Stereoselective glycosylation of exo-glycals by microwave-assisted Ferrier rearrangement

Article abstract of DOI:10.1016/j.tetasy.2004.11.044

exo-Glycosyl carbonates were shown to be efficient glycosyl donors in microwave-assisted glycosylation. In these reactions α-glycosyl additions occurred with excellent stereoselectivity and were complete in 4-8 min with 75-92% yield. Interestingly exo-glycals were found to have higher activity than endo-glycals and common glycosides, the reactions of which can be improved by the addition of Lewis acid to result in a higher yield and enhanced stereoselectivity.

Full text of DOI:10.1016/j.tetasy.2004.11.044

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 297–301
Stereoselective glycosylation of exo-glycals by microwave-assisted
Ferrier rearrangement
Hui-Chang Lin,a Chih-Chun Chang,a Jia-Yi Chena and Chun-Hung Lina,b,
*
aInstitute of Biological Chemistry, Academia Sinica, No 128 Academia Road Section 2, Nan-Kang, Taipei 11529, Taiwan
bInstitute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 10617, Taiwan
Received 8 November 2004; accepted 19 November 2004
Available online 5 January 2005
Abstract—exo-Glycosyl carbonates were shown to be efficient glycosyl donors in microwave-assisted glycosylation. In these reac-
tions a-glycosyl additions occurred with excellent stereoselectivity and were complete in 4–8 min with 75–92% yield. Interestingly
exo-glycals were found to have higher activity than endo-glycals and common glycosides, the reactions of which can be improved
by the addition of Lewis acid to result in a higher yield and enhanced stereoselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
Glycals are unsaturated sugars with a double bond at
the anomeric center. They are categorized as endo- and
exo-glycals according to the double bond located inside
or outside the sugar ring, respectively. endo-Glycals have
been extensively investigated and numerous applications
were developed for various synthetic purposes. Espe-
cially the method of Ôglycal assemblyÕ, utilizing endo-gly-
cals as both glycosyl donors and acceptors, has carried
out various glycosylation reactions in an iterative fash-
BnO
OBn
O
OBn
O
OH
OAc
BnO
BnO
BnO
OBn
OBn
1
2
BnO
OBn
O
3, X = COC(CH3)3 (t-butyl carbonate)
4, X = COC6H5 (phenyl carbonate)
5, X = H
OX
BnO
OBn
ion with minimal protecting group manipulation.1
A
Figure 1. Structures of compounds 1–5.
number of complex oligosaccharides, glycosylated natu-
ral products and tumor-associated carbohydrate anti-
gens have been successfully prepared by Danishefsky
et al. starting from endo-glycals.2–6
figuration.11 The enhanced activity was owing to
allylic rearrangement, commonly known as the Ferrier
reaction. In search of a better promoter for glycosidic
bond formation, carbonates 3 and 4 are considered as
better glycosyl donors because the decarboxylation
occurs to release carbon dioxide during the heating pro-
cess, as an extra driving force to increase further the
reactivity. The strategy was previously used in the
inter-12,13 and intra-molecular14,15 glycosidations. The
carbonate is able to serve as a good leaving group, as
well as a linker to connect the donor and acceptor (in
the latter case). Herein we report the microwave-induced
glycosylation of exo-glycals. The microwave method
was found to be superior to the traditional heating,
representing a coherent conclusion with the previous
reports.16 Despite a growing interest in the studies of
microwave-assisted reactions in organic synthesis since
1986,17 their application in carbohydrate chemistry is
rather restricted.18–20
Furthermore, exo-glycals have been shown great prom-
ise in the synthesis of C-glycosides, ketoses, and keto-
sides, and N-glycosides.7 In particular, we recently
established an expeditious two-step method to prepare
exo-glycals in a good overall yield starting from sugar
lactones.8,9 The procedure is not only suitable for
various monosaccharyl precursors including gluco-,
galacto-, manno-, and fuco-types, but also applicable to
generate exo-glycals with different substituents.10
Among them compounds 1 and 2 (Fig. 1) were found
to be highly reactive in Lewis acid-catalyzed glycosyl-
ation to afford various glycosides with exclusive a-con-
*
Corresponding author. Tel.: +886 2 2789 0110; fax: +886 2 2651
4705; e-mail: chunhung@gate.sinica.edu.tw
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.044

