Stereoselective glycosylation of exo-glycals accelerated by Ferrier-type rearrangement.

Article abstract of DOI:10.1021/ol034130z

[reaction: see text] Owing to the driving force of the Ferrier-type rearrangement, the exo-glycals are highly reactive with various alcohols to afford glycosides and glycoconjugates with exclusive alpha-configuration. The resulting vinyl group in these gl

Full text of DOI:10.1021/ol034130z

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1087-1089
Stereoselective Glycosylation of
exo-Glycals Accelerated by Ferrier-Type
Rearrangement
Hui-Chang Lin,†,§ Wen-Bin Yang,‡,§ Yu-Feng Gu,† Chen-Yin Chen,†
,†
Chung-Yi Wu,† and Chun-Hung Lin*
Institute of Biological Chemistry, Academia Sinica, No. 128, Academia Road Section 2,
Nan-Kang, Taipei, 11529, Taiwan, and Graduate Institute of Pharmacognosy Science,
Taipei Medical UniVersity, Taiwan
chunhung@gate.sinica.edu.tw
Received January 23, 2003
ABSTRACT
Owing to the driving force of the Ferrier-type rearrangement, the exo-glycals are highly reactive with various alcohols to afford glycosides and
glycoconjugates with exclusive r-configuration. The resulting vinyl group in these glycosylation products can be further elaborated for general
applications, including the synthesis of spiro derivatives and glycosylation of 2-ketoaldonic acids.
Glycosidic bond formation is the prerequisite to incorporate
appropriate glycoforms into various biomolecules. It is well-
known that endo-glycals (1,2-unsaturated sugars) are utilized
as versatile building blocks in chemical glycosylations such
as the Ferrier reaction and Danishefsky’s glycal assembly
procedure. Both methods have been developed as effective
methods to synthesize various glycoconjugates, including
Lewis and blood group determinants, gangliosides, and
tumor-associated antigens,1-5 as well as many bioactive
natural products (e.g., forskolin6 and cyclophellitol7,8). A
Michael addition to 2-nitrogalactal, recently demonstrated
by Schmidt et al., is another example to utilize endo-glycal
for the synthesis of TN, STN antigens, and other glycopep-
tides.9 Therefore, it is reasonable that exo-glycals should be
also synthetically valuable because these molecules can not
only generate C-glycosidic linkages but also serve as useful
glycosyl donors as aforementioned endo-glycals. However,
the chemistry of exo-glycals is either rare or tedious in
comparison with endo-glycals.10 In search of a way to solve
this problem, a general and efficient method has been devised
by our group to prepare exo-glycals based on a nucleophilic
† Academia Sinica.
‡ Taipei Medical University.
§ Both authors equally contributed to this work.
(8) (a) McDevitt, R. E.; Fraser-Reid, B. J. Org. Chem. 1994, 59, 3250.
(b) For a detailed review, please see: Fraser-Reid, B. Acc. Chem. Res. 1996,
29, 57.
(9) (a) Winterfeld, G. A.; Schmidt, R. R. Angew. Chem., Int. Ed. 2001,
40, 2654. (b) Winterfeld, G. A.; Ito, Y.; Ogawa, T.; Schmidt, R. R. Eur. J.
Org. Chem. 1999, 1167. (c) Das, J.; Schmidt, R. R. Eur. J. Org. Chem.
1998, 1609.
(10) (a) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G. Raphoz, C.
Tetrahedron Lett. 1997, 38, 8185. (b) Molina, A.; Czernecki, S.; Xie, J.
Tetrahedron Lett. 1998, 39, 7507. (c) Alcaraz, M.-L.; Griffin, F. K.;
Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 8183. (d)
Griffin, F. K.; Murphy, P. V.; Paterson, D. E., Taylor, R. J. K. Tetrahedron
Lett. 1998, 39, 8179. (e) Griffin, F. K.; Paterson, D. E.; Murphy, P. V.;
Taylor, R. J. K. Eur. J. Org. Chem. 2002, 1305. (f) Belica, P. S.; Franck,
R. W. Tetrahedron Lett. 1998, 39, 8225. (g) Yang, G.; Franck, R. W.;
Bittman, R.; Samadden, P.; Arthur, G. Org. Lett. 2001, 3, 197.
(1) Williams, L. J.; Garbaccio, R. M.; Danishefsky, S. J. In Carbohydrates
in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-
VCH Verlag GmbH: Weinheim, Germany, 2000; Vol. 1, pp 61-92.
(2) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685.
(3) (a) Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1998, 37, 786. (b) Zheng, C.; Seeberger, P. H.; Danishefsky, S. J.
J. Org. Chem. 1998, 63, 1126. (c) Seeberger, P. H.; Eckhardt, M.;
Gutteridge, C. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064.
(4) (a) Ferrier, R. J. J. Chem. Soc. 1964, 5443. (b) Ciment, D. M.; Ferrier,
R. J. J. Chem. Soc. C 1966, 441.
(5) Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F., Jr. J. Am. Chem.
Soc. 1982, 104, 360.
(6) Tsang, R.; Fraser-Reid, B. J. Org. Chem. 1992, 57, 1065.
(7) (a) Vite, G. D.; Alonso, R.; Fraser-Reid, B. J. Org. Chem. 1989, 54,
2268. (b) Henry, K. J.; Fraser-Reid, B. J. Org. Chem. 1994, 59, 5128.
10.1021/ol034130z CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/06/2003

