Palladium-catalyzed glycosylation: Novel synthetic approach to diverse n -heterocyclic glycosides

Article abstract of DOI:10.1021/ol5037437

An efficient and highly stereoselective method for the construction of N-heterocyclic glycosides is reported. This method is based on a palladium-catalyzed allylation which proceeded to provide N-heterocyclic glycosyl compounds in good-to-excellent yields with β- or α-selectivity. Various N-nucleophiles were examined for this reaction and selected N-glycosyl isatin substrates were further elaborated to bis-indole sugars which have potential as antiproliferative drugs.

Full text of DOI:10.1021/ol5037437

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Glycosylation: Novel Synthetic Approach to
Diverse N‑Heterocyclic Glycosides
Li Ji,† Shao-Hua Xiang,† Wei-Lin Leng, Kim Le Mai Hoang, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: An efficient and highly stereoselective method for the construction of N-heterocyclic glycosides is reported. This
method is based on a palladium-catalyzed allylation which proceeded to provide N-heterocyclic glycosyl compounds in good-to-
excellent yields with β- or α-selectivity. Various N-nucleophiles were examined for this reaction and selected N-glycosyl isatin
substrates were further elaborated to bis-indole sugars which have potential as antiproliferative drugs.
N-Heterocyclic glycosides and glycoconjugates widely exist in
many natural products and play significant roles in many
biological processes.1 Nucleosides, in particular, possess great
potential as antitumor and antiviral drugs due to their
functionality manipulating genetic processes involving N-
glycosidic linkages.2 Due to their biological importance,
nucleosides have attracted much attention. With the develop-
ment of glycobiology, an increasing number of N-glycosylated
heterocycle-containing structures, such as Akashine A3 and
Staurosporine,4 have been found to be valuable in the
pharmaceutical field (Figure 1). Moreover, the activities of
methods for C−N bonds formation are based on palladium-
catalyzed reactions.8
For N-heterocyclic glycosylation, we preferred glycal type
donors since the coordination between the palladium catalyst
and the double bond in the sugar ring could potentially lead to
improved stereoselectivity through a classic Ferrier rearrange-
ment and provide versatile synthetic building blocks for further
functionalization.9 The difficulties of generating Pd-π-allyl
intermediates and their poor reactivities as glycosyl donors
have limited the development of palladium-catalyzed glyco-
sylation.10 The trifluoroacetyl group,11 which can increase the
reactivity of the donor by acting as a good leaving group, was
therefore introduced to solve these problems. Meanwhile,
various coordinating groups such as imidate12 and cyano13 are
widely used to exert stereocontrol in glycosylations while a
picoloyl group offers an alternative for glycosylation as a good
leaving and directing group.14 Our group has been focusing on
palladium-catalyzed glycosylation from glycal derivatives for
years, and various acceptors have been successfully employed to
construct different types of glycosidic bonds with a Pd-π-allyl
intermediate as the donor.8f,15 As a further expansion of this
strategy, herein, we report a palladium-catalyzed glycosylation
reaction involving diverse N-heterocyclic nucleophiles including
isatins, imides, and imidazole analogues.
Figure 1. Natural products containing N-glycosylated bis-indole
structure.
In our initial attempts, a model study was conducted using
compounds 1a as the glycosyl donor and 2a as the acceptor
with Pd(PPh3)4 as the catalyst. Reaction optimization was first
carried out by screening various ligands in anhydrous
acetonitrile at 70 °C, and the results are depicted in Table 1.
Among the ligands we examined, JohnPhos, SPhos, and
some other bioactive natural products such as bis-indole-
occurring compounds can be significantly increased by
incorporating a sugar moiety through an N-glycosidic bond.5
However, to date, there are very few synthetic methods to
construct this kind of glycosidic linkages.6 Transition metals
have demonstrated their catalytic capability for the formation of
C−N bonds with high efficiency and selectivity.7 Among them,
palladium is the most widely used catalyst, and many good
Received: December 29, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol5037437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions with
Isatin Acceptor
Scheme 1. Substrate Scope of N-Glycosylation with Glucal
Donors
a
a b c
, ,
b
c
entry
ligand
solvent
temp (°C)
yield (%)
β:α
1
2
3
4
5
6
7
8
9
JohnPhos
SPhos
DPPF
RuPhos
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
toluene
CH2Cl2
THF
70
−
−
35
−
−
6:1
70
70
70
−
−
9:1
70
50
39
42
12
87
85
70
N.D.
7:1
reflux
reflux
70
N.D.
8.8:1
8.8:1
d
10
THF
70
a
Unless otherwise specified, all reactions were carried out with 0.1
mmol of 1a, 0.2 mmol of 2a, 10% Pd(PPh3)4, 20% DPPB in 3 mL of
b
c
solvent for 24 h. Isolated yield. All the ratios were determined by 1H
d
NMR. The reaction was carried out for 12 h.
RuPhos failed to catalyze this reaction (entries 1, 2, and 4),
while DPPF successfully furnished the desired N-glycosylation
product in 35% yield with incomplete conversion of 1a (entry
3). DPPB was found to be the best ligand to afford a 50% yield
after 24 h with incomplete conversion of starting material
1
(entry 5). The stereoselectivity observed from crude H NMR
a
Unless otherwise specified, all reactions were carried out with 0.1
mmol of 1, 0.2 mmol of 2, 10% Pd(PPh3)4, 20% DPPB in 3 mL of
