Zn(OTf)2-catalyzed glycosylation of glycals: Synthesis of 2,3-unsaturated glycosides via a Ferrier reaction

Article abstract of DOI:10.1055/s-0033-1340552

A mild, catalytic, and efficient protocol has been developed for the synthesis of 2,3-unsaturated glycosides or 'pseudo-glycals' using Zn(OTf) ₂. Stereoselective glycosylation of glycal donor with various acceptors comprising of alcohols, phenols, thiols, and sugar aglycones proceeds smoothly to afford the corresponding 2,3-unsaturaed glycosides in good to excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340552

LETTER
▌523
letter
Zn(OTf)2-Catalyzed Glycosylation of Glycals: Synthesis of 2,3-Unsaturated
Glycosides via a Ferrier Reaction
Synthesis of 2,3-Unsaturated Glycosides
Gundeboina Narasimha, Batthula Srinivas, Palakodety Radha Krishna,* Sudhir Kashyap*
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Fax +91(40)27160387; E-mail: skashyap@iict.res.in
Received: 07.11.2013; Accepted after revision: 09.12.2013
pounds,1b
modified
carbohydrate
derivatives,7
Abstract: A mild, catalytic, and efficient protocol has been devel-
oped for the synthesis of 2,3-unsaturated glycosides or ‘pseudo-gly-
cals’ using Zn(OTf)2. Stereoselective glycosylation of glycal donor
with various acceptors comprising of alcohols, phenols, thiols, and
nucleosides, and oligosaccharides.2,5,6 Although, 2,3-un-
saturated glycosides have been widely utilized, their ex-
ceptional synthetic versatility offers considerable
sugar aglycones proceeds smoothly to afford the corresponding 2,3- potential for further functionalization and hence they are
unsaturaed glycosides in good to excellent yields.
employed as glycosyl donors in the synthesis of natural
products containing 2,3-dideoxy8a and 2-deoxy moi-
Key words: glycosylation, glycosides, stereoselective synthesis,
Ferrier reaction, glycal
eties.10
Since the development of the Ferrier reaction in 1969,3 al-
lylic rearrangement with nucleophilic substitution (SN2′)
Glycal templates have proven to be useful sugar scaffolds
for diversity oriented synthesis to access small molecules
with complex and diverse molecular structures with defi-
nite stereochemistry.1 Owing to the presence of the enol
ether functionality, glycals are utilized as versatile chiral
building blocks in Danishefsky’s glycal assembly2 for the
synthesis of many biologically important oligosaccha-
rides and glycoconjugates including Lewis and blood-
group determinants, gangliosides, and tumor-associated
antigens and in chemical glycosylations such as the Ferri-
er reaction.3 The Ferrier reaction involves displacement of
a leaving group at the C-3 position of the glycal (a carbo-
hydrate with an endocyclic alkene) in the presence of a
Lewis acid catalyst or promoter. Subsequently, the nu-
cleophile attacks at the anomeric position of the cyclic
allyloxycarbenium ion intermediate with quasi-axial ori-
entation leading to the formation of 2,3-unsaturated gly-
cosides (Figure 1).
of glycals has been widely employed in the stereoselective
synthesis of 2,3-unsaturated glycosides, using a wide va-
riety of Lewis acid catalysts,11 Brønsted acids,12 and oxi-
dants.13 However, many existing strategies experience
several drawbacks such as the need for high reaction tem-
peratures, strongly acidic conditions, and extensive work-
up. Besides, the catalysts used may be strong oxidants,
highly air-sensitive, or require excess loadings or even to
be used in stoichiometric amounts. In addition, some of
the protocols require a large excess of nucleophile, offer
low anomeric stereoselectivity, deliver low yields, and
sometime produce byproducts. Therefore, there continues
to be a need for a mild, inexpensive, and efficient catalytic
promoter for the Ferrier reaction.
The scope of Zn(II)-catalyzed glycosylation has been
demonstrated for ester-protected glycopyranoside donors.
