Yb(OTf)3-catalyzed C-glycosylation: Highly stereoselective synthesis of C-pseudoglycals

Article abstract of DOI:10.1016/S0040-4039(01)00628-1

A variety of functionalized C-pseudoglycals (pseudoglycal C-glycosides or C-hex-2-enopyranosides) have been obtained in excellent yields and stereoselectivity from the Yb(OTf)₃-catalyzed reaction of tri-O-acetyl glucal with silylated nucleophil

Full text of DOI:10.1016/S0040-4039(01)00628-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4053–4056
Yb(OTf)3-catalyzed C-glycosylation: highly stereoselective
synthesis of C-pseudoglycals
Mohamed Takhi, Adel A.-H. Abdel Rahman and Richard R. Schmidt*
Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany
Received 8 February 2001; accepted 11 April 2001
Abstract—A variety of functionalized C-pseudoglycals (pseudoglycal C-glycosides or C-hex-2-enopyranosides) have been
obtained in excellent yields and stereoselectivity from the Yb(OTf)3-catalyzed reaction of tri-O-acetyl glucal with silylated
nucleophiles such as allyl and propargyl silanes and silyl enol ethers. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis of C-glycosides1 has been the subject of
intense study for various reasons: (1) the discovery of
naturally occurring C-nucleosides with important phar-
macological properties2 gave impetus to synthetic
efforts for preparing active carbohydrate analogs; (2)
the synthesis of biologically significant macromolecules
such as palytoxin,3 spongistatin4 and halichondrin5
requires C-glycosides as chiral building blocks; (3) C-
glycosides are potential inhibitors of carbohydrate pro-
cessing enzymes and they are stable analogues of
glycans involved in important intra- and intercellular
processes.6 Among these C-glycosides, C-pseudogly-
cals, i.e glycals possessing the double bond between
C(2) and C(3), represent a very important class of
compounds because the double bond may be easily
modified, for instance, by hydroxylation, hydrogena-
tion, epoxidation and aminohydroxylation.
TMSOTf,10 montmorillonite,11 and InCl3 are also
known to promote C-glycosylation of glycals. A two-
step process involving Tebbe methylenation and ther-
mal Claisen rearrangement to produce C-b-pseudo-
glycals is a recent addition.13 However, many of these
procedures have limitations in terms of yields, stereose-
lectivities, reaction temperatures, compatibility with
other functional groups present in the molecule and
amounts of catalyst or reagent used. Therefore, there is
still a great demand to find a potentially general
method for this transformation. Recently, we reported
an expeditious approach to the synthesis of O- and
S-pseudoglycals by Yb(OTf)3-catalyzed Ferrier glycosy-
lation.14 The continued interest of our research group in
the synthesis of C-glycosides1 has prompted us to
explore the same catalyst in C-glycosylation as well. We
now report our findings on the synthesis of C-pseudo-
glycals starting from tri-O-acetyl glucal and silylated
species as acceptors in the presence of catalytic
amounts of Yb(OTf)3 (Scheme 1). Our results are sum-
marized in Table 1.
12
For the C-glycosylation of glycals with carbon nucleo-
philes furnishing C-pseudoglycals, a strong Lewis acid
7
8
such as BF3·OEt2 or TiCl4 is generally required as an
activator. Other reagents such as DDQ,9 AlCl3,10
OAc
O
OAc
10 mol% Yb(OTf)3
AcO
O
AcO
AcO
C-Nucleophile (2a-9a),
CH2Cl2, RT
Nu
(2b-9b) mainly α
1
Nu= allyl or propargylsilane or
silyl enol ether
Scheme 1.
Keywords: glycal; pseudoglycal; C-glycosides; ytterbium triflate; catalysis.
* Corresponding author. Tel.: +49-7531-88 2538; fax: +49-7531-88 3135; e-mail: richard.schmidt@uni-konstanz.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00628-1

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M. Takhi et al. / Tetrahedron Letters 42 (2001) 4053–4056
Table 1. Glycosidation of 1 with silylated nucleophiles in the presence of 10 mol% of Yb(OTf)3
In a test case, 1 equiv. of 1 was treated with 1.2 equiv.
of allyl trimethylsilane 2a (entry 1, Table 1) and 10
mol% of Yb(OTf)3 to furnish exclusively the known
C-allyl a-glycoside 2b7b in 92% yield. Encouraged by
these findings, a cross section of silylated nucleophiles
was chosen to react with 1 in the presence of 10 mol%
Yb(OTf)3. Substituted allylsilanes such as 2-bromo-
allylsilane 3a (entry 2, Table 1) and 2-acetoxymethyl-
allylsilane 4a (entry 3, Table 1) smoothly afforded the
corresponding C-a-glycosides 3b and 4b15 in 88 and
90% yield, respectively. The reaction of propargylsilane
5a (entry 4, Table 1) with 1 at 0°C for 16 h provided
C-a-allenylglycoside 5b,16 which is a useful precursor
for our ongoing program of enzyme inhibitor synthesis.
We focused our attention further on the reactivity of
silyl enol ethers with 1 under the same conditions. In
order to check this, commercially available silyl enol
ether 6a (entry 5, Table 1) was reacted with 1 to
produce the corresponding C-a-glycoside 6b7a as the
major product. Silyl enol ether 7a (entry 6, Table 1)
also behaved identically to give C-glycoside 7b in 86%
yield. The success of C-glycosylation of 1 with silyl enol
ether 8a furnishing 8b (entry 7, Table 1) is notable,
since this indicates that similar Boc-protected
aminoacid derivatives will be suitable substrates for
these reaction conditions, thereby allowing access to
C-glycosyl amino acids, which have become objects of
synthetic interest.17 The general applicability of this

