One-pot synthesis of β-N-glycosyl imidazole analogues via a palladium-catalysed decarboxylative allylation

Article abstract of DOI:10.1039/c3cc48041k

A concise and highly efficient strategy for the synthesis of N-glycosyl imidazole analogues is reported. This reaction is based on a palladium catalysed decarboxylative allylation and three steps, namely, carbamation, decarboxylation and allylation are involved. All the substrates can afford the desired products with excellent yields and selectivities. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc48041k

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One-pot synthesis of b-N-glycosyl imidazole
analogues via a palladium-catalysed
decarboxylative allylation†
Cite this: Chem. Commun., 2014,
50, 4222
Received 19th October 2013,
Accepted 28th February 2014
Shaohua Xiang, Jingxi He, Jimei Ma and Xue-Wei Liu*
DOI: 10.1039/c3cc48041k
www.rsc.org/chemcomm
A concise and highly efficient strategy for the synthesis of N-glycosyl
imidazole analogues is reported. This reaction is based on a palladium
catalysed decarboxylative allylation and three steps, namely, carbamation,
decarboxylation and allylation are involved. All the substrates can afford
the desired products with excellent yields and selectivities.
N-Glycosides consist of a class of important structures in
carbohydrate chemistry. They play significant roles in organisms
in the form of N-linked glycopeptides and glycoproteins,1 and the
N-glycoside scaffold shows great potential in the field of medicinal
chemistry.2 Therefore, due to their unique characteristics, the
synthesis of various N-glycosides has always been a popular topic
in carbohydrate chemistry during the past few years.3 However,
Scheme 1 The decarboxylation of the carbamates without a palladium
catalyst. Reaction conditions: glycal 1 0.2 mmol, CDI 2a (1,10-carbonyl-
diimidazole) 0.3 mmol, DCM 4 mL; The ratios were detemined by 1H NMR.
compared to O-glycosides and C-glycosides, reports pertaining to The nucleophilic addition between the two active intermediates
the synthesis of N-glycosides, especially with high efficiency and generated from the decarboxylation afforded the N-glycosyl imidazole
stereoselectivity, are significantly fewer in the literature.
product. However, only moderate yields and poor selectivities were
Decarboxylative allylation has been widely used to form carbon– obtained. Notably, as the results in Scheme 1 show, the a-isomers
carbon and carbon–heteroatom bonds as established with the were the major products and the ratios were determined by 1H NMR
efforts of several pioneer groups.4–7 Meanwhile, glycals are versatile spectroscopy of crude products.
intermediates and have been commonly employed in the formation
This came as a surprise to us as from our previous studies,9,10
of glycosidic bonds in our previous studies.8 Considering the wide excellent b-selectivities were observed when palladium catalysts
availability of glycals, we endeavored to apply the strategy of were introduced in the decarboxylative glycosylation. Intrigued
decarboxylative allylation to the formation of glycosidic bonds. by these results, we postulated that if a palladium catalyst is
Gratifyingly, a wide variety of C- and O-glycosides were achieved employed under the reaction conditions, the carbamate inter-
with high regio- and stereo-selectivity in our previous work.9,10 As a mediates could be readily converted to b-products once they
further expansion of this strategy, herein, we demonstrate its were formed. We thus sought to confirm our hypothesis by
application to the synthesis of N-glycosyl imidazole analogues.
carrying out the reaction of 4,6-para-methoxybenzylidene-glucal
During the preparation of the carbamates 3 for the further study 1a with CDI 2a in the presence of Pd(PPh3)4 in THF at room
of palladium catalysed glycosylation, it was found that some of the temperature for 2 h. To our delight, the desired product 4a was
carbamates were unstable and the decarboxylation occurred very afforded in 45% yield, with a conversion percentage of 60%
fast during the reaction or the purification by column chromato- of starting material 1a. Thereafter, various catalysts, ligands,
graphy on silica gel, even after pre-treatment of the silica with Et3N. solvents were screened to optimize the reaction conditions. As
shown in Table 1, the effect of the solvent was first studied.