298
H.-C. Lin et al. / Tetrahedron: Asymmetry 16 (2005) 297–301
O
O
KOH (cat)
+
OH
N
N
N
O
toluene, 60 oC
N
N
N
quant.
BnO OBn
O
BnO
OBn
O
O
NaH
DMF, 25 oC
O
O
OH
N
tBuO
OtBu
+
BnO
BnO
N
OBn
OBn
90%
5
3
BnO OBn
O
BnO OBn
O
O
O
pyridine
CH2Cl2, 25 oC
OH
Cl
PhO
OPh
+
BnO
BnO
OBn
O
OBn
4
5
Scheme 1. Preparation of exo-glycosyl carbonates 3 and 4 as the glycosylation donors.
To prepare compounds 3 and 4 is straightforward. As
shown in Scheme 1, the reaction of 1-(Z)-(20-hydroxy-
ethylidene)-2,3,4,6-tetra-O-benzyl-D-galacto-pyranoside
5 with t-butoxycarbonylimidazole (synthesized quantita-
tively by the condensation of 1,10-carbonyldiimidazole
and t-butanol)21 in the presence of 1equiv sodium
hydride afforded the desired product 3 in 90% yield from
5. Likewise compound 4 can be synthesized by a similar
coupling reaction of 5 with phenyl chloroformate. How-
ever, instability made exo-glycal 4 less suitable for long-
term storage and routine investigation.
The reaction of exo-glycal 3 with allyl alcohol took 20 h
under the reflux condition in DMF to afford the desired
product in 83% yield. A higher yield (92%) with shorter
reaction time (4 min) was observed by using microwave
irradiation. Table 1 demonstrates the microwave-
assisted glycosylations of exo-glycals 3 and 4 to produce
Table 1. Microwave-assisted glycosylation of exo-glycals 3 and 4
O
OBn
O
BnO
BnO
BnO
OX
OBn
O
O
microwave
+ ROH
BnO
3, X = tBu
4, X = Ph
BnO
OBn
O
R
Entry
Donor
Acceptor (ROH)a
OH
Time (min)
Product [yield (%)]b
6 (90%)
i
3
3
8
8
MeO
ii
7 (85%)
OH
OH
iii
iv
3
3
4
8 (87%)
9 (75%)
OH
20
v
3
8
10 (85%)
OH
vi
3
3
4
4
11 (78%)
12 (92%)
HO
OH
vii
OH
OH
O
O
O
viii
ix
3
4
30
13 (75%)c
O
O
2
6 (81%)
OH
a The glycosyl additions were all under a solvent-free condition with the presence of excessive alcohol nucleophile (>30 equiv), except for the entry viii
in which 3 equiv of the acceptor was dissolved in nitropropane (solvent).
b All the reactions were carried out at 150 °C with 200 W of microwave energy.
c In addition to the desired product, hydrolyzed product 14 (10%) was observed.

