Different reaction routes found in acid-catalyzed glycosylation of endo- and exo-glycals: Competition between Ferrier rearrangement and protonation

Article abstract of DOI:10.1016/j.tetlet.2005.05.061

Acid-mediated glycosylations of endo- and exo-glycals have been carried out in good to excellent yields, in which a mixture of two products is often obtained resulting from Ferrier rearrangement and protonation. The former reaction exclusively takes place

Full text of DOI:10.1016/j.tetlet.2005.05.061

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5071–5076
Different reaction routes found in acid-catalyzed glycosylation of
endo- and exo-glycals: competition between Ferrier
rearrangement and protonation
Hui-Chang Lin,a Wen-Ping Du,a Chih-Chun Changa 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 20 April 2005; revised 13May 2005; accepted 16 May 2005
Abstract—Acid-mediated glycosylations of endo- and exo-glycals have been carried out in good to excellent yields, in which a mix-
ture of two products is often obtained resulting from Ferrier rearrangement and protonation. The former reaction exclusively takes
place with the t-butyl carbonate or hydroxyl substituent at the C3position of endo-glycals, while the latter mainly occurs in the
glycosylation of exo-glycals with allyl benzyl ether or acetate. In addition to the substituent effect, protecting groups are critical
to determine the activity and favored reaction pathway. Furthermore, the method is applicable to O-, C-, and N-nucleophiles.
Ó 2005 Elsevier Ltd. All rights reserved.
Glycals are versatile building blocks in synthetic chemis-
try and have been extensively investigated for the syn-
thesis of various important molecules, including
tumor-associated antigens (such as Lewis y, globo H,
and KH-1) and bioactive natural products (including
ciclamycin, allosamidin, KS-502, and rebeccamycin).1
The glycosylation of endo-glycals can be carried out in
a number of manners. For example, several Lewis acids
were reported to catalyze Ferrier glycosylation2 to afford
2,3-unsaturated glycosides.3,4 Danishefskyꢀs glycal
assembly successfully utilized glycals as both glycosyl
donors and acceptors in an iterative fashion5–8 so that
the procedure can be operated in solid phase.9 NIS or
NBS-mediated glycosylations were developed by Tats-
uta et al. and Theim et al. for the synthesis of 2-deoxy-
glycosides.10,11 Although the same products can be
prepared by the acid-catalyzed addition of alcohol
nucleophiles to glycals, appearing to be a simpler and
more direct way of glycosidation, so far only few studies
were reported including the methods using triphenyl-
phosphine hydrogenbromide,12 Dowex-50 resin [H+]
with the presence of LiBr,13 and TMSOTf–NEt3.14
One major challenge in the preparation of 2-deoxyglyco-
sides originates from the tendency of the cyclic enol
ether toward allylic rearrangement, which is usually ob-
served to complicate many studies. Herein we report
acid-catalyzed glycosyl additions of glycals, in which
two products are generated in association with Ferrier
rearrangement and protonation. With a suitable substi-
tuent introduced at the allylic position, the former reac-
tion pathway can be exclusively formed in the
glycosylation of endo-glycals whereas the latter is fa-
vored in that of exo-glycals. Major factors are examined
to understand how they function to affect the reaction
outcome.
Previously, we demonstrated that exo-glycals 1–4 are
highly reactive as glycosyl donors in BF3ÆOEt2-catalyzed
reaction or under microwave radiation (Scheme 1).15
The reactions gave exclusively a-glycosidation products
that contain a vinyl group at the anomeric position,
indicating the occurrence of allylic rearrangement.15
On the other hand, the trifluoroacetic acid (TFA)-cata-
lyzed glycosylation exhibited a different scenario (Table
1) where a mixture of two structurally similar products
was obtained. In addition to the minor product rising
from the aforementioned Ferrier reaction, the major
one contained the acetoxyethyl group at the anomeric
center, as evidenced by the corresponding characteristic
Keywords: Glycosylation; Protonation; Rearrangement.
*
13
signals in 1H and C NMR spectra.16 The analysis
Corresponding author. Tel.: +886 2 2789 0110; fax: +886 2 2651
4705; e-mail: chunhung@gate.sinica.edu.tw
based on the NOESY spectra indicated that the group
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.061

