Easy access to L -mannosides and L -galactosides by using cih activation of the corresponding 6-deoxysugars

Article abstract of DOI:10.1002/anie.201206880

Rare sugars by CH activation: The title compounds have been prepared from the corresponding 6-deoxysugars by an intramolecular CiH activation in high yields. Diethyl silane is attached to the 4-OH group followed by formation of a SiiC bond; both transformations are catalyzed by iridium in a one-pot fashion. The subsequent Fleming-Tamao oxidation provided the L-sugars. Copyright

Full text of DOI:10.1002/anie.201206880

Angewandte
Chemie
DOI: 10.1002/anie.201206880
Sugar Synthesis
À
Easy Access to l-Mannosides and l-Galactosides by Using C H
Activation of the Corresponding 6-Deoxysugars**
Tobias Gylling Frihed, Mads Heuckendorff, Christian Marcus Pedersen,* and Mikael Bols*
The two l-sugars l-galactose and l-mannose are found in
nature, but not easily accessible. l-Galactose has been found
in a marine octocoral[1] and is a constituent in some plant
biopolymers. This sugar has furthermore been successfully
used as mimic in sialyl LewisX structures.[2] l-Mannose is
found in some bacteria cell-wall polysaccharides.[3] With the
appearance of l-sugars in nature and their application in the
development of biologically active biomimetic compounds,
there is an increasing interest in their efficient synthesis. Most
l-sugars are however rare in nature, but in some cases their
corresponding 6-deoxysugars, such as l-fucose and l-rham-
nose (the 6-deoxy analogues of l-galactose and l-mannose
respectively), are more widespread and therefore easily
available.
a Fleming–Tamao oxidation to give the corresponding
methylene alcohol. The procedure was applied for simple
substrates and for more complex steroid-based structures, but
not for densely functionalized compounds, such as carbohy-
drates. Herein we investigate the scope of this reagent system
in carbohydrate chemistry by synthesizing rare l-sugars from
their more common 6-deoxy-analouges.
À
The substrates for the C H activation were readily
available in a few synthetic transformations from the com-
mercially available l-rhamnose and l-fucose. The l-rhamno-
model compound was synthesized by a Fischer glycosylation
of l-rhamnose in methanol affording the methyl glycoside,
which was directly 2,3-isopropylidinated to give the substrate
1, having a 4-OH group ready for silylation (Scheme 1).[10]
With the first substrate in hand, the Hartwig procedure
was investigated (on milli- to multiple gram scale). The 2,3-
Synthesis of l-galactose and l-mannose has been known
since the early days of carbohydrate chemistry and can be
carried out from l-lyxose and l-arabinose
respectively through chain elongation. This
approach is, however, not straightforward,
since diastereomeric mixtures are obtained.
Other syntheses have also appeared, starting
from other building blocks, but they all have
the complexity and many steps in common.[4,5]
À
Scheme 1. Unoptimized synthesis of cyclic silyl ether through C H activation.
Phen=1,10-phenanthroline, cod=cycloocta-1,5-diene.
De novo syntheses have been developed and
are continuously improved to meet the
demands for rare l-sugars.[6] A direct synthesis
from the abundant 6-deoxy-sugars is therefore
very desirable. Another aspect is the synthesis of b-l-
rhamnosides — one of the unsolved problems in carbohydrate
chemistry. Crich and Li[7] recently showed that l-mannosyl
donors can solve this problem. However, the synthesis of
these donors demanded more than 10 steps, which limited its
practical use, and an easier access to the l-sugars from their
respective 6-deoxysugars would also be an advantage here. To
date this has however not been possible owing to the inherent
lack of reactivity of the methyl group (C6).
protected methyl l-rhamnoside was dissolved in THF, and
subsequently the catalyst was added together with the diethyl
silane under strictly inert atmosphere (Scheme 1). After
complete conversion excess of the silane was removed
in vacuo and additional catalyst, ligand, and norbornene (H2
À
scavenger) were added together with THF. The C H
activation reaction was monitored by using GC–MS, and
only a slow progress was observed when the reaction was
carried out at 808C. Raising the temperature to 1208C in
a sealed vial significantly enhanced the reaction rate, and
almost full conversion was achieved after four days. To obtain
full conversion more catalyst was used (2.0 mol% in total).
