Synthesis of CH2-linked α(2,3)sialylgalactose analogue: On the stereoselectivity of the key Ireland-Claisen rearrangement

Article abstract of DOI:10.1021/ol801519j

(Chemical Equation Presented) A CH₂-linked α(2,3) sialylgalactose analogue was efficiently synthesized using an Ireland-Claisen rearrangement, which was developed recently by our group for constructing a CF₂-sialoside. The reaction conditions of the rearrangement were optimized for α-stereoselective formation of the CH₂-sialoside. On the basis of the observed temperature effects, the origin of the stereoselectivity of the Ireland-Claisen rearrangement is discussed. Moreover, reconstruction of the 2α-hydroxyl group on the galactose unit of the rearrangement product was achieved by means of stereoselective dihydroxylation and deoxygenation.

Full text of DOI:10.1021/ol801519j

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4167-4170
Synthesis of CH2-Linked
r(2,3)Sialylgalactose Analogue: On the
Stereoselectivity of the Key
Ireland-Claisen Rearrangement
Toru Watanabe,† Go Hirai,† Marie Kato,† Daisuke Hashizume,† Taeko Miyagi,‡ and
Mikiko Sodeoka*,†
RIKEN, Hirosawa, Wako 351-0198, Japan, DiVision of Biochemistry, Miyagi Cancer
Center Research Institute, Natori 981-1293, Japan, and CREST,
JST Kawaguchi 332-1102, Japan
sodeoka@riken.jp
Received July 8, 2008
ABSTRACT
A CH2-linked r(2,3)sialylgalactose analogue was efficiently synthesized using an Ireland-Claisen rearrangement, which was developed recently
by our group for constructing a CF2-sialoside. The reaction conditions of the rearrangement were optimized for r-stereoselective formation
of the CH2-sialoside. On the basis of the observed temperature effects, the origin of the stereoselectivity of the Ireland-Claisen rearrangement
is discussed. Moreover, reconstruction of the 2r-hydroxyl group on the galactose unit of the rearrangement product was achieved by means
of stereoselective dihydroxylation and deoxygenation.
The R(2,3)sialylgalactose structure (1, Figure 1A) is widely
found at the nonreducing end of glycoproteins and glycolip-
ids and is recognized as one of the most important units in
carbohydrate molecules. For example, sialyl Lewisx and sialyl
Lewisa, which are ligands of L-, E-, and P-selectin, are
composed of 1.1 Gangliosides also contain the same structure,
and are thought to make important contributions2 to cell
signaling and cell surface interactions. But, the physiological
roles of 1 are still not fully clarified. Dynamic metabolism
of R-sialosides in living cells, involving hydrolysis of
R-sialoside linkages by sialidases and their formation by
sialyltransferases, is associated with complex signalling
networks. Biologically stable analogues could serve as useful
chemical probes for clarifying the biological functions of
these molecules.
C-Glycoside analogues of R(2,3)sialylgalactose structure
(C-sialoside), in which the anomeric oxygen atom of sialic
acid is replaced by a carbon atom, are particularly attractive
candidate molecules as mimics of native O-sialosides.
Recently, we reported the synthesis of the CF2-linked
R(2,3)sialylgalactose 2 (Figure 1A), because the difluorom-
ethylene group is expected to be a good bioisostere of the
oxygen atom.3 Indeed, CF2-linked ganglioside GM4 showed
† RIKEN.
‡ Miyagi Cancer Center Research Institute and CREST.
(1) Kannagi, R.; Izawa, M.; Koike, T; Miyazaki, K.; Kimura, N. Cancer
Sci. 2004, 95, 377.
(2) (a) Hakomori, S. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 225. (b)
Yoon, S.-J.; Nakayama, K.; Hikita, T.; Handa, K.; Hakomori, S. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 18987.
(3) Hirai, G.; Watanabe, T.; Yamaguchi, K.; Miyagi, T.; Sodeoka, M.
J. Am. Chem. Soc. 2007, 129, 15420.
10.1021/ol801519j CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

