Facile synthesis of conjugated exo-glycals

Article abstract of DOI:10.1016/S0040-4039(01)01427-7

Two efficient methods were explored for the synthesis of various conjugated exo-glycals: (i) by nucleophilic addition of sugar lactones with a subsequent dehydration, and (ii) by selenylation of C-glycosides with subsequent selenoxide elimination. These reactions occurred in a stereoselective manner to give exclusively or predominantly the (Z)-isomers of exo-glycals.

Full text of DOI:10.1016/S0040-4039(01)01427-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6907–6910
Facile synthesis of conjugated exo-glycals
Wen-Bin Yang, Chung-Yi Wu, Che-Chien Chang, Shwu-Huey Wang,† Chin-Fen Teo and
Chun-Hung Lin*
Institute of Biological Chemistry, Academia Sinica, No.128, Academia Road Section 2, Nan-Kang, Taipei, 11529, Taiwan
Received 12 July 2001; revised 1 August 2001; accepted 6 August 2001
Abstract—Two efficient methods were explored for the synthesis of various conjugated exo-glycals: (i) by nucleophilic addition of
sugar lactones with a subsequent dehydration, and (ii) by selenylation of C-glycosides with a subsequent selenoxide elimination.
These reactions occurred in a stereoselective manner to give exclusively or predominantly the (Z)-isomers of exo-glycals. © 2001
Elsevier Science Ltd. All rights reserved.
1,2-Unsaturated sugars (endo-glycals) have been
demonstrated as versatile building blocks in the synthe-
sis of various biomolecules. For example, Danishefsky
et al. have successfully synthesized a great number of
glycosylated natural products and complex oligosaccha-
rides based on the epoxidation of endo-glycals.1–6 1-
Exomethylene sugars (exo-glycals; R,R%=H) have
drawn increasing attention from synthetic chemists
because these molecules have been utilized as valuable
glycosidase inhibitors7 and applied for the preparation
of C-glycosides.8 Although 1-exomethylene sugars have
been synthesized according to known procedures
including the methylenation of sugar lactones by Tebbe
reagent9 and the elimination of pyranoketosyl bro-
mide,10 there are no general methods to prepare substi-
tuted or functionalized exo-glycals (R,R%"H). We
herein demonstrate two novel approaches to prepare
conjugated exo-glycals 3a–e, 6a–e and 10.
make a variant of compound 3e.14 Taylor and his
co-workers have converted S-glycosides to a series of
exo-glycals
via
Ramburg–Ba¨cklund
rearrange-
ments.15,16 A [2,3]-Wittig sigmatropic rearrangement
has been also reported to prepare an exo-glycal ana-
logue of glycosyl serine.17 However, general utilization
of these methods in preparation of other functionalized
exo-glycals has not been exploited.
The fully protected benzylated lactone 1 was prepared
from the commercially available 2,3,4,6-tetra-O-benzyl-
D
-glucopyranose by oxidation with DMSO and acetic
anhydride in 95% yield. The sugar lactone 1 was a good
substrate for nucleophilic additions,18 thus it reacted
with a variety of nucleophiles to give the pyranoketoses
2a–e in good to excellent yields (Table 1). Dehydration
of 2a–e was realized by treatment with trifluoroacetic
anhydride (TFAA) and pyridine to generate conjugated
exo-glycals 3a–e.19 The Z isomers were exclusively pro-
duced except for the reaction of 2a giving a mixture of
Z and E isomers in a ratio of 5:1. The configuration of
these products was rigorously determined by NOE
experiments and/or comparison with the NMR data in
literature.11–16 The stereochemical outcome was consis-
tent with those reported in literature.10–17
OP
O
R
PO
PO
P = H or protecting group
R'
OP
The exo-glycal ester 3a has been prepared by Wittig
olefination of sugar lactones.11 exo-Glycals 3b12 and
3c13 have been obtained as the side products of deoxy-
genation (of anomeric hydroxyl group) and glycosyla-
tion reactions, respectively. Praly et al. have reported
the application of Keck reaction for glycosyl dihalide to
In order to extend the conjugation, aldehyde 4 was
synthesized in 81% yield by ozonolysis of 2e. As shown
in Table 2, aldehyde 4 reacted with hydrazine and
phosphorus ylides to give the condensation products
5a–e in high yields. The subsequent dehydration with
TFAA and pyridine thus afforded the conjugated exo-
glycals 6a–e. The Wittig reaction product 5b showed
two vinyl protons with a large coupling constant of 16
Hz, in agreement with the E configuration. Compounds
* Corresponding
author.
Fax:
+886-2-2651-4705;
e-mail:
chunhung@gate.sinica.edu.tw
† Taipei Medical University.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01427-7

