A Pd-catalyzed approach to (1→6)-linked C-glycosides

Article abstract of DOI:10.1021/ol101625p

A flexible and robust method for the assembly of (1→6)-linked C-glycosidic disaccharides is presented. The key reaction is a Pd-catalyzed coupling of 1-iodo-or 1-triflato-glycals with alkynyl glycosides. Reinstallation of the native hydroxyl group pattern

Full text of DOI:10.1021/ol101625p

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3934-3937
A Pd-Catalyzed Approach to
(1f6)-Linked C-Glycosides
Dennis C. Koester, Markus Leibeling, Roman Neufeld, and Daniel B. Werz*
Institut fu¨r Organische und Biomolekulare Chemie der Georg-August-UniVersita¨t
Go¨ttingen, Tammannstr. 2, D-37077 Go¨ttingen, Germany
dwerz@gwdg.de
Received July 14, 2010
ABSTRACT
A flexible and robust method for the assembly of (1f6)-linked C-glycosidic disaccharides is presented. The key reaction is a Pd-catalyzed
coupling of 1-iodo- or 1-triflato-glycals with alkynyl glycosides. Reinstallation of the native hydroxyl group pattern is achieved after selective
hydrogenation of the triple bond using Raney-nickel. Epoxidation with DMDO and reductive epoxide opening gives access to either the r- or
the ꢀ-derivative, depending on the hydride source.
Carbohydrates have become a major focus of current
biological, biochemical, and medicinal research.1 Besides
their hydrophilicity and complexity, a particular problem for
the application of carbohydrates as drugs is the in ViVo
lability of the glycosidic bond. To address this issue stable
mimetics have to be prepared. One possibility inter alia is
the replacement of the anomeric oxygen by carbon func-
tionalities to provide carbohydrate mimetics that are called
C-glycosides.2 Aryl C-glycosides are often found in natural
products;3 however, C-glycosidic bonds between monosac-
charide units are only rarely found in nature. In recent
decades several synthetic approaches to access C-glycosidic
bonds have been developed.4,5 The stability of such com-
pounds against hydrolysis, acids, and especially enzymatic
degradation makes their synthesis and biological evaluation
an interesting journey in the realm of medicinal chemistry.6
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M. A.; Timmers, C. M.; van der Marel, G. A.; van Boom, J. H.; Mallet,
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10.1021/ol101625p  2010 American Chemical Society
Published on Web 08/05/2010

