Heck-type cross-coupling between halo-exo-glycals and endo-glycals: A practical way to achieve C-glycosidic disaccharides

Article abstract of DOI:10.1016/j.tetlet.2013.08.118

An effective Heck-type cross-coupling reaction between halo-exo-glycals and endo-glycals to achieve C-glycosidic disaccharides has been developed. Using Pd(OAc)₂ as the catalyst, dppp as ligand and K₂CO ₃ as base, the reac

Full text of DOI:10.1016/j.tetlet.2013.08.118

Tetrahedron Letters 54 (2013) 6101–6104
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Heck-type cross-coupling between halo-exo-glycals and endo-glycals:
a practical way to achieve C-glycosidic disaccharides
⇑
⇑
Yongfeng Tao, Ning Ding , Sumei Ren, Yingxia Li
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Rd., Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective Heck-type cross-coupling reaction between halo-exo-glycals and endo-glycals to achieve
C-glycosidic disaccharides has been developed. Using Pd(OAc)2 as the catalyst, dppp as ligand and
K2CO3 as base, the reactions gave C-glycosidic products in good to excellent yields with exclusive
stereochemistry.
Received 27 June 2013
Revised 21 August 2013
Accepted 29 August 2013
Available online 6 September 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Heck reaction
Cross-coupling
C-glycosides
Halo-exo-glycals
endo-Glycals
Despite attracting growing interest in biological and medicinal
research, carbohydrates still have several limitations blocking their
application as drugs, particularly among which is the liability of the
glycosidic bond.1 In this context, C-glycosides, congeners compara-
tively stable against hydrolysis, acids and especially enzymatic deg-
radation, seem to serve as possible surrogates.2 Prevalent in
abundant natural products, C-glycosides have been found to display
diverse biological properties, suggesting their potential to act as
enzyme inhibitors and antibacterial or antitumor reagents.3 Conse-
quently, they are currently attracting expansive synthetic interests.
In recent years, a variety of synthetic methods such as the transition
metal mediated coupling of glycals with aryl halides or arylboronic
acids have been developed for the preparation of C-glycosides.4
However, there have been only limited reports concerning the
synthetic approaches to access C-glycosidic bonds between saccha-
ride units.5 Therefore, a practical approach for the assembly of
C-glycosidic disaccharides would be highly desirable.
Exo-Glycals are interesting compounds from a biological stand-
point and have been used as glycosidase inhibitors, suggesting
their value in drug discovery and research.6 On the other hand,
exo-glycals have also been well recognized as important synthetic
intermediates due to their capability for further elaboration result-
ing from the enol ether double bond. Previous work has demon-
strated that halo-exo-glycals (for example, 3a and 3b) can be
used for the preparation of aryl substituted exo-glycals through
various ways like Suzuki reaction and Sonogashira reaction.7 In-
spired by these results, taking into consideration pertinent exam-
ples of transition metal mediated coupling of glycals with aryl
halides , we deemed it worth a trial to apply halo-exo-glycals and
endo-glycals as key building blocks to achieve C-glycosidic disac-
charides via Heck reaction as reported herein.
The precursors for this study were prepared from methylena-
tion of sugar derived lactones 1a-c (by Petasis reagent), which
upon stereoselective iodination with iodonium dicollidinium tri-
flate (IDCT) afforded desired halo-exo-glycals 3a-c (Scheme 1).7
We first explored the reaction of gluctopyranose derived alke-
nyl iodide (3a) with 3,4,6-tri-O-benzyl-
D
-glucal (4a) as model
OBn
OBn
OBn
I
O
O
O
O
a
b
R2
R2
R2
OBn
OBn
OBn
R1
R1
R1
OBn
OBn
OBn
1a R1 = OBn, R2 = H
1b R1 = H, R2 = OBn
2a R1 = OBn, R2 = H; 87% 3a R1 = OBn, R2 = H; 67%
2b R1 = H, R2 = OBn; 82% 3b R1 = H, R2 = OBn; 62%
O
O
I
O
O
O
O
O
a
b
O
O
O
79%
63%
O
O
O
O
O
O
3c
2c
1c
⇑
Corresponding authors. Tel.: +86 21 51980120; fax: +86 21 51980127.
E-mail addresses: dingning@fudan.edu.cn (N. Ding), liyx417@fudan.edu.cn
Scheme 1. Synthesis of halo-exo-glycals 3a–c. Reagents and conditions: (a) Petasis
reagent, toluene, 75 °C; (b) IDCT, DCM, rt.
(Y. Li).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.118