M. Takhi et al. / Tetrahedron Letters 42 (2001) 4053–4056
4055
protocol was further exemplified by the synthesis of a
(1-5)-linked C-disaccharide derivative 9b from 9a
(entry 8, Table 1) in 86% yield.
Konobe, M.; Goto, T. Carbohydr. Res. 1987, 171, 193.
8. Danishefsky, S.; Keerwin, J. F. J. Org. Chem. 1982, 47,
3803.
9. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.
Chem. Lett. 1993, 2013.
10. Dawe, R. D.; Fraser-Reid, B. J. Chem. Soc., Chem.
Commun. 1981, 1180.
11. Toshima, K.; Miyamito, N.; Matsuo, G.; Nakata, M.;
Matsumura, S. J. Chem. Soc., Chem. Commun. 1996,
1379.
12. Ghosh, R.; De, D.; Shown, B.; Mait, S. B. Carbohydr.
Res. 1999, 321, 1.
In summary, Yb(OTf)3 has been demonstrated as an
efficient catalyst for highly stereoselective C-glycosyla-
tions to produce a variety of functionalized C-pseudo-
glycals, which are useful intermediates for various
applications. In addition, the catalyst recovered from
the reaction mixture can be reused without serious
loss of activity.18 The non-hazardous and low toxic
nature of lanthanoids should also be emphasized.
13. Godage, H. Y.; Fairbanks, A. J. Tetrahedron Lett.
2000, 41, 7589.
14. Takhi, M.; Abdel-Rahman, A. A.-H.; Schmidt, R. R.
Synlett 2001, 427.
General procedure: To a mixture of tri-O-acetyl glucal
1 (1 equiv.) and nucleophile (1.2 equiv.) in CH2Cl2
was added Yb(OTf)3 (10 mol%) at room
temperature19 and stirred. The contents were stirred
for the required time (Table 1) and the reaction was
monitored by TLC. Water (20 ml) was added to the
reaction mixture and extracted twice with CH2Cl2.
The combined organic layers were dried over Na2SO4,
filtered and concentrated. The residue was purified by
column chromatography with mixtures of petroleum
ether/ethyl acetate to furnish the products.
15. Compound 4ba: [h]2D1 +14.1 (c=1.1, CHCl3); 1H NMR
(CDCl3, 600 MHz): l 2.05 (s, 3 H, COCH3), 2.07 (s, 3
H, COCH3), 2.08 (s, 3 H, COCH3), 2.27 (dd, J1%a,1=5.0
Hz, J1%a,1%b=14.7 Hz, 1 H, 1%-Ha), 2.47 (dd, J1%b,1=8.8
Hz, J1%b,1%a=14.7 Hz, 1 H, 1%-Hb), 3.93 (ddd, J5,6a=3.4
Hz, J5,6b=6.3 Hz, J5,4=9.9 Hz, 1 H, 5-H), 4.14 (dd,
J6a,5=3.4 Hz, J6a,6b=11.9 Hz, 1 H, 6-Ha), 4.21 (dd,
J6b,5=6.3 Hz, J6b,6a=11.9 Hz, 1 H, 6-Hb), 4.38 (ddd,
J1,2=2.4 Hz, J1,1%a=5.0 Hz, J1,1b=8.8 Hz, 1 H, 1-H),
4.58 (d, J3%a,3%b=13.4 Hz, 1 H, 3%-Ha), 4.59 (d, J3%b,3%a
=
13.4 Hz, 1 H, 3%-Hb), 5.06 (s, 1 H, 4%-Ha, terminal
methylene), 5.11 (dd, J4,3=2.3 Hz, J4,5=9.9 Hz, 1 H,
4-H), 5.16 (s, 1 H, 4%-Hb, terminal methylene), 5.80 (dd,
Acknowledgements
This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemis-
chen Industrie. We are grateful to Dr. Armin Geyer
for his help in the structural assignments.
J
3,4=2.3 Hz, J3,2=10.4 Hz, 1 H, 3-H), 5.91 (dd, J2,1=
2.4 Hz, J2,3=10.4 Hz, 1 H, 2-H). 13C NMR (CDCl3,
150 MHz): 20.7, 20.8, 21.0, 36.9, 62.7, 64.8, 66.6, 69.6,
70.4, 115.4, 123.9, 132.7, 140.1, 170.3, 170.5, 170.7. MS
(EI): 326 (M+), 267 (M+−C2H3O2).
16. Compound 5ba: [h]2D1 +86.9 (c=1, CHCl3); 1H NMR
(CDCl3, 600 MHz): l 2.05 (s, 3 H, COCH3), 2.06 (s, 3
H, COCH3), 3.88 (ddd, J5,6a=2.9 Hz, J5,6b=5.4 Hz,
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M. Takhi et al. / Tetrahedron Letters 42 (2001) 4053–4056
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