Rh(II) carbene-promoted activation of the anomeric C-H bond of carbohydrates: A stereospecific entry toward α- And β-ketopyranosides

Article abstract of DOI:10.1021/ja1054065

In this communication we report a new strategy toward ketopyranosides based on a carbene-mediated activation of the anomeric C-H bond of carbohydrates. By forming a new carbon-carbon bond after a glycosylation step, this approach enables the preparation o

Full text of DOI:10.1021/ja1054065

Published on Web 10/20/2010
Rh(II) Carbene-Promoted Activation of the Anomeric C-H Bond of
Carbohydrates: A Stereospecific Entry toward r- and
ꢀ-Ketopyranosides
Me´lissa Boultadakis-Arapinis,† Pascale Lemoine,‡ Serge Turcaud,† Laurent Micouin,† and
Thomas Lecourt*,†
Laboratoire de Chimie The´rapeutique (UMR CNRS 8638), and Laboratoire de Cristallographie et RMN Biologique
(UMR CNRS 8015), UniVersite´ Paris Descartes, Faculte´ des Sciences Pharmaceutiques et Biologiques, 4, aVenue de
l’ObserVatoire, 75006 Paris, France
Received June 21, 2010; E-mail: Thomas.Lecourt@parisdescartes.fr
Scheme 2. Carbene-Mediated Synthesis of Ketopyranosides
Abstract: In this communication we report a new strategy toward
ketopyranosides based on a carbene-mediated activation of the
anomeric C-H bond of carbohydrates. By forming a new
carbon-carbon bond after a glycosylation step, this approach
enables the preparation of both R- and ꢀ-ketopyranosides from
advanced precursors.
New synthetic tools in carbohydrate chemistry have attracted
tremendous interest over the past decades due to the important
role of complex oligosaccharides in many fundamental biological
processes.1 In this context, quaternarization of a specific position
represents a highly potent entry toward chemical tools for
glycobiology.2 However, such a modification of the sugar
backbone requires a multistep, time-consuming approach relying
on: (1) selective protection/deprotection of a given position, (2)
meric assistance,9 and after conversion into a diazoacetate,10 would
oxidation of the resulting alcohol, (3) addition of an organo-
then promote a carbene insertion11 into the anomeric C-H bond
(Scheme 2).
metallic reagent. Following this strategy,3,4 R-ketopyranosides,
with the anomeric position quaternarized by an independent
equatorial chain, can be prepared from δ-lactones by formation
of a new anomeric C-C bond before a glycosylation step
(Scheme 1).
As this transformation could be dramatically hampered by
intermolecular12 or oxonium ylide-mediated13 competitive path-
ways, as well as nonselective insertions, we first investigated
activation of the anomeric C-H bond on model compounds.
Starting from orthogonally protected methyl-pyranosides 1 and
2, bromoacetylation followed by diazotransfer delivered diaz-
oacetates 3 and 4 in good yield (Scheme 3). Decomposition
by various Rh(II) salts14 established that Rh2(OAc)4 was suitable
to reach γ-lactones 5 and 6 (Table 1, entries 1 and 6). Inter-
estingly, a weakly electrophilic carbene generated under Rh2-
(acam)4 catalysis could also promote highly efficient insertion
into axially orientated C-H bonds (entry 8). However, Rh(II)
salts with bulky or strongly electron-withdrawing ligands were
Scheme 1. Synthesis of Ketopyranosides from δ -Lactones
Table 1. Catalytic Decomposition of 3 and 4
The scope of this approach is, however, strongly limited by the
glycosylation step. Thus, glycosylation of sterically demanding
acceptors with ketopyranoside donors are usually low yielding.5,6
Moreover, coupling with 2-O-acylated donors offers poor diaste-
reocontrol by anchimeric assistance.7 In this context, the precise
one-step substitution of the anomeric C-H bond carries consider-
able appeal for the formation of a new anomeric C-C bond after
glycosylation, thus providing a new entry toward both R- and
ꢀ-ketopyranosides.8 Herein, we report such an approach where a
bromoacetate at position 2 should play a dual role. This protecting
group would first induce a stereoselective glycosylation by anchi-
entry
diazo-sugar
catalyst (mol %)
γ-lactone
yield (%)
1
2
3
4
5
6
7
8
9
10
3
3
3
3
3
4
4
4
3
4
Rh2(OAc)4 (2)
Rh2(oct)4 (2)
Rh2(tfa)4 (2)
5
5
5
5
5
6
6
6
5
6
73a
49a
13a
9a
Rh2(cap)4 (2)
Rh2(acam)4 (2)c
Rh2(OAc)4 (2)
Rh2(tfa)4 (2)
35a
72a
10a
85a
77b
90b
Rh2(acam)4 (2)c
Rh2(OAc)4 (0.5)
Rh2(OAc)4 (0.5)
a Estimated by 1H NMR of the crude product; b Isolated yield after
purification by chromatography; c Use of 4 Å MS as additive.
† Laboratoire de Chimie The´rapeutique.
‡ Laboratoire de Cristallographie et RMN Biologique.
9
10.1021/ja1054065  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 15477–15479 15477