6102
Y. Tao et al. / Tetrahedron Letters 54 (2013) 6101–6104
Table 1
experiment (Table 1). Treatment of 3a with 4a at room tempera-
ture in DMF catalyzed by 10 mol% Pd(OAc)2 with K2CO3 as base
in the presence of tetra-butyl ammonium chloride (TBACl) as phase
transfer catalyst for 24 h afforded the corresponding C-glycoside
5a as a single diastereomer in 23% yield (entry 1). While the sol-
vent was changed to dichloromethane (DCM), no desired product
was detected within 24 h (entry 2). A similar result was obtained
when triethylamine (TEA) was used as the base instead, giving only
trace coupling product 5a in DMF detected by TLC (entry 3). On the
other hand, when the reaction temperature was raised to 80 °C,
with K2CO3 and DMF as the optimal base and solvent, respectively,
the yield of 5a was increased to 50% (entry 4). Based on this condi-
tion, when 20 mol% PdCl2(PPh3)2 was employed as a surrogate for
Pd(OAc)2, the coupling reaction could also proceed fairly well,
though in a slightly lower yield (entry 5). Further investigation
demonstrated that the ligand effect was crucial for this coupling
(entries 6-8). Among the screened ligands, 1,3-bis(diphenylphos-
phino)propane (dppp) gave an outstanding performance, which in-
duced a 90% yield of product within a 3 h reaction time (entry 7).
Thus, the best coupling condition for the preparation of C-glyco-
sidic disaccharides 5a was elaborated as described in entry 7. Nota-
bly, the solvent does not require thorough desiccation, nor does the
reaction need inert gas protection.
Screening of conditions of the Heck type cross coupling of 3a and 4aa
OBn
BnO
O
OBn
I
OBn
O
O
O
BnO
BnO
conditions
+
1
BnO
OBn
BnO
H
H
3
OBn
OBn
BnO
OBn
OBn
3a
4a
5a
Entry Catalyst
Base
Ligand Solvent
T
(°C)
Time
(h)
Yield
(%)
(10 mol %)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2CO3
K2CO3
TEA
K2CO3
K2CO3
K2CO3 PPh3
K2CO3 dppp
K2CO3 P(Tol)3 DMF
—
—
—
—
—
DMF
DCM
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
80
80
80
80
80
24
24
24
24
18
4
23
—
Trace
50
44
66
90
b
3
4
71
With the optimal coupling condition in hand, the scope of the
reaction was investigated by varying both the halo-exo-glycals
and the endo-glycals (Table 2).8 In each case, the desired cross-cou-
pling product was obtained in a good yield as a single anomer. The
anomeric configuration of the coupling products was determined
a
In all the entries, 1 equiv of 3a and 3 equiv of 4a were used in the presence of
1 equiv of TBACl.
b
20 mol % PdCl2(PPh3)2 was used.
Table 2
Heck type cross-coupling of halo-exo-glycal and endo-glycala
Entry
Halo-exo-glycal
Glycal
Product
Yield (%)
I
O
OBn
BnO
BnO
O
BnO
O
BnO
BnO
OBn
O
OBn
OBn 4a
OBn
1
3a
90
BnO
BnO
1 H
H
3
OBn
OBn
5a
O
OBn
O
BnO
BnO
BnO
OBn
OBn 4b
2
3
4
3a
92
92
87
O
BnO
BnO
OBn
OBn
OBn
5b
I
O
BnO
BnO
OBn
O
BnO
OBn
OBn
3b
4a
O
BnO
BnO
OBn
OBn
5c
BnO
BnO
OBn
O
3b
4b
O
BnO
BnO
OBn
OBn
5d