Therefore, a flexible and robust approach for the assembly
of a variety of C-glycosides (R- and ꢀ-anomers) starting from
relatively simple building blocks would be highly desirable.
In this communication we present our recent studies that
address this issue with respect to the (1f6)-linkage.
We made use of Pd-catalyzed coupling reactions in
assembling the subunits, these being appropriately function-
alized monosaccharide building blocks. The two coupling
partners, the 1-iodoglycal 1 and the alkynyl glycosides (2-4),
underwent Sonogashira-Hagihara-type reaction to afford the
pseudodisaccharides 5-7 (Scheme 1).
Scheme 2
.
TIPS Deprotection and Hydrogenation of 5 To Yield
(1f6)-Linked 2-Deoxy-C-glycoside 12
We next explored the scope of this approach in accessing
(1f6)-linked C-glycosides. Attempts to prepare the unknown
1-iodogalactals were fruitless. For this, we had examined
lithiation of the anomeric carbon and subsequent iodination
of the intermediate carbanion. However, for silylated galac-
tals this procedure resulted in some decomposition.10 There-
fore, we investigated the viability of the process with triflates
as electrophiles in the coupling reaction.
Scheme 1
.
Sonogashira-Hagihara Reaction for the Synthesis of
C-Glycosidic Pseudodisaccharides 5-7
The corresponding galactal triflate 16 could be prepared
in excellent yield via an acid-mediated addition of water to
the perbenzylated galactal 13, yielding an R:ꢀ-mixture of
the hemiacetal 14.11 Subsequent oxidation to the lactone
under modified Swern conditions,12 followed by the final
transformation of the corresponding enolate with PhNTf2,13
gave rise to the respective triflate 16 (Scheme 3). Because
Scheme 3
.
Synthesis of the Galactal Triflate and Subsequent in
Situ Cacchi Coupling To Yield 17-19
Iodoglucal 1 can easily be prepared starting from D-glucose
according to methods well documented in the literature.7 The
6-alkynyl glycoside derivatives were synthesized in one step
under Ohira-Bestmann conditions from the respective
aldehydes.8 The coupling reaction that produces 5-7 occurs
under standard Sonogashira conditions in good to excellent
yield (Scheme 1). As alkynyl components congeners with
gluco-, galacto-, and manno-configuration were used.9
The enyne system in the respective pseudodisaccharides
opens up several possibilities for further transformation.
Whereas a complete reduction would afford a (1f6)-linked
2-deoxy-C-glycoside, a reduction of the alkyne moiety
followed by an oxidative-reductive functionalization of the
double bond would produce the respective C-glycosidic
disaccharide with the native hydroxyl group pattern. With 5
we performed a cleavage of the TIPS groups by using TBAF
as fluoride source. Afterward a hydrogenation of the enyne
system together with a deprotection of the Bn groups yielded
the (1f6)-linked 2-deoxy-C-glycoside 12. The reaction
under a hydrogen atmosphere using Pearlman’s catalyst
proceeded smoothly in a highly substrate-controlled fashion
to afford 12 in an R/ꢀ ratio of 1:10 (Scheme 2).
of concerns regarding the stability of these compounds, they
were not isolated but coupled in situ with a variety of
(7) Potuzak, J. S.; Tan, D. S. Tetrahedron Lett. 2004, 45, 1797–1801.
(8) (a) Lehmann, J.; Thieme, R. Liebigs Ann. 1983, 525–532. (b) Roth,
G. J.; Liepold, B.; Mu¨ller, S. G.; Bestmann, H. J. Synthesis 2004, 59–62.
(9) Che´nede´, P.; Pothier, P.; Sollogoub, M.; Fairbanks, A. J.; Sinay¨,
P. G. J. Chem. Soc., Chem. Commun. 1995, 1373–1374.
(10) We assume that in the case of the galactal a deprotonation at the
C-4 followed by subsequent ring opening occurs. The proton H-4 is acidified
due a parallel arrangement of the C4-H and the C5-O bonds.
(11) Wild, R.; Schmidt, R. R. Liebigs Ann. 1995, 455–764.
Org. Lett., Vol. 12, No. 17, 2010
3935

Table 1. Synthesis of C-Glycosidic Disaccharides
different glycosyl alkynes to yield the desired pseudodisac-
charides 17-19.5 In order to reinstall the native hydroxyl
group pattern, we became interested in the behavior of the
enyne system with respect to oxidation and reduction.
Attempts to epoxidize the electron-rich double bond without
affecting the triple bond proved to be unsuccessful. In
contrast, a screening of various hydrogenation catalysts
revealed that Raney-nickel under hydrogen atmosphere was
able to reduce the triple bond much faster to an ethano unit
than it affected the more electron-rich double bond. Encour-
aged by this result, we further tried to optimize the reaction
conditions in order to obtain only the enol ether system and
not the fully reduced disaccharides. Finally, a mixture of
MeOH and THF (2:1) and a reaction time of about 3 h under
an atmosphere of hydrogen proved to be the best choice for
effecting the desired transformation (Table 1).
(12) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419–3421.
(13) (a) Fujiwara, K.; Tsunashima, M.; Awakura, D.; Murai, A.
Tetrahedron Lett. 1995, 36, 8263–8266. (b) Sasaki, M.; Ishikawa, M.; Fuwa,
H.; Tachibana, K. Tetrahedron 2002, 58, 1889–1911.
3936
Org. Lett., Vol. 12, No. 17, 2010