C O M M U N I C A T I O N S
Scheme 3. Carbene-Mediated Activation of the Anomeric C-H Bond on Model Compoundsa
a Reactions and conditions: (a) BrCH2COBr, CH2Cl2, pyridine, 0 °C; (b) BrCH2COBr, CH2Cl2, DMAP, 0 °C; (c) TsNHNHTs, DBU, THF, 0 °C, 73% for
3 and 74% for 4 over two steps; (d) Rh2L4 (see Table 1), 1,2-dichloroethane, reflux.
Chart 1. ORTEP Representations of 5 and 6
Scheme 4. Influence of 3-O-Protecting Groupsa
a Reagents and conditions: (a) Rh2L4 1 mol % (see Table 2), 1,2-
dichloroethane, 4 Å MS, reflux.
Table 2. Catalytic Decomposition of 3-O-Benzylated and
3-O-Silylated Compounds
entry
diazo-sugar
catalystc
γ-lactone
yield (%)
detrimental to the quaternarization process (entries 2-4 and 7).
Diminishing catalyst loading to 0.5 mol % (entries 9-10) finally
delivered 5 and 6 in 77% and 90% yield, respectively, without any
competitive dimerization. The selective activation was confirmed by
X-ray structure analysis of compounds 5 and 6 (Chart 1). We next
studied the influence of protecting groups close to the highly reactive
metal carbene intermediate.
1
2
3
4
5
6
7
7
8
8
9
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(acam)4
Rh2(OAc)4
Rh2(OAc)4
11
11
12
12
13
14
20a,c
10a
35a,d
35a,e
94b
10
92b
a Estimated by 1H NMR of the crude product; b Isolated yield after
purification by chromatography; c Additional 51% of 1,7-C-H insertion
into the benzylic position; d Additional 35% of 1,7-C-H insertion into
the benzylic position. e Additional 21% of dimerization.
Thus, position 3 of model compounds was selectively
protected as benzyl or tert-butyldimethylsilyl ethers. Bro-
moacetylation and diazotransfer under Fukuyama’s conditions
provided carbene precursors 7, 8, 9, and 10 in good yield
(Scheme 4). As expected, catalytic decomposition of 3-O-
benzylated compounds 7 and 8 by Rh2(OAc)4 gave γ-lactones
11 and 12 in moderate yield because of competitive 1,7-C-H
insertion into the benzylic position (Table 2, entries 1 and 3).
Interestingly, this side reaction can be fully avoided using
Rh2(acam)4 as catalysis (entry 4). In this case, pure γ-lactone
12 could be obtained, albeit in a modest 35% yield because of
competitive dimerization.
delivered R-mannopyranoside 17 as a single anomer in 65% yield
over two steps. After conversion into the diazo-sugar 18,
selective insertion into the anomeric C-H bond was promoted
by Rh2(OAc)4 to give the quaternarized R-mannopyranoside 19
in 65% yield. Following a similar approach, stereocontrolled
glycosylation and diazotransfer delivered the ꢀ-gluco carbene
precursor 20. However, selective activation of its anomeric C-H
bond appeared more challenging. Thus, decomposition of 20 with
1 mol % of Rh2(OAc)4 in refluxing 1,2-dichloroethane gave the
targeted compound 21 as well as byproducts resulting from
competitive intramolecular insertion processes, as assessed by
mass spectrometry. A selective activation of the anomeric C-H
bond was finally achieved in 61% yield under Rh2(acam)4
catalysis (Scheme 6).
Changing the benzyl protecting groups to O-silylated carbene
precursors 9 and 10 nicely delivered γ-lactones 13 and 14 in 94%
and 92% yield, respectively (entries 5 and 6).
We next turned our attention to the functionalization of the
anomeric C-H bond of disaccharides (Scheme 5). Coupling the
2-O-bromoacetyl-mannopyranosyl donor 15 with 16 under NIS/
TfOH conditions resulted in
and orthoester. Subsequent TMSOTf-promoted rearrangement
a
mixture of disaccharide
Finally, ring-opening of γ-lactones 5 and 6 under Lewis-acid
conditions delivered R- and ꢀ-ketopyranosides 22 and 23, with
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C O M M U N I C A T I O N S
Scheme 5. Dual Role of a Bromoacetate in Carbene-Mediated Activation of the Anomeric C-H bond of a Disaccharidea
a Reagents and conditions: (a) NIS, TfOH, 4 Å MS, CH2Cl2, -20 °C; (b) TMSOTf, 4 Å MS, CH2Cl2, 0 °C, 65% over two steps; (c) TsNHNHTs, DBU,
THF, 0 °C, 84%; (d) Rh2(OAc)4 0.5 mol %, 1,2-dichloroethane, reflux, 65%.
Scheme 6. Insertion into the Axial C-H bond of a ꢀ-disaccharidea
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Acknowledgment. Financial support of this work by CNRS
(Research Fellowship to T.L) and Universite´ Paris Descartes (MESR
Grant to M.B.A.) is gratefully acknowledged.
Supporting Information Available: Preparation of 1, 2, 7, 8, 9,
10, 15, 16, and 20, experimental procedures, characterization data,
crystallographic data for 5 and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA1054065
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