Copper(II) triflate as a mild and efficient catalyst for ferrier glycosylation: Synthesis of 2,3-unsaturated o -glycosides

Article abstract of DOI:10.1055/s-0033-1341232

Various acceptors including carbohydrates, amino acids, natural products, and hydroxylamine derivatives were coupled with 3,4,6-tri-O-acetyl-d-glucal in the presence of Cu(OTf)₂ as catalyst. The protocol offers facile and efficient Ferrier glycosylation for the synthesis of 2,3-unsaturaed O-glycosides in good yields and high anomeric selectivity.

Full text of DOI:10.1055/s-0033-1341232

LETTER
▌1325
lCettoerpper(II) Triflate as a Mild and Efficient Catalyst for Ferrier Glycosylation:
Synthesis of 2,3-Unsaturated O-Glycosides
2,3-Unsaturated O-Glycosides
Batthula Srinivas, Thurpu Raghavender Reddy, 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: 20.02.2014; Accepted after revision: 24.03.2014
to effect the Ferrier rearrangement. However, many of the
Abstract: Various acceptors including carbohydrates, amino acids,
existing protocols suffer from lack of generality because
natural products, and hydroxylamine derivatives were coupled with
strong acidic conditions restrict the use of acid-labile sub-
strates. In addition, many of these methods have limita-
3,4,6-tri-O-acetyl-D-glucal in the presence of Cu(OTf)2 as catalyst.
The protocol offers facile and efficient Ferrier glycosylation for the
synthesis of 2,3-unsaturaed O-glycosides in good yields and high tions such as high reaction temperature, extensive
anomeric selectivity.
workup, use of expensive, moisture-sensitive, toxic met-
als, and strong oxidizing reagents, require excess loading
of reagents and nucleophiles, offer low anomeric selectiv-
ity, or provide poor yields of the desired products. Over
the years, a variety of metal triflates have been used to ef-
fect the Ferrier reaction3c of glycals with various nucleo-
philes. However, the use of toxic metals is limited for the
synthesis of active pharmaceutical ingredients (APIs) be-
cause tedious workup and metal-scavenging is required to
reduce the amount of residual metals to acceptable limits
in the desired products.14 Therefore, the development of
mild protocols that use low quantities of environmental
friendly, non-toxic catalysts, is of crucial importance for
the synthesis of glycoside and saccharide functionalized
molecules.
Key words: glycosides, glycosylation, glycoconjugates, Ferrier re-
action, Lewis acid
Sugar scaffolds are crucial for the development of thera-
peutic agents due to the role played by saccharides and
glycoconjugates in many biological processes.1 Owing to
the presence of enol ether functionality, glycals are among
the most utilized chiral intermediates for the synthesis of
carbohydrate derivatives and they serve as building
blocks for various molecules of biological significance.2
The synthetic potential of the stereochemically rigid
structure of glycal systems has been demonstrated in di-
versity-oriented synthesis of small molecules with com-
plex structures2a,b and Danishefsky’s glycal assembly for
the preparation of various biologically active molecules
and glycoconjugates.2c However, Ferrier glycosylation3
remains the most investigated chemical transformation on
glycals. The Ferrier reaction is an allylic rearrangement
that involves displacement of a leaving group at the C-3
position of a glycal ester in the presence of a Lewis acid
catalyst. Subsequently, the nucleophile attacks at the ano-
meric position of the cyclic allylic oxocarbenium ion in a
quasi-axial orientation leading to the formation of 2,3-un-
saturated glycosides or ‘pseudo-glycals’.
In recent years, Cu(OTf)2 has become a valuable reagent
for various reactions such as trifluoromethylation,15a cya-
notrifluoromethylation,15b and hydroalkoxylation of al-
kenes.15c In a recent report, a combination of Cu(OTf)2
and ascorbic acid has been employed to effect the C-gly-
cosylation of glycals with unactivated alkynes.15d The
success of Cu(OTf)2 as a non-toxic, moisture- and air-sta-
ble catalyst encouraged us to use this reagent as a Lewis
acid in Ferrier glycosylation. In a continuation of our in-
terest in the development of new glycosylation methods
and synthesis of glycosides,16 herein, we report the use of
Cu(II) triflate as an efficient catalyst for the synthesis of
2,3-unsaturated O-glycosides.
