Copper mediated stereoselective synthesis of C-glycosides from unactivated alkynes

Article abstract of DOI:10.1039/c3cc44250k

A highly stereoselective rapid C-glycosylation reaction has been developed between glycal and unactivated alkynes in the presence of coppertriflate and ascorbic acid at low catalyst loading and at room temperature. A wide variety of glycals and aryl acetylenes participate in the reaction smoothly. TfOH generated during the reduction of Cu(OTf)₂ by ascorbic acid may be the active catalyst for the glycosylation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc44250k

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Copper mediated stereoselective synthesis of
C-glycosides from unactivated alkynes†‡
Anil Kumar Kusunuru,ab Madhubabu Tatina,ab Syed Khalid Yousuf*c and
Debaraj Mukherjee*ab
Cite this: Chem. Commun., 2013,
49, 10154
Received 5th June 2013,
Accepted 19th August 2013
DOI: 10.1039/c3cc44250k
www.rsc.org/chemcomm
A highly stereoselective rapid C-glycosylation reaction has been
developed between glycal and unactivated alkynes in the presence
of coppertriflate and ascorbic acid at low catalyst loading and at
room temperature. A wide variety of glycals and aryl acetylenes
participate in the reaction smoothly. TfOH generated during the
reduction of Cu(OTf)2 by ascorbic acid may be the active catalyst
for the glycosylation.
C-glycosides have been the subject of considerable interest in
carbohydrate, enzymatic and metabolic chemistry, as well as
in organic synthesis.1 C-glycosidation is of great significance in
the synthesis of optically active compounds, since it allows the
Fig. 1 Prior art for synthesis of sugar acetylene (a) activation of alkyne partner;
(b) coupling of glucal with activated alkyne.
introduction of carbon chains into sugar chirons and the use starting material and a moderate overall yield. Moreover, direct
of sugar nuclei as a chiral pool as well as a carbon source.2 use of terminal alkynes as coupling partners in glycal alkynyla-
C-glycosides are versatile chiral building blocks for the synthe- tion has no precedent yet. Therefore, the development of mild
sis of many biologically interesting polyether natural products and efficient methods for stereoselective synthesis of sugar
such as palytoxin, spongistatin, halichondrin, etc.3 Moreover, acetylenes directly from alkynes is desirable.
specifically C-alkynyl glycosides are attractive due to the
In recent years copper acetylides11 have become valuable
presence of a triple bond that can be easily transformed into reagents for various C–C bond forming reactions, and as an
other chiral molecules4 such as ciguatoxin,5 tautomycin6 and alternative we sought to use copper acetylide as a nucleophile
carbohydrate analogues.
on the electrophilic anomeric centre of glycal. The bottleneck in
The direct formation of C–C bonds at the anomeric center of this case was that the Ferrier glycosylation12 is usually carried out
sugar nuclei still presents a significant challenge to synthetic under acidic conditions while generation of copper acetylides
chemists and several solutions to this problem have evolved. requires basic conditions. In an effort to fine tune our reaction
The most widely accepted method for the synthesis of C-alkynyl conditions, we decided to examine the generation and reaction
glycosides involves two steps namely activation of alkynes7 and chemistry of Cu(I)-alkynyl reagents prepared from Cu(II) salts in
thereafter Ferrier type alkynylation of glucals using activated the presence of reducing agents.13 We anticipated that such a
alkynes (Fig. 1).8–10 It is important to note that in the above procedure would not only lead to the facile generation of Cu(I)-
cases, the active species, i.e., acetylide is generated separately alkynyl reagents avoiding basic conditions, but also preclude
using deprotonation, halogenation or TMS-generation followed oxidative acetylide coupling while ensuring glycal activation.
by transmetallation, leading to intricacy in preparation of
For this purpose, tri-O-acetyl-D-glucal (1) and phenylacety-
lene (2) were chosen as starting materials and acetonitrile as
solvent. The reaction of 1 with 2 in the presence of Cu(OTf)2
however failed to give the desired product and the starting
materials were recovered unchanged (Table 1, entry 1). The
failure of reaction was an indication that acetylene is not
activated only by Lewis acid. Thus, sodium ascorbate was also
added to the reaction mixture, but again the desired product
was not obtained (Table 1, entry 2). The success story of ascorbic
a Academy of Scientific and Innovative Research, India
b CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
E-mail: dmukherjee@iiim.ac.in; Fax: +91-011-256-9111
c Indian Institute of Integrative Medicine Br. Srinagar, 190005, India.
E-mail: khalidiiim@gmail.com
† IIIM Publication Number-IIIM/1546/2013.