The combination of trimethylsilyl halide and a Lewis acid
such as ZnBr2 with diglyme as an additive is required for
the success of this transformation.11z In a recent report,11y
Liu and coworkers demonstrated the use of ZnCl2 impreg-
nated on activated alumina (ZnCl2/Al2O3) to effect Ferrier
aza-glycosylation. However, Ferrier reaction utilizing
ZnCl2 as a Lewis acid catalyst has only been reported with
a narrow range of substrates, providing low anomeric se-
lectivity.11f
Lewis
acid
AcO
AcO
X
AcO
AcO
AcO
AcO
Nu–
O
O
O
+
– X–
Nu
X = OAc or leaving group
allyloxycarbenium ion
α-glycoside
Figure 1 Mechanistic representation of Ferrier reaction
In our approach to glycosylation and the synthesis of gly-
coconjugates,14 we considered Zn(II) triflate as a catalyst
for the Ferrier reaction to synthesize 2,3-unsaturated gly-
cosides. Herein, we report the development of a Ferrier
protocol utilizing Zn(II) triflate as a less expensive, mild-
er, reusable, and efficient catalyst for the expeditious syn-
thesis of 2,3-unsaturated glycopyranosides. The current
protocol features a mild, simple, and stereoselective syn-
thesis of α-glycosides with variety of O- and S-nucleo-
philes in the presence of other functionalities such as allyl,
propargyl, isopropylidene, benzyl, and isopropyl groups,
olefins, and ether linkages.
2,3-Unsaturated glycosides or ‘pseudo-glycals’ have re-
ceived wide attention in recent years, particularly in the
synthesis of antibiotics,4 oligosaccharides,5 uronic acids,6
complex carbohydrates, and several biologically active
natural products.7 In addition, these molecules also serve
as chiral synthons and key intermediates for various natu-
ral products,8 glycopeptides,9 natural product like com-
SYNLETT 2014, 25, 0523–0526
Advanced online publication: 14.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340552; Art ID: ST-2013-D1037-L
© Georg Thieme Verlag Stuttgart · New York

524
G. Narasimha et al.
LETTER
Initial experiments were performed with 3,4,6-tri-O-ace- a characteristic signal due to the anomeric proton of glucal
tyl glucal (1) as the donor and benzyl alcohol (2a) as a 1 at δ = 6.47 ppm (d, J1–2 = 6.17 Hz, 1 H) had disappeared.
model acceptor, the results are shown in Table 1. In the Furthermore, olefinic resonances between δ = 5.84–5.92
first set of reactions, glycal 1 (1 mL CH2Cl2) and 2a (1.2 ppm and the presence of signals at δ = 5.14 ppm (br s) for
equiv) were reacted with 5 mol% of Zn(OTf)2 under an in- the α-anomer and δ = 5.20 ppm for the β-anomer integrat-
ert atmosphere at room temperature for 16 hours, a 50% ing as 88:12 (α/β) confirmed the product with good stereo-
conversion was observed, and benzyl 2,3-unsaturated glu- selectivity in favor of the α-anomer. In the 13C NMR
copyranoside (3a) was isolated in 78% yield based on re- spectrum of 3a, olefinic carbon resonances at δ = 126.7
covered staring material. Increasing the amount of and 137.4 ppm and the presence of the anomeric carbon
catalyst to 10 mol% in CH2Cl2 resulted in 70% conversion resonance at δ = 93.5 ppm further verified the major prod-
in 16 hours. Moreover, changing the solvent from CH2Cl2 uct as an α-glycoside.
to 1,2-dichloroethane resulted in the completion of reac-
tion in three hours, furnishing 3a in excellent yield (Table
1, entry 3).
Notably, Zn(OTf)2 not only acts as a stable and efficient
catalyst but can be easily recovered by simple filtration of
the reaction mixture and reused for a second transforma-
tion without losing its activity (Table 1, entry 6).
Table 1 Optimization of Zn(OTf)2-Catalyzed Glycosylation of Gly-
cal 1 with Benzyl Alcohol (2a)a
A highly polar solvent such as MeCN led to very low con-
version, while a rise in reaction temperature led to com-
AcO
AcO
AcO
AcO
AcO
HO
O
O
pletion within one hour (Table 1, entry 5). However, the
anomeric ratio of products was found to be independent of
reaction conditions such as solvent, temperature, or cata-
lytic quantity of the promoter.
Zn(OTf)2
+
1
O
2a
3a
Entry
Catalyst
(mol%)
Solvent
Time
(h)
Conv.
(%)
Yield
(%)b
Next, the applicability and scope of this protocol were fur-
ther examined in the context of various alcohols 2b–i. All
the reactions proceeded cleanly and efficiently and fur-
nished the corresponding 2,3-unsaurated α-O-glycosides
3b–i in good yields (Table 2).