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H.-C. Lin et al. / Tetrahedron Letters 46 (2005) 5071–5076
Scheme 1. exo-Glycals 1–4 are efficient glycosyl donors.
is located at b-position and thus the acceptor should ap-
proach from a-position of the sugar ring during the gly-
cosidation.17 In consistence with the previous reports,15
a-stereoselectivity was always obtained in the reactions.
occur. As a result, proper combination of substituent
and conformation likely contributes to the exclusive
occurrence of the Ferrier rearrangement in entries i–vi.
Other issues, however, may be part of the cause here
and cannot be simply ruled out.
Table 1 demonstrates the glycosidations of exo-glycals
1, 3, and 5–9. The reactions were simple for operation
to give products 10–29. With addition of TFA (10 equiv)
to the mixture of exo-glycosyl donor and alcohol accep-
tor, the majority of reactions were complete in a short
period of time (minutes to few hours) to give 77–95%
yields. As shown by the 20-fold difference of reaction
time in entries i and v, the –CH3 group of fucose made
a significant contribution to enhance the reactivity, con-
sistent with the report by Wong and co-workers.18 fuco-
Type donors 5–9 varied extremely in reaction rates,
clearly supporting a critical role played by the olefin
substituent (e.g., the comparison between entries v and
viii, the one between entries x and xiii). The formation
of both protonation and rearrangement products was
observed in most of the reactions. As a consequence,
the proposed oxonium ion develops during the glycosyl-
ation to proceed with two pathways of the rearrange-
ment and protonation (Scheme 2). Apparently, the
latter reaction is favored in the competition. It is inter-
esting that a relatively higher percentage of the Ferrier
reaction products were obtained in the reactions of
exo-glycals 3 and 6 (entries iv, vi, and xi).
On the other hand, the replacement of C3functionality
with acetate (32) or benzyl ether (33) resulted in the
formation of both protonation and rearrangement prod-
ucts (entries vii–ix). Surprisingly, the production of 2-
deoxygalactosides is relatively favored. The contrasting
result to those of 30 and 31 provides additional evidence
that the functional group at the allylic position cannot
only fine–tune the reactivity, but also dominate, which
reaction pathway is preferred. Recently, Vankar et al.
reported that 3,4,6-tri-O-acetyl-D-glucal was used in
the HClO4–SiO2-mediated synthesis of 2,3-unsaturated
glycosides.19 Applying our TFA method for the glyco-
sylation of 3,4,6-tri-O-acetyl-D-galactal (33a) also led
to occurrence of the Ferrier reaction only. The results
of peracetylated glycosyl donors were different from
those of the analogous substrates 32 and 33 (entries
vii–ix), revealing that protecting groups may serve as an-
other essential factor. In general, the protecting groups
of glycosyl donors are a determinant on the glycosyl-
ation rate,18,20 depending on if they stabilize or destabi-
lize the putative cationic transition state. We propose
that electron-donating groups (e.g., benzyl ethers) facil-
itate the protonation pathway, which is possibly due to
the p*-stabilization by the interaction either from direct
r(C–O) or from oxygen lone pair electron through
space, especially when electron donating protective
group is introduced. On the contrary, the existence of
electron-withdrawing groups (e.g., acetates) makes the
oxonium ion relatively less stable so that allylic rear-
rangement has the advantage to form a more stable
a,b-conjugated oxonium ion (similar to the top transi-
tion state in Scheme 2). The results of Tables 1 and 2
are thus contributed by the effects of the allylic substitu-
ent and protecting group, which may need more sup-
porting evidence for further corroboration.
Alternatively, the reactions of endo-glycals 30–33 repre-
sent an intriguing distinction from the prior result. As
shown in Table 2, the glycosylation reactions of various
4,6-di-O-benzyl-D-galactals were carried out in TFA-
containing CH2Cl2 to generate glycosides 34–41. Alco-
hol acceptors (2–3equiv) were used in the reactions.
The substituents of t-butyl carbonate (30) and hydroxyl
group (31) at C3position led to the formation of 2,3-
unsaturated glycosides exclusively (entries i–vi), which
echoed to the studies of exo-glycals 3 and 6 (see Table
1, entries iv, vi, and xi), suggesting the possibility to de-
velop a positive (or partial positive) charge at C3to trig-
ger the Ferrier reaction. The relatively more constrained
conformation of endo-glycals (with two sp2 carbons in
the sugar ring), in comparison with that of exo-glycals
(with one sp2 carbon), also favors the rearrangement to
Substitution of TFA with various acids was also carried
out. Like the synthesis of 2-deoxyglycosides by a cata-
lytic amount of triphenylphosphine hydrogenbromide