6908
W.-B. Yang et al. / Tetrahedron Letters 42 (2001) 6907–6910
Table 1. Preparation of five conjugated exo-glycals 3a–e via the nucleophilic addition products 2a–e
entry
(see Table 1)
R
OBn
O
OBn
O
OBn
O
1
2
3
4
5
CO2Et
(CF3CO)2O
pyr
CH3 R / base
(see Table 1)
BnO
BnO
BnO
BnO
BnO
BnO
PO(OMe)2
SO2(OEt)
C6H5
R
R
O
BnO
OH
OBn
BnO
3a−e
2a−e
1
CH=CH2
Entry
CH3–R/base
Addition product
Dehydration product
1
2
3
4
5
CH3–CO2Et/LHMDS
2a (95%)
2b (92%)
2c (81%)
2d (95%)
2e (82%)
3a (90%)a
3b (81%)
3c (83%)
3d (87%)
3e (85%)
CH3–PO(OMe)2/nBuLi
CH3–SO2(OEt)/nBuLi
ClMgCH2–C6H5
ClMgCH2–CHꢀCH2
a Compound 3a existed as a mixture of Z and E isomers (5/1). Compounds 3b–e all have the Z configuration.
Table 2. Preparation of five conjugated exo-glycals 6a–e via the condensation products 5a–e
OBn
O
OBn
O
O3; Ph3P
81%
nucleophile
BnO
BnO
BnO
BnO
O
entry
(see Table 2)
R
X
N
(see Table 2)
BnO
BnO
H
NH2
HC CN
HC COMe
HC CHO
HC CO2Et
1
2
3
4
5
OH
OH
4
2e
OBn
O
OBn
4
O
(CF3CO)2O
pyr
2'
BnO
BnO
BnO
BnO
X
R
2
R
X
1'
BnO
3'
BnO
OH
6a−e
5a−e
Entry
Nucleophile
Addition product
Dehydration product
1
2
3
4
5
H2N–NH2
Ph3PꢀCH–CN
Ph3PꢀCH–COMe
Ph3PꢀCH–CHO
Ph3PꢀCH–CO2Et
5a (–)a
6a (80%)
6b (95%)
6c (88%)
6d (87%)
6e (91%)
5b (83%)
5c (82%)
5d (92%)
5e (84%)
a The formation of compound 5a was not observed. Instead, 6a was directly obtained in the addition reaction.
Scheme 1.
We also investigated an alternative method for the
5c–e with E configuration were similarly determined by
1H NMR analysis. The dehydration products 6a–e all
existed as single isomers, which were assigned to have
the (1%Z,3%E) configuration20 by analogy to that of
3a–3e.
preparation of conjugated exo-glycals via selenoxide
elimination21 (Scheme 1). C-Glycoside 7 was synthe-
sized by allylation of perbenzylated glucoside according
to the known procedure.22 Subjection to ozonolysis

