An efficient synthesis of β-C-glycosides based on the conformational restriction strategy: Lewis acid promoted silane reduction of the anomeric position with complete stereoselectivity

Article abstract of DOI:10.1021/ol048525+

(Chemical Equation Presented) The reduction of glyconolactols having an anomeric carbon substituent by Et₃SiH/TMSOTf proceeded with complete stereoselectivity to produce the corresponding β-C-glycosides when the substrates were conformationally restricted in the ⁴C ₁-chair form by a 3,4-O-cyclic diketal or a 4,6-O-benzylidene protecting group. Thus, the efficient construction of β-C-glycosides was achieved on the basis of the conformation restriction strategy.

Full text of DOI:10.1021/ol048525+

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3751-3754
An Efficient Synthesis of
-C-Glycosides Based on the
â
Conformational Restriction Strategy:
Lewis Acid Promoted Silane Reduction
of the Anomeric Position with Complete
Stereoselectivity
Masaru Terauchi, Hiroshi Abe, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity, Kita-12, Nishi-6,
Kita-ku, Sapporo 060-0812, Japan
shu@pharm.hokudai.ac.jp
Received July 27, 2004 (Revised Manuscript Received September 13, 2004)
ABSTRACT
The reduction of glyconolactols having an anomeric carbon substituent by Et3SiH/TMSOTf proceeded with complete stereoselectivity to produce
the corresponding
-C-glycosides when the substrates were conformationally restricted in the 4C1-chair form by a 3,4-O-cyclic diketal or a
â
4,6-O-benzylidene protecting group. Thus, the efficient construction of
strategy.
â-C-glycosides was achieved on the basis of the conformation restriction
C-Glycosides are of interest as stable mimics of natural
O-glycosides with biological activity.1,2 Although various
effective methods for providing R-C-glycosides have been
developed, the stereoselective synthesis of â-C-glycosides
has been more challenging.1-7 In the course of our synthetic
studies on C-glycoside trisphosphates as novel myo-inositol
trisphosphate receptor ligands,2 we needed a highly stereo-
selective method for the construction of various â-C-
glycosides.
An efficient procedure for providing â-C-glycosides has
been developed by Kishi and co-workers. It involves addition
of an organometallic reagent to a glyconolactone to give an
anomeric mixture of the corresponding lactols that is reduced
stereoselectively by trialkylsilane under Lewis acidic condi-
tions to give the â-C-glycoside (Scheme 1).4 â-C-Glucosides
and -galactosides have been stereoselectively synthesized by
this method. A drawback is that the stereochemical outcome
(1) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599. (b)
Jaramillo, C.; Kanapp S. Synthesis 1994, 1-20. (c) Leavy, D. E.; Tang, C.
The Chemistry of C-Glycosides; Pergamon: Oxford, 1995. (d) Postema,
M. H. D. C-Glycoside Synthesis; CRC: Boca Raton, 1995. (e) Du, Y.;
Linhardt, R. J.; Vlahow, I. R. Tetrahedron 1998, 54, 9913-9959.
(2) (a) Yahiro, Y.; Ichikawa, S.; Shuto, S.; Matsuda, A. Tetrahedron
Lett. 1999, 40, 5527-5531. (b) Shuto, S.; Yahiro, Y.; Ichikawa, S.; Matsuda,
A. J. Org. Chem. 2000, 65, 5547-5557. (c) Shuto, S.; Terauchi, M.; Yahiro,
Y.; Abe, H.; Ichikawa, S.; Matsuda, A. Tetrahedron Lett. 2000, 41, 4151-
4155. (d) Abe, H.; Shuto, S.; Matsuda, A. Tetrahedron Lett. 2000, 41, 2391-
2394. (e) Abe, H.; Shuto, S.; Matsuda, A. J. Org. Chem. 2000, 65, 4315-
4325 and references therein.
(6) Tamura, S.; Abe, H.; Matsuda, A.; Shuto, S. Angew. Chem., Int. Ed.
2003, 42, 1021-1023.
(3) (a) Abe, H.; Shuto, S.; Matsuda, A. J. Am. Chem. Soc. 2001, 123,
11870-11882. (b) Abe, H.; Terauchi, M.; Matsuda, A.; Shuto, S. J. Org.
Chem. 2003, 68, 7439-7447.
(7) Examples of â-C-glycoside synthesis by Kishi’s Lewis acid prompted
silane reduction; see: (a) Lancelin, J.-M.; Zollo, P. H. A.; Sinay¨, P.
Tetrahedron Lett. 1983, 24, 4833-4836. (b) Kraus, G. A.; Molina, M. T.
J. Org. Chem. 1988, 53, 752-753. (c) Czernecki, S.; Ville, G. J. Org. Chem.
1989, 54, 610-612. (d) Dondoni, A.; Marra, A.; Scherrmann, M.-C.
Tetrahedron Lett. 1993, 34, 7323-7326. (e) Xie, J.; Durrat, F.; Vale´ry,
J.-M. J. Org. Chem. 2003, 68, 7896-7898.
(4) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978. (b) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992,
57, 468-481. (c) See ref 1d; pp 57-60.
(5) Minehan, T. G.; Kishi, Y. Tetrahedron Lett. 1997, 38, 6815-6818.
10.1021/ol048525+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/23/2004

