Iron(iii) chloride-tandem catalysis for a one-pot regioselective protection of glycopyranosides

Article abstract of DOI:10.1039/c0cc04398b

Tandem catalysis by using iron(iii) chloride hexahydrate leads to carbohydrate building blocks displaying an orthogonal protecting group pattern as illustrated by the regioselective protection of trehalose and maltose disaccharides.

Full text of DOI:10.1039/c0cc04398b

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COMMUNICATION
Iron(III) chloride-tandem catalysis for a one-pot regioselective protection
of glycopyranosidesw
ab
Yann Bourdreux,ab Aurelie Lemetais, Dominique Urbanab and Jean-Marie Beau*ab
´
´
Received 13th October 2010, Accepted 14th December 2010
DOI: 10.1039/c0cc04398b
Tandem catalysis by using iron(III) chloride hexahydrate leads to
carbohydrate building blocks displaying an orthogonal protecting
group pattern as illustrated by the regioselective protection of
trehalose and maltose disaccharides.
In our initial studies, we examined the prototype reductive
etherification of per-O-silylated a-methyl-D-glucopyranoside 1
with benzaldehyde (3 equiv) and triethylsilane (1.1 equiv) in
the presence of a catalytic amount of iron(III) chloride, following
our previously optimized solvent conditions (CH2Cl2 : CH3CN
ratio of 4 : 1).2 The tandem acetalation–reductive etherification
proceeded well with 5 mol% of FeCl3ꢁ6H2O to afford 3-O-
benzyl-4,6-O-benzylidene-D-glucopyranoside 311 (entry 1, Table 1)
in a 77% yield.z Lowering the loading of catalyst to 1 mol%
resulted in a lower 66% yield (entry 2). In contrast with our
previous study using copper(II) triflate, this catalytic system is
not air sensitive and the reaction could be performed easily on
a gram-scale.
For the selective preparation of complex oligosaccharides and
glycoconjugates requiring typically lengthy multi-step routes
for the construction of building blocks, the development of
alternative and efficient strategies continues to be of major
importance in synthetic carbohydrate chemistry. Among the
approaches utilized, catalyzed reactions in tandem are very
attractive since this method increases the efficiency of the
process by reducing the number of chemical steps and the
time-consuming isolation and purification of intermediates.1
We have recently reported a regioselective one-pot protection
of carbohydrates, optimized on persilylated monosaccharides,
employing, as a single catalyst, copper(II) triflate (0.5 to 10 mol%)
usable under easy conditions (0 1C or room temperature).2 A
wide range of useful D-glucopyranose building blocks was also
constructed with a very similar strategy employing trimethyl-
silyltriflate (24 to 64–112 mol%) at ꢀ86 1C/ꢀ78 1C.3,4 These
one-pot tandem procedures utilize triflate-containing reagents.
As a continuation of these studies, we report here the successful
development of the same sequential tandem Lewis acid
catalysis with the inexpensive and stable iron(III) chloride
hexahydrate. Iron salts have recently attracted considerable
attention as inexpensive and environmentally friendly agents
in a wide range of selective processes in organic synthesis.5
When used for its acidic properties, the hexahydrate complex
was mostly applied for hydrolytic reactions.6,7 We show that
this simple hydrated catalyst is useful for programming
in tandem acetal formation, reductive etherification and
acylation, all transformations previously reported as single
reactions with the anhydrous salt.8–10 We also show that the
unprecedented regioselective reductive opening of arylidenes
catalyzed by this salt can be added as a terminating step.
The use of other iron catalysts was studied next
(entries 3–7, Table 1). Anhydrous iron chloride provided the
expected compound in a similar yield (entry 3). The Fe(acac)3
and (FeCl3)2(TMEDA)3 complexes, known to be less hygroscopic
than FeCl3,12 were inefficient under these reaction conditions
(entries 4 and 5). The complex Fe(NO3)3ꢁ9H2O led to the expected
compound in a low 14% yield whereas FeCl2ꢁ4H2O catalyzed only
the acetalation reaction in 53% yield (entries 6 and 7).
