β-type glycosidic bond formation by palladium-catalyzed decarboxylative allylation

Article abstract of DOI:10.1002/chem.201303241

The efficient and stereoselective construction of glycosidic linkages is of great significance in carbohydrate chemistry due to the ubiquitous existence of numerous biologically active natural products and saccharides. Although great efforts have been devoted to stereoselective glycosylations in the past few decades, constructing glycosidic bonds with high efficiency and selectivity remains a challenge and continues to be an important area in carbohydrate research. Phenols are widely used as nucleophiles in palladium-catalyzed allylation. In contrast, the possibility of using aliphatic alcohols as nucleophiles is not as thoroughly explored. The modified reaction conditions were then applied to other substrates. Originating from easily prepared carbonates, various glycosides, such as phenolic Oglycosides, thiophenolic S-glycoside, aliphatic O-glycosides, and even disaccharides, were synthesized in good yields by means of a palladium-catalyzed decarboxylative allylation.

Full text of DOI:10.1002/chem.201303241

COMMUNICATION
DOI: 10.1002/chem.201303241
b-Type Glycosidic Bond Formation by Palladium-Catalyzed Decarboxylative
Allylation
Shaohua Xiang, Zhiqiang Lu, Jingxi He, Kim Le Mai Hoang, Jing Zeng, and
Xue-Wei Liu*[a]
The efficient and stereoselective construction of glycosidic
linkages is of great significance in carbohydrate chemistry
due to the ubiquitous existence of numerous biologically
active natural products and saccharides.[1] Although great ef-
forts have been devoted to stereoselective glycosylations in
the past few decades, constructing glycosidic bonds with
high efficiency and selectivity remains a challenge and con-
tinues to be an important area in carbohydrate research.[2]
In particular, 2,3-unsaturated glycosides are of interest in or-
ganic synthesis as the olefin moiety can be functionalized
readily.[3] Among methods and reagents developed to access
such glycosides, the Lewis acid catalyzed Ferrier rearrange-
ment, established from commercially available glycals, is
one of the most commonly used strategies to form 2,3-unsa-
turated a-O-glycosides.[4] In addition, metals such as Pd and
Au have also exhibited potent capability in catalyzing Ferri-
er-type glycosylation from glycals with leaving groups at the
C3 position. Generally, a-isomers are always obtained as the
major product in Ferrier-type reactions.[5] However, a Pd-
catalyzed Ferrier-type O-glycosylation strategy reported by
Lee employed zinc(II) alkoxides as activators and afforded
Scheme 1. Palladium-catalyzed O-glycosylation.
both a- and b-O-glycosides with high selectivity through the
choice of different ligands (Scheme 1, a).[5a] The Pd–p-allyl
intermediates generated from glycals and Pd catalysts pos-
sess low electrophilicity in the absence of an activator.
Therefore, direct O-glycosylation from glycal derivatives is
very difficult to achieve.[6] Considering this limitation,
a non-Ferrier-type glycosylation employing cyclic pyranones
to form more electrophilic Pd–p-allyl intermediates as the
glycosyl donors was developed almost concurrently by Fer-
inga (Scheme 1, b) and OꢀDoherty (Scheme 1, c).[7] By vary-
ing the chirality at the C1 position of the starting material,
both a- and b-O-glycosides could be obtained in high selec-
tivity. Although many other efforts have been made, the de-
velopment of new strategies to synthesize O-glycosides se-
lectively, especially from glycal synthons, remains a chal-
lenge.
Metal-catalyzed decarboxylative allylation, with the effort
of many pioneers such as Tunge,[8] Trost,[9] and Stoltz,[10] has
proven its synthetic utility in organic chemistry in general.[11]
Recently, we have developed a palladium-catalyzed decar-
boxylative b-C-glycosylation by employing this strategy.[12]
As a continuation of our efforts in discovering new glycosy-
lation methods,[13] We present herein a palladium-catalyzed
decarboxylative allylation approach to the synthesis of vari-
ous b-O-glycosides, including oligosaccharides, from glycal
carbonates (Scheme 1, d).
Our studies commenced with carbonate 1a as the starting
material, which can be prepared easily from glucal and 4-
methoxyphenyl chloroformate with a yield of 95%. This
substrate was chosen on the basis that the para-methoxy
group on phenol can increase the nucleophilicity of the gen-
erated nucleophile. Hence, the nucleophilic addition should
be easier after formation of the Pd–p-allyl intermediate. By
screening different Pd sources, ligands, solvents, tempera-
tures, and times, the optimized reaction conditions were re-
[a] S. Xiang,+ Dr. Z. Lu,+ J. He, K. L. M. Hoang, J. Zeng, Prof. X.-W. Liu
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371 (Singapore)
E-mail: xuewei@ntu.edu.sg
[+] These authors contributed equally.
solved as follows: [Pd2ACHTNUTRGNE(NUG dba)3] catalyst, 1,1’-bis(diisopropyl-
phosphino)ferrocene (DiPPF) ligand, and toluene at 608C
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303241.
