Reducing the conformational flexibility of carbohydrates: Locking the 6-hydroxyl group by cyclopropanes

Article abstract of DOI:10.1039/c1cc14025f

The 6-hydroxyl group of hexopyranosides was stereochemically locked by the spiroannelation of a cyclopropane unit at C-5. The corresponding glucose and mannose derivatives were prepared and their behaviour in glycosidation reactions was studied.

Full text of DOI:10.1039/c1cc14025f

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COMMUNICATION
Reducing the conformational flexibility of carbohydrates: locking the
6-hydroxyl group by cyclopropanesw
Christian Brand,a Markus Granitzka,b Dietmar Stalkeb and Daniel B. Werz*a
Received 5th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1cc14025f
The 6-hydroxyl group of hexopyranosides was stereochemically
locked by the spiroannelation of a cyclopropane unit at C-5. The
corresponding glucose and mannose derivatives were prepared
and their behaviour in glycosidation reactions was studied.
Carbohydrates are important in a variety of intercellular
recognition events including cell adhesion, viral infection and
cancer metastasis.1 Therefore, carbohydrate mimetics are of
paramount importance in order to fine-tune their biological
behaviour.2 C-Glycosides have been used to enhance the
Scheme 1 Retrosynthetic analysis of monosaccharides of type 3 with a
stability of the glycosidic bond,3 fluorinated carbohydrate
locked 6-hydroxyl group by a spiroannelated three-membered ring at C-5.
derivatives were prepared due to their similar polarity in
comparison with the native counterparts,4 hybrids of sugars
the carbohydrate, but specifies the direction of the hydroxyl group
and aromatics were prepared5 and iminosugars were often
and thus reduces the rotational flexibility of the C6–O bond.
employed as enzyme inhibitors,6 just to name a few examples.
Our retrosynthetic considerations for hydroxycyclopropanated
pyranosides are depicted in Scheme 1. The enol acetate 4 can be
prepared in two steps from the corresponding monosaccharide 6
with an unprotected 6-hydroxyl group by oxidation to the
respective aldehyde 5 and further enolisation followed by
subsequent protection with acetate. Endo- and exocyclic enol
ethers have previously been shown to be valuable substrates
for cyclopropanation reactions.10
Only little work in the field of carbohydrate mimetics was
devoted to pre-adjust specific conformations of mono- or
oligosaccharides7 although the conformation of sugars is of
crucial importance for the hydrolysis of the glycosidic bond.8
In this communication we present our recent studies to lock the
direction of the 6-hydroxyl group of pyranosides. To address this
issue we made use of a spiroannelated three-membered ring at C-5
bearing one hydroxyl group (Fig. 1).9 The small cyclopropane
ring in 2 has only a minimal impact on the structural integrity of
The starting point of our syntheses was methyl glucoside 7
that was subjected to a Swern oxidation followed by subsequent
enolisation in acetic anhydride under the influence of potassium
carbonate.11 Two diastereomeric enol acetates 8 and 9 were
obtained in a ratio of 1 : 8 and could be separated by careful
column chromatography. The electron-rich double bond allowed
a cyclopropanation under Simmons–Smith–Furukawa conditions
(Scheme 2).12
To our delight, we observed facial selectivity in the three-
membered ring formation. This transformation allows access
to the depicted products which result from a bottom-attack of the
organometallic species, for both glucose-derived diastereomers 10
and 11 (Scheme 2). The corresponding cyclopropane derivatives
resulting from a top-attack were observed in minor amounts
only (see ESIw). The configuration of all the diastereomers was
determined by extensive 2D-NMR spectroscopy and NOESY
investigations. Potassium carbonate in methanol gave access to
the hydroxycyclopropane derivatives 12 and 13. Hydrogenolysis
afforded the cyclopropanated methyl glucopyranosides 14 and
15, respectively.
Fig. 1 Carbohydrate 1 with a flexible glycosidated 6-hydroxyl group
and analogue 2 with reduced flexibility at the glycosidated 6-hydroxyl.
a Institut fur Organische und Biomolekulare Chemie der
¨
Georg-August-Universitat Gottingen, Tammannstr. 2, D-377077
¨
Gottingen, Germany. E-mail: dwerz@gwdg.de;
¨
¨
Fax: +49(551)399476; Tel: +49(551)393251
b Institut fur Anorganische Chemie der Georg-August-Universitat
¨
Gottingen, Tammannstr. 4, D-377077 Gottingen, Germany
¨
¨
¨
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H and 13C NMR data, analytical data for
all new compounds and crystallographic data for 33. CCDC 832491.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc14025f
Having found suitable reaction conditions for the glucose
derivative, an analogous sequence was conducted for the
c
10782 Chem. Commun., 2011, 47, 10782–10784
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Scheme 4 Reagents and conditions: (a) 23, TMSOTf, CH2Cl2, 0 1C,
71%; (b) NaOMe/MeOH, MeOH, rt, 93%; (c) H2, Pd/C, MeOH/
CH2Cl2/EtOAc, rt, quant.
Scheme 2 Reagents and conditions: (a) 1. (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 1C; 2. K2CO3, Ac2O, CH3CN, reflux, 8 (9%), 9 (70%);
(b) ZnEt2, CH2I2, ClCH2CH2Cl, 50 1C, 10 (35%), 11 (64%);
(c) K2CO3, MeOH/H2O, rt, 12 (77%), 13 (55%); (d) H2, Pd/C,
MeOH/ CH2Cl2/EtOAc, rt, 14 (quant.), 15 (quant.).
