Glycosylations of cyclopropyl-modified carbohydrates: Remarkable β-selectivity using a mannose building block

Article abstract of DOI:10.1021/ol3024133

A mannosyl donor bearing a spiroannulated cyclopropane unit at C-5 has been prepared, and its behavior in glycosylation reactions investigated. Selectivities in favor of the β-anomer were observed. Corresponding di- and trisaccharides incorporating the ri

Full text of DOI:10.1021/ol3024133

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Glycosylations of Cyclopropyl-Modified
Carbohydrates: Remarkable β‑Selectivity
Using a Mannose Building Block
Christian Brand, Katharina Kettelhoit, and Daniel B. Werz*
€
Institut fu€r Organische und Biomolekulare Chemie der Georg-August-Universitat
€
Gottingen, Tammannstr. 2, D-37077 Gottingen, Germany
€
dwerz@gwdg.de
Received August 30, 2012
ABSTRACT
A mannosyl donor bearing a spiroannulated cyclopropane unit at C-5 has been prepared, and its behavior in glycosylation reactions investigated.
Selectivities in favor of the β-anomer were observed. Corresponding di- and trisaccharides incorporating the rigid cyclopropane motif were assembled.
Carbohydrates play a major role in the transfer of bio-
logical information, e.g. cellÀcell recognition, bacterial
and viral infection, and signal transduction events.1,2 In
protein science numerous efforts are known to preadjust
specific conformations.3 The incorporation of rigid sub-
units or special amino acids such as hydroxyproline has
paved the way toward decreasing the number of accessible
peptide conformations. Especially, cyclopropane motifs
havebeen widelyusedtorigidify peptide sequences(e.g., 1a
in Figure 1).4 Different classes of carbohydrate mimetics5
have been developed in recent decades. However, most of
this work has been concentrated in the field of either
linkage modification (C-, S-, and N-glycosides)6 or carba-
and iminosugars. Only a small amount of work has been
devoted to the preadjustment of sugar hydroxyl groups.7
Figure 1 shows an example of GM3 derivative 1b in which
the conformational freedom of the sialic acid is reduced by
an ether bridge to the adjacent galactose moiety.
(1) (a) Varki, A. Glycobiology 1993, 3, 97–130. (b) Dwek, R. A. Chem.
Rev. 1996, 96, 683–720. (c) Seeberger, P. H.; Werz, D. B. Nature 2007,
446, 1046–1051. (d) Seeberger, P. H.; Werz, D. B. Nat. Rev. Drug
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Discovery 2005, 4, 751–763. (e) Oberli, M. A.; Bindschadler, P.; Werz,
D. B.; Seeberger, P. H. Org. Lett. 2008, 10, 905–908. (f) Tamborrini, M.;
Werz, D. B.; Frey, J.; Pluschke, G.; Seeberger, P. H. Angew. Chem., Int.
Ed. 2006, 45, 6581–6582.
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390–412. (b) Horlacher, T.; Oberli, M. A.; Werz, D. B.; Krock, L.;
Bufali, S.; Mishra, R.; Sobek, J.; Simons, K.; Hirashima, M.; Niki, T.;
Seeberger, P. H. ChemBioChem 2010, 11, 1563–1573. (c) Lorenz, B.; de
Cienfuegos, L. A.; Oelkers, M.; Kriemen, E.; Brand, C.; Stephan, M.;
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Sunnick, E.; Yuksel, D.; Kalsani, V.; Kumar, K.; Werz, D. B.; Janshoff, A.
J. Am. Chem. Soc. 2012, 134, 3326–3329. (d) Koester, D. C.; Awan, S. I.;
Werz, D. B. ChemBioChem 2011, 12, 1975–1977.
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(3) (a) Dumy, P.; Keller, M.; Ryan, D. E.; Rohwedder, B.; Wohr, T.;
Mutter, M. J. Am. Chem. Soc. 1997, 119, 918–925. (b) Wittelsberger, A.;
Keller, M.; Scarpellino, L.; Patiny, P.; Acha-Orbea, H.; Mutter, M.
Angew. Chem., Int. Ed. 2000, 39, 1111–1115. (c) Sewald, N.; Jakubke,
H.-D. Peptides: Chemistry and Biology; Wiley-VCH: Weinheim, 2009.
(4) (a) Urman, S.; Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.; De Pol,
S.; Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 3976–3978. (b) De Pol, S.;
Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew. Chem., Int. Ed. 2004, 43,
511–514. (c) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603–1623.
(5) (a) Koester, D. C.; Holkenbrink, A.; Werz, D. B. Synthesis 2010,
3217–3242. (b) Ernst, B.; Magnani, J. L. Nat. Rev. Drug Discovery 2009, 8,
661–677. (c) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–
2324. (d) Awan, S. I.; Werz, D. B. Bioorg. Med. Chem. 2012, 20, 1846–1856.
Figure 1. Rigidified peptide mimetic 1a using cyclopropane
motifs and conformationally locked GM3 derivative 1b.
r
10.1021/ol3024133
XXXX American Chemical Society

