the presence of 1.5 equiv. or 4 equiv. of the phos- streamlining the synthesis of oligosaccharides.
phite, respectively, afforded glycoside 19 in 8% and 15% iso-
lated yields.
Experimental
General remarks
Conclusions
The whole procedures for glycosylation reactions were per-
In conclusion, we have reported a new method for the syn- formed under air without the use of any drying agent. Solvents
thesis of α-glycosides involving the use of glycosyl chlorides eventually used in the glycosylation procedures described
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below (e.g. for the initial co-evaporation of the donor and solution in a minimal amount of DCM which was readily dis-
acceptor or, where needed, for the in situ addition of the accep- tilled off as the glycosylation step was performed). The flask
tor to the reaction flask) were technical grade solvents which was allowed to cool to room temperature and then the crude
were used as supplied, without any drying pre-treatment. mixture was concentrated under vacuum and subjected to
Reactions were primarily monitored by TLC analysis. After silica-gel chromatography to isolate the pure glycosylation
elution, detection of compounds was performed by soaking product (yields of the obtained products are indicated in
the plates in 5% H2SO4 in ethanol and subsequent heating at Tables 3 and 4).
230 °C. Eventual detection of UV-visible compounds under a
UV lamp preceded the acid treatment. NMR spectra were
recorded in a 400 MHz device.
Conflicts of interest
General procedure for the solvent-free synthesis of
There are no conflicts to declare.
α-glycosides from glycosyl chlorides
The requisite glycosyl acceptor (0.05 mmol, 1 equiv.) and glyco-
syl chloride donor (0.075 mmol, 1.5 equiv.) were first separ-
ately weighted, then dissolved in DCM, combined in a small
round-bottom flask and co-evaporated under reduced pressure
until complete removal of the solvent. Tetrabutylammonium
bromide (4.8 mg, 0.015 mmol, 0.3 equiv.), triethylphosphite
(6.1 μL, 0.035 mmol, 0.7 equiv.) and DIPEA (30.5 μL,
0.175 mmol, 3.5 equiv.) were sequentially added and the
mixture was heated at 90 °C under vigorous stirring, to ensure
the achievement of a homogeneous exposure of all reagents to
each other (e.g. no residues should be left on the neck or other
parts of the flask which fall out of the stirring area). Upon
completion of the reaction (see Table 2 for reaction times), the
flask was allowed to cool to room temperature and the crude
mixture was subjected to silica-gel chromatography to isolate
the pure glycosylation product in the yield indicated in
Table 2.
Acknowledgements
S. T. acknowledges the University of Naples Federico II –
Department of Chemical Sciences for a research fellowship
providing financial support to the present work.
Notes and references
1 G.-J. Boons, Contemp. Org. Synth., 1996, 3, 173.
2 (a) X. Zhu and R. R. Schmidt, Angew. Chem., Int. Ed., 2009,
48, 1900; (b) A. V. Demchenko, Curr. Org. Chem., 2003, 7,
35.
3 (a) S. S. Nigudkar and A. V. Demchenko, Chem. Sci., 2015,
6, 2687; (b) R. A. Mensink and T. J. Boltje, Chem. – Eur. J.,
2017, 23, 17637.
4 (a) T. J. Boltje, J.-H. Kim, J. Park and G.-J. Boons, Org. Lett.,
2011, 13, 284; (b) D. Crich and S. Sun, J. Org. Chem., 1997,
62, 1198.
5 S. K. Mulani, W.-C. Hung, A. B. Ingle, K.-S. Shiau and K.-K.
T. Mong, Org. Biomol. Chem., 2014, 12, 1184.
6 L. Sun, X. Wu, D.-C. Xiong and X.-S. Ye, Angew. Chem., Int.
Ed., 2016, 55, 8041.
7 F. Yu, J. Li, P. M. DeMent, Y.-J. Tu, H. B. Schlegel and
H. M. Nguyen, Angew. Chem., 2019, 131, 7031.
8 R. U. Lemieux, K. B. Hendriks, R. V. Stick and K. James,
J. Am. Chem. Soc., 1975, 97, 4056.
9 (a) B. Doboszewski and A. Zamojski, Carbohydr. Res., 1987,
164, 470; (b) K. Takeo and H. Maeda, J. Carbohydr. Chem.,
1988, 7, 309; (c) A. K. Sarkar, A. K. Ray and N. Roy,
Carbohydr. Res., 1989, 190, 181; (d) D. A. Niedbal and
It is noteworthy that in order to prove the applicability of
the procedure at a larger scale, the synthesis of model disac-
charide 3 was also performed with 1 mmol of a glycosyl accep-
tor with reproducible reaction time, yield and stereoselectivity
as reported in Table 1, entry 20.
General procedure for the solvent-free synthesis of
α-glycosides from 1-hydroxy sugars
The sugar hemiacetal (0.075 mmol) was weighed in a small
round-bottom flask, and then powdered triphenylphosphine
(29.5 mg, 0.113 mmol) and trichloroacetonitrile (11.3 μL,
0.113 mmol) were sequentially added. The mixture was heated
at 70 °C under vigorous stirring, to ensure achieving a homo-
geneous exposure of all reagents to each other (e.g. no residues
should be left on the neck or other parts of the flask which fall
out of the stirring area). Upon completion of the chlorination
step (2 h), the flask was temporarily brought out of the oil bath
R.