synthesis of CF2-sialoside based on Ireland-Claisen rear-
rangement using ester 4 having a one-carbon-elongated
galactose unit was convergent, and the key rearrangement
proceeded smoothly at room temperature with complete
R-stereoselectivity (Figure 1B).3 Thus, we planned to extend
our Ireland-Claisen strategy to the synthesis of the CH2-
linked R(2,3)-sialylgalactose unit. Herein we report an
efficient synthesis of the CH2-linked R(2,3)-sialylgalactose
lactone unit 21 using this approach.
Rearrangement precursor 10a was prepared via a three-
step sequence from 63 in good yield, as shown in Scheme
1. Ireland-Claisen rearrangement of 10a proceeded at ambient
Figure 1. (A) Structure of O-, CF2-, and CH2-sialoside (1-3). (B)
Ireland-Claisen strategy for the synthesis of CF2-sialoside.
Scheme 1. Synthesis of CH2-Sialoside
similar biological profiles to native GM4 and inhibitory
activity toward human sialidase NEU2 and NEU4. Recently
CF2-glycosides have attracted attention as nonhydrolyzable
glycoside mimics, but systematic studies on the effects of
fluorine on the biological activity and conformational proper-
ties of the C-glycosides are still limited.4 Thus, we envisioned
the synthesis of the simple CH2-linked R(2,3)sialylgalactose
(CH2-sialoside 3, Figure 1A) for a comparison of its
biological activity and chemical properties with those of the
CF2-sialoside. Stereoselective syntheses of the C-linked
R(2,3)-sialylgalactose unit have been reported by two
groups.5-7 Linhardt reported a convergent synthesis of
CH(OH)-linked R(2,3)sialylgalactose via SmI2-mediated
coupling reaction,5a but they noted that all attempts to remove
the pseudoanomeric hydroxyl group were unsuccessful.8
Schmidt reported a synthesis of 3 via a long linear sequence.6
Although various synthetic methods for C-glycosides have
already been reported,9 few are applicable to the synthesis
of both CH2- and CF2-glycoside.10,11 Among them, our
(4) (a) Denton, R. W.; Cheng, X.; Tony, K. A.; Dilhas, A.; Herna´ndez,
J. J.; Canales, A.; Jime´nez-Barbero, J.; Mootoo, D. R. Eur. J. Org. Chem.
2007, 645. (b) Pe´rez-Castells, J.; Herna´ndez-Gay, J. J.; Denton, R. W.; Tony,
K. A.; Mootoo, D. R.; Jime´nez-Barbero, J. Org. Biomol. Chem. 2007, 5,
1087. (c) Denton, R. W.; Tony, K. A.; Herna´ndez-Gay, J. J.; Canada, F. J.;
Jime´nez-Barbero, J.; Mootoo, D. R. Carbohydr. Res. 2007, 342, 1624.
(5) (a) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J. J. Am. Chem. Soc.
1997, 119, 1480. (b) Poveda, A.; Asensio, J. L.; Polat, T.; Bazin, H.;
Linhardt, R. J.; Jime´nez-Barbero, J. Eur. J. Org. Chem. 2000, 1805, and
references therein.
temperature on treatment with LHMDS and TMSCl in THF
(-78 °C, then rt). The desired product 11r was obtained as
the major product, but a significant amount of the undesired
isomer 11ꢀ was also formed (11r:11ꢀ ) 5:1, Table 1, entry
2). Thus, we examined the reaction temperature for rear-
rangement after formation of the silyl ketene acetal of 10a,
which should be generated by the treatment with LHMDS
and TMSCl at -78 °C for 30 min. To increase the selectivity,
the reaction temperature was lowered to -20 °C (entry 1).
Rearrangement proceeded slowly even at this temperature,
but the selectivity was further decreased (1.8:1). Interestingly,
(6) Notz, W.; Hartel, C.; Waldscheck, B.; Schmidt, R. R. J. Org. Chem.
2001, 66, 4250
.
(7) CH(OH)-linked and CH2-linked SiaR(2,6)-GalNAc derivatives: (a)
Kuberan, B.; Sikkander, S. A.; Tomiyama, H.; Linhardt, R. J. Angew. Chem.,
Int. Ed. 2003, 42, 2073. (b) Abdallah, Z.; Doisneau, G.; Beau, J.-M. Angew.
Chem., Int. Ed. 2003, 42, 5209
(8) Wang, Q.; Wolff, M.; Polat, T.; Du, Y.; Linhardt, R. J. Bioorg. Med.
Chem. Lett. 2000, 10, 941.
.
(9) For recent C-glycoside reviews: (a) Beau, J.-M.; Vauzeilles, B.;
Skrydstrup, T. C-Oligosaccharide Synthesis. In Glycoscience: Chemistry
and Chemical Biology; Fraiser-Reid, B. O., Tatsuta, K., Thiem, J., Eds.;
Springer: Heidelberg, Germany, 2001; Vol. 3, p 2679. (b) Postema,
M. H. D.; Piper, J. L.; Betts, R. L. Synlett 2005, 1345. (c) Yuan, X.; Linhardt,
R. J. Curr. Top. Med. Chem. 2005, 5, 1393.
(10) (a) Kovensky, J.; Burrieza, D.; Colliou, V.; Cirelli, A. F.; Sinay,
P. J. Carbohydr. Chem. 2000, 19, 1. (b) Jime´nez-Barbero, J.; Demange,
R.; Schenk, K.; Vogel, P. J. Org. Chem. 2001, 66, 5132. (c) Tony, K. A.;
Denton, R. W.; Dilhas, A.; Jime´nez-Barbero, J.; Mootoo, D. R Org. Lett.
2007, 9, 1441, and references therein.
(11) Other examples and reviews of CF2-glycoside: (a) Herpin, T. F.;
Motherwell, W. B.; Tozer, M. J. Tetrahedron: Asymmetry 1994, 5, 2269.
(b) Plantier-Royon, R.; Portella, C. Carbohydr. Res. 2000, 327, 119. (c)
Berber, H.; Brigaud, T.; Lefebvre, O.; Plantier-Royon, R.; Portella, C.
Chem.-Eur. J. 2001, 7, 903.
4168
Org. Lett., Vol. 10, No. 19, 2008