H.-C. Lin et al. / Tetrahedron Letters 46 (2005) 5071–5076
Table 1. Glycosylations of exo-glycals 1, 3, 5–9 with various alcoholsa
5073
Entry
i
Donor
Acceptor (ROH)
Time (min)
60
Protonation + rearrangement
products (yield)
1
10 (85%)
11 (10%)
ii
1
1
90
12 (75%)
14 (70%)
13 (10%)
15 (7%)
iii
120
iv
3
5
6
7
8
9
5
6
7
8
9
90
3
16 (66%)
18 (71%)
20 (46%)
21 (76%)
22 (78%)
23 (94%)
24 (85%)
26 (50%)
27 (72%)
28 (70%)b
29 (77%)
17 (22%)
19 (12%)
19 (38%)
19 (8%)
— (0%)
— (0%)
25 (9%)
25 (29%)
25 (10%)
— (0%)
v
vi
15
vii
viii
ix
40
1440
2
x
30
xi
40
xii
xiii
xiv
70
2880
80
— (0%)
˚
a All reactions were carried out at 0–25 °C in CH2Cl2 with alcohol nucleophiles in the presence of TFA (10 equiv) and molecular sieves (4 A).
b Twenty percentage of the starting material was recovered.
(TPHB),12 the reaction of exo-glycal 1 with 1-butanol
gave only the protonation product (10). The TPHB-
mediated glycosylation only allowed the protonation
pathway to take place in preference to the Ferrier rear-
rangement, which was well interpreted based on soft–
hard principle, that is, the protonation occurring at
the softer b-enolic carbon instead of the harder allylic
oxygen.12 It will be intriguing to examine if the TPHB
method (or the preferential protonation at the b-enolic
carbon) is subjected to the effects of substituent and pro-
tecting group. Meanwhile, the studies with other acids
turned out to be less desirable owing to lower yield or/
and lower selectivity in our hands. Scheme 3 shows
two examples to utilize methanesulfonic acid, which
are analogous to the first two entries of Table 1. Addi-
tionally, the acid catalyzed-glycosylation was found use-
ful for the use of C- and N-nucleophiles. Table 3
presents that endo- and exo-glycals react with allyl-,
propargyl-, and azido-trimethylsilane to obtain glyco-
sides 42–48. Interestingly, except for entry vii, the

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H.-C. Lin et al. / Tetrahedron Letters 46 (2005) 5071–5076
Scheme 2. Two possible pathways proposed to explain the formation of both rearranged and protonated products.
Table 2. Glycosylations of endo-glycals 30–33 with various alcoholsa
Entry
i
Donor
Acceptor (ROH)
Time (min)
60
Protonation + rearrangement
products (yield)
30
— (0%)
34 (85%)b
ii
30
120
— (0%)
35 (83%)b
iii
iv
v
30
31
31
120
30
— (0%)
— (0%)
— (0%)
36 (75%)b
37 (86%)b
35 (78%)b
30
vi
31
32
32
30
60
30
— (0%)
38 (75%)b
35 (24%)
vii
viii
39 (64%)
40 (51%)
38 (30%)
37 (24%)
ix
x
33
150
150
41 (61%)
33a
— (0%)
37a (82%)c
a All reactions were carried out at 0–25 °C in CH2Cl2 with alcohol nucleophiles in the presence of TFA (10 equiv) and molecular sieves (4 A).
b The a-anomer is predominant with a/b ratio of 8/1–15/1 on the basis of 1H NMR integration.
c Product 37a is the same as 37 except for the acetate protecting group.
˚

H.-C. Lin et al. / Tetrahedron Letters 46 (2005) 5071–5076
5075
Scheme 3. Glycosylation reactions catalyzed by methanesulfonic acid or boron trifluoride etherate.
Table 3. Reactions of glycals with C- and N-nucleophilesa
Entry
Donor
Acceptor (ROH)
Product (yield)
i
1
42 (85%)
ii
1
TMSN3
43 (82%)
iii
iv
1
5
44 (65%)
45 (78%)
TMSN3
v
30
30
30
46 (84%)
47 (79%)
48 (83%)
vi
vii
TMSN3
viii
33
46 (85%)
a All reactions were carried out at 0–25 °C in CH2Cl2 with nucleophiles in the presence of TFA (10 equiv) and molecular sieves (4 A).
˚