With the improved conditions the focus was turned to the
Fleming–Tamao oxidation[11] of the cyclic silyl ether
(Scheme 2). The initial experiments with the manno-deriva-
tive 3 resulted in a one-to-one mixture of two compounds,
À
C H activation of otherwise unreactive substrates has
become a “hot topic” in chemistry with an amazing develop-
ment the last few years.[8] Recently Simmons and Hartwig[9]
À
published a very elegant iridium-catalyzed C H activation of
methyl groups to introduce a carbon–silicon bond followed by
[*] T. G. Frihed, M. Heuckendorff, Dr. C. M. Pedersen, Prof. Dr. M. Bols
Department of Chemistry, University of Copenhagen
Universitetsparken 5, DK-2100 Copenhagen Ø (Denmark)
E-mail: cmp@chem.ku.dk
bols@chem.ku.dk
[**] This work was supported by the Lundbeck Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206880.
Scheme 2. Fleming–Tamao-type oxidation to give the diols.
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which were acetylated and purified by chromatography to
give the desired l-mannoside as well as the acetylated starting
l-rhamnoside (15, Table 1), as a result of a competing
protodesilylation reaction. The modest yield in the initial
With the improved oxidation condition the reaction time
in the one-pot sequence was optimized by monitoring the
À
progress by GC–MS (Scheme 3). It was observed that the C
H activation reaction time could be reduced to 24 h when
Table 1: Optimizing conditions for Fleming–Tamao oxidation versus
proto-desilylation in the sugar substrates.[f]
Entry Reagents &
Fluoride Solvent
T
(t)
Yield of Yield of (5a
15 [%][a] & 5b) [%][b]
additives
1[c]
2[c]
3
30% H2O2,
KHCO3
–
THF/
MeOH (16 h)
1:1
THF/
MeOH (44 h)
1:1
THF/
MeOH (44 h)
1:1
NMP
DMF
DMF
508C
21
16
17
20[d]
(25)
Scheme 3. Optimized one-pot sequence for the synthesis of fully
protected l-mannoside 5.
30% H2O2,
KHCO3
–
508C
54[e]
(64)
57[e]
(69)
a second load of iridium catalyst and Me4Phen were added
after 18 h. Moreover, the oxidation was completed in six
hours giving the diol 4, which was acetylated in one hour to
afford the desired fully protected l-mannoside 5a in 82%
yield over four steps (Scheme 3, one pot, > 95% per step)
together with 15% of the protodesilylated l-rhamnoside (15).
A major challenge in carbohydrate chemistry is to
distinguish similar hydroxy groups by protective groups.
30% H2O2,
KHCO3
KHF2
508C
4
5
6
PhMe2COOH, TBAF
KH
tBuOOH,
CsOH·H2O
m-CPBA
RT
17
20
18
15[d]
(18)
46[d]
(58)
40[d]
(49)
(22 h)
758C
(8 h)
RT
TBAF
KHF2
(5 h)
Obviously the primary hydroxy group in the diol
4
[a] Yield of isolated product. [b] Yield of isolated 5 starting from methyl-
2,3-O-isopropylidene-a-l-rhamnopyranoside 1 (four steps). The yield in
brackets is based on recovered starting material or the protodesilylated
product 1. [c] The difference between entry 1 and 2 is the work-up
procedure (see the Supporting Information). The product was also found
to be in the water phase. [d] Pure 5a. [e] Consisting of methyl-4,6-di-O-
acetyl-2,3-O-isopropylidene-a-l-mannopyranoside (5a) and methyl-
2,3,4,6-tetra-O-acetyl-a-l-mannopyranoside (5b; 4:1). [f] m-CPBA=
m-chlorperbenzoic acid, TBAF=tetrabutylammonium fluoride,
DMAP=4-(dimethylamino)pyridine.