addition of sugar lactones and the subsequent dehydration,11
which was found to be applicable to various saccharide
precursors (including gluco-, galacto-, manno-, and fuco-
types) and stereoselective to give the products of (Z)-
configuration.11c
In our previous study,12 exo-glycosyl ester 1 (Figure 1)
reacted with several primary alcohols (e.g., allyl, ethyl, and
Table 1. Glycosylations of exo-Glycals 2 and 3 with Various
Alcohols
Figure 1. Structures of exo-glycals 1-3.
benzyl alcohols) to afford unusual glycosides with both O-
and C-glycosidic linkages. However, the yields of such
Michael reactions with more hindered nucleophiles (e.g.,
cyclohexanol) decreased dramatically. Fortunately, we found
that exo-glycosyl alcohol 2 (85% yield obtained from the
reduction of 1) and acetate 3 (derived from galactonolactone)
were superior glycosyl donors. Herein we demonstrate that
such exo-glycals undergo glycosylation reactions to give
novel glycosides and glycoconjugates with excellent stereo-
selectivity.
In the presence of BF3‚OEt2, exo-glycals 2 and 3 reacted
smoothly with a variety of alcohols ranging from simple to
hindered ones to give exclusively R-glycosidation products
4-14 (Table 1). It is noted that all the products contain a
vinyl group at the anomeric positions as characterized by
the chemical shifts in their 1H and 13C NMR spectra.
Therefore, the glycosylations of 2 and 3 should proceed via
allylic rearrangement, reminiscent of the Ferrier reaction in
the glycosylation of endo-glycals. All reactions led to the
same stereochemical outcome at the anomeric centers,
consistent with a nucleophilic attack from the bottom face
of the sugar ring. All product structures were rigorously
determined by DEPT and NOESY spectra in addition to other
spectroscopic properties.13 The three-bond carbon-proton
coupling constant 3JC,H (∼1.6 Hz), related to the orientation
of the H2′ and vinyl carbon (-CHd), supported the anomeric
configuration of keto-glycosides in solution.14 The structure
of 8 was also corroborated by comparison with the reported
NMR spectral data.14b
The cross-coupling of acetate 3 was relatively clean in
comparison with the reaction of alcohol 2, which might be
(11) (a) Yang, W.-B.; Chang, C.-F.; Wang, S.-H.; Teo, C.-F.; Lin, C.-
H. Tetrahedron Lett. 2001, 42, 4657. (b) Yang, W.-B.; Wu, C.-Y.; Chang,
C.-C.; Wang, S.-H.; Teo, C.-F.; Lin, C.-H. Tetrahedron Lett. 2001, 42, 6907.
(c) Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang, S.-H.; Chang, C.-C.; Lin,
C.-H. J. Org. Chem. 2002, 67, 3773.
a All reactions were carried out at 0 °C in CH2Cl2 with the alcohol
nucleophile (1-2 equiv) in the presence of BF3OEt2 (1 equiv) and molecular
sieves (4 Å).
(12) Chang, C.-F.; Yang, W.-B.; Chang, C.-C.; Lin, C.-H. Tetrahedron
Lett. 2002, 43, 6515.
(13) For instance, the NOESY spectra of product 10 indicated the cross-
peaks among H5′ (δ 3.89), H6a (δ 3.50), and H6b (δ 3.65). The data thus
verified that the C-vinyl group is located at the â-position.
(14) (a) Tvaroska, I.; Taravel, F. R. AdV. Carbohydr. Chem. Biochem.
1995, 51, 15.(b) Li, X.; Ohtake, H.; Takahashi, H.; Ikegami, S. Tetrahedron
2001, 57, 4297. (c) Li, X.; Takahashi, H.; Ohtake, H.; Shiro, M.; Ikegami,
S. Tetrahedron 2001, 57, 8053. (d) Schlesselmann, P.; Fritz, H.; Lehmann,
J.; Uchiyama, T.; Brewer, C. F.; Hehre, E. J. Biochemistry 1982, 21, 6606.
accompanied by small amounts (∼10%) of the rearranged
product 15 and the self-coupling product 16 (Figure 2).
Glycosylation of 15 has been carried out to give 8.15
(15) Some keto-glycosides including compound 8 have been studied for
the glycosylation. Please see ref 14b for the details.
1088
Org. Lett., Vol. 5, No. 7, 2003