1
5
10
10
10
10
10
CH2Cl2
CH2Cl2
DCE
16
16
3
50
70
78
85
98
–
2
In addition, we investigated the generality and efficiency
of our procedure with thiols as nucleophiles. Accordingly,
reaction of 1 with 2j and 2k under similar conditions15 af-
forded the corresponding 2,3-unsaturated thioglycosides
3j–k in good yields without any byproducts (Table 2, en-
try 9 and 10). Furthermore, the success and efficiency of
the Zn(OTf)2 as the Lewis acid in the Ferrier reaction is
well illustrated using monosaccharides acceptors. Cou-
pling of 1 with sugar nucleophiles 2l and 2m afforded the
corresponding disaccharides 3l and 3m in good yield (Ta-
ble 2, entry 11 and 12). However, reactions involving
phenols such as 1-naphthol (2n) gave mixtures of C-gly-
cosides, it can be postulated that rearrangement16 of O- to
C-glycosides occurs in the presence of Lewis acids (Table
2, entry 13).
3
100
trace
100
80
4
MeCN
DCE
24
1
5c
6d
97
90
DCE
8
a Reaction conditions: glucal 1 (0.37 mmol), BnOH (0.44 mmol).
b Isolated yields based on the recovery of starting material.
c Reaction temperature 40 °C.
d Reaction was performed with recovered catalyst.
The stereochemistry at the anomeric position was estab-
lished unambiguously based on H NMR and 13C NMR
1
1
spectroscopy. The H NMR spectrum of 3a revealed the
absence of the C-2 proton at δ = 5.34 ppm (br s, 1 H) and
Table 2 Zn(OTf)2-Catalyzed Ferrier Reaction on Glycal 1a
Entry Acceptor
Product
Time
1 h
Yield (%)b α/β ratioc
AcO
AcO
O
O
O
1
2b
3b
98
87:13
HO
HO
O
O
O
AcO
AcO
2
3
2c
3c
3 h
98
97
85:15
88:12
AcO
AcO
CF3
HO
2d
3d
20 min
CF3
Synlett 2014, 25, 523–526
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2,3-Unsaturated Glycosides
525
Table 2 Zn(OTf)2-Catalyzed Ferrier Reaction on Glycal 1a (continued)
Entry Acceptor
Product
Time
4 h
Yield (%)b α/β ratioc
AcO
AcO
O
O
HO
HO
4
2e
3e
95
87:13
OEt
O
O
OEt
AcO
AcO
5
6
2f
3f
10 min
86
98
90:10
90:10
AcO
AcO
O
O
HO
HO
2g
3g
3 h
Cl
O
O
Cl
AcO
AcO
7
8
2h
2i
3h
3i
8 h
88
78
89:11
91:9
AcO
AcO
H
O
H
HO
6 h
H
H
O
AcO
AcO
O
O
HS
HS
9
2j
3j
1 h
2 h
92
90
79:21
72:28
S
AcO
AcO
10
2k
3k
CF3
S
CF3
O
AcO
AcO
OH
O
O
O
O
O
O
11
2l
3l
4 h
74
88:12
O
O
O
O
O
AcO
AcO
HO
AcO
AcO
OAc
O
O
O
O
OMe
AcO
AcO
12
13
2m
2n
3m
3n
16 h
1 h
72
72
85:15
67:33
O
OMe
OAc
AcO
AcO
OH
HO
a All reactions were performed with glucal 1 (0.37 mmol), 1.2 equiv of acceptor with 10 mol% of Zn(OTf)2 in DCE at r.t.
b Isolated and unoptimized yields.
c The α/β ratios were examined by 1H NMR by integrating anomeric hydrogen.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 523–526

526
G. Narasimha et al.
LETTER
Synlett 2000, 1281. (c) Takhi, M.; Abdel-Rahman, A. A.-H.;
Schmidt, R. R. Synlett 2001, 427. (d) Swamy, N. R.;
Venkateswarlu, Y. Synthesis 2002, 598. (e) Hotha, S.;
Tripathi, A. Tetrahedron Lett. 2005, 46, 4555.
In summary, we report a new and practical method for
constructing the α-glycosidic linkage via Ferrier reaction
of glycals using mild conditions. A diverse range of
acceptors was incorporated into glucal donors with high
stereoselectivity using Zn(OTf)2 as catalyst.