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H.-C. Lin et al. / Tetrahedron Letters 46 (2005) 5071–5076
2. (a) Ferrier, R. J. J. Chem. Soc. 1964, 5443; (b) Ciment, D.
M.; Ferrier, R. J. J. Chem. Soc. C 1966, 441.
selectivity was greatly enhanced here in comparison with
the glycosylation of O-nucleophiles, including the a-
stereoselectivity and selective product formation from
a preferential pathway. Nevertheless, the parallel reac-
tions using other Lewis acids often afforded undesired
product(s). For example, a diene product 49 was
obtained owing to the direct substitution of exo-glycal
1 with allyl trimethylsilane in the presence of BF3ÆOEt2.
The same condition with TMSN3 gave azide adduct 50
as the major product (75%).
3. (a) Takhi, M.; Abdel-Rahman, A. A.-H.; Schmidt, R. R.
Synlett 2001, 427; (b) Yadav, J. S.; Reddy, B. V. S.;
Murphy, C. V. S. R.; Kumar, G. M. Synlett 2000, 1451.
4. (a) Das, S. K.; Reddy, K. A.; Roy, J. Synlett 2003, 1607–
1610; (b) Swamy, N. R.; Venkateswarlu, Y. Synthesis
2002, 598.
5. (a) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res.
1998, 31, 685; (b) Seeberger, P. H.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 1997, 36, 491; (c) Danishefsky, S.
J.; Bilodeau, M. T. Angew. Chem., Int. Ed. 1996, 35, 1318.
6. (a) Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 1998, 37, 786; (b) Goering, B. K. Ph.D.
Dissertation, Cornell University, 1995.
7. Zheng, C.; Seeberger, P. H.; Danishefsky, S. J. J. Org.
Chem. 1998, 63, 1126.
8. (a) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064; (b)
Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F., Jr.
J. Am. Chem. Soc. 1982, 104, 360.
9. Roberge, J. Y.; Beebe, X.; Danishefsky, S. J. Science 1995,
269, 202.
10. Tatsuta, K.; Fujimoto, K.; Kinoshita, M.; Umezawa, S.
Carbohydr. Res. 1977, 54, 85.
11. Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696.
12. Bolitt, V.; Mioskowski, C.; Lee, S.-G.; Falck, J. R. J. Org.
Chem. 1990, 55, 5812.
13. Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5468.
14. (a) Kolar, C.; Kneissl, G. Angew. Chem. Int. Ed. Engl.
1990, 29, 809; (b) Kaila, N.; Blumenstein, M.; Bielawska,
H.; Franck, R. W. J. Org. Chem. 1992, 57, 4576.
15. (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) Lin,
H.-C.; Chang, C.-C.; Chen, J.-Y.; Lin, C.-H. Tetrahedron:
Asymmetry 2005, 16, 297; (c) Chang, C.-F.; Yang, W.-B.;
Chang, C.-C.; Lin, C.-H. Tetrahedron Lett. 2002, 43, 6515.
16. For example, the 1H NMR spectra of the glycosylation
product 10 indicated the H-100 resonance appeared at d
2.08 (t, J = 7.3Hz, 2H), H-2 00 at d 3.90 (m, 1H) and 4.12
(m, 1H), and CH3CO– at d 1.90 (s, 3H). The signals at d
20.89 and 170.8 corresponding to the CH3CO– and
CH3CO– resonances, respectively, were found in the 13C
NMR spectra of the same molecule. Please see the
numbering structure in Scheme 3.
In conclusion, we have conducted in detail the investiga-
tion of acid-catalyzed glycosylation of endo- and exo-
glycals that are simple and can be finished efficiently in
good to excellent yields. The reactions can be applied
for the glycosyl additions of O-, C-, and N-nucleophiles.
The carbonate or hydroxyl group at C3position exclu-
sively adopted the Ferrier reaction pathway in the reac-
tions of endo-glycals, while the acetate and benzyl ether
substituents predominantly gave a protonation product
in those of exo-glycals. Particularly the former reactions
are useful for the synthesis of 2,3-unsaturated-a-glyco-
sides. In addition to providing an expeditious glycosyl-
ation procedure, our work represents the first report to
clearly display the different reactivity between endo-
and exo-glycals, and demonstrate both reaction path-
ways to be in the control of the allyl substituent and
protecting group. Current efforts are in progress to
study if other factors play a role in the competition
and will be published in due course.
Acknowledgements
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.
Supplementary data
17. The NOESY spectra of 10, for instance, exhibited the
cross-peaks between H2 (d 3.97) and H100 (d 2.08), as well
as H5 (d 3.80) and H10 (d 3.43).
18. Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.;
Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121,
734.
1H and 13C NMR spectra of 45 compounds are available
(75 pages). Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2005.05.061.
19. Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004,
69, 6137.
References and notes
20. The effect has been long recognized. Please see (a) Paulson,
H.; Richter, A.; Sinnwell, H.; Stenzel, W. Carbohydr. Res.
1974, 38, 312; (b) Fraser-Raid, B.; Bocter, B. Can. J.
Chem. 1969, 47, 393; (c) Feather, M. S.; Harris, J. F. J.
Org. Chem. 1965, 30, 153.
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.