W.-B. Yang et al. / Tetrahedron Letters 42 (2001) 6907–6910
6909
gave aldehyde 8, which was treated with phenylselenyl
chloride to give a-selenylated product 9 as an insepara-
ble diastereomeric mixture in a ratio of 5:2 according to
the 1H NMR analysis. Oxidation of 9 with NaIO4,
followed by an in situ selenoxide elimination provided
the conjugated aldehyde 10 containing a mixture of E
and Z isomers (5:2). The isomers were separated by
column chromatography, and the Z isomer condensate
with a phosphorus ylide afforded the conjugated exo-
glycal 6b in 90% yield as a mixture of E and Z isomers.
5. Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. J. Org.
Chem. 1998, 63, 1126.
6. Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Dan-
ishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064.
7. (a) Hehre, E. J.; Brewer, C. F.; Uchiyama, T.; Schlessel-
mann, P.; Lehmann, J. Biochemistry 1980, 19, 3557; (b)
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P. Carbohydr. Res. 1983, 113, 71; (d) Brewer, C. F.;
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P.; Briner, K.; Bernet, B.; Panza, L.; Husi, R. Helv. Chim.
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8225; (c) Lay, L.; Nicotra, F.; Panza, L.; Russo, G.;
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Lett. 1984, 25, 395; (b) Haudrechy, A.; Sinay, P. J. Org.
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1991, 47, 1655; (e) Faivre-Buet, V.; Eynard, I.; Nga, H.
N.; Descotes, G.; Grouiller, A. J. Carbohydr. Chem. 1993,
12, 349.
As previously mentioned, exo-glycals have shown
inhibitory activities against glycosidases, and we
intended to evaluate the inhibitory effect of the depro-
tective forms of the products on glycosidases. The
catalytic hydrogenolysis of 3a and 3c was carried out
on 10 wt% Pd/C (20 mol%) to remove the benzyl
groups at 25°C for 2 h with EtOH/CHCl3/hexanes
(4/1/1). The exocyclic CꢀC bonds were retained under
such reaction conditions; e.g. for the reaction of 3a, the
desired product (12) was obtained in 55% yield, in
addition to the saturated product (40%, the double
bond was reduced). The preliminary assay of glucosi-
dase inhibition looked promising.23
In summary, we have established two expeditious pro-
cedures to prepare conjugated exo-glycals. The depro-
tection and inhibitory assay of these molecules are
currently pursued and will be published in a due course.
Furthermore, these unusual glycosides may be elabo-
rated to other biologically interesting molecules such as
isosteric phosphonate analogues of glycosyl 1-phos-
phates,12 and the mimetics of sugar nucleotides. The
latter compounds have been confirmed to be potent
inhibitors of glycosyltransferases.24
10. Hahn, S.; Flath, F.-J.; Lichtenthaler, F. W. Liebigs Ann.
1995, 2081.
11. Xie, J.; Molina, A.; Czernecki, S. J. Carbohydr. Chem.
1999, 18, 481.
12. Dondoni, A.; Marra, A.; Pasti, C. Tetrahedron: Asymme-
try 2000, 11, 305.
13. Borbas, A.; Szabovik, G.; Antal, Z.; Herczegh, P.; Agocs,
A.; Liptak, A. Tetrahedron Lett. 1999, 40, 3639.
14. Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G.; Raphoz,
C. Tetrahedron Lett 1997, 38, 8185.
15. (a) Alcaraz, M.-L.; Griffin, F. K.; Paterson, D. E.; Tay-
lor, R. J. K. Tetrahedron Lett. 1998, 39, 8183; (b) Griffin,
F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 8179.
Acknowledgements
16. For a detailed review, see: Taylor, R. J. K. J. Chem. Soc.,
Chem. Commun. 1999, 217.
17. Lay, L.; Meldal, M.; Nicotra, F.; Panza, L.; Russo, G. J.
Chem. Soc., Chem. Commun. 1997, 1469.
18. (a) Yang, W.-B.; Tsai, C.-H.; Lin, C.-H. Tetrahedron
Lett. 2000, 41, 2569; (b) Yang, Y.-Y.; Yang, W.-B.; Teo,
C.-F.; Lin, C.-H. Synlett 2000, 1634; (c) Yang, W.-B.;
Chang, C.-F.; Wang, S.-H.; Teo, C.-F.; Lin, C.-H. Tetra-
hedron Lett. 2001, 42, 4657.
We are indebted to Professor Jim-Min Fang at the
National Taiwan University for his valuable sugges-
tions and encouragement. The work is financially sup-
ported by National Science Council (NSC-89-
2113-M-001-058), National Health Research Institute
(NSC-90-2323-B-001-004) and the Heritage Prize of the
Lee Foundation (for C.-H. Lin).
19. Schmidt and co-workers have described the additions of
sugar lactones and subsequent eliminations. However, the
outcome was different from ours, please see: Streicher,
H.; Reiner, M.; Schmidt, R. R. J. Carbohydr. Chem.
1997, 16, 277.
20. In addition to the analysis based on coupling constants,
NOE experiments were executed. For instance, a 6.3%
enhancement of H-1% in compound 5b was observed by
irradiation of H-2, whereas a 4.9 and 2.7% enhancement
of H-3% and H-2 in compound 5b was found by irradia-
tion of H-1%.
References
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: Weinheim, Germany,
2000; Vol. 1, pp. 61–92.
2. Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res.
1998, 31, 685.
3. Seeberger, P. H.; Beebe, X.; Sukenick, G. D.; Pochapsky,
S.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1997,
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21. March, J. Advanced Organic Chemistry; John Wiley and
Sons: New York, 1992; pp. 1022–1023.
4. Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. Angew.
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W.-B. Yang et al. / Tetrahedron Letters 42 (2001) 6907–6910
23. Compounds 2a, 2c, 3a and 3c have been successfully
deprotected and assayed for glucosidase inhibition (a-glu-
cosidase from Saccharomyces sp. and b-glucosidase from
sweet almond) which shows that the conjugated
molecules are more potent than the hydrated ones. For
example, deprotecting the benzyl groups of 2a and 3a
generated products 11 and 12, respectively. In the pres-
(the chromogenic substrate), and compounds 11 or 12
(200 mM), the former molecule resulted in 98% remaining
activity, whereas the latter gave 30% activity in compari-
son with the control experiment (which contained the
substrate only). IC50 of 12 was estimated to be about 150
mM. All the detailed inhibitory results will be published in
a due course.
ence of b-glucosidase, p-nitrophenyl-b-
D
-glucopyranoside
24. Schafer, A.; Thiem, J. J. Org. Chem. 2000, 65, 24.