Madsen,
Tetrahedron,
2016,
72,
415;
(e) S. A. Verkhnyatskaya, V. B. Krylov and N. E. Nifantiev,
Eur. J. Org. Chem., 2017, 710.
and the requisite glycosyl acceptor (0.05 mmol), TBAB (2.4 mg, 10 (a) M. J. Hadd and J. Gervay, Carbohydr. Res., 1999, 320, 61;
0.0075 mmol), P(OEt)3 (6.1 μL, 0.035 mmol) and DIPEA
(30.5 μL, 0.175 mmol) were added to the mixture. The flask
was placed in an oil bath at 90 °C (temperature required for
(b) S. N. Lam and J. Gervay-Hague, Org. Lett., 2002, 4, 2039;
(c) S. N. Lam and J. Gervay-Hague, J. Org. Chem., 2005, 70,
2387.
the glycosylation reaction) and kept under stirring until com- 11 (a) Y. Nishida, Y. Shingu, H. Dohi and K. Kobayashi, Org.
pletion of the second step (reaction times indicated in Tables
3 and 4) (N.B.: the acceptor was weighed in a small tube and
directly added to the reaction flask as a powder; only if
needed, as in the case of oily compounds, it was added as a
Lett., 2003, 5, 2377; (b) Y. Shingu, Y. Nishida, H. Dohi and
K. Kobayashi, Org. Biomol. Chem., 2003, 1, 2518;
(c) Y. Shingu, A. Miyachi, Y. Miura, K. Kobayashi and
Y. Nishida, Carbohydr. Res., 2005, 340, 2236;
Org. Biomol. Chem.
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View Article Online
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Paper
(d) J. M. Nogueira, S. H. Nguyen and C. S. Bennett, Org. 15 J. D. C. Codée, L. J. van den Bos, R. E. J. N. Litjens,
Lett., 2011, 13, 2814; (e) J. M. Nogueira, J. P. Issa, A.-H.
H. S. Overkleeft, C. A. A. van Boeckel, J. H. van Boom and
A. Chu, J. A. Sisel, R. S. Schum and C. S. Bennett,
G. A. van der Marel, Tetrahedron, 2004, 60, 1057.
Eur. J. Org. Chem., 2012, 4927; (f) I. Pongener, K. Nikitin 16 D. Comegna, E. Bedini, A. Di Nola, A. Iadonisi and
and E. M. McGarrigle, Org. Biomol. Chem., 2019, 17, 7531; M. Parrilli, Carbohydr. Res., 2007, 342, 1021.
(g) M. B. Tatina, D. T. Khong and Z. M. A. Judeh, 17 (a) R. S. Thombal and V. H. Jadhav, J. Carbohydr. Chem.,
Eur. J. Org. Chem., 2018, 2208.
2016, 35, 57; (b) U. Aich and D. Loganathan, Carbohydr.
Res., 2007, 342, 704; (c) S. Rat, D. Mathiron, P. Michaud,
J. Kovensky and A. Wadouachi, Tetrahedron, 2007, 63,
12424; (d) W. Du and Y. Hu, Synth. Commun., 2006, 36,
2035.
12 (a) B. A. Garcia and D. Y. Gin, J. Am. Chem. Soc., 2000, 122,
4269; (b) B. A. Garcia, J. L. Poole and D. Y. Gin, J. Am.
Chem. Soc., 1997, 119, 7597.
13 M. Mossotti and L. Panza, J. Org. Chem., 2011, 76, 9122.
14 (a) M. Giordano and A. Iadonisi, Tetrahedron Lett., 2013, 18 (a) P. R. Patil and K. P. R. Kartha, J. Carbohydr. Chem.,
54, 1550; (b) M. Giordano and A. Iadonisi, J. Org. Chem.,
2014, 79, 213; (c) S. Traboni, E. Bedini and A. Iadonisi,
Beilstein J. Org. Chem., 2016, 12, 2748; (d) S. Traboni,
2008, 27, 411; (b) M. Tyagi, D. Khurana and K. P. R. Kartha,
Carbohydr. Res., 2013, 379, 55; (c) K. P. Sethi and
K. P. R. Kartha, Carbohydr. Res., 2016, 434, 132.
E. Bedini and A. Iadonisi, ChemistrySelect, 2017, 2, 4906; 19 (a) V. Kumar, N. Yadav and K. P. R. Kartha, Carbohydr. Res.,
(e) S. Traboni, E. Bedini, M. Giordano and A. Iadonisi, Adv.
Synth. Catal., 2015, 357, 3562; (f) S. Traboni, F. Liccardo,
E. Bedini, M. Giordano and A. Iadonisi, Tetrahedron Lett.,
2014, 397, 18; (b) V. Kumar, N. Taxak, R. Jangir,
P. V. Bharatam and K. P. R. Kartha, J. Org. Chem., 2014, 79,
3427.
2017, 58, 1762; (g) S. Traboni, E. Bedini and A. Iadonisi, 20 F. W. Hoffmann, R. J. Ess and R. P. Usinger Jr., J. Am.
ChemistrySelect, 2018, 3, 1616; (h) S. Traboni, E. Bedini, Chem. Soc., 1956, 78, 5817.
M. Giordano and A. Iadonisi, Tetrahedron Lett., 2019, 60, 21 H. Kondo, S. Aoki, Y. Ichikawa, R. L. Halcomb, H. Ritzen
1777.
and C.-H. Wong, J. Org. Chem., 1994, 59, 864.
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