Novel zinc (II)-mediated epimerization of 2′-carbonylalkyl-α-C-glycopyranosides to their β-anomers

Article abstract of DOI:10.1021/ja017430p

2-Aldehydes and 2-ketones of α-C-glycosides, including the gluco-, galacto-, and manno- series, were epimerized exclusively to their β-anomers in good-to-excellent yields under basic conditions and in the presence of zinc acetate. The β-stereoselectivity

Full text of DOI:10.1021/ja017430p

Published on Web 02/16/2002
Novel Zinc (II)-Mediated Epimerization of
2′-Carbonylalkyl-r-C-glycopyranosides to Their â-Anomers
Huawu Shao, Zerong Wang, Edith Lacroix, Shih-Hsiung Wu,† Harold J. Jennings, and Wei Zou*
Institute for Biological Sciences, National Research Council of Canada, 100 Sussex DriVe,
Ottawa, Ontario K1A 0R6, Canada, and Institute of Biological Chemistry, Academy Sinica,
Taipei, Taiwan, Republic of China
Received October 30, 2001
Scheme 1
C-glycosides occur as subunits of a variety of biologically
important natural products with antitumor, antibacterial, or antiviral
activity,1 and as stable metabolic mimics of their natural O- and
N-counterparts may serve as biological tools and potential thera-
peutics.2 The stereoselective synthesis of C-glycosides has attracted
considerable interest and the synthetic methodology has advanced
significantly in the past decade.1,3 However, most of the methods
available are more suited for the synthesis of R-C-glycosides.
Although stereoselective routes to â-C-glycosides exist, in practice
their use is very limited because of their low yields, poor selectivity,
or lack of general applicability due to the complicated procedures
involved. Typically, â-C-glycosides can be made by addition of a
nucleophilic reagent to a sugar lactone, giving the corresponding
hemiketal or exoglycal, which is then reduced by various reagents,4
or by a Wittig or Grignard reaction at the anomeric position, forming
an unsaturated, open-chain intermediate, followed by an intramo-
lecular cyclization.5 The stereoselectivity of these reactions are
subject to the influence of the neighboring group at 2-O-position
of the sugar substrates. Consequently, these procedures are limited
to selectively preparing gluco- and galacto-â-C-glycosides, but are
ineffective for the stereoselective preparation of manno- and other
2-deoxy sugar â-C-glycosides. Samarium and 1,2-anhydrosugar-
based C-glycosylation methods for the synthesis of 1,2-trans-C-
glycosides also fail to yield manno-â-C-glycosides.6 Currently, the
best stereoselective syntheses of manno-â-C-glycosides can be
achieved (1) by using a tethered approach, which involves placing
a silicon-alkynyl group at the 2-O-position in combination with
activation of C1 by pyridyl sulfone,7 (2) by a modified Keck
reaction,8 in which glycosyl dihalides are first reacted with allyltin
reagents to form halo C-allyl glycosides, followed by radical
reduction of halide, or (3) by condensation of mannopyranose with
a sulfur ylide to an epoxide, followed by intramolecular cyclization.9
Obviously, more effective and general methods are needed for
the preparation of â-C-glycosides, especially in the case of manno-
â-C-glycosides. Considering the easy accessibility of R-C-glyco-
sides a facile transformation of R-C-glycosides to â-C-anomers
would be particularly attractive. The strategy could lead to the use
of fewer building blocks and create more flexibility in the syntheses
of complex structures. Previously, we had attempted a C1 epimer-
ization on R-C-2-ulosides with the objective of preparing â-anomers
without success. Instead, ring-contracted cyclopentenones were
obtained.10 We now report a general procedure, which effectively
converts 2′-carbonylalkyl-R-C-glycosides (aldehydes and ketones)
to their respective â-anomers including manno-â-C-glycosides.
Allyl-R-C-glucoside was ozonolized and reduced by Zn/HOAc
to aldehyde 1. Without further purification, treatment with NaBH4
in ethanol afforded exclusively, following acetylation (Ac2O/Py),
the â-C-glucoside (2) in good yield, and not the expected R-ano-
mer.11 We were encouraged by this serendipitous observation to
pursue this reaction further, and after careful examination of the
reaction conditions a plausible mechanism was hypothesized which
is illustrated in Scheme 1. We hypothesized that the epimerization
at C1 is initiated by the formation of Zn-enolate and it is known
that Zn-enolate adopts exclusively the Z-configuration,12 which can
be stabilized by intramolecular chelation to the pyranose ring
oxygen to form a syn chair-boat structure. Due to the activation
generated by the Zn-O coordination, fission of the C1-O bond
occurs, leading to opening of the pyranose ring, which is spontane-
ously followed by a change in conformation. The more stable anti
chair-boat transition state is favored, and the subsequent hetero-
intramolecular Michael addition results in the formation of â-C-
glycoside in a ring-closure step.
We performed the reaction with such a mechanism in mind. Thus,
aldehyde 1 was first converted to Zn-enolate by treatment with
ZnO(Ac)2 in NaOMe/MeOH,13 which led to C1 epimerization.
NaBH4 was then added to reduce the aldehyde which followed
by acetylation (Ac2O/py) afforded â-C-glucoside 2 in 77% yield