Recently, we locked the 6-hydroxyl groups of glucose
and mannose acceptors by making use of a spiroannulated
cyclopropane ring at C-5 bearing one hydroxyl group.8,9
In the present communication, we report on the prepara-
tion of the corresponding mannosyl donor, its behavior in
glycosylation reactions, and its incorporation in model
trisaccharides.
by NOE experiments. In a SimmonsÀSmithÀFurukawa
reaction13 the olefinic moiety was transformed into the
three-membered cyclopropane ring. While the total yield
was good, almost no facial selectivity was observed. With
the assumption that both axially oriented OR groups in
position 1, as well as in position 2, coordinate to the zinc,
the result would be an equal probability of attack from the
top or bottom side. Both diastereoisomers 5a and 5b were
unequivocally assigned by NOE investigations (see Sup-
porting Information). Attempts to remove the MP group
from 5a/5b proved to be challenging. Earlier investigations
using the bulky thexyldimethylsilyl (TDS) group at the
anomeric position were futile. Fluoride sources and the use
of HCl generated in situ were not compatible with the
electron-rich cyclopropane moiety. Commonly, the oxidiz-
ing agent cerium ammonium nitrate (CAN) to remove MP
groups is employed in a three-component solvent mix-
ture of acetonitrile, toluene, and water.14 However, due to
the cerium(III) and the ammonium, the pH value of the
aqueous phase is lowered significantly. Thus, using com-
mon deprotection conditions also led to complete decom-
position of the product. However, the use of a buffered
solution (phosphate buffer, pH 7) leveraged a successful
cleavage of the anomeric MP group leading to the produc-
tion of hemiacetal 6. The latter was transformed under
common conditions into the trichloroacetimidate 7;15 in
this step the R-trichloroacetimidate was formed as the
major anomer.
Investigations into the use of previously prepared cyclo-
propyl-modified methyl glycosides as donors, similar to
Hotha’s workusingAucatalysis,10 wereinvain. Therefore,
we decided to prepare conventional trichloroacetimidates
via the respective hemiacetals. The challenge was to iden-
tify a suitable, easily cleavable anomeric protecting group
without destroying the doubly donor-substituted cyclo-
propane motif. The latter is accessible via an exocyclic enol
ether as previously demonstrated.8,11 Since our main inter-
est was to determine how the three-membered ring affects
the glycosylation behavior, we chose a protected mannose
with a nonparticipating group in position 2. The β/R ratio
obtained in a respective glycosylation should give a hint
about whether the stiff cyclopropane, as in the case of the
4,6-benzylidene group, might be similarly influential.
We commenced the preparation of such a mannosyl
donor by using R-methoxyphenyl (MP) mannoside 212
(Scheme 1). The primary hydroxyl group of 2 was effi-
ciently protected with TIPSCl. Perbenzylation and TIPS de-
protection afforded 3. The latter compound was subjected to
Swern oxidation and the resulting aldehyde was subsequently
transformed to the respective enol acetate 4 in a solution of
acetic anhydride, acetonitrile, and potassium carbonate.
Surprisingly, high selectivity for the (Z)-configured dia-
stereomer 4 (72% over two steps) was observedand proven
With this donor 7r in hand we studied its behavior in
glycosylation reactions (Table 1). Several acceptors 8aÀ8f
bearing primary and secondary hydroxyl groups were
employed. In almost all cases good yields were obtained
(42À88%); the three-membered ring remained untouched
in the products 9À14. A careful analysis of the two anomers
Scheme 1. Synthesis of Cyclopropyl-Modified Mannosyl
Trichloroacetimidate 7
(6) Selected examples: (a) Postema, M. H. D.; Piper, J. L.; Komanduri,
V.; Liu, L. Angew. Chem., Int. Ed. 2004, 43, 2915–2918. (b) Dondoni, A.;
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(8) Brand, C.; Granitzka, M.; Stalke, D.; Werz, D. B. Chem. Com-
mun. 2011, 47, 10782–10784.
(9) Spiroannulated cyclopropanes without hydroxyl groups were syn-
thesized before: Bluechel, C.; Ramana, C. V.; Vasella, A. Helv. Chim. Acta
2003, 86, 2998–3036.
(10) Vidadala, S. R.; Hotha, S. Chem. Commun. 2009, 2505–2507.
(11) Exo- and endocyclic enol ethers proved to be highly reactive
substrates for cyclopropanation reactions: (a) Brand, C.; Rauch, G.;
Zanoni, M.; Dittrich, B.; Werz, D. B. J. Org. Chem. 2009, 74, 8779–8786.
(b) Schneider, T. F.; Kaschel, J.; Dittrich, B.; Werz, D. B. Org. Lett.
2009, 11, 2317–2320. (c) Schneider, T. F.; Kaschel, J.; Awan, S. I.;
Dittrich, B.; Werz, D. B. Chem.;Eur. J. 2010, 16, 11276–11288.
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B
Org. Lett., Vol. XX, No. XX, XXXX