‡ Electronic supplementary information (ESI) available: Detailed experimental
procedures and compound characterization data. See DOI: 10.1039/c3cc44250k
c
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Table 1 Standardisation of reaction conditions for C-alkynylation of glycals
Time
(h)
Yieldc
Conversionb (%)
Entry Reagentsa
a : bd
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Sodium ascorbate/Cu(OTf)2 10
Et3N/Cu(OTf)2
DIPEA/Cu(OTf)2
Cs2CO3/Cu(OTf)2
K2CO3/Cu(OTf)2
DBU/Cu(OTf)2
DABCO/Cu(OTf)2
Ascorbic acid/Cu(OTf)2
10
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
70
—
—
—
—
—
—
—
—
10
10
10
10
10
10
0.08 100
99 : 1
a
In all cases 1 mmol of 1, 1.1 equiv. of 2, 10 mol% of Cu(OTf)2 and
b
10 mol% of other reagents were used with CH3CN as solvent. Deter-
c
mined through TLC. Isolated yield obtained using column chromato-
graphy. Determined by 1H NMR and 13C NMR along with NOE
d
spectra.
Table 2 Optimisation of solvent for C-alkynylation
Entry
Solventa
Conversion
Yieldb (%)
a : bc
1
2
3
4
5
DCM
DCE
DMF
THF
80
85
—
—
100
53
58
—
—
70
90 : 10
92 : 8
—
—
99 : 1
CH3CN
a
In all cases 1 mmol of 1, 1.1 equiv. of 2, 10 mol% of Cu(OTf)2 and
10 mol% of ascorbic acid were used with 1.5 mL of solvent indicated.
b
c
Isolated yield obtained using column chromatography. Determined
by 1H NMR.
Fig. 2 Substrate scope of the reaction process under optimised reaction
conditions.
acid in combination with transition metals14 and its ability to products. It was found that all the reactions proceeded effi-
reduce Cu(II) to Cu(I) under neutral conditions13 (pH 7.2) encour- ciently yielding the sugar acetylenes in good to excellent yield
aged us to use it in combination with copper. We were delighted to with >99% a-selectivity except for pyridine 2-acetylide, which
see the colour change of the reaction mixture within a minute of failed to react at all. In general acetylenes with electron donat-
addition of ascorbic acid. TLC analysis indicated complete conver- ing groups react faster than those having electron withdrawing
sion of the starting material leading to the formation of 1a as the ones. All the compounds were characterised through various
sole product. The structure and stereochemistry of compound 1a spectroscopic techniques (ESI‡). The results are summarized in
were determined through spectroscopic analysis and also by com- Fig. 2. Encouraged by the results, other glycals with both ether
parison with the reported data.7 The fact that there are cross peaks and ester protecting groups like tri-O-benzyl-D-glucal and tri-O-
between H-1 and bH-4 as well as bH-6 in the NOE spectrum of 1a benzoyl-D-glucal were also subjected to the same reaction to
(see ESI‡) proved that the reaction is completely a-selective. The obtain the corresponding products (Fig. 2, entries 8a–12a).
effect of the solvent in this reaction on the yield and diastereo- Similarly, tri-O-acetyl-D-galactal was also subjected to reaction
selectivity was noteworthy. Using solvents DCM and DCE, the with phenyl acetylene under standardised reaction conditions.
C-glycoside was obtained in 53 and 58% yields, respectively, with The reaction proceeded to its logical end within a minute
90 : 10 and 92 : 8 a:b selectivity (Table 2, entries 1 and 2). Using leading to acetylene galactoside 13a in high yield with excellent
N,N-dimethylformamide and THF as solvents, no product could be stereoselectivity. Other acetylenes were also allowed to react
obtained (Table 2, entries 3 and 4). Thus, this alkynylation reaction with tri-O-acetyl-D-galactal to afford the galactosides 14a–15a.
takes place best when using acetonitrile as the solvent.
Tri-O-benzoyl-D-galactal also undergoes the same reaction
In order to determine the substrate scope of the reaction, under optimised reaction conditions to afford 16a in 68% yield.
these conditions were applied to the reaction of 3,4,6-tri-O- It has been observed that in general the glucal series reacted
acetyl-D-glucal 1 with various phenylacetylenes carrying either faster than the galactal series (product 1a vs. 13a, 5a vs. 14a, 3a
electron donating or electron withdrawing groups (Fig. 2, vs. 15a in Fig. 2). Again tri-O-acetyl glycal reacted faster than the
entries 3a–7a) to afford the corresponding acetylene glycoside tri-O-benzyl glycal (compound 1a vs. 8a in Fig. 2).
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1 minute. A similar colour change as observed in the main
reaction course was noticed. Recording the mass spectrum of
the reaction mixture confirmed the generation of TfOH (ESI‡).
In summary, we have developed an efficient synthetic strat-
egy for the direct synthesis of alkynylglycosides from glycals
and unactivated aryl acetylenes. A simple experimental proce-
dure, high stereoselectivity, a wide substrate scope, short reac-
tion time, low catalyst loading and high yield are some of the
advantages of the process.
Scheme 1 Reaction of 3,4-di-O-acetyl-L-rhamnal with 2.
Notes and references
1 R. A. Dwek, Chem. Rev., 1996, 96, 683.
2 (a) M. H. D. Postema, Tetrahedron, 1992, 48, 8545; (b) S. Hanessian,
Total Synthesis of Natural Products: The Chiron Approach, Pergamon
Press, Oxford, 1984.