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for 12 h.[14] Under the optimized reaction conditions, the de-
sired O-glycoside 2a was afforded in 93% with exclusive b-
selectivity (Scheme 2). The stereochemistry of the product
was confirmed by the X-ray diffraction crystallographic
analysis.[15]
did not provide any of the desired product. This is due to
the oxidative addition of the aromatic ring being the pre-
ferred reaction under these conditions (2k).[16] Next, a thio-
phenolic substrate was examined, and gratifyingly, the reac-
tion proceeded smoothly to give thiophenolic glycoside (2l)
with a yield of 76%. As well as
4,6-para-methoxybenzylidene-
protected glucals, a 4,6-di-tert-
butylsilyl-protected glucal was
also tested for this reaction.
However, a diminished yield of
52% was obtained due to the
sterically
bulky
protecting
group (2m).
Scheme 2. Palladium-catalyzed O-glycosylation. Reaction conditions: compound 1 (1.0 equiv), [Pd
(0.1 equiv) and DiPPF (0.2 equiv) in toluene (20 mLmmolÀ1) were stirred at 608C for 12 h.
2ACHTUNGTNER(NUNG dba)3]
Phenols are widely used as
nucleophiles in palladium-cata-
lyzed allylation. In contrast, the
With the optimized conditions in hand, the scope and gen-
erality of this method were investigated. A range of phenol-
ic carbonate substrates were prepared from 4,6-para-me-
thoxybenzylideneglucal and various phenolic acyl chlorides
in 90–98% yield and were then subjected to the optimized
reaction conditions. The results are summarized in
Scheme 3. As shown, glucal carbonate containing a phenol
group without any substituents provided a good yield of
81% (2b). Substrates with alkyl-substituted phenolic groups
furnished the products in excellent yields (2c–2e). Biphenyl
O-glycoside and 2-naphthalenolic O-glycoside were ob-
tained in moderate yields due to the steric hindrance effect
(2 f and 2g). Substrates with halide moieties gave lower
yields (2h–2j) and the 2-iodo substituted phenolic substrate
possibility of using aliphatic alcohols as nucleophiles is not
as thoroughly explored. To expand the generality of this pal-
ladium-catalyzed decarboxylative b-O-glycosylation, we
next directed our attention towards aliphatic O-glycosides.
Carbonate compound 3a was selected as the model sub-
strate and examined under the optimized reaction condi-
tions for the syntheses of phenolic O-glycosides. Unfortu-
nately, only 30% of the product 4a was obtained and 70%
of the starting material was recovered as indicated by the
crude 1H NMR spectrum. Hence, the reaction conditions
were modified. To our delight, when the ligand was varied
from DiPPF to 1,1’-bis(di-tert-butylphosphino)ferrocene
(DtBPF) and the reaction temperature was raised to
808C, the conversion increased to 99%, and an isolated
yield of 95% was obtained
(Scheme 4).[17]
The modified reaction condi-
tions were then applied to
other substrates. A variety of
carbonates 3 which were pre-
pared with 50–93% yields pro-
duced the corresponding ali-
phatic O-glycosides in good to
excellent yields. As summarized
in Scheme 5, it is evident that
primary alcohol substrates can
participate in this reaction to
afford high yields (4b–4d).
Starting from a substrate with
a long alkyl chain bearing elec-
tron-withdrawing fluoride ions
afforded the desired product in
70% yield (4e). A bulky alco-
hol could also be delivered pro-
viding a yield of 77% (4 f). The
reactions of substrates prepared
from benzyl alcohol (4g) and
furfuryl alcohol (4h) proceeded
smoothly and furnished the cor-
Scheme 3. The substrate scope of phenolic glycosides.
responding products in 84 and
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Glycosidic Bond Formation
COMMUNICATION
and 4q gave yields of only 35 and 40%, respectively due to
steric hindrance.
Further investigation of this methodology was conducted
by examining the scope of protecting groups and glycals. As
presented in Scheme 6, subjecting carbonates 5, which have
different protecting groups and were prepared from glycals
and ethyl chloroformate with 72–90% yields, to the opti-
mized conditions provided the desired O-glycosides in mod-
erate to good yields in most cases (6a–6 f). A galactal sub-
strate was also examined, but
Scheme 4. Palladium-catalyzed O-glycosylation. Reaction conditions:
compound 3 (1.0 equiv), [Pd
2ACHTUNGTERN(NUNG dba)3] (0.1 equiv) and DtBPF (0.2 equiv) in
toluene (20 mLmmolÀ1) were stirred at 808C for 12 h.
only 20% yield of product was
obtained when the benzyl
group was selected as the pro-
tecting group (6g). When bulky
4,6-di-tert-butylsilyl was used as
the protecting group, only trace
amount of products were de-
tected for both the glucal and
galactal substrates (6h and 6i).