The stereoselective synthesis of 2,3-unsaturated glyco-
sides is of particularly importance due to their usefulness
as key intermediates in the synthesis of several biological-
ly important molecules such as antibiotics,4 oligosaccha-
rides,5 uronic acids,6 and complex carbohydrates,7 various
natural products,8a glycopeptides,9 nucleosides,7,8b and
modified carbohydrate derivatives.7 The presence of a
2,3-olefinic group in ‘pseudo-glycals’ has further added to
the diversity, hence, they are employed in various com-
plexity-generating reactions.10
As a first step, Ferrier glycosylation was performed with
3,4,6-tri-O-acetyl glucal (1) as glycosyl donor and benzyl
alcohol (2a) as a model acceptor, being a relatively fast
reactant. Initially, we observed only 50% conversion at
room temperature after 16 hours in the presence 10 mol%
Cu(OTf)2 and dichloromethane as solvent. Notably, the
rate of reaction was accelerated with incremental rise in
temperature, and 90% conversion of 1 was observed after
8 hours at 40 °C to obtain benzyl glycoside 3a in 76%
yield. The temperature and solvent played an important
role in this transformation in terms of yield and stereo-
chemistry.
So far, a large number of catalysts including Lewis ac-
ids,11 Brønsted acids,12 and oxidants13 have been reported
SYNLETT 2014, 25, 1325–1330
Advanced online publication: 10.04.2014
DOI: 10.1055/s-0033-1341232; Art ID: st-2014-d0145-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Optimization of reaction conditions was then carried out
in different solvents; the results are summarized in Table

1326
B. Srinivas et al.
LETTER
1. Using 1,2-dichloroethane as a solvent resulted in only cosylation with 2a in acetonitrile with varying amounts of
10% conversion after 16 hours at room temperature, and Cu(OTf)2 at room temperature. As indicated in Figure 1,
80% conversion was observed at 40 °C in 8 hours, as in- Cu(OTf)2 mediated Ferrier reactions in the presence of 10
dicated by TLC. Notably, the best result was obtained and 5 mol% catalyst were complete within 10 and
when the Ferrier reaction between 1 and 2a was carried 40 minutes, respectively. The use of 2 mol% catalyst suf-
out in acetonitrile as solvent at room temperature. Re- ficed to give almost quantitative conversion (100%) after
markably, the reaction was completed within 10 minutes, 1 hour, as indicated by TLC analysis. Further decreasing
and benzyl glucoside 3a was isolated in 98% yield as an the catalytic amount to 1 mol% extended the required re-
88:12 α/β-mixture. Other solvents such as diethyl ether, action time, however, the reaction with 0.5 mol%
toluene, or tetrahydrofuran were either ineffective or re- Cu(OTf)2 was not complete even after a prolonged reac-
sulted in very poor conversions even after prolonged reac- tion time.
tion times at high temperature (Table 1).
Table 1 Standardization of Ferrier Glycosylation Conditionsa
AcO
AcO
O
AcO
HO
O
Cu(OTf)2
(10 mol%)
AcO
+
AcO
O
1
2a
3a
Entry Solvent
Time
(h)
Temp
(°C)
Conv.
(%)b
Yield
(%)c
Figure 1 The effect of a catalytic amount of Cu(OTf)2 on the con-
version in the Ferrier glycosylation of glycal 1 with 2a
d
1
2
CH2Cl2
DCE
16
8
r.t.
40
50
90
–
76
Having optimized the conditions, we established the gen-
erality of the protocol with a range of alcohols including
allyl (2b), butyne (2c), trifluoroethanol (2d), secondary
butanol (2e), thiophenol (2f), alicyclic (2g, 2h), hydroxyl-
amine derivatives (2i, 2j), and 9-fluorenemethanol (9FM,
2k). Generally, the current protocol was sufficiently mild
to tolerate various sensitive functionalities such as esters,
carbamates, and diacetonide to afford 2,3-unsaturated
glycosides in high yield and with good anomeric selectiv-
ity (Table 2). It is pertinent to mention that Ferrier reac-
tion of glycal 1 with hydroxylamine derivatives such as N-
hydroxysuccinimide (2i) and N-hydroxyphthalimide (2j)
proceeded efficiently to afford the corresponding ‘pseu-
do-glycals’ in high anomeric selectivity in favor of the α-
anomers (Table 2, entries 8 and 9). It is noteworthy that
the use of a thiol such as 4-trifluoromethyl thiophenol (2f)
as nucleophile worked equally well, giving thioglycoside
3f in 72% yield with the α-anomer as the major product
(Table 2, entry 5). Substrates with a nucleophile-contain-
ing tertiary nitrogen such as 3-quinuclidinol (2l) failed to
react under similar conditions (Table 2, entry 11).
d
16
8
r.t.