(f) Bettadaiah, B. K.; Srinivas, P. Tetrahedron Lett. 2003,
44, 7257. (g) Kim, H.; Men, H.; Lee, C. J. Am. Chem. Soc.
2004, 126, 1336. (h) Swamy, N. R.; Srinivasulu, M.; Reddy,
T. S.; Goud, T. V.; Venkateswarlu, Y. J. Carbohydr. Chem.
2004, 23, 435. (i) Rafiee, E.; Tangestaninejad, S.; Habibi, M.
H.; Mirkhani, V. Bioorg. Med. Chem. Lett. 2004, 14, 3611.
(j) Babu, J. L.; Khare, A.; Vankar, Y. D. Molecules 2005, 10,
884. (k) Naik, P. U.; Nara, J. S.; Harjani, J. R.; Salunkhe, M.
M. J. Mol. Catal. A: Chem. 2005, 234, 35. (l) Procopio, A.;
Dalposso, R.; De Nino, A.; Nardi, M.; Oliverio, M.; Russo,
B. Synthesis 2006, 2608. (m) Procopio, A.; Dalpozzo, R.; De
Nino, A.; Maiuolo, L.; Nardi, M.; Oliverio, M.; Russo, B.
Carbohydr. Res. 2007, 342, 2125. (n) Balamurugan, R.;
Kopollu, S. R. Tetrahedron 2009, 65, 8139. (o) Rodriguez,
O. M.; Colinas, P. A.; Bravo, R. D. Synlett 2009, 1154.
(p) Gorityala, B. K.; Lorpitthaya, R.; Bai, Y.; Liu, X.-W.
Tetrahedron 2009, 65, 5844. (q) Nagaraj, P.; Ramesh, N. G.
Tetrahedron Lett. 2009, 50, 3970. (r) Chen, P.-R.; Wang, S.-
S. Tetrahedron 2012, 68, 5356. (s) Freitas, J. C. R.; Couto,
T. R.; Paulino, A. A. S.; de Freitas Filho, J. R.; Malvestiti, I.;
Oliveira, R. A.; Menezes, P. H. Tetrahedron 2012, 68,
10611. (t) Descotes, G.; Martin, J.-C. Carbohydr. Res. 1977,
56, 168. (u) Bhate, P.; Horton, D.; Priebe, W. Carbohydr.
Res. 1985, 144, 331. (v) Zhang, G.; Shi, L.; Liu, Q.; Wang,
J.; Li, L.; Liu, X. Tetrahedron 2007, 63, 9705. (w) Zhang,
G.; Liu, Q. Synth. Commun. 2007, 37, 3485. (x) Tayama, E.;
Otoyama, S.; Isaka, W. Chem. Commun. 2008, 4216.
(y) Ding, F.; William, R.; Gorityala, B. K.; Ma, J.; Wang, S.;
Liu, X.-W. Tetrahedron Lett. 2010, 51, 3146. (z) Higashi,
K.; Susaki, H. Chem. Pharm. Bull. 1992, 40, 2019.
(12) (a) Gorityala, B. K.; Cai, S.; Lorpitthaya, R.; Ma, J.;
Pasunooti, K. K.; Liu, X.-W. Tetrahedron Lett. 2009, 50,
676. (b) Zhou, J.; Zhang, B.; Yang, G.; Chen, X.; Wang, Q.;
Wang, Z.; Zhang, J.; Tang, J. Synlett 2010, 893. (c) Hadfield,
A. F.; Sartorelli, A. C. Carbohydr. Res. 1982, 101, 197.
(d) Engler, T. A.; Letavic, M. A.; Combrink, K. D.;
Takusagawa, F. J. Org. Chem. 1990, 55, 5812. (e) Yadav, J.
S.; Satyanarayana, M.; Balanarsaiah, E.; Raghavendra, S.
Tetrahedron Lett. 2006, 47, 6095. (f) Agarwal, A.; Rani, S.;
Vankar, Y. D. J. Org. Chem. 2004, 69, 6137. (g) Misra, A.
K.; Tiwari, P.; Agnihotri, G. Synthesis 2005, 260.
Acknowledgment
This research was supported by DST, New Delhi (GAP 0397). The
authors are grateful to the Director CSIR-IICT for providing the ne-
cessary infrastructure. S.K is grateful to Prof. S. Hotha and Dr. G.
V. M. Sharma for their considerable encouragement.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
References and Notes
(1) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Hotha, S.;
Tripathi, A. J. Comb. Chem. 2005, 7, 968.