Scheme 1. Synthesis of C-Glycosides via the Lewis Acid
Scheme 2. Working Hypothesis for the Kinetic Anomeric
Effect-Dependent Silane Reduction Forming the â-C-Glycosides
Prompted Silane Reduction
of reduction depends on the starting sugar structure, and the
stereoselectivity is not always high.4 For example, when the
method was applied to mannose derivatives, the reduction
was almost nonstereoselective.4 We report here a completely
stereoselective construction of â-C-glycosides via the Lewis
acid-promoted Et3SiH reduction by manipulation of the
anomeric effect through use of the conformationally restricted
substrates.
The anomeric effect8,9 is a stereoelectronic effect ascribed
to n f σ* hyperconjugation between the nonbonding orbital
on the ring oxygen and the antibonding orbital of the
anomeric carbon-heteroatom bond.8-10 When this kind of
orbital interaction stabilizes the transition state during
anomeric bond-forming (or bond-cleavage) processes, it is
referred to as the kinetic anomeric effect.8-10 We have shown
that, in radical and Lewis acid promoted C-glycosidation
reactions, the kinetic anomeric effect can be manipulated by
the substrate conformation. Depending on whether the
conformation of the substrates is restricted to the 4C1- or the
1C4-form, R- or â-selective reactions can be made to occur
highly stereoselectively.3,6
In the Lewis acid-promoted silane reduction (Scheme 1),
hydride attack on the oxocarbenium intermediate seems to
occur predominantly from the R-axial direction4a due to the
kinetic anomeric effect, at least in the cases of glucose and
galactose derivatives. We expected that the stereoselectivity
of the reduction could be improved even further by enhancing
the kinetic anomeric effect through placing conformational
restrictions in the substrates employed. The conformation
of the transition state and the intermediate can be strongly
influenced by conformational effects, which stabilize the
ground-state conformation.3,6,9,11 Therefore, as shown in
Scheme 2, in the reduction of substrate A conformationally
restricted to a C1-chair form, the transition state would
4
assume the 4C1-chairlike form B, where the anomeric center
would be pyramidal. Accordingly, the â-C-glycosidic product
C could be produced highly selectively. The axial attack
transition state B in the 4C1-restricted form would be
significantly stabilized by the interaction between the anti-
bonding σ*q of the newly forming anomeric C-H bond and
the orbital of a nonbonded electron pair (nO) on the ring
oxygen because of their planar arrangement.12
Based on this hypothesis, we planned to examine the Lewis
acid promoted Et3SiH reduction with the various conforma-
tionally restricted and unrestricted substrates. In this study,
the glucose- and mannose-type substrates were employed to
compare their stereochemical outcomes, since these two were
considered the typical stereoselective and nonselective
substrates in the reductions reported previously.4,7 Thus, we
designed the conformationally restricted substrates 2a-c,
4a-c, and 5 and the corresponding conformationally unre-
stricted substrates 1a-c and 3a-c (Table 1), derived from
D-glucose or D-mannose. The conformation of the pyranose
ring of the substrates 2a-c and 4a-c bearing a 3,4-O-cyclic
diketal group and the substrate 5 bearing a 4,6-O-benzylidene
group would be restricted in the desired 4C1-form due to the
trans-decalin-type ring system.3,6,13,14
The conformationally unrestricted substrates 1a-c and
3a-c were prepared by the previously reported method.4a,7c,15
The conformationally restricted substrates 2a-c and 4a-c
were synthesized from 1-thiophenyl-2,3,4,6,-tetra-O-acetyl
sugars 6 or 7 via mannolactones 1016 or 11 (Scheme S1 in
the Supporting Information). Similarly, another conforma-
(12) In the transition state of nucleophilic addition reactions to carbonyls,
the energy of the transition state can be lowered by hyperconjugation
between an antiperiplanar vicinal σ-bond to the antibonding component (σ*q)
of the newly forming bond; see: (a) Cieplak, A. S. J. Am. Chem. Soc.
1981, 103, 4540-4552. (b) Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J.
Am. Chem. Soc. 1989, 111, 8447-8462. (c) Cieplak, A. S. Chem. ReV.
1999, 99, 1265-1336.
(13) (a) Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W. J. Org.
Chem. 1996, 61, 3897-3899. (b) Hense, A.; Ley, S. V.; Osborn, H. M. I.;
Owen, D. R.; Poisson, J.-F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc.,
Perkin Trans. 1 1997, 2023-2032.
(14) For a highly â-stereoselective O-glycosylation using conformation-
ally restricted 4,6-O-benzylidenemannose donors, see: Crich, D.; W. Cai,
W.; Dai, Z. J. Org. Chem. 2000, 65, 1291-1297.
(15) Li, X.; Ohtake, H.; Takahashi, H.; Ikegami, S. Tetrahedron 2001,
57, 4297-4309.
(8) (a) Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019-5087. (b)
The Anomeric Effect and Associated Stereoelectronic Effects; Thatcher, G.
R. J., Ed.; ACS Symposium Series 539; American Chemical Society:
Washington, DC, 1993. (c) Juaristi, E.; Cuevas, G. The Anomiric Effect;
CRC: Boca Raton, 1995. (d) Thibaudeau, C.; Chattopadhyaya, J. Stereo-
electronic Effects in Nucleosides and Nucleotides and their Structural
Implication; Uppsala University: Uppsala, 1999.
(9) Pothier, N.; Goldstein, S.; Deslongchamps, P. HelV. Chim Acta 1992,
75, 604-620.
(10) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
(11) For a stereoelectronic model explaining the stereoselective nucleo-
philic reactions via six membered-ring oxocarbenium ions, see: Romero,
J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122,
168-189.
3752
Org. Lett., Vol. 6, No. 21, 2004