was β:α = 9:1. The major isomer could be easily purified by
column chromatography, and the stereochemistry of the
anomeric center was confirmed by X-ray diffraction crystallo-
graphic analysis.16 In our attempts to improve the yield, the
solvents were screened. Poor yields were obtained when the
reactions were carried out in toluene at both 70 °C and reflux
conditions due to the poor solubility of the reactants (entries 6
and 7). CH2Cl2 was also unable to give a good yield (entry 8).
To our delight, the yield was improved significantly when THF
was used (entry 9). Reducing the reaction time from 24 to 12 h
resulted in no significant change in the yield (entry 10).
Therefore, the optimized reaction conditions were concluded as
follows: the reaction was performed with compound 1a (1.0
equiv) and isatin 2a (2.0 equiv) in the presence of Pd(PPh3)4
(0.1 equiv) and DPPB (0.2 equiv) in THF at 70 °C for 12 h.
With the optimized reaction conditions in hand, we
proceeded to examine the scope and limitations of this
method. The results are summarized in Scheme 1. A range of
isatin nucleophiles with various substituents on the aromatic
ring were screened. The reaction with an unsubstituted isatin
resulted in better selectivity, albeit lower yield (3b). When we
employed other isatins bearing electron-donating groups, good
yields were obtained, with slightly diminished selectivities (3c,
3d). Isatins bearing electron-withdrawing groups, such as 5-Cl,
5-NO2, or 5-CF3, were also screened, but they failed to give the
desired N-glycosides. Next, we synthesized various glycosyl
donors to examine the effect of protecting groups. Exclusive β-
selectivities were detected with moderate-to-good yields when
electron-donating protecting groups were used (3e−3i). We
further employed our reaction conditions for other types of N-
nucleophiles. Imidazole and its derivatives were then
investigated to further expand the substrate scope. When
compound 1a was utilized as the donor, imidazole, 2-
methylimidazole, 4,5-diphenylimidazole, benzimidazole, and
b
c
THF at 70 °C for 12 h. Isolated yield. All the ratios were determined
by H NMR.
1
pyrazole successfully provided the corresponding N-glycosides
in good yields and excellent selectivities (3j−3n).
Later on, we employed α-type 2,3-unsaturated hexopyrano-
side 1′17 as the donor,8a which proved to be effective in
achieving the desired α-N-glycosides (Scheme 2). Exclusive α-
selectivities were obtained in all reactions (3′a−3′d) with
compound 1′ as the starting material, and the stereochemistry
of compound 3′c was confirmed by X-ray diffraction crystallo-
graphic analysis.18
On the basis of experimental results, the plausible reaction
mechanism was outlined in Scheme 3. Initially, palladium
coordinated simultaneously to the nitrogen of the picoloyl
group as well as the double bond of glucal at the β-face to
generate intermediate II (Scheme 3a). Next, cleavage of the
picoloyl acid species afforded the Pd-π-allyl system as shown in
intermediate III. Subsequent coordination of the N-nucleophile
to the palladium released the picoloyl acid giving intermediate
IV accordingly.
Finally, the β-N-glycoside was yielded through an intra-
molecular nucleophilic addition. Meanwhile, the palladium
catalyst I was regenerated to complete the reaction cycle. When
α-type 2,3-unsaturated hexopyranoside 1′ was employed as the
donor, the key intermediate was formed with α-orientation by a
double coordination of palladium to compound 1′ (Scheme
3b). The α-isomer was generated by a similar pathway.
In order to demonstrate the applicability of our method, N-
glycosylated isatins were chosen as precursors to construct the
indirubin analogues.5c Potentially biological active N-glycosy-
B
DOI: 10.1021/ol5037437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of N-Glycosylation with
Hexopyranoside Donor
Scheme 4. Synthesis of Indirubin N-Glycosides 4a, 4b, and
4c
a b c d
, , ,
a
and α-anomers, respectively. Glycosyl donors with different
kinds of protecting groups and a wide variety of glycosyl
acceptors such as isatins, imides, and imidazole derivatives were
screened. Most of the substrates could yield the desired
products in good-to-excellent yields and stereoselectivities. The
applicability of our methodology was demonstrated by
synthesizing the glycosylated indirubins, which are potent
inhibitors toward various kinases.5
Unless otherwise specified, all reactions were carried out with 0.1
mmol of 1′, 0.2 mmol of 2, 10% Pd(PPh3)4, 20% DPPB in 3 mL of
b
c
THF at 70 °C for 12 h. Isolated yield. All the ratios were determined
by H NMR. Compound 1′ is unstable even stored at −20 °C.
d
1
Scheme 3. Plausible Mechanism for the Synthesis of N-
Glycosides
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, copies of NMR spectra (for new
compounds), and X-ray crystallographic data of 3a, 1′, and 3′c.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Xuewei@ntu.edu.sg.
Author Contributions
†L.J. and S.-H.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support by Nanyang Techno-
logical University (RG6/13), Singapore. We thank Dr. Yong-
Xin Li and Dr. Ganguly Rakesh in the division of chemistry and
biological chemistry, Nanyang Technological University for X-
ray analysis.
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methodology for the stereoselective synthesis of N-heterocyclic
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DOI: 10.1021/ol5037437
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Organic Letters
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