product 13r with much better selectivity and chemical yield
(13r:13ꢀ ) 15:1, Table 1, entry 5).
To understand the interesting stereoselectivity of the
Ireland-Claisen rearrangement, we considered the transition
state (TS) models shown in Figure 2. Ireland-Claisen
Table 1. Ireland-Claisen Rearrangement of 10
temp
ratio
yield
entry allylester product
[°C]
t [min] (R:ꢀ) (2 steps)
1
2
3
4
5
10a
10a
10a
10b
10c
11
11
11
12
13
-20
25
reflux
reflux
reflux
840
40
15
10
10
1.8:1a
5:1b
25%
73%
66%
86%
82%
10:1a
10:1b
15:1b
a Ratio was determined by HPLC. b Ratio was determined by 1H NMR.
when the reaction was conducted at the reflux temperature
of THF, we found that the selectivity was greatly improved
(10:1, entry 3). Isomers 11r and 11ꢀ were separated by
PTLC, and their stereochemistries were confirmed by
examination of the HMBC spectra, in which a strong
correlation between R-H3′ and C1′ in 11r or between R-H3′
and C3′′ in 11ꢀ was observed. Similarly, reaction of 10b
also proceeded to give 12r and 12ꢀ in a ratio of 10:1 (entry
4). Next, we tried to remove the 4-methoxybenzylidene group
of 12, but this was unsuccessful. As shown in Scheme 2,
Figure 2. Plausible TS for constructing CH2-sialoside.
Scheme 2. Attempts at Deprotection of 4,6-Benzylideneacetal
rearrangement is known to prefer a chairlike transition state.
Therefore, it is reasonable that this rearrangement proceeds
via chairlike TS I to give the major isomer 11r-13r after
formation of the expected (Z)-silyl ketene acetal from
10a-10c.13 But, to form this favorable chairlike TS I giving
the desired R-isomer, in which the C2-O bond has peudo-
axial configuration, the conformation of the galactose unit
must be changed from chair to boat. The undesired ꢀ-isomer
would be formed via the boat-like TS II, in which the
conformational change of the galactose unit is not required.
It is likely that 10a and 10b, having the rigid 4,6-acetal group,
strongly favor the chair conformation of the galactose unit,
whereas the 4,6-non- protected 10c would be more flexible.
As a result, conformational change of the galactose unit of
10c is expected to be easier than in the cases of 10a/10b,
and this may be the reason why higher R-selectivity was
achieved with 10c. In the case of the previously reported
difluoro-olefin 4, the chair conformation of the galactose unit
seems to be destabilized due to the allylic strain between
the fluorine atom and the C2-oxygen atom, even though 4
has a 4,6-acetal group. As a result, the R-isomer was obtained
exclusively from 4. The observed unique temperature
dependency would also be explained by the conformational
change of the galactose unit. As higher temperature favors
this conformational change of the galactose unit of 10a, even
treatment of 12 with 80% acetic acid gave a mixture of 14
and 15, and none of the desired product 16 was obtained,
indicating that the allylic and anomeric OMP group was
hydrolyzed much faster than methoxybenzylidene acetal.
Moreover, the furan derivative was easily formed after
removal of the 4,6-protecting group from 14.12 This was
unexpected, because deprotection reaction of the difluoro
derivative 5 proceeded without difficulty under the same
conditions.3 This fact indicated that the strongly electron-
withdrawing fluorine atoms stabilize the anomeric OMP
group. To solve this problem, we decided to remove the 4,6-
benzylidene moiety before the Ireland-Claisen rearrangement.
The desired diol 10c was obtained without difficulty by acid
hydrolysis of 10b. To our delight, reaction of 10c at the reflux
temperature in THF proceeded smoothly to give the desired
(13) Selected examples of Ireland-Claisen rearrangement of R-alkox-
yester: (a) Bartlett, P. A.; Tanzella, D. J.; Barstow, J. F. J. Org. Chem.
1982, 47, 3941. (b) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J. J. Org.
Chem. 1983, 48, 5221. (c) Kallmerten, J.; Gould, T. J. Tetrahedron Lett.
1983, 24, 5177.
(12) A similar transformation was reported in the case of glycal
derivatives: (a) Gonzalez, F.; Lesage, S.; Perlin, A. S. Carbohydr. Res. 1975,
42, 267. (b) Agarwal, A.; Rani, S.; Vankar, Y. D J. Org. Chem. 2004, 69,
6137, and references therein.
Org. Lett., Vol. 10, No. 19, 2008
4169