To better understand the
mechanism of this palladium-
catalyzed decarboxylative gly-
cosylation, the following com-
petitive experiments were con-
ducted (Scheme 7). From the
results, it can be inferred that
when the reaction of carbonate
3b was performed in the pres-
ence of one equivalent of
NaOEt, the competing 4b was
obtained in 90% yield. Mean-
while, when 3a was examined
in the presence of one equiva-
lent of NaOMe, 4a was ob-
tained as the dominant product
in 93% yield. Increasing the
amount of NaOMe to two
equivalents and four equiva-
lents showed limited influence
Scheme 5. The substrate scope of aliphatic O-glycosides and disaccharides. Reaction conditions: compound 5
(1.0 equiv), [Pd
12 h.
to the results, as confirmed by
2ACHTUNGTRENNUNG
(dba)3] (0.1 equiv) and DtBPF (0.2 equiv) in toluene (20 mLmmolÀ1) were stirred at 808C for
1H NMR spectroscopy.
Based on previous mechanis-
tic studies of palladium-cata-
lyzed
decarboxylation[5b,8d,9c]
79% yields, respectively. The versatility of the present meth-
odology was further explored by applying it to the syntheses
of disaccharides. Symmetric 4,6-para-methoxybenzylidene-
glucal carbonate 3i was first examined and the desired dis-
accharide was afforded in 60% yield (4i). The substrates
prepared from 6-OH glucals gave the desired products in
higher yields (4j and 4k). Similar results were also obtained
for the carbonate substrates prepared from 6-OH galactose
(4l) and 6-OH glucose (4m). When bulkier substrates, such
as 4-OH glucose (4n) and 3-OH (4o) glucose carbonates
were treated under the same conditions, the corresponding
disaccharides could be synthesized, albeit in lower yields.
Mannose substrates were also tested; however, products 4p
and our results from the above experiments, we propose the
following mechanism for this reaction (Scheme 8): the cata-
lytic cycle begins with the formation of the palladium–
DiPPF or –DtBPF complex I. After the binary coordination
of complex I to both the double bond of the olefin and the
carbonyl group of the glycal carbonate from the b-face, in-
termediate II is produced. Postulation that the palladium
species approaches the glycal from the b-face can justify the
lower yields obtained with galactal substrate compared to
glucal substrates. In nonpolar solvents such as toluene,[9c]
a subsequent decarboxylation of the intermediate II gener-
ates an ion-pair intermediate III. The intramolecular nucleo-
philic addition and the elimination of the palladium complex
Chem. Eur. J. 2013, 19, 14047 – 14051
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X.-W. Liu et al.
I result in the desired b-prod-
uct, completing the catalytic
cycle.
In conclusion, we have dem-
onstrated a new approach to-
wards O-glycosidic bond forma-
tion. Originating from easily
prepared carbonates, various
glycosides, such as phenolic O-
glycosides, thiophenolic S-gly-
coside, aliphatic O-glycosides,
and even disaccharides, were
synthesized in good yields by
means of a palladium-catalyzed
decarboxylative allylation. Dif-
ferent protecting groups and
glycals were also screened and
most of the substrates gave rea-
sonable to excellent yields. In
contrast to existing methods,
this strategy starts from glycal
synthons without the need for
an activator and all products
were obtained with excellent b-
selectivity. The generated 2,3-
unsaturated glycosides also
serve as useful synthetic inter-
mediates which can be used to
Scheme 6. The substrate scope of glycals with various protecting groups.
synthesize
different
sugars
through functionalization of the
olefin group. Efforts aimed at
applying this methodology in
the total synthesis of natural
products are currently ongoing
in our laboratory.
Experimental Section
Toluene (2 mL) was added to a mixture
of DtBPF (0.02 mmol), [Pd2ACHTUNGTRENNUNG(dba)3]
Scheme 7. Competition experiments.
(0.01 mmol), and aliphatic carbonate
3a (0.1 mmol) under an atmosphere of
argon. After stirring at 808C for 12 h,
the solvent was removed under re-
duced pressure to give crude product which was purified by column chro-
matography to afford the desired glycoside 4a in a yield of 93%.
Acknowledgements
We gratefully acknowledge the support by Nanyang Technological Uni-
versity (RG50/08) and support by an NMRC grant (H1N1 R/001/2009)
from Ministry of Health, Singapore. We thank Dr. Yong-Xin Li and Dr.
Ganguly Rakesh for X-ray analysis.
Keywords: allylation · carbonates · glycals · glycosylation ·
Scheme 8. Proposed mechanism of decarboxylative glycosylation.
palladium
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Glycosidic Bond Formation
COMMUNICATION
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Received: August 16, 2013
Published online: September 17, 2013
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