40
10
80
–
64
3
4
MeCN
Et2O
10 min
r.t.
100
98
d
16
16
r.t.
40
trace
20
–
d
5
6
THF
16
16
r.t.
40
no reaction
trace
–
d
toluene
16
16
r.t.
40
no reaction
trace
–
a Reaction conditions: glycal 1 (0.37 mmol), BnOH (0.44 mmol).
b Progress of reaction was monitored by TLC analysis at a given time
and temperature.
c Isolated and unoptimized yields.
d Not isolated.
1
In the H NMR spectrum of 3a, the appearance of reso-
nances corresponding to olefin protons between δ = 5.85–
5.89 ppm were observed, while the anomeric proton was
identified at δ = 5.14 ppm (br, s) integrating for one pro-
ton, thereby confirming that the product was formed with
good stereoselectivity in favor of the α-anomer (α/β,
88:12). Furthermore, the 13C NMR spectrum of 3a
showed the characteristic resonances of two olefinic car-
bon atoms at δ = 126.7 and 137.4 ppm and the presence of
an anomeric carbon at δ = 93.5 ppm along with all other
signals expected for the assigned structure and in com-
plete agreement with literature data.16g
The versatility and scope of the present method was fur-
ther explored to obtain ‘pseudo-glycals’ incorporated
with biologically important molecules. Accordingly, nat-
ural biomolecules such as L-menthol (2m) and cholesterol
(2n) were coupled with glycal 1 to obtain unsaturated gly-
cosides in satisfactory yields and high anomeric selectivi-
ty (Scheme 1). The Ferrier reaction of cholesterol (2n)
was performed in a mixed solvent system of dichloro-
methane and acetonitrile (1:1) due to the poor solubility of
2n in acetonitrile.
We then examined the optimal catalytic quantity of
Cu(OTf)2 that would deliver acceptable rates of conver-
sion. Accordingly, glucal 1 was subjected to Ferrier gly-
Synlett 2014, 25, 1325–1330
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,3-Unsaturated O-Glycosides
1327
Table 2 Substrate Scope of the Cu(OTf)2-Mediated Ferrier Glycosylation under Optimized Conditionsa
Entry
1
Acceptor (NuH)
Product
Time (h)
Yield (%)b
α/β ratioc
AcO
AcO
O
O
HO
2
9616g
91:9
O
O
2b
3b
AcO
AcO
HO
2
3
4
4
2
1
9416g
8416g
7811k
85:15
90:10
92:8
2c
3c
AcO
AcO
O
O
CF3
HO
CF3
O
O
2d
3d
AcO
AcO
HO
2e
3e
AcO
AcO
O
HS
5
S
2
7616f
α only
CF3
CF3
2f
3f
AcO
AcO
O
O
O
HO
6
7
1
1
9211z
85:15
87:13
O
O
2g
3g
AcO
AcO
HO
9616g
2h
3h
AcO
AcO
O
O
HO
N
O
N
8
9
1
1
9511y
α only
O
O
2i
3i
AcO
AcO
O
O
O
HO
N
O
N
8711y
α only
O
O
2j
3j
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1325–1330

1328
B. Srinivas et al.
LETTER
Table 2 Substrate Scope of the Cu(OTf)2-Mediated Ferrier Glycosylation under Optimized Conditionsa (continued)
Entry
10
Acceptor (NuH)
Product
Time (h)
Yield (%)b
α/β ratioc
AcO
AcO
OH
O
O
2
88
89:11
2k
2l
3k
OH
N
11
no reaction
a Reaction conditions: 3,4,6-tri-O-acetyl glucal (1 equiv), acceptor (1.2 equiv), 2 mol% Cu(OTf)2, MeCN, r.t.
b Isolated and unoptimized yields.
c The α/β ratios were examined by 1H NMR analysis by integrating the anomeric hydrogen signal.