Division of Chemistry and Biological Chemistry, School of Physical and
When CH3CN was used as the solvent, only a trace amount of
product was formed (Table 1, entry 2). However, the reaction did
not proceed in DMF or toluene (Table 1, entries 3, 4). Interestingly,
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore. E-mail: xuewei@ntu.edu.sg
† Electronic supplementary information (ESI) available: Experimental procedures
when this reaction was carried out in DCM, a product yield of 93%
was obtained (Table 1, entry 5). Next we attempted to examine the
and characterization of new compounds. CCDC 957218. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc48041k
4222 | Chem. Commun., 2014, 50, 4222--4224
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Table 1 Optimization of the reaction conditionsa
With the optimized reaction conditions in hand, we next
investigated the scope and generality of this one pot reaction. As
illustrated in Scheme 2, reactions involving glucals containing
different kinds of protecting groups were performed first. It is
apparent that the reactions proceeded smoothly and gave the
desired products with 85–96% yields (4b–4h). The substrates which
gave mixtures of a- and b-anomers without a palladium catalyst can
afford pure b-products (4b–4d), further confirming our hypothesis.
Exclusive b-selectivity was also obtained for most of the other
substrates tested (4e–4g). However, a ratio of b:a = 17:1 of the
mixture was obtained when tert-butylsilyl was selected as the
protecting group of glucal (4h). Next, galactal substrates were
employed for this reaction. Similarly, the desired products were
obtained in high yields of 93% and 83% with exclusive b-selectivity
(4i, 4j). Subsequently, various CDI analogues were also screened to
ascertain the substrate tolerance of the reaction. 2-Methyl and
2-phenyl substituted CDI analogues provided the corresponding
products in excellent yields and exclusive b-selectivity (4k–4n).
Disubstituted compounds, such as 2,4-dimethyl or 4,5-diphenyl
CDI analogues, were then treated under the optimized reaction
conditions, and the desired products were furnished in 92% and
75% yields with b-selectivity (4o–4p). The corresponding b-type
of benzimidazole and 2-methyl benzimidazole glycosides can also
be prepared in 85% and 78% yields (4q–4r). Moreover, since
hexopyranosyl nucleosides are present in various bioactive nature
products, we then extended toward the preparation of this type of
N-glycosides. Fortunately, purine and adenine type hexopyranosyl
nucleosides were obtained successfully in 83% and 42% yields
(4s–4t). Since both nitrogens are nucleophilic in the addition step,
4t was afforded as a mixture while 4s was obtained with good
selectivity.12 Similar results were obtained when 1,10-carbonylbis-
(1,2,4-triazole) was utilized to furnish the desired N-glycosides with
a ratio of 1 : 10 and 1 : 5 correspondingly (4u–4v).
Entry
Catalyst
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
PdCl2
No
No
No
No
THF
45
CH3CN
Toluene
DMF
DCM
DCM
DCM
DCM
DCM
DCM
Trace
NRc
NR
93
30
41
NR
NR
NR
No
PPh3
PPh3
PPh3
PPh3
PPh3
Pd(TFA)2
Pd(PPh3)2Cl2
a
Reaction conditions: 0.2 mmol glycal 1a, 0.3 mmol CDI 2a, 0.01 mmol Pd
source, in 4 mL solvent at r.t. for 2 h. b Isolated yield. NR = no reaction.
c
effect of catalyst and ligand. It was discovered that Pd(PPh3)4 was
superior to any other catalyst and ligand systems tested (Table 1,
entry 6–10). It is worth noting that all the reactions gave the
products with excellent b-selectivity and the stereochemistry of
the product was further confirmed by the X-ray diffraction
crystallographic analysis of compound 4a.11 Thus, we concluded
the optimized reaction conditions as follows: the reaction was
conducted with glucal 1a (1.0 equiv.) and CDI 2a (1.5 equiv.) in the
presence of Pd(PPh3)4 (0.05 equiv.) in DCM at room temperature
for 2 h.
To investigate the mechanism of this decarboxylative reaction,
compound 5 with a 3,5-trans structure was then prepared. When
compound 5 was treated with CDI under the optimized reaction
conditions, the a-isomer was obtained as the major product as
expected, with a ratio of a:b = 17:1 (Scheme 3).13
Furthermore, to confirm that the reaction indeed involves a
carbamate intermediate, compound 3a was prepared and sub-
sequently treated with Pd(PPh3)4 in DCM for 2 h. The reaction
gave pure b-product 4a in 95% yield. Meanwhile, the reaction of
1a and CDI in the presence of Pd(PPh3)4 in CDCl3 monitored by
1H NMR showed the existence of the carbamate intermediate 3a
(for details, see ESI†).