H.-C. Lin et al. / Tetrahedron: Asymmetry 16 (2005) 297–301
299
glycosides 6–13 in an open vessel. The CEM ÔDiscoverÕ
Focused MicrowaveTM Synthesis System is the instru-
ment to provide microwave energy. Except for entry viii,
all the reactions were studied under a solvent-free condi-
tion and the majority of the reactions were complete at
150 °C with 200 W of microwave energy within 4–8 min
with 75–92% yield. No reaction was found for the reac-
tion with 1,2:3,4-di-O-propylidene-a-D-glucopyranoside
in the absence of solvent. When nitropropane was used
as the reaction solvent, the desired product was obtained
in 75% yield with concomitant formation of the rear-
ranged product 14 (10% yield, resulting from the addi-
tion of water). Because the reactions were carried out
without cooling, the radiation energy declined to main-
tain the constant temperature during the microwave
process. Therefore, the same reactor with simultaneous
cooling is likely to finish reaction in a shorter time.
108.44 and 109.11) of the isopropylidene groups. The
NOESY spectra of 13 (Fig. 2) exhibited the cross-peaks
between H50 (d 4.16) and H6a (d 3.50), as well as H20 (d
3.84) and H100 (d 5.95), which thus verified that the C-vi-
nyl group is located at the b-position. In addition, the
3
three-bond carbon–proton coupling constant JC,H
(ꢀ1.6 Hz), related to the orientation of the H20 and vi-
nyl carbon (–CH@), also confirmed the expected stereo-
chemical outcome.22
Despite the low stability, the phenyl-substituted exo-gly-
cal 4 can be possibly used as the glycosyl donor provid-
ing that the compound is freshly made before the
glycosylation. In the reaction with n-hexanol (entry ix),
the formation of the desired product was finished within
2 min in 81% yield by the microwave method, in con-
trast to the 64% yield (plus 20% of an unknown product)
obtained by the conventional heating at 100 °C for
30 min. Consistent with the previous result, this compar-
ison clearly indicates that the microwave irradiation has
the advantages of shorter reaction time and cleaner
reactions.
BnO OBn
6'
1"
BnO OBn
O
4'
O
BnO
2"
1'
BnO
BnO
O
O
BnO
6
OH
O
Additionally, there are a number of factors affecting the
reactivity, as shown in Table 2. The glycosylation of
exo-glycosyl acetate 2 (entries i and ii) took a longer
time than that of 3, which echoes the previous result that
t-butyl and phenyl carbonates have dissimilar rates.
Interestingly the carbonate functionality exerts varied
activity in exo-glycal, endo-glycal, and glycoside. endo-
Glycal 15 is less reactive than analogous exo-glycal 3,
as indicated by the longer reaction time and incomplete
reaction in entries iii, v, vi, and viii (in comparison with
entries i–iv of Table 1, respectively), even though the
latter molecule exhibits more steric hindrance. The form-
ation of hydrolyzed product 21 was only observed for
the microwave irradiation of t-butylcarbonyl 2,3,4,6-O-
tetrabenzyl-a-D-galactoside 16, as shown in the parallel
studies of entries x and xi. The addition of Lewis acid
O
13
14
1
3
O
O
Consistent with our earlier work,11 the glycosylation
reactions displayed exclusive stereoselectivity. All the
reactions occurred via a-glycosyl additions, that is, the
nucleophilic attack from the bottom face of the sugar
ring, to result in the vinyl group at the b-position. The
product structures were either rigorously determined
by DEPT, NOESY and other spectroscopic spectra, or
in good agreement with the reported NMR spectral
data. For example, the DEPT spectra of the glycosyl-
ation product 13 indicated the C-10 resonance appeared
at d 99.96, besides the other two quaternary carbons (d
Figure 2. NOESY spectra of product 13. The arrows designate the cross-peaks between H50 and H6a, as well as H20 and H100.

300
H.-C. Lin et al. / Tetrahedron: Asymmetry 16 (2005) 297–301
Table 2. Glycosylation reactions of carbonate donors 2, 15, and 16
OBn
O
BnO
BnO
16
BnO OBn
OBn
O
BnO
BnO
O
OAc
O
BnO
O
OBn
O
OtBu
OtBu
2
15
O
Entry
i
Substrate
Nucleophile
Time (min)
10
Producta,b [yield (%), a/b ratio]
BnO OBn
O
2
12 (80%)
BnO
OH
BnO
O
BnO
OBn
O
MeO
ii
2
30
BnO
7 (80%)
OH
BnO
O
OMe
BnO OBn
O
iii
iv
v
15
15
15
30
17 (50%, 5/1)c
17 (91%, 7/1)
18 (74%, 4/1)c
OH
OH
O
2 (With InCl3)
BnO OBn
O
MeO
40
OH
O
O
OMe
BnO OBn
O
19 (70%, 7/1)c
19 (75%, 13/1)
20 (25%, 7/1)c
20 (85%, 11/1)
21 (90%)
OH
vi
15
15
15
15
16
16
16
30
OH
vii
viii
ix
2 (With InCl3)
BnO OBn
O
OH
30
O
OH
2 (With InCl3)
OBn
O
BnO
BnO
MeO
x
30
OH
OH
BnO
xi
––d
20
21 (93%)
OBn
O
BnO
BnO
xii
4 (With InCl3)
22 (85%, 5/1)
HO
OH
O
BnO
OH
a All reactions were carried out at 150 °C with 200 W of microwave energy in a solvent-free condition with the alcohol acceptor in excess (>30 equiv),
except for entry xi.
b The a/b ratio was determined on the basis of 1H NMR integration.
c The reactions of entries iii, v, and viii were not complete with the remaining starting materials of 40%, 20%, and 70%, respectively.
d DMF was the solvent.
will enhance the glycosylation activity. In the presence
of InCl3 (0.2 equiv), for instance, the reaction of endo-
glycal 15 with n-hexanol (entry vi) was complete in
2 min to produce the desired glycoside (91%).19 Similar
improvements in the yield, reaction time and stereoselec-
tivity were made in the case of benzyl alcohol (entry vii)