(Scheme 3) can easily be distinguished by bulky protective
groups leaving the 4-OH group free. A direct protection of
the 4-OH group would be desirable, and therefore it was
investigated, whether activation of the silyl group with
fluoride followed by addition of an electrophile[11d,14] would
lead to the protected 6-silylene compound, and whether this
compound could be easily transformed into the l-mannoside
having a free 6-OH group. Indeed this approach successfully
afforded the 6-OH l-mannoside 7 in 30% yield again over
four steps together with the dimer 8 (12%, Scheme 4).
The synthesis of l-galactosides from the corresponding l-
fucoside was investigated using the model compound 10
(Scheme 5). BDA (butane-2,3-diacetal) was chosen as the
protective group owing to its common use in carbohydrate
reaction was found to be caused by loss of the polar diol 4
(Table 1, entries 1,2) during aqueous work-up; that is, when
the water phase was concentrated and the residue was
acetylated, the yield increased significantly.
À
chemistry and to investigate the regioselectivity of the C H
To diminish the protodesilylation side reaction, some
experimentation with the reagents system was required.
Addition of fluoride ions did not improve the product
formation significantly (Table 1, entry 3). The use of other
oxidants, such as cumene peroxide,[12] which has been found to
suppress the protodesilylation side reaction, did not improve
the yield of the desired l-mannoside (Table 1, entry 4).
Neither tert-butyl peroxide[13] nor m-CPBA[11a] increased the
yield of the l-mannoside, but shortened the reaction time.
With the optimal conditions, that is, 30% H2O2, (KHF2),
KHCO3 in THF/MeOH (Table 1, entry 2), the protected
rhamnoside could be transformed into the fully protected
mannoside in a four-step one-pot procedure with only one
final purification to give the fully protected l-mannosides in
69% yield (based on recovered starting material, see Table 1).
Scheme 4. Fluoride-mediated activation of silicon followed by 4-O-
benzoylation and Fleming–Tamao oxidation to give orthogonally
protected 7.
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Methyl-4,6-di-O-acetyl-2,3-O-(2’,3’-dimethoxybutane-2’,3’-diyl)-
a-l-galactopyranoside (14). Methyl-2,3-O-(2’,3’-dimethoxybutane-
2’,3’-diyl)-a-l-fucopyranoside (10, 640 mg, 2.19 mmol) was weighed
into a 25 mL flask, coevaporated twice with toluene and dried at
a Schlenk line for at least 30 min. Then, the flask was transferred to an
N2-filled glove bag and [Ir(cod)OMe]2 (7.4 mg, 11 mmol, 0.5 mol%)
was added followed by dry and degassed THF (4 mL). Subsequently,
Et2SiH2 (0.34 mL, 2.63 mmol, 1.2 equiv) was added (CAUTION: H2
evolution!), and the reaction was left at room temperature under
argon for 16 h, after which TLC (Rf 0.53, heptane/EtOAc 3:1) and
GC–MS (m/z 363.2 (2.4% [MÀMe]+)) indicated complete conversion
to the diethyl(hydrido)silyl ether 11. Then, the solvent was removed
by purging the mixture with nitrogen. The excess Et2SiH2 was
removed by placing the flask under high vacuum at the Schlenk line
for one hour. The crude diethyl(hydrido)silyl ether was dissolved in
dry THF (3 mL) and cannulated to a dry argon-filled sealed vial
containing norbornene (247 mg, 2.63 mmol, 1.2 equiv), [Ir-
(cod)OMe]2 (10 mg, 17 mmol, 0.7 mol%), and 3,4,7,8-tetramethyl-
1,10-phenanthroline (6 mg, 24 mmol, 1.1 mol%). The reaction mix-
ture was heated at 1208C for 28 h after which the corresponding
oxasilolane 12 formed as determined by GC–MS (m/z 361.2 (1.0%
[MÀMe]+), 345.2 (2.9% [MÀOMe]+)) and TLC (Rf 0.29, heptane/
EtOAc 1:1). To push the reaction to completion an extra load of
catalyst dissolved in THF (1 mL) was added through cannulation
([Ir(cod)OMe]2, (10 mg, 17 mmol, 0.8 mol%) and ligand (6 mg,
24 mmol, 1.1 mol%)) after 22 h and stirred for additional six hours.