This optimized procedure was also extended to thiogluco-
pyranoside 2, affording product 4 in a 71% yield (entry 8),
Table 1 Iron salt-catalyzed transformations of persilylated D-gluco-
pyranoside derivatives
Entry
X
Catalyst
Mol%
Yield%
1
2
3
4
5
6
7
8
a-OMe
a-OMe
a-OMe
a-OMe
a-OMe
a-OMe
a-OMe
b-SPh
FeCl3ꢁ6H2O
FeCl3ꢁ6H2O
FeCl3
5
1
5
5
2.5
5
5
77
66a
75
b
Fe(acac)3
—
—
b
(FeCl3)2(TMEDA)3
Fe(NO3)3ꢁ9H2O
FeCl2ꢁ4H2O
FeCl3ꢁ6H2O
14a,c
a
´
`
´
Universite Paris-Sud, Laboratoire de Synthese de Biomolecules,
Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay,
F-91405 Orsay, France. E-mail: jean-marie.beau@u-psud.fr;
Fax: +33 1 69 85 37 15; Tel: +33 1 69 15 79 60
a,d
—
71
5
a
b
c
Overnight reaction. Starting material was recovered. The 4,6-O-
d
benzylidene derivative was obtained in 68% yield. CH2Cl2 was used
b CNRS, Orsay, F-91405, France
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data and copies of 1H and 13C NMR
spectra for new compounds. See DOI: 10.1039/c0cc04398b
instead of CH2Cl2/CH3CN; only the 4,6-O-benzylidene derivative was
isolated in 53% yield.
c
2146 Chem. Commun., 2011, 47, 2146–2148
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Table 2 Iron chloride hexahydrate-catalyzed one-pot regioselective
protection of D-glucopyranosides 1 and 2
to silylated thioglucopyranoside 2 afforded the 3,6-di-O-
benzyl derivative 8 in a similar yield (entry 3).14 It is note-
worthy that the single reductive opening of benzylidene 3
under these conditions (FeCl3ꢁ6H2O, 5 mol%; Et3SiH, 5 equiv;
CH2Cl2/CH3CN: 4/1 rt, overnight) provided benzyl compound
7 in only 41% yield, emphasizing the interest of the tandem
process. This transformation did not proceed using BH3ꢁTHF
as a reducing agent probably due to a complexation with the
catalyst (entry 5).
This tandem protocol was also applied to per-O-silylated-
a,a-D-trehalose 9 obtained in 92% yield from trehalose
(TMSCl, 10 equiv; pyridine; rt, overnight). a,a-D-Trehalose
is a basic core in a number of biologically important glyco-
conjugates playing pivotal roles in many organisms.15,16 The
symmetric compound 10 was isolated in good yield with the
same regioselectivity for the reductive etherification employing
procedure B (FeCl3ꢁ6H2O, 5 mol%; PhCHO, 6 equiv; Et3SiH,
2.2 equiv; CH2Cl2/CH3CN: 4/1 0 1C to rt, 3 h, Scheme 1). This
procedure could be extended to a multi-gram scale without
affecting the isolated yields.17
Entrya
X
Electrophile (5 equiv) Temperature Yield%
1
2
3
4
a-OMe Ac2O
b-SPh Ac2O
a-OMe C15H31COCl
a-OMe Piv2O
rt
rt
rt
45 1C
5a: 64b
6: 60b
5b: 58
5c: 60
a
Procedure A: FeCl3ꢁ6H2O 5 mol%, PhCHO (3 equiv), Et3SiH
b
(1.1 equiv), CH2Cl2/CH3CN: 4/1, 0 1C to rt, 1.5–2 h. The major
by-product (15–20%) was the 2,3-di-O-Ac-4,6-O-benzylidene derivative.
without affecting the thioglycoside functionality. In contrast,
this transformation could not be performed with Cu(OTf)2
catalysis in solution at room temperature,2 without the forma-
tion of the 3,6 di-O-benzyl derivative as a side product,
resulting from the reductive opening of the acetal.
Adding, to the tandem sequence, a one-pot acetylation with
an excess of acetic anhydride (10 equiv) and 5 mol% more
of FeCl3ꢁ6H2O furnished the expected 2,20-di-O-acetylated
a,a-D-trehalose 11 in an isolated 41% yield. Finally, ending
with a one-pot bis-reductive opening of the benzylidene acetals
by a sequential addition of 10 equivalents of Et3SiH and
15 mol% of the catalyst afforded the expected compound 12
in a very moderate yield of 28%, reaching the limit for this
tandem procedure.18,19
The possibility of expanding further the tandem process by
a ‘‘terminating’’ acylation step to obtain the orthogonally
protected monosaccharide was also examined. Hence, terminal
addition of acetic anhydride or palmitoyl chloride afforded the
acylated compounds in good yields (entries 1–3, Table 2),
including pivaloylation, which required a higher temperature
to proceed (entry 4).
Finally, the utility of this one-pot regioselective protection
was examined on a-methyl maltoside 13 (Scheme 2). With this
disaccharide, a higher load of the catalyst (15 mol%) was
required to provide a practical yield (51%) of the benzylidene
bis-benzyl derivative 14.
We then focused on a successive regioselective reductive ring
opening of the 4,6-O-benzylidene acetal. This carbon–oxygen
bond cleavage associating an acidic catalyst and a reducing
agent is very well documented,13 although iron salts were
never employed before. Accordingly, persilylated pyranoside
1, treated with procedure A followed by a further addition in
the same pot of 5 equivalents of Et3SiH, led to the 3,6-di-O-
benzyl compound 7 in 45% yield (entry 1, Table 3).