AcO
AcO
saccharides by using easily accessible starting materials
under mild reaction conditions.17 We have also demon-
strated the applicability of the method for various natural
products of biological significance (3m–t). Another high-
light of present reagent system is the tolerance of this
methodology to various sensitive functionalities. Use of
economical and environmentally friendly catalyst, easy
work-up, and high anomeric selectivity are added advan-
tages.
AcO
AcO
AcO
O
O
Cu(OTf)2 (2 mol%)
MeCN, r.t, 12 h
+
ROH
OR
1
2m–t
3m–t
R =
H
H
O
H
O
H
3m (83%, 90:10)
3n (78%, α only)
OBn
O
O
Acknowledgment
O
O
BnO
O
BzO
BzO
BnO
BnO
O
This research is supported by the Department of Science and Tech-
nology, New Delhi. The authors are grateful to the Director CSIR-
IICT for providing necessary infrastructure. S.K. is thankful to Prof.
S. Hotha for his encouragement and valuable suggestions. B.S. ack-
nowledges a UGC Fellowship.
BnO
BzO
BnO
OMe
3p (60%, α only)
OMe
OMe
3o (63%, 88:12)
3q (62%, 86:14)
O
O
O
O
O
O
O
O
Supporting Information for this article is available online at
O
O
O
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
FmocHN
CO2Me
O
O
general synthesis information, characterization data, and 1H and 13
C
3s (63%, 90:10)
3t (64%, 88:12)
3r (60%, α only)
NMR spectra of all the compounds.SnugIiofop
r
imaotrtnSungIpif
om
rorat
n
t
Scheme 1 Screen of natural products, saccharides, and amino acid
containing acceptors16g
References and Notes
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efficiently to give the corresponding disaccharides 3p and
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© Georg Thieme Verlag Stuttgart · New York

LETTER
2,3-Unsaturated O-Glycosides
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(17) Cu(OTf)2 Mediated Ferrier Glycosylation; Typical
Procedure: To a stirred solution of 3,4,6-tri-O-acetyl-D-
glucal 1 (1 equiv) and acceptor (1.2 equiv) in anhydrous
MeCN (2 mL/mmol) under an atmosphere of argon was
added Cu(OTf)2 (2 mol%) at r.t. The reaction mixture was
stirred until complete consumption of the starting material
(glycal). The solvent was concentrated in vacuo, the crude
residue was re-dissolved in dichloromethane and loaded on
a silica gel column. The product was purified by silica gel
chromatography (hexane–EtOAc) to afford the 2,3-
unsaturated O-glycosides in excellent yields. The identities
of all the Ferrier products were confirmed by IR, 1H NMR,
13C NMR and MS/HRMS spectroscopic analysis.
p-Trifuoromethylphenyl 4,6-Di-O-acetyl-2,3-dideoxy-
erythro-hex-2-eno-1-thio-α-D-pyranoside (3f): Yellow
oil; [α]D +222.368 (c 19.0, CHCl3). IR (CHCl3): 3019, 2955,
2929, 1743, 1606, 1370, 1325, 1226, 1166, 1124, 1061,
1015, 952, 833, 772, 750, 667, 599 cm–1. 1H NMR (300
MHz, CDCl3): δ = 7.64 (d, J = 8.1 Hz, 2 H, Ar-H), 7.56 (d,
J = 8.3 Hz, 2 H, Ar-H), 6.05 (dt, J = 11.3, 1.2 Hz, 1 H, H-3),
5.92 (dt, J = 10.1, 1.5 Hz, 1 H, H-2), 5.87 (br s, 1 H, H-1),
5.41 (dd, J = 9.4, 1.9 Hz, 1 H, H-4), 4.42 (m, 1 H, H-5), 4.29
(d, J = 12.1, 5.6 Hz, 1 H, Ha-6), 4.24 (dd, J = 12.1, 2.6 Hz,
1 H, Hb-6), 2.12 (s, 3 H), 2.04 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 170.6, 170.2, 130.2, 128.3, 127.8, 125.7, 125.6,
82.7, 67.6, 64.9, 62.8, 20.9, 20.6. MS (ESI): m/z (%) = 408
(100) [M + NH4]+.
Cycloproylmethyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (3g): Colorless oil. IR
(CHCl3): 3017, 2920, 2852, 1741, 1370, 1219, 1036, 972,
907, 751, 667 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.91–
5.885 (m, 2 H, H-3, H-2), 5.31 (dd, J = 9.5, 1.4 Hz, 1 H, H-
4), 5.08 (br s, 1 H, H-1), 4.23 (dd, J = 11.9, 5.3 Hz, 1 H, Ha-
6), 4.18 (dd, J = 11.8, 2.4 Hz, 1 H, Hb-6), 4.15 (m, H-5), 3.51
(dd, J = 10.4, 7.3 Hz, 1 H, OHCH), 3.43 (dd, J = 10.4,
6.9 Hz, 1 H, OHCH), 2.09 (s, 3 H, OAc), 2.09 (s, 3 H, OAc),
1.15–1.09 (m, 1 H, cyclopropyl), 0.59–0.55 (m, 2 H,
cyclopropyl), 0.28–0.20 (m, 2 H, cyclopropyl). 13C NMR
(75 MHz, CDCl3): δ = 170.6, 170.2, 128.9, 127.8, 93.8, 73.4,
(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.
(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,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1325–1330

1330
B. Srinivas et al.
LETTER
9-Fluorenylmethyl 4,6-Di-O-acetyl-2,3-dideoxy-α-D-
erythro-hex-2-enopyranoside (3k): Viscous liquid;
[α]D +68.750 (c 0.8, CHCl3). IR (CHCl3): 2923, 1743, 1447,
1371, 1231, 1038, 741, 610 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.77 (d, J = 7.5 Hz, 2 H, Ar-H), 7.63 (m, 2 H,
Ar-H), 7.40 (t, J = 7.5 Hz, 2 H, Ar-H), 7.31 (d, J = 7.5 Hz,
2 H, Ar-H), 5.94–5.93 (m, 2 H, H-3, H-2), 5.32 (d,
66.8, 65.2, 63.0, 20.9, 20.7, 10.5, 3.2, 3.0. MS (ESI): m/z (%)
= 302 (100) [M + NH4]+.
(2,5-Dioxopyrrolidine-1-yl)-oxy 4,6-Di-O-acetyl-2,3-
dideoxy-α-D-erythro-hex-2-enopyranoside (3i): Colorless
oil; [α]D +150.000 (c 10.4, CHCl3). IR (CHCl3): 2926, 2853,
1724, 1432, 1370, 1220, 1206, 1108, 1045, 907, 814, 771,
650, 606 cm–1. 1H NMR (500 MHz, CDCl3): δ = 6.15 (d,
J = 10.2 Hz, 1 H, H-3), 6.01 (dt, J = 10.2, 2.1 Hz, 1 H, H-2),
5.57 (br s, 1 H, H-1), 5.45 (ddd, J = 10.1, 3.4, 1.7 Hz, 1 H,
H-4), 4.60 (dt, J = 10.1, 2.8 Hz, 1 H, H-5), 4.32 (dd,
J = 12.5, 3.4 Hz, 1 H, Ha-6), 4.18 (dd, J = 12.5, 2.3 Hz, 1 H,
Hb-6), 2.74 (s, 4 H, COC2H4CO), 2.12 (s, 3 H, OAc), 2.10 (s,
3 H, OAc). 13C NMR (75 MHz, CDCl3): δ = 171.1, 170.7,
170.2, 133.5, 122.9, 98.1, 68.2, 64.2, 61.8, 25.5, 20.9, 20.7.
MS (ESI): m/z (%) = 345 (100) [M + NH4]+.
J = 9.3 Hz, 1 H, H-4), 5.12 (br s, 1 H, H-1), 4.23–4.17 (m,
2 H, Ha-6, OHCH), 4.16–4.12 (m, 2 H, OHCH, H-5), 4.10
(dd, J = 9.3, 7.5 Hz, 1 H, Hb-6), 3.75 (dd, J = 9.3, 7.6 Hz,
1 H, OCH2CH), 2.12 (s, 3 H, -OAc), 1.93 (s, 3 H, -OAc). 13
NMR (75 MHz, CDCl3): δ = 170.6, 170.2, 144.6, 144.4,
C
141.0, 129.2, 127.6, 127.4, 126.8, 125.0, 119.8, 94.7, 71.2,
67.1, 65.2, 65.2, 62.8, 47.7, 20.9, 20.5. MS (ESI): m/z (%) =
431.10 (100) [M + Na]+. HRMS (ESI): m/z calcd for
C24H28NO6+ [M + NH4]+ 426.19116; found 426.19118.
Synlett 2014, 25, 1325–1330
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