After that, we turned to examine the syntheses of N-furanosides
using this method since nucleosides, the most important
N-glycosides, exist as N-furanosides. Initially, the desired product
Scheme 2 The scope of N-glycosyl imidazole analogues. Reaction con-
ditions: 0.2 mmol glycal 1, 0.3 mmol 2, 0.01 mmol Pd(PPh3)4, in 4 mL DCM
at room temperature for 2 h. Isolated yields; a inseparable mixture with a
Scheme 3 The reaction of compound 5. Reaction conditions: 0.2 mmol
glycal 5, 0.3 mmol CDI, 0.01 mmol Pd(PPh3)4, in 4 mL DCM at room
temperature for 2 h; Isolated yield; The ratios were determined by 1H NMR.
1
ratio of 1 : 9 from H NMR; b inseparable mixture with a ratio of 1 : 10 from
1H NMR; c inseparable mixture with a ratio of 1 : 5 from 1H NMR.
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was obtained under the same conditions.14 However, poor stereo- screened for this reaction and all the substrates gave the desired
selectivity as compared to N-pyranosides was observed, possibly due products with excellent yields and stereoselectivities. By varying
to the difference in conformation and reactivity of intermediates. the chirality of the C3 position of the glycal substrates, both a- and
Although the result is less than satisfactory, it may provide an access b-isomers can be obtained with high stereoselectivities.
to the formation of the N-furanosyl linkage and further investigation
is currently ongoing in our laboratory.
We gratefully acknowledge the support by Nanyang Technological
University (RG50/08) and support by an NMRC grant (H1N1 R/001/
To explain the selectivities of palladium catalysed glycosylation, 2009) from Ministry of Health, Singapore. We thank Yong-Xin Li and
the steric effect of the C3 substituent was always mentioned.15 Dr Ganguly Rakesh for X-ray analysis.
However, this hypothesis does not match the results from our
previous studies in a few cases.9,16 Recently, a double coordination
Notes and references
1 (a) L. A. Lasky, J. E. Groopman and C. W. Fennie, et al., Science, 1986,
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tion.17 Based on the above results, a double coordination effect
233, 209; (b) A. Kobata, Acc. Chem. Res., 1993, 26, 319; (c) R. A. Dwek,
mechanism is therefore proposed as follows (Scheme 4): the first
step involved the formation of the carbamate intermediate 3 from
the reaction of glycal 1 and CDI analogues. Without any catalyst, an
allylic cation II and an imidazole anion III were then generated in situ
through the decarboxylation of unstable intermediate I. Under
this set of conditions, the a-isomer was furnished as the major
product due to the anomeric effect, which made the heteroatomic
substituent III prefer axial orientation. Meanwhile, the lower energy
chair-form transition state of nucleophilic addition from the a-face
may further enhance a-selectivity. On the other hand, in the presence
of Pd(PPh3)4, double coordination of the palladium catalyst involving
the double bond of glycal and the lone pair of the nitrogen atom
resulted in the formation of key intermediate IV with the palladium
species on the b-face. Subsequently, intermediate V was generated
through a decarboxylative reaction promoted by the palladium
catalyst. Thereafter, nucleophilic addition gave compound 4 with
b-selectivity and the elimination of the palladium catalyst completed
the catalytic cycle. For asymmetric CDI analogues, since both of the
nitrogen can work as a nucleophile in the next step, two different
products can be obtained.
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In conclusion, we have developed a concise and highly efficient
strategy for the synthesis of N-glycosyl imidazole analogues. This
reaction was based on a palladium catalysed decarboxylative
allylation and three sequential steps of carbamation, decarboxyla-
tion and allylation were involved in this one-pot reaction. Different
kinds of protecting groups, glycals and various CDI analogues were
10 S. Xiang, Z. Lu, J. He, K. L. M. Hoang, J. Zeng and X.-W. Liu,
Chem.–Eur. J., 2013, 19, 14047.
11 For more details, see CCDC number 957218.
12 S. R. Mellegaard-Waetzig, D. K. Rayabarapu and J. A. Tunge, Synlett,
2005, 2759.
13 For the decarboxylative reaction of compound 5 derivative, only a
mixture of a : b = 1 : 1 C-glycoside was obtained in ref. 9.
14 The 5-TBDPS protected furanosyl glycal was prepared according to
Pedersen’s method. For more details, see ESI†.
15 H.-H. Li and X.-S. Ye, Org. Biomol. Chem., 2009, 7, 3855.
16 Y. Bai, K. L. M. Hoang, H. Liao and X.-W. Liu, J. Org. Chem., 2013,
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Scheme 4 Plausible reaction mechanism.
17 B. P. Schuff, G. J. Mercer and H. M. Nguyen, Org. Lett., 2007, 9, 3173.
4224 | Chem. Commun., 2014, 50, 4222--4224
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