cyclic protecting groups on the conformational stability was
1
unclear at least from the H NMR analysis.
Table 1. Reduction of the Conformationally Restricted and
Unrestricted Substrates with Et3SiH/TMSOTfa
The reduction of these substrates was carried out with Et3-
SiH (1.1 equiv) and TMSOTf (1.1 equiv) in CH2Cl2 at -78
°C,17 and the results are summarized in Table 1.18 The
stereoselectivity was first examined with the glucose-type
substrates, which were the conformationally unrestricted
1a-c and the restricted 2a-c (entries 1-6). The silane
reduction of 1-carbon-substituted glucolactols having benzyl
protecting groups is known to occur stereoselectively to
produce the corresponding â-C-glucosides.4,7 In accord with
these previous results, the 1-methyl substrate 1a and the
1-phenyl substrate 1b were reduced with a complete stereo-
selectivity to give the â-products (entries 1 and 2). The
corresponding conformationally restricted substrates 2a and
2b also gave the â-C-glucosides as the sole product (entries
4 and 5), where the yields were higher than those in the cases
of the unrestricted substrates. Although, in the reduction of
the conformationally unrestricted substrate 1c having an
anomeric allyl substituent the â-selectivity decreased some-
what (R/â ) 10:90, entry 3), the corresponding conforma-
tionally restricted substrate 2c was reduced to only the â-C-
glucoside in high yield (entry 6). These reactions with the
glucose substrates showed that the conformational restriction
improved the yield of the â-C-glucosides, probably due to
the stabilized transition state.
The reduction of the mannose substrates, the conforma-
tionally restricted lactols 4a-c and 5, and the unrestricted
lactols 3a-c was next examined (entries 7-13). In the
reduction of the conformationally unrestricted tetra-O-benzyl
substrates, the 1-phenyl mannose derivative 3b was converted
into the â-product with complete selectivity in moderate yield
(entry 8). However, the â-stereoselectivity in the reduction
of the 1-methyl substrate 3a and the 1-allyl substrate 3c was
poor, in accord with the previous results with the 1-substi-
tuted mannolactols.4 When the 4C1-restricted substrates were
used, the stereoselectivity was significantly improved as
expected (entries 10, 11, and 13). Reduction of the 1-methyl
and the 1-phenyl lactols 4a and 4b with the 3,4-cyclic ketal
protection occurred with complete stereoselectivity to give
the desired â-products (entries 10 and 11). On the other hand,
reduction of the conformationally restricted 1-allyl substrate
4c was very slow, and most of the starting material was
recovered. When the 4,6-O-benzylidene-protected lactol 5
was employed as the conformationally restricted substrate,
the reduction proceeded effectively to produce the desired
1-allyl-â-C-mannoside as the sole product in 95% yield.
Thus, the 4C1-conformational restriction effectively improved
the stereoselectivity as well as the yield in the Et3SiH
reduction.
a Reaction was carried out with Et3SiH (1.1 equiv) and TMSOTf (1.1
equiv) in CH2Cl2 at -78 °C for 60 min, and the products were purified by
silica gel column chromatography. b The R or â is based on the configuration
of the anomeric hydroxyl, and the ratio was determined by 1H NMR.
c Substrate was recovered in entries 2 (18%), 8 (22%), 10 (18%), and 12
(64%). d Determined by isolated yields for entry 3 and by 1H NMR for
entries 7 and 9. e Yield of the mixture of the R- and â-C-glycosides. f The
reaction time was 75 min.
As shown in Table 1, while all of the 1-substituted lactol
substrates used in this study mainly included the R-hydroxy
tionally restricted substrate 5 was prepared (Scheme S2 in
the Supporting Information), and the conformation of these
substrates was analyzed by their 1H NMR spectra. As
summarized in Table S1 (Supporting Information), these
coupling constants suggested that, irrespective of the protect-
(16) de Kort, M.; Regenbogen, A. D.; Valentijn, A. R. P. M.; Challiss,
R. A. J.; Iwata, Y.; Miyamoto, S.; van der Marel, G. A.; van Boom, J. H.
Chem. Eur. J. 2000, 6, 2696-2704.
(17) When F3B‚OEt2 was used as the Lewis acid, the 3,4-cyclic ketal
moiety of the conformationally restricted substrates was partially reduced.
(18) The stereochemistry of the C-glycosidic products was determined
by the J1,2 values for the C-glucosides or by NOE experiments for the
C-mannosides.
4
ing groups, all of the substrates seem to prefer the C1-
chairlike conformation. Thus, the effect of the constrained
Org. Lett., Vol. 6, No. 21, 2004
3753