The simultaneous addition of 5 mol% of the iron catalyst
increased the yield to 55% (entry 2). These conditions applied
Table 3 Reductive ring opening of acetal mediated by FeCl3ꢁ6H2O
Scheme
1 One-pot regioselective protection of a,a-D-trehalose.
Entrya
X
Reducing agent Added FeCl3ꢁ6H2O Yield%
Procedure B: FeCl3ꢁ6H2O, 5 mol%; PhCHO, 6 equiv; Et3SiH,
2.2 equiv; CH2Cl2/CH3CN: 4/1 0 1C to rt, 3 h.
1
2
3
5
a-OMe Et3SiH
a-OMe Et3SiH
b-SPh
a-OMe BH3ꢁTHF
—
45
5%
5%
—
55b
54c
Et3SiH
d
—
a
Procedure A: FeCl3ꢁ6H2O 5 mol%, PhCHO (3 equiv), Et3SiH
b
(1.1 equiv), CH2Cl2/CH3CN: 4/1, 0 1C to rt, 1.5–2 h. 20% of the
mono-3-O-benzyl derivative were also formed. 8% of the 2,3,6-tri-O-
d
benzyl derivative were also formed. Only acetal 3 was isolated in
67% yield.
c
Scheme 2 One-pot regioselective protection of a-methyl maltoside.
Chem. Commun., 2011, 47, 2146–2148 2147
c
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In conclusion, we have developed an efficient one-pot
procedure for the regioselective protection of D-glucopyranoside
derivatives by tandem catalysis mediated by FeCl3ꢁ6H2O. Our
method provides a very fast access to orthogonally protected
saccharides in one vessel under very mild conditions and has
been applied to the a,a-D-trehalose disaccharide and a-methyl
maltoside. It is interesting to note that all four reactions, which
conventionally require anhydrous conditions or dehydrating
agents to be carried out, are conveniently catalyzed in this
work by the easy-to-handle hydrated iron complex. Extension
of this protocol to other mono-, di- and oligosaccharides of
interest is currently in progress in our laboratory and will be
reported in due course.
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We thank the Ministere de la Recherche for a grant to AL
and the CNRS for financial support.
10 Acylation: (a) F. Dasgupta, P. P. Singh and H. C. Srivastava,
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A. K. Mahalingam, M. Nagarjan, A. Ilangovan and
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Synthesis, 2008, 3407.
11 The regioselectivity of the reductive etherification was determined
through chemical correlation after acetylation of the hydroxyl
function and was in agreement with previous work. See ref. 2
and C.-C. Wang, J.-C. Lee, S.-Y. Luo, H.-F. Fan, C.-L. Pai,
W.-C. Y, L.-D. Lu and S.-C. Hung, Angew. Chem., Int. Ed.,
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Notes and references
z Representative procedure (synthesis of compound 3): To an ice-cold
solution of the per-O-silylated a-methyl glucopyranoside 1 (3 g, 6.2 mmol)
and benzaldehyde (1.89 mL, 18.6 mmol, 3 equiv) in dichloromethane
(11.0 mL), a solution of FeCl3ꢁ6H2O in acetonitrile (84.0 mg, 5 mol%,
in 2.7 mL of CH3CN) and triethylsilane (1.09 mL, 6.8 mmol, 1.1 equiv)
was added dropwise. The reaction was stirred at room temperature
and monitored by TLC. After consumption of the starting material,
tetra-n-butylammonium (10.0 mL of a 1 M solution in THF) was
added. The solution was diluted with ethyl acetate and neutralized
with a saturated aqueous NaHCO3 solution. The aqueous layer was
extracted twice with EtOAc. The combined organic layers were dried
over Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by silica gel chromatography to give the expected
compound 3 (1.78 g, 77% yield).
12 G. Cahiez, V. Habiak, C. Duplais and A. Moyeux, Angew. Chem.,
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13 For a recent work see: K. Daragics and P. Fugedi, Tetrahedron
¨
Lett., 2009, 50, 2914 and references cited therein.
14 This sequential addition of the iron catalyst (5 mol% twice) was
more efficient than adding 10 mol% at the onset of the tandem
process.
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17 Under the same conditions, but with a higher concentration, the
reaction mediated by copper(II) triflate provided only 30% yield of
the same compound 10.
18 Higher loadings of catalyst did not improve the yield, probably due
to the concomitant hydrolysis of the benzylidene acetals. See
ref. 6b.
19 The direct bis reductive opening of the benzylidene acetals in
compound 10 under identical conditions led to a complex mixture
of partially reduced and/or hydrolyzed products, highlighting
again the interest of the tandem procedure.
¨
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´ ´
c
2148 Chem. Commun., 2011, 47, 2146–2148
This journal is The Royal Society of Chemistry 2011