H.-C. Lin et al. / Tetrahedron: Asymmetry 16 (2005) 297–301
301
and cyclohexanol (entry ix).23 This approach was also
effective to the glycosyl addition of galactoside 16 (entry
xii). As a consequence, the presence of Lewis acid is
complementary to microwave-assisted glycosylation.
10. Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang, S.-H.;
Chang, C.-C.; Lin, C.-H. J. Org. Chem. 2002, 67, 3773.
11. (a) Lin, H.-C.; Yang, W.-B.; Gu, Y.-F.; Chen, C.-Y.; Wu,
C.-Y.; Lin, C.-H. Org. Lett. 2003, 5, 1087–1089; (b)
Chang, C.-F.; Yang, W.-B.; Chang, C.-C.; Lin, C.-H.
Tetrahedron Lett. 2002, 43, 6515.
12. Mukaiyama, T.; Sasaki, T.; Iwashita, E.; Matsubara, K.
Chem. Lett. 1995, 455–456.
13. (a) Mukaiyama, T.; Miyazaki, K.; Uchiro, H. Chem. Lett.
1998, 635–636; (b) Mukaiyama, T.; Wakiyama, Y.;
Miyazaki, K.; Takeuchi, K. Tetrahedron Lett. 1997, 38,
2943–2946.
In summary, this report not only demonstrates the high
efficiency of the microwave-induced glycosylation of
exo-glycals, but also compares the activity among
exo-glycals, endo-glycals and general glycosides. Further
investigation to understand the basis underlying the rate
difference is in progress and will be published in due
course.
14. Iimori, T.; Shibazaki, T.; Ikegami, S. Tetrahedron Lett.
1996, 37, 2267–2270.
15. Azumaya, I.; Niwa, T.; Kotani, M.; Iimori, T.; Ikegami, S.
Tetrahedron Lett. 1999, 40, 4683–4686.
Acknowledgements
16. Cleophax, J.; Liagre, M.; Loupy, A.; Petit, A. Org. Process
Res. Dev. 2000, 4, 498–504; Also see the comprehensive
review: Perreux, L.; Loupy, A. In Microwaves in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH Verlag GmbH:
Weinheim, Germany, 2002; pp 76–110.
17. (a) Gedge, R. N.; Smith, F.; Westaway, K.; Ali, H.;
Baldisera, L.; Laberage, L.; Rousell, J. Tetrahedron Lett.
1986, 27, 279–282; (b) Giguere, R. J.; Bray, T. L.; Duncan,
S. M.; Majetich, G. Tetrahedron Lett. 1986, 27, 4945–
4949.
The authors thank the financial support from the
National Science Council of Taiwan (NSC93-2113-
M-001-003 and NSC93-2113-M-001-034) and Academia
Sinica, Taiwan.
References
18. Oliveiva, R. N.; Filho, J. R. F.; Srivastava, R. M.
Tetrahedron Lett. 2002, 43, 2141–2143.
19. Das, S. K.; Reddy, K. A.; Roy, J. Synlett 2003, 1607–
1610.
20. Mathew, F.; Jayaprakash, K. N.; Fraser-Reid, B.;
Mathew, J.; Scicinski, J. Tetrahedron Lett. 2003, 44,
9051–9054.
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. Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 1998, 37, 786; Goering, B. K. Ph.D.
Dissertation, Cornell University, 1995.
4. Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. J. Org.
Chem. 1998, 63, 1126.
5. Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064.
6. Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F., Jr.
J. Am. Chem. Soc. 1982, 104, 360.
7. Taillefumier, C.; Chapleur, Y. Chem. Rev. 2004, 104, 263–
292.
21. Rannard, S. P.; Davis, N. J. Org. Lett. 1999, 1, 933–936.
22. (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.
23. The stereochemistry of compounds 17–20 was determined
by the integration of the H NMR spectra. In order for
1
clear assignment, the a-form (major) of 20 was hydroge-
nated to saturate the double bond at 25 °C over Pd/C in
EtOAc containing Et3N. The resulting product 23 has the
anomeric H1resonance at d 5.02. The small J1,2 value
(3.0 Hz) confirms the a-configuration.
8. Yang, W.-B.; Chang, C.-F.; Wang, S.-H.; Teo, C.-F.; Lin,
C.-H. Tetrahedron Lett. 2001, 42, 4657.
9. Yang, W.-B.; Wu, C.-Y.; Chang, C.-C.; Wang, S.-H.; Teo,
C.-F.; Lin, C.-H. Tetrahedron Lett. 2001, 42, 6907.