Having reduced the triple bond of the enyne system
selectively, the remaining enol ether was targeted for
reinstallation of the native hydroxyl group pattern. Formally
a regio- and diastereoselective addition of water to the enol
ether was needed. Studies with different borane complexes
revealed that hydroboration with BH3·THF diastereoselec-
tively gave access to ꢀ-configured gluco products (Table 1,
entries 3, 6, and 7).14 However, we sought a method that
would allow for the formation of both R- and ꢀ-configured
pseudoanomeric centers, depending only on the reagents
used. For unsubstituted glycals dimethyldioxirane (DMDO)
is the reagent of choice to convert these compounds into
gluco-configured glycosyl building blocks.15 Therefore, we
tested the DMDO-mediated epoxidation with our compounds
as well. Indeed, high facial selectivity in favor of the gluco
configuration (>20:1) was observed. We were optimistic that
the epoxide opening by a hydride would afford only R- or
ꢀ-configured pseudoanomeric centers, which could be ad-
justed by the right choice of the hydride source.
borohydride afforded the C-glycosidic ꢀ-mannoses 41 or 42
(Scheme 4). The chiral induction resulted exclusively from the
substrate.19
Scheme 4. Synthesis of C-Glycosidic ꢀ-Mannosides
First we elucidated the potential of DIBAL as a hydride
transfer reagent.16 We anticipated the formation of ꢀ-products
due to coordination of the aluminum with the epoxide oxygen
and resulting hydride transfer from the same side (Table 1,
entries 1 and 2). By contrast, the use of superhydride
(LiBHEt3) exclusively led to installation of the R-linkage.17
As a result of its high nucleophilicity, an SN2-type ring
opening of the three-membered ring occurs. With these
methods in hand a variety of (1f6)-linked C-glycosides were
created (Table 1). Global deprotection to afford the disac-
charide mimetics was performed in almost quantitative yield
by using a hydrogen atmosphere and Pearlman’ s catalyst
(Table 1). The stereochemistry of the products was confirmed
by HOMO-decoupling NMR experiments (see Supporting
Information).
In summary, we have developed a robust and flexible
approach for the synthesis of various (1f6)-linked C-
glycosidic disaccharides starting from appropriately func-
tionalized monosaccharide building blocks. The key to our
sucess was a Pd-catalyzed coupling of an 1-iodo or 1-triflato
glycal with an alkynyl glycoside. Further transformation of
the resulting enyne system provides access to R- and
ꢀ-configured C-glycosidic disaccharides, as well as 2-deoxy-
C-glycosides. Extension of this approach to other C-
glycosidic bonds such as (1f4)-linkages using different Pd-
mediated coupling reactions is in progress.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie (Emmy Noether Fellowship and Liebig
Fellowship to D.B.W., Ph.D. Fellowship to D.C.K). D.C.K.
is grateful to the Studienstiftung des deutschen Volkes for
an undergraduate fellowship. M.L. thanks the State of Lower
Saxony for a CaSuS fellowship. The authors acknowledge
R. Machinek (University of Go¨ttingen) for support with
respect to structure elucidation by NMR spectroscopy and
Professor Dr. Lutz F. Tietze (University of Go¨ttingen) for
helpful discussions and generous support of our work.
The epoxidation procedure with DMDO led only to gluco-
configured products. Because of the highly sensitive acetalic
epoxide that is formed, acidic or basic epoxidation reagents that
might lead to a different facial selectivity are not suitable.
Therefore, we employed a well-known trick to convert glucose
moieties into mannose moieties.18 An oxidation of the newly
formed 2-hydroxyl group of 21 or 24, respectively, with
Dess-Martin periodinane (DMP) to the respective ketone 39
or 40 and subsequent diastereoselective reduction by sodium
(14) (a) Hanessian, S.; Martin, M.; Desai, R. C. J. Chem. Soc., Chem.
Commun. 1986, 926–927. (b) Schmidt, R. R.; Preuss, R.; Betz, R.
Tetrahedron Lett. 1987, 28, 6591–6594.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661–6666.
(16) Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier, J. D.
Chem.sEur. J. 2006, 12, 1736–1746.
OL101625P
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M. J. Org. Chem. 2004, 69, 2797–2804. (b) Krishnamurthy, S.; Schubert,
R. M.; Brown, H. C. J. Am. Chem. Soc. 1973, 95, 8486–8487.
(18) Lichtenthaler, F. W.; Schneider-Adams, T.; Immel, S. J. Org. Chem.
1994, 59, 6735–3738.
(19) Attempts to reduce the corresponding ketone arising from the
corresponding R-derivative (see 39R in Supporting Information) led back
to the starting material indicating an inverted chiral induction.
Org. Lett., Vol. 12, No. 17, 2010
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