glycosylation reactions. Glycopeptides 13 and 14 mimic the
essential core structure of TN antigen.19 The vinyl-containing
products 5-14 are ready for further transformations. For
instance, compound 6 was subjected to ozonolysis and
followed by the treatment of Me2S to generate aldehyde 18
(80% yield from 6, Figure 2). This aldehyde provides a good
opportunity for conjugation with biomolecules and attach-
ment to solid supports. In addition to metathesis,20 compound
4 was also subjected to ozonolysis and a subsequent reductive
amination to afford a novel spiro molecule 19 (70% yield
from 4). Our method can be considered a way to achieve
R-glycosylation reactions of 2-ketoaldonic acids (e.g., sialic
acids21 and KDO) because the vinyl group in the products
can be converted to an ester via the intermediacy of aldehyde.
For example, disaccharide ester 20 was obtained by oxidation
of 18 with Ag2O in MeOH.
In conclusion, this report represents the first investigation
to apply the Ferrier reaction for the glycosidic bond formation
of exo-glycals. The glycosylation of exo-glycals is success-
fully established to prepare various glycosides and glyco-
conjugates with the enhanced reactivity. The efficient
glycosylations, even with hindered alcohol substrates, usually
complete within 1 h at 0 °C. All functional groups on the
sugar ring remain intact, contrary to the analogous reactions
of endo-glycals in which two chiral centers at C2 and C3
are always missing. The glycosylation product contains a
vinyl group that can be further elaborated for general
purposes, such as in the preparation of spiro derivatives and
glycosides of 2-ketoaldonic acid conjugates. At this stage,
the latter application provides the products with O-glycosidic
linkage in the axial position that is the same as KDO-
containing glycosides but opposite to sialosides. It is possible
to obtain the other stereochemical outcome by manipulating
factors such as neighboring group participation and solvent
effect. The investigation is currently in progress.
Figure 2. Structures of compounds 15-20.
Nevertheless, under the same condition, in our hands the
glycosylation of 15 with cyclohexanol in the presence of
BF3‚OEt3 only afforded a low yield (<15%) of glycosylation
product 5, in contrast to the high yielding (80%) reaction of
2 (entry b of Table 1). This example demonstrated that the
Ferrier-type rearrangement greatly facilitated the glycosy-
lations of the exo-glycal alcohol 2, in comparison with an
analogous mixed ketalization.16
Our current method is applicable to the synthesis of
disaccharides (e.g., 6-11), glycolipids (e.g., 12), and gly-
copeptides (e.g., 13 and 14) having quaternary anomeric
centers,17 which have exerted difficulty in the preparation
of spiro compounds and carbohydrate synthesis. In the
development of glycosyltransferase inhibitors, for instance,
it is synthetically challenging to accommodate both glycosyl
donor and acceptor. Schmidt and co-workers reported a new
type of disubstrate-analogue inhibitors 17.18 Despite the
potent inhibition exhibited by their molecules, the preparation
was laborious. Furthermore, our results also show other
significant features besides the high efficiency of the
Acknowledgment. The authors thank Prof. Jim-Min Fang
at National Taiwan University for his critical reading of this
manuscript, and the financial support from the National
Science Council of Taiwan and Academia Sinica, Taiwan.
1
Supporting Information Available: H NMR spectra of
compounds 1-16 and 18-20 and NOESY spectra of
compounds 6, 8, and 10 to indicate the correlation in space
of H2′ and the vinyl proton (-CHdCH2), as well as H5′
and H6. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) For representative examples, please see: (a) Trost, B. M.; Edstrom,
E. D. Angew. Chem., Int. Ed. Engl. 1990, 29, 520. (b) Trost, B. M.; Edstrom,
E. D.; Carter-Petillo, M. B. J. Org. Chem. 1989, 54, 4489.
OL034130Z
(17) Typical Glycosylation Procedure.To a stirred solution of a glycosyl
acceptor (1.0-2.0 equiv) and exo-glycal 2 or 3 (1.0 equiv) in anhydrous
CH2Cl2 at 0 °C was added dropwise BF3‚OEt2 (1.0 equiv) in the presence
of 4 Å molecular sieves. The reaction was usually complete within 1 h.
The reaction mixture was quenched by addition of saturated NaHCO3 and
extracted with CH2Cl2 for three times. The collected organic layers were
washed with brine, dried over MgSO4, and evaporated in vacuo. The
resulting residue was subjected to silica gel chromatography (with hexanes
and EtOAc) to afford the product.
(19) (a) Hirohashi, S.; Clausen, H.; Yamada, T.; Shimosato, Y.; Haka-
mori, S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7039. (b) Takahashi, H.
K.; Metoki, R.; Hakamori, S. Cancer Res. 1988, 48, 4361.
(20) van Boom et al. also synthesized a series of spiroacetals by ring-
closing metathesis of compound 4 and analogues. Please see: van Hooft,
P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.;
van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron Lett. 1998, 39, 6061.
(21) (a) Cheng, M.-C.; Lin, C.-H.; Khoo, K.-H.; Wu, S.-H. Angew.
Chem., Int. Ed. 1999, 38, 686. (b) Cheng, M.-C.; Lin, C.-H.; Wang, H.-Y.;
Lin, H.-R.; Wu, S.-H. Angew. Chem., Int. Ed. 2000, 39, 772.
(18) Waldscheck, B.; Streiff M.; Notz, W.; Kinzy, W.; Schmidt, R. R.
Angew. Chem., Int. Ed. 2001, 40, 4007.
Org. Lett., Vol. 5, No. 7, 2003
1089