isomer, the stereoretained â-C-glycoside was always obtained
as the major product, indicating that the reduction proceeded
mainly via an SN1 or an analogous mechanism. In the
glucose-type substrates, the reduction selectively occurred
from the R-face even without conformational restriction.
However, in the conformationally unrestricted mannose-type
substrates, the â-selectivity was low, and the conformational
restriction effectively improved the stereochemical outcome.
The tetra-O-benzyl glucosubstrates 1a-c would be more
In conclusion, we have developed an efficient method for
providing â-C-glycosides based on the conformationally
restricted strategy. The present study together with our
previous results3,6 suggests that the kinetic anomeric effect
can be manipulated by the substrate conformation to increase
the stereoselectivity in the anomeric reactions.
Supporting Information Available: Schemes S1 and S2,
Table S1, and experimental details on the synthesis of the
reaction substrates and the Lewis acid promoted silane
reduction; 1H NMR spectra of 3b, 5, and the silane reduction
products from 2c and 4a. This material is available free of
charge via the Internet at http://pubs.acs.org.
4
stable in the C1-chair conformation, due to the 2,3,4-all-
equatorial substituents on the pyranose ring, than the
corresponding manno substrates 3a-c having an axial
substituent at the 2-position. Accordingly, the kinetic ano-
meric effect may work rather effectively even in the
conformationally unrestricted gluco substrates 1a-c.
OL048525+
3754
Org. Lett., Vol. 6, No. 21, 2004