when a rigid 4,6-acetal group is present, the R-selectivity
would increase temperature-dependently.14
Finally, the rearrangement product 13 was converted to
the key CH2-linked R(2,3)sialyl-galactose lactone unit 21 as
shown in Scheme 3. First, the stereoisomeric mixture 13r,ꢀ
hydrogenolysis of four BOM groups, together with removal
of the TBS group, gave the CH2-linked R(2,3)sialylgalactose
lactone unit 21. The stereochemical assignment of newly
formed chiral carbon centers (C2′, C2, C3) was confirmed
by X-ray crystallographic analysis of 21 (Figure 3). The
Scheme 3. Synthesis of CH2-Linked R(2,3)Sialylgalactose
Figure 3. X-ray structure of 21.
overall yield of this CH2-linked sialoside unit 21 from 6b
was 23% (14 steps).
In conclusion, the CH2-linked R(2,3)sialylgalactose unit
was synthesized in a highly stereoselective manner. This
synthesis is more efficient in terms of short and convergent
reaction sequences and high overall yield compared to the
reported synthesis of CH2-linked R(2,3)sialylgalactose.6
Moreover, we succeeded in synthesizing two electronically
different types of C-linked R(2,3)sialylgalactose unit, CF2-
and CH2-linked derivatives, by using the same strategy and
the same starting materials, 6 and 9.3 This indicates that our
Ireland-Claisen strategy would also be applicable to the
synthesis of various other types of C-sialosides such as CHF-
linked sialoside, which would be useful for further detailed
study of the effect of the fluorine atom. Synthesis of
oligosaccharide or glycoconjugate analogues such as GM3
and Sialyl-Lewisx from 21, and biological experiments using
CH2-linked ganglioside analogs are currently under way.
was converted to the conformationally fixed lactone 17 by
removal of the TMS group, saponification of the methyl ester,
selective δ-lactone formation, and protection of the primary
alcohol with a TBS group. Since only the desired R-isomer
provided a δ-lactone derivative, the undesired ꢀ-isomer was
easily separated at this stage. Upon treatment of the lactone
17 with a stoichiometric amount of OsO4, dihydroxylation
proceeded in a completely stereoselective manner to afford
the diol 18.15 Next, to remove the C3-hydroxyl group, diol
18 was converted into cyclic thiocarbonate 19. Radical
reduction proceeded in a regio- and stereoselective manner
with freshly opened Bu3SnH to give 20 in 83% yield. Finally,
Acknowledgment. We thank Dr. Hiroyuki Koshino
(RIKEN) for 1D and 2D-NMR measurements. We also thank
Prof. Shin-ichiro Shoda (Tohoku University) for helpful
discussion.
Supporting Information Available: Experimental pro-
cedure, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) For further discussion on the stereoselectivity, see Supporting
Information.
(15) Transformation of 2,3-olefin in galactose by hydroboration or
epoxidation failed due to the low reactivity of 2,3-olefin.
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Org. Lett., Vol. 10, No. 19, 2008