Y. Tao et al. / Tetrahedron Letters 54 (2013) 6101–6104
6103
Table 2 (continued)
Entry
Halo-exo-glycal
Glycal
Product
Yield (%)
I
OBn
O
O
O
BnO
OBn
O
O
O
O
5
6
7
4a
79
72
63
O
O
3c
O
O
O
5e
OBn
BnO
OBn
O
O
3c
3a
3b
4b
O
O
O
5f
O
OTBDMS
TBDMSO
O
O
OTBDMS
TBDMSO
4c
OTBDMS
O
OBn
BnO
OBn
5g
OBn
O
OTBDMS
OTBDMS
O
OBn
8
4c
53
O
BnO
OBn
5h
OBn
a
General conditions: 1 equiv of halo-exo-glycal, 3 equiv of endo-glycal, 1 equiv of TBACl, 2.5 equiv of K2CO3, 0.1 equiv of Pd(OAc)2, 0.1 equiv of dppp, 80 °C in DMF.
OBn
OTBDMS
O
OTBDMS
O
n
O
BnO
O
TBDMSO
TBDMSO
OAc
TBDMSO
OBn
OTBDMS
5g,h
Pd
O
(Ln)
B
OTBDMS
OBn
OTBDMS
n
n
O
O
O
O
O
Pd(Ln)OAc
D
O
TBDMSO
TBDMSO
G
BnO
BnO
Pd(Ln)OAc
OPd(Ln)OAc
I
H
H
O
TBDMSO
C
n = 0, 1
Pd(0)
A
OTBDMS
OTBDMS
O
OBn
n
(Ln)
Pd
O
O
Pd(Ln)OAc
F
O
AcO
H
TBDMSO
BnO
5a-f
O
OTBDMS
E
OBn
L = ligand
Scheme 2. Proposed mechanism of the coupling reaction.
as
a
by analyzing the 1H and 13C NMR spectra, which was in agree-
crease in yield was observed when mannofuranosyl type halo-
exo-glycal 3c was employed as the halide partner (entries 5 and 6).
Interestingly, when tert-butyl(dimethyl)silyls (TBDMS) protected
endo-galactal 4c was employed to be coupled with halo-exo-glycals
3a or 3b, further isomerized ketone product was provided instead,
with comparatively a lower yield (entries 7 and 8).
ment with mechanistic considerations and literature descriptions
of similar compounds.9 NOEs between the 1-H (vinylic protons)
and 3-H protons (as indicated in the structure of 5a) suggested a
Z configuration of the exo-cyclic double bond.7
The glucto- and galactopyranose derived alkenyl iodides 3a and
3b reacted with endo-glycals 4a or 4b efficiently and afforded the
products 5a-d in excellent yields (87%–92%, entries 1–4). A slight de-
Although the details are still in obscurity, the possible reaction
mechanism was proposed as described in Scheme 2. The mechanism

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Y. Tao et al. / Tetrahedron Letters 54 (2013) 6101–6104
involves the oxidative addition of the halide (A to B), insertion of the
olefin (B to C and B to D), and delivery of the product by a b-hydride
elimination process (C to 5a–f and D to E). A base then regenerated
the palladium (0) catalyst. When the benzyl protected glycals (4a
and 4b) served as the olefin parts, the reactions stopped after b-hy-
dride elimination to afford compounds 5a–f. While for the TBDMS
protected product E, a further oxidative addition occurred (E to F)
due to the liability of the silyl group on enol ether under this reaction
condition4g, which ultimately resulted in the ketone products 5g and
5h through intermediate G.
References and notes
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B.; Rao, C. L. Tetrahedron Lett. 2008, 49, 863.
In summary, an efficient Heck-type cross coupling between
halo-exo-glycals and endo-glycals was developed. A set of C-glyco-
sidic disaccharides were obtained in good to excellent yields with
complete stereo control both on the sugar anomeric center and the
exo-cyclic double bond. Further investigations to reveal the power
of this methodology as a synthetic tool for the construction of nat-
ural products and bioactive compounds are on the way and will be
reported in due course.
4. (a) Dondoni, A.; Marra, A.; Mizuno, M.; Giovannini, P. P. J. Org. Chem. 2002, 67,
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Acknowledgments
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2910–2920.
This work was supported by the Grants of ‘Zhuo Xue’ Talent
Plan of Fudan University, National Natural Science Foundation of
China (21002014), the Fundamental Research Funds for the Central
Universities (10FX061), and Scientific Research Foundation for the
Returned Overseas Chinese Scholars (41th).
8. Typical experimental procedure for Heck type cross-couplings between halo-
exo-glycals and endo-glycals: to a round bottom bottle was added successively
1 equiv of halo-exo-glycal, 3 equiv of endo-glycal, 1 equiv of TBACl, 2.5 equiv of
K2CO3, 0.1 equiv of Pd(OAc)2, 0.1 equiv of dppp and DMF (no inert gas protection
was needed). The reaction was carried out at 80 °C for 3 h. The reaction mixture
was then diluted with water, extracted with ether, dried over anhydrous
Na2SO4, and then concentrated. The crude material was purified by flash column
chromatography on silica gel eluted with petroleum ether/EtOAc to afford 5a–h.
9. (a) Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57, 4612–4616; (b)
Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford, S. P. Org. Lett.
2001, 3, 2571–2573.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.118.