3 (a) M. D. Lewis, J. K. Cha and Y. Kishi, J. Am. Chem. Soc., 1982,
104, 4976; (b) I. Paterson and L. E. Keown, Tetrahedron Lett., 1997,
38, 5727; (c) K. Horita, Y. Sakurai, M. Nagasawa, S. Hachiya and
O. Yonemitsu, Synlett, 1994, 43.
4 M. Isobe, R. Nishizawa, S. Hosokawa and T. Nishizawa, Chem.
Commun., 1998, 2665.
Scheme 2 Plausible mechanism of Cu(OTf)2 mediated reaction of acetylene
and glucal.
5 (a) Y. Ichikawa, K. Tsuboi, Y. Jiang, A. Naganawa and M. Isobe,
Tetrahedron Lett., 1995, 36, 7101; (b) Y. Jiang and M. Isobe, Tetra-
hedron, 1996, 52, 2877; (c) K. Tsuboi, Y. Ichikawa, Y. Jiang,
A. Naganawa and M. Isobe, Tetrahedron, 1997, 53, 5123.
6 M. Isobe, C. Yenjai and S. Tanaka, Synlett, 1994, 916; C. Yenjai and
M. Isobe, Tetrahedron, 1998, 54, 2509.
7 Alkynes activation ref: (a) A. R. Yeager, G. K. Min, J. A. Porco, Jr. and
S. E. Schaus, Org. Lett., 2006, 8, 5065; (b) S. E. Denmark and
S.-M. Yang, Tetrahedron, 2004, 60, 9695; (c) H. A. Stefani, R. C.
Adriano and S. Vieira, Tetrahedron, 2007, 63, 3623; (d) J. S. Yadav, B.
V. S. Reddy, C. V. Rao and M. Sridhar Reddy, Synthesis, 2003,
247–250; (e) R. Saeeng, U. Sirion, P. Sahakitpichan and M. Isobe,
Tetrahedron Lett., 2003, 44, 6211; ( f ) D. C. Koester, M. Leibeling,
R. Neufeld and D. B. Werz, Org. Lett., 2010, 12, 3934; (g) D. C.
Koester and D. B. Werz, Beilstein J. Org. Chem., 2012, 8, 675.
8 (a) Y. Ichikawa, M. Isobe, M. Konobe and T. Goto, Carbohydr. Res.,
1987, 171, 193; (b) M. Isobe, R. Nishizawa, S. Hosokawa and
T. Nishikawa, Chem. Commun., 1998, 2665.
Next we turned our attention to study the fate of the
deoxysugar 3,4-di-O-acetyl-L-rhamnal 17. Interestingly, reaction
of 17 with 2 afforded the desired C-glycoside 18a in 68% yield
(Scheme 1) with excellent stereoselectivity (b : a and 96 : 4).
Another C-glycoside 19a was also obtained in satisfactory yield
(65%) from 17.
The mechanism for the present catalytic reaction is not yet
clear. Based on the present result and the known coppertriflate
chemistry given in the literature,15 we propose a possible
pathway for this C-glycosylation as shown in Scheme 2. There
is evidence in the literature15 which suggests that metal triflates
particularly copper triflate can act as sources of TfOH in the
presence of reductants. Thus, it can be argued that TfOH
generated during the reduction of Cu(OTf)2 by ascorbic acid
9 N. Lubin-Germain, A. Hallonet, F. Huguenot, S. Palmier, J. Uziel and
J. Auge, Org. Lett., 2007, 9, 3679.
is the active catalyst for eliminative formation of an oxocarbo- 10 A. S. Vieira, P. F. Fiorante, T. L. S. Hough, F. P. Ferreira, D. S. Lu¨dtke
and H. A. Stefani, Org. Lett., 2008, 10, 5215.
11 M. Meldal and C. W. Tornøe, Chem. Rev., 2008, 108, 2952.
12 (a) R. J. Ferrier and O. A. Zubkov, Org. React., 2003, 62, 569;
nium ion (Y) and suggests that Cu(I)OTf plays a key role in the
formation of copper acetylide (X), the attacking C-nucleophile.
The stereochemistry should largely be determined by the coordi-
nation between two p-electron orbitals of the oxocarbonium ion
and acetylene groups, while the stereoelectronic control allows
(b) R. J. Ferrier and J. O. Hoberg, Adv. Carbohydr. Chem. Biochem.,
2003, 58, 55; (c) R. J. Ferrier, Top. Curr. Chem., 2001, 215, 153;
(d) A. A. Ansari, R. Lahiri and Y. D. Vankar, ARKIVOC, 2013,
Pt. ii), 316.
the a-pseudo-axial orbital to make the bond. To confirm the 13 V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angew.
Chem., Int. Ed., 2002, 41, 2596.
14 M. B. Davies, Polyhedron, 1992, 11, 285.
15 M. J.-L. Tschan, C. M. Thomas, H. Strub and J. Carpentier, Adv.
afore-suggested generation of TfOH by reduction of Cu(OTf)2 in
the presence of ascorbic acid, in a blank experiment, Cu(OTf)2
and ascorbic acid were allowed to stir at room temperature for
Synth. Catal., 2009, 351, 2496.
c
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10156 Chem. Commun., 2013, 49, 10154--10156