(2) Review: Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1380.
(3) (a) Ferrier, R. J. J. Chem. Soc. 1964, 5443. (b) Ciment, D. M.
Ferrier R. J. J. Chem. Soc. C 1966, 441. (c) Ferrier, R. J.;
Sankey, G. H. J. Chem. Soc. C 1966, 2345. (d) Ferrier, R. J.;
Prasad, N. J. Chem. Soc. C 1969, 570.
(4) Williams, N. R.; Wander, J. D. The Carbohydrates in
Chemistry and Biochemistry; Academic Press: New York,
1980, 761.
(5) Bussolo, V. D.; Kim, Y. J.; Gin, D. Y. J. Am. Chem. Soc.
1998, 120, 13515.
(6) (a) Schmidt, R. R.; Angerbauer, R. Carbohydr. Res. 1981,
89, 159. (b) Angerbauer, R.; Schmidt, R. R. Carbohydr. Res.
1981, 89, 193. (c) Schmidt, R. R.; Angerbauer, R.
Carbohydr. Res. 1979, 89, 272.
(7) (a) Schmidt, R. R.; Angerbauer, R. Angew. Chem., Int. Ed.
Engl. 1977, 16, 783. (b) Durham, T. B.; Miller, M. J. Org.
Lett. 2002, 4, 135. (c) Williams, D. R.; Heidebrecht, R. W.
Jr. J. Am. Chem. Soc. 2003, 125, 1843. (d) Panarese, J. D.;
Waters, S. P. Org. Lett. 2009, 11, 5086. (e) Rusin, A.;
Zawisza-Puchalka, J.; Kujawa, K.; Gogler-Piglowska, A.;
Wietrzyk, J.; Switalska, M.; Glowala-Kosinska, M.; Gruca,
A.; Szeja, W.; Krawczyk, Z.; Grynkiewicz, G. Bioorg. Med.
Chem. 2011, 19, 295. (f) Bozell, J. J.; Tice, N. C.; Sanyal,
N.; Thompson, D.; Kim, J.-M.; Vidal, S. J. Org. Chem.
2008, 73, 8763.
(8) (a) Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. Rev.
1993, 62, 579. (b) Reddy, B. G.; Vankar, Y. D. Tetrahedron
Lett. 2003, 44, 4765. (c) Lewis, A.; Stefanuti, I.; Swain, S.
A.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42,
5549. (d) Patterson, L.; Keown, L. E. Tetrahedron Lett.
1997, 38, 5727.
(9) (a) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J.
Tetrahedron: Asymmetry 2005, 16, 45. (b) Dorgan, B. J.;
Jackson, R. F. W. Synlett 1996, 859.
(10) (a) Borisova, S. A.; Guppi, S. R.; Kim, H. J.; Wu, B.; Penn,
J. H.; Liu, H.; O’Doherty, G. A. Org. Lett. 2010, 12, 5150.
(b) Fraser-Reid, B. Acc. Chem. Res. 1985, 18, 347.
(c) Ferrier, R. J. Adv. Carbohydr. Chem. Biochem. 1969, 24,
199.
(13) (a) Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.;
Kinoshita, M. J. Chem. Soc., Chem. Commun. 1993, 704.
(b) Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35,
3661. (c) Koreeda, M.; Houston, T. A.; Shull, B. K.;
Klemke, E.; Tuinman, R. J. Synlett 1995, 90. (d) Lopez, J.
C.; Gomez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org.
Chem. 1995, 60, 3851. (e) De, K.; Legros, J.; Crousse, B.;
Bonnet-Delpon, D. Tetrahedron 2008, 64, 10497.
(14) (a) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128,
9620. (b) Hotha, S.; Kashyap, S. Tetrahedron Lett. 2006, 47,
2021. (c) Kashyap, S.; Vidadala, S. R.; Hotha, S.
Tetrahedron Lett. 2007, 48, 8960. (d) Vidadala, S. R.;
Thadke, S. A.; Hotha, S.; Kashyap, S. J. Carbohydr. Chem.
2012, 31, 241. (e) Hotha, S.; Kashyap, S. J. Org. Chem.
2006, 71, 364.
(15) See Supporting Information.
(16) Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron Lett.
1992, 33, 306.
(11) (a) Babu, B. S.; Balasubramanian, K. K. Tetrahedron Lett.
2000, 41, 1271. (b) Masson, C.; Soto, J.; Bessodes, M.
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