(see Table 1, entry 1). The structure and the stereochemistry of the
1
anomeric carbon were unambiguously determined by various H
NMR experiments. An upfield shift of the H-1 chemical resonance
from δH 4.25 ppm (R-anomer, J1,2 6.5 Hz) to δH 3.37 ppm (J1,2 9.5
Hz) for â-C-glucoside is observed. In addition, also observed are
nOe’s among H-1, H-3, and H-5 that confirm the â-configuration.
Similarly, galacto-R-C-glycoside 3 was also easily rearranged to
its â-anomer 4 (entry 2) and to 5 after reduction and acetylation
(entry 3).
The ultimate challenge for the method would be the synthesis
of manno-â-C-glycosides and to test its applicability to this synthesis
two R-C-mannosides (6 and 8) (entries 4 and 5) were subjected to
above conditions. Without difficulty both were converted to â-ano-
mers (7 and 9) exclusively. Hence, epimerization was successfully
performed in gluco-, galacto-, and manno-C-glycosides. Unlike
other C-glycosylation methods4-7 2-O-substitution and the config-
† Institute of Biological Chemistry, Academy Sinica.
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2130 VOL. 124, NO. 10, 2002 J. AM. CHEM. SOC.
10.1021/ja017430p CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Epimerization to â-C-glycosidesa
Supporting Information Available: Experimental procedures and
1H, COSY, NOESY, and 13C NMR spectra of products (2, 4, 5, 7, 9,
11, 13, 14) and R-C-glycosides (10 and 12) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Reagents and conditions: 5-10 equiv Zn(OAc)2 in 4% NaOMe/MeOH
at rt overnight. b Isolated yields with essentially one product based on TLC.
c Reduced (NaBH4) and acetylated.
uration of the 2-O-substituent do not affect the â-stereoselectivity
of this epimerization. Thus, this communication describes a novel
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which is particularly useful for the preparation of manno-â-C-
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To illustrate the scope of this method, we extended this procedure
to 2′-ketones of R-C-glycosides. In the presence of Zn(OAc)2 and
NaOMe both 2′-ketones (10 and 12)14 were completely epimerized
to their â-anomers (entries 6 and 7). The products were isolated
without NaBH4 reduction and were consistent with the mechanism
as shown in Scheme 1.15 Although â-C-glycoside 13 from epimer-
ization of ketone 12 was isolated, the major product was 14, which
was formed by further Michael addition of MeO- to 13. Both
diastereomers were formed in this case in the ratio of 1:1 as
1
indicated by H NMR analysis.
(8) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G.; Raphoz, C. Tetrahedron
Lett. 1997, 47, 8185-8188.
The amount of Zn(OAc)2 used in the experiments (entry 4)
described above varied from 0.5 to 10 equiv and had no effect on
either the yield or stereoselectivity of the epimerization. Therefore,
this rearrangement probably proceeds using catalytic amounts of
Zn (II). However, the base used has to be strong enough to achieve
complete C1 epimerization.
In summary we have discovered a broadly applicable method
for the synthesis of 2′-carbonylalkyl-â-C-glycosides. This novel zinc
(II)-mediated epimerization has been applied to 2′-aldehydes and
2′-ketones of gluco-, galacto-, and manno-â-C-glycosides. Obvi-
ously, the utility of these functional groups may be further exploited.
The procedure described is very simple and reliable without use of
toxic and special reagents. This method may also be applied to the
epimerization of other pyranose compounds.
(9) Lo´pez-Herrera, F. J.; Sarabia-Garc´ıa, F.; Heras-Lo´pez, A.; Pino-Gonza´lez,
M. S. J. Org. Chem. 1997, 62, 6056-6059.
(10) Zou, W.; Wang, Z.; Laroix, E.; Wu, S.-H.; Jennings, H. J. Carbohydr.
Res. 2001, 334, 223-231.
(11) We observed that the â-C-glucoside 2 was obtained when the reduction
of aldehyde 1 was performed with an excess amount of NaBH4 and the
reaction was unusually slow (12 h, reflux) probably due to enolation. The
reduction was fast (0.5 h at rt) with less NaBH4 used, and only R-C-
glycoside (δH 4.25 ppm, H-1, J1, 6.5 Hz) was obtained.
2
(12) (a) van der Steen, F. H.; Kleijn, H.; Britovsck, G. J. P.; Jastrzebski, J. T.
B. H.; van Koten, G. J. Org. Chem. 1992, 57, 3906-3916. (b) Lorthiois,
E.; Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63, 2442-2450.
(13) We also treated aldehydes (1 and 6) with 5% Zn in 1% NaOEt/EtOH.
After reduction (NaBH4) and acetylation (Ac2O/Py) epimerized products
(2 and 7) were also obtained in moderate yields (30-50%).
(14) Allyl 2,3,4,6-tetra-O-benzyl-R-C-galactopyranoside was treated with
Hg(OAc)2, the resultant 2′-alcohol was oxidized to ketone (10) using
DMSO-Ac2O. Another ketone 12 was synthesized from 3 in two steps:
(1) Grignard reaction (allylMgBr) and (2) DMSO-Ac2O oxidation.
(15) We have no spectroscopic data to support the intermediate structures and
stereochemistry illustrated in Scheme 1. However, the similar intermediates
have been previously reported (ref 5).
Acknowledgment. This is NRCC publication No.42449; this
work is supported in part by National Research Council of Canada
(to W.Z.) and National Science Council of Taiwan (to S.W.).
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