Then, the solution was allowed to reach room temperature, trans-
ferred to a reaction flask, and concentrated. The crude reaction
mixture (ca. 675 mg, 2.19 mmol) was sequentially treated with 1:1
THF/MeOH (4 mL), KHCO3 (548 mg, 5.48 mmol, 2.5 equiv), and
H2O2 (30% solution in H2O, 2.3 mL, 21.90 mmol, 10 equiv). The
resulting mixture was stirred for 13 h at 508C (CAUTION: CO2
evolution!) after which TLC indicated full conversion (Rf 0.22,
heptane/EtOAc 1:4) to the diol 13. Afterwards, the reaction was
coevaporated twice with toluene. The crude diol was dissolved in 4:1
CH2Cl2/Et3N (10 mL), and the resulting solution was treated with
DMAP (13 mg, 0.11 mmol, 0.05 equiv) and Ac2O (2.0 mL,
21.90 mmol, 10 equiv). After being stirred at room temperature for
1.5 h the solution was coevaporated with toluene and concentrated.
The crude was purified by dry column chromatography (eluent:
heptane with a 1.7% gradient of EtOAc) to give the desired product
14 as a syrup in 67% yield (577 mg).
Scheme 5. “One-pot” synthesis of fully protected l-galactoside through
À
C H activation and Fleming–Tamao oxidation. a) 1. AcCl, MeOH,
reflux, 19 h; 2. diacetyl, CH(OMe)3, camphorsulfonic acid (CSA),
MeOH, reflux, 81% (a/b 1.7:1, two steps), b) 1. MeOH, IR-120 H+,
reflux, 47% (a/b 1:0); 2. diacetyl, CH(OMe)3, CSA, MeOH, reflux,
13 h, 94% (a/b 3.8:1), c) 1. MeOH, IR-120 H+, reflux, 47% (a/b 1:0);
2. diacetyl, CH(OMe)3, CSA, MeCN/MeOH (3:1), 20 h, 90% (a/b 1:0).
activation (6 methyl groups are present). Transformation of l-
fucose into its 2,3-BDA-protected methyl a-l-fucoside was
found to be more difficult than expected. Fischer glycosyla-
tion catalyzed by AcCl in refluxing methanol and subsequent
2,3-BDA protection[15] mediated by diacetyl, trimethyl ortho-
formate, and CSA in refluxing methanol[16] yielded an
inseparable anomeric mixture (a/b 1.7:1) in 81% over two
steps. Pure methyl a-fucoside could however easily be
fractionally crystallized from an anomeric mixture of methyl
l-fucoside in 47% yield[17] but gave again an inseparable
anomeric mixture (a/b 3.8:1) for the BDA protection of 10 in
94%, when applying the before-mentioned conditions
(Scheme 5). To avoid anomerization a milder modification
of the original procedure was developed. The methyl a-l-
fucoside was treated with diacetyl, trimethyl orthoformate,
and BF3·OEt2 (0.1 equiv) in MeCN/MeOH (3:1) at room
temperature, giving the a-product 10 in 90% yield
(Scheme 5). When 10 was submitted to the conditions
optimized for the l-mannoside synthesis described above,
the l-galactoside 14 was obtained in 67% yield (one pot, four
steps, > 90% per step) after one final purification. No
Received: August 24, 2012
Published online: October 29, 2012
Keywords: C-H activation · Fleming–Tamao oxidation ·
.
l-galactosides · l-mannosides · synthetic methods
À
protodesilylation and no C H activation of other nearby
methyl groups were observed in the l-galactoside synthesis.
In conclusion we have developed a method for easy and
effective access to l-sugars from their deoxy derivatives in
a few steps with only one final purification giving the desired
product in outstanding yields. With four or six methyl groups
in the substrates a high regioselectivity is observed, and it has
furthermore been demonstrated that the reaction is inde-
pendent of the relative stereochemistry (trans vs. cis) of the 4-
OH and the methyl groups.
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