60–76%. Both deprotection reactions, saponification as well
as hydrogenolysis proceeded smoothly.
In order to elucidate whether the spiroannelated three-
membered ring alters the conformation of the chair-like
pyranose to a major extent we tried to get crystals of the
Scheme 3 Reagents and conditions: (a) 1. (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78 1C; 2. K2CO3, Ac2O, CH3CN, reflux, 17 (12%), 18
(66%); (b) ZnEt2, CH2I2, ClCH2CH2Cl, 50 1Cz; (c) K2CO3, MeOH/
H2O, rt, 19 (54%), 20 (46%); (d) H2, Pd/C, MeOH/CH2Cl2/EtOAc, rt,
21 (quant.), 22 (69%).
corresponding mannose-derived enol ethers 17 and 18
(Scheme 3).11 Although the axial OBn-group in position 2
should hinder the attack of the methylene-transferring agent in
the Simmons–Smith reaction we did not observe a better facial
selectivity to yield 19 and 20 than in the case of glucose. The
hydroxylated methyl mannosides 21 and 22 were obtained by
saponification and subsequent hydrogenolysis.
With the cyclopropanated glucose and mannose derivatives
12, 13, 19 and 20 in hand, we investigated their behaviour in
glycosidation reactions. Therefore, methyl glucopyranoside 12
with a free hydroxyl group at the cyclopropane moiety was
reacted with perbenzoylated glucosyl trichloroacetimidate 2313
to form the pseudodisaccharide 24 in 71% yield (Scheme 4).
Global deprotection was accomplished by sodium methoxide in
methanol to cleave the benzoates and treatment with Pd/C under
an atmosphere of hydrogen to remove all benzyl protecting
groups. Analogous experiments were carried out with the
respective diastereomer 13 and the mannose-derivatives 19 and
20 to afford disaccharide mimetics 27, 29 and 31, respectively
(Scheme 5). The yields of the glycosylation range from
Scheme 5 Reagents and conditions: (a) 23, TMSOTf, CH2Cl2, 0 1C,
60%; (b) NaOMe/MeOH, MeOH, rt, 78%; (c) H2, Pd/C, MeOH/
CH2Cl2/EtOAc, rt, quant; (d) 23, TMSOTf, CH2Cl2, 0 1C, 76%;
(e) NaOMe/MeOH, MeOH, rt, 77%; (f) H2, Pd/C, MeOH/CH2Cl2/
EtOAc, rt, quant. (g) 23, TMSOTf, CH2Cl2, 0 1C, 60%; (h) NaOMe/
MeOH, MeOH, rt, 94%; (i) H2, Pd/C, MeOH/CH2Cl2/EtOAc, rt, 98%.
c
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We are grateful to the Deutsche Forschungsgemeinschaft
(Emmy Noether Fellowship to D.B.W.), the Fonds der
Chemischen Industrie (Liebig Fellowship to D.B.W.) and to
BASF Aktiengesellschaft for the donation of chemicals.
We are also grateful to the DNRF funded CMC for funding
(D.S., M.G.) Furthermore, we thank Prof. Dr Lutz F. Tietze
for helpful discussions and generous support of our work.
Notes and references
z Separation of the two diastereomers was only possible after acetate
Scheme 6 Reagents and conditions: (a) 32, pyridine, DMAP, CH2Cl2,
0 1C, 80%.
removal. Yield for the cyclopropanation reaction, see ESIw.
y Crystal data for 33 at 100(2) K: C39H44O9, Mr = 656.74, 0.2 ꢁ
0.06 ꢁ 0.06 mm, monoclinic, P21, a = 6.249(2), b = 16.225(3), c =
16.620(3) A, b = 91.93(2), V = 1684.1(7) A3, Z = 2, rcalcd
=
1.295 Mg mꢀ3, m (Mo Ka) = 0.091 mmꢀ1, 2ymax = 551, 39 222
reflections measured, 4052 independent (Rint = 0.0459), R1 = 0.031
(I 4 2s(I)), wR2 = 0.0760 (all data), res. density peaks: 0.198 to
ꢀ0.156 e Aꢀ3
.
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Fig. 2 Molecular structure of the camphor-derived cyclopropanated
glucopyranoside 33. Anisotropic displacement parameters are
depicted at 50% probability level. Hydrogen atoms are omitted for
the sake of clarity. Oxygen atoms are shown in red.15
5 M. Leibeling, D. C. Koester, M. Pawliczek, S. C. Schild and
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all these experiments proved to be unsuccessful. Therefore,
compound 13 was transformed with (ꢀ)-camphanic acid
chloride (32) in pyridine to the respective camphanoyl ester
33 (Scheme 6).14
6 P. Compain and O. R. Martin, Iminosugars from synthesis to
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With this compound we were able to grow single crystals suitable
for X-ray analysis.w The molecular structure of 33 in the solid
state15 is depicted in Fig. 2. Although slightly distorted, the general
chair-like conformation of the six-membered ring is preserved.
The hydroxyl groups at positions 2–4 are equatorial, because
of the stiffness of the cyclopropane the 6-hydroxyl adopts a
distinct position.y Stereochemical flexibility as in common
glucose does not exist any more.
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In conclusion, we have developed an approach to reduce the
conformational flexibility of the 6-hydroxyl group of pyranosides.
The key to attain this goal is a spiroannelation of a hydroxy-
cyclopropane at C-5 of the monosaccharide. This structural
feature was accessed by the Simmons–Smith–Furukawa
reaction of the corresponding enol ether acetates. The resulting
cyclopropanated monosaccharides with a free hydroxyl group
at the three-membered ring were smoothly glycosidated with
glycosyl trichloroacetimidates. Extension of this approach to
other monosaccharide units as well as an incorporation of this
structural motif into glycosyl donors and then in larger
oligosaccharides is in progress. The respective mimetics might
be of great value for biochemical and medicinal studies.
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10784 Chem. Commun., 2011, 47, 10782–10784
This journal is The Royal Society of Chemistry 2011