with an axial H.17 As an example, Figure 2 depicts the
anomeric regions of the two diastereoisomers 9r and 9β.
Each section shows two doublets: in both spectra the
broadened signal (1J = 166 Hz) is the result of the
equatorial proton at the reducing end whereas the sharp
one is the result of the other anomeric proton. Broadening
Table 1. Glycosidation Studies of the Cyclopropyl-Modified
Mannosyl Trichloroacetimidate 7
3
of the former is ascribed to long-range JC,H couplings
(to H-2 and the Me group). As depicted the β-anomer 9β
reveals a 1JC,H coupling constant of 159 Hz (top) whereas
the respective R-anomer 9r shows a splitting of 169 Hz.
Figure 2. Anomeric region of the 1H-coupled 13C NMR spectra
of disaccharide 9β (top) and 9r (bottom). The spectra were
measured at 125 MHz in CDCl3.
In the pioneering work of Crich for the synthesis of
β-mannosides, a 4,6-benzylidene acetal was the prerequisite
for high β-selectivity.18 It has been argued that such a
protecting group forces the mannose unit into a chair-
like conformation hampering the oxocarbenium forma-
tion. Another point that was raised in favor of the high
β-selectivity of the 4,6-benzylidene protecting group was the
destabilizing electronic effect due to the antiparallel place-
ment of the O-6 dipole to a hypothetical oxocarbenium ion.6b
Although the β-selectivities of our cyclopropanated
mannosyl donors are worse compared with those achieved
with a 4,6-benzylidene protecting group, our β-selectivity
is in contrast to that observed with 2,3,4-tribenzylated-
6-acetylated mannosyl trichloroacetimidate.19 Thus, we
a For all reactions donor 7r (1.3 equiv) was used. b Isolated yield of
the β/R-mixture. c Determined by integration of corresponding anomeric
13C NMR signals.
revealed that in all cases the β-mannoside proved to be
the major product (β/R = 6.7:1À1.3:1).16 The highest
β-selectivities were found when 6-hydroxyl groups were
employed as nucleophile (entries 1À3). But also in other
cases using 3- and 4-hydroxyl groups and even in the case
of highly reactive pent-4-en-1-ol (8e), the formation of the
β-product was slightly favored.
The stereochemistry of all the products was unequivo-
1
cally assigned by the anomeric JC,H coupling constants.
Therefore, a 1H-coupled 13C NMR spectrum was recorded
for each of the two anomers. It is well-known that anome-
1
(17) (a) Bock, K.; Lundt, I.; Pedersen, C. Tetrahedron Lett. 1973, 14,
1037–1040. (b) Kalinowski, H.-O.; Berger, S.; Braun, S. 13C NMR-
Spektroskopie; Thieme-Verlag: Stuttgart, 1984.
ric JC,H coupling constants reveal ∼10 Hz larger values
when they are derived from an equatorial H in comparison
(18) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506–4507.
(b) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223.
(c) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348.
(16) With donor 7β the β/R ratios were worse.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthesis of Cyclopropyl-Modified Trisaccharide 18r
Scheme 3. Synthesis of Cyclopropyl-Modified Trisaccharide 18β
In summary, we have prepared a mannosyl-like donor
with a spiroannulated cyclopropane at C-5. The crucial reac-
tion to obtain this structural feature is the SimmonsÀ
SmithÀFurukawa reaction of an exocyclic enol acetate.
The glycosylation behavior of the respective mannosyl donor
was investigated. Selectivities in favor of the β-anomer were
observed in all cases. Larger structures up to trisaccharides
were prepared and completely deprotected. Further studies
on the incorporation of such units in biologically active
glycans and elucidation of their conformational behavior
will be performed in our laboratory in the future.
assume that the spiroannulated cyclopropane motif leads
to a similar fixation of the chairlike conformation as in
4,6-benzylidene protected analogs. Unfortunately, to date
we could not generate the enol ether of mannose with the
double bond in the (E)-configuration in high yield leading
to an antiparallel placement of the 6-hydroxyl. Such a
compound would be of great value to further investigate
the different influences directing the anomeric configura-
tion of mannoside-like structures.
In order to demonstrate the stability of the three-
membered ring in further transformations, the acetate
group of the pseudodisaccharides 9r and 9β was cleaved
by K2CO3 in methanol/water (Schemes 2 and 3). Free hy-
droxyls were glycosidated with a perbenzoylated glucose
building block 1620 affording the pseudotrisaccharides17r
and 17β, respectively. Global deprotection leading to the
naked carbohydrate mimetics 18r and 18β was achieved
by saponification and subsequent hydrogenolysis using
palladium on charcoal.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie (Emmy Noether Fellowship and
Dozentenstipendium to D.B.W.). We thank Annika Ries
€
and Dennis C. Koester (both University of Gottingen) for
the preparation of some starting materials. Furthermore,
we are grateful to Professor Dr. Lutz F. Tietze (University
€
of Gottingen) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds. This material is free of charge via the Inter-
net at http://pubs.acs.org.
(19) Hewitt, M. C.; Snyder, D. A.; Seeberger, P. H. J. Am. Chem. Soc.
2002, 124, 13434–13436.
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2003, 3435–3445. (b) Schmidt, R. R.; Michel, J.; Moos, M. Liebigs Ann.
Chem. 1984, 1343–1357.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX