Oxidant-controlled heck-type C-glycosylation of glycals with arylboronic acids: Stereoselective synthesis of aryl 2-deoxy-C-glycosides

Article abstract of DOI:10.1021/ol900273d

Oxidative Heck-type C-glycosylations of glycals with various arylboronic acids using Pd(OAc)₂ as catalyst in the presence of oxidant were developed. The corresponding ketone, enol ether, and enone types of C-glycosides were predictably obtained

Full text of DOI:10.1021/ol900273d

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1709-1712
Oxidant-Controlled Heck-Type
C-Glycosylation of Glycals with
Arylboronic Acids: Stereoselective
Synthesis of Aryl 2-Deoxy-C-glycosides
De-Cai Xiong, Li-He Zhang, and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs, Peking UniVersity, and School
of Pharmaceutical Sciences, Peking UniVersity, Xue Yuan Rd No. 38,
Beijing 100191, China
xinshan@bjmu.edu.cn
Received February 9, 2009
ABSTRACT
Oxidative Heck-type C-glycosylations of glycals with various arylboronic acids using Pd(OAc)2 as catalyst in the presence of oxidant were
developed. The corresponding ketone, enol ether, and enone types of C-glycosides were predictably obtained with benzoquinone (BQ), Cu(OAc)2/
O2, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as oxidants, respectively. This method provides a simple, mild, and stereoselective
synthesis of aryl 2-deoxy-C-glycosides.
Carbohydrate analogues possessing a key carbon-carbon
(C-C) glycosidic bond between the aglycon and the ano-
meric carbon of the attached sugar moiety are called
C-glycosides. Among C-glycosides, the importance of aryl
C-glycosides is evident from their occurrence in natural
products, their various biological activities,1 and their value
as chiral synthetic building blocks.2 In particular, the aryl
2-deoxy-C-glycoside structure is embodied in a variety of
therapeutically important natural products such as pluramy-
cins, angucyclines, and benzoisochromanequinones.1 Transi-
tion-metal-catalyzed coupling reactions are extremely pow-
erful tools for carbon-carbon bond formation. Although
several methods are available for the preparation of aryl-C-
∆2,3-glycosides using the transition-metal-catalyzed carbon-
Ferrier reaction of glycals,3 methods for aryl 2-deoxy-C-
glycosides are quite limited.4
We have been particularly interested in investigating an
approach that involves palladium(II)-catalyzed oxidative
Heck-type reaction of arylboronic acids with glycals to obtain
aryl 2-deoxy-C-glycosides. The reasons include the follow-
(3) (a) Steihuebel, D. P.; Fleming, J. F.; DuBios, J. Org. Lett. 2002, 4,
293–295. (b) Price, S.; Edwards, S.; Wu, T.; Minehan, T. Tetrahedron Lett.
2004, 45, 5197–5201, and references therein. (c) Ramnauth, J.; Poulin, O.;
Rakhit, S.; Maddaford, S. P. Org. Lett. 2001, 3, 2013–2015.
(1) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22,
742–760, and references therein.
(2) (a) Qin, H.-L.; Lowe, J. T.; Panek, J. S. J. Am. Chem. Soc. 2007,
129, 38–39. (b) Reddy, C. R.; Reddy, G. B.; Rao, C. L. Tetrahedron Lett.
2008, 49, 863–866.
(4) (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.
10.1021/ol900273d CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society

ing: (1) σ-Aryl-Pd complexes can undergo aryl palladation
to glycal double bonds to generate the organopalladium
σ-adduct with perfect regiospecificity and stereospecificity.5
(2) According to Daves’ work,6 the organopalladium σ-ad-
ducts are versatile chiral intermediates, as σ-adduct decom-
position with elimination of palladium and a ꢀ-substituent
(H, OH, OAc, alkoxy) or protonolysis are likely to furnish
various products. (3) The efficiency of the transmetalation
from boron to palladium to form the σ-aryl-Pd complex was
previously demonstrated in the cross-coupling reaction.7 (4)
Among the various organometallic reagents, organoboronic
acids are one of the most popular reagents due to their air
and moisture stability, their broad commercial availability,
and their low toxicity.8 Maddaford3c and de la Figuera9
investigated the carbon-Ferrier reaction of glycals with
arylboronic acids; they all showed syn addition of the
σ-aryl-Pd bond to the R-face of the glycal double bond
followed by anti elimination of the heteroatom to yield 2,3-
dihydroarylglycopyrans, but the Heck-type ꢀ-hydride elimi-
nation product was not observed. Herein we report control-
lable Heck-type C-glycosylation of glycals with arylboronic
acids.
To begin our study, the reactions of glucals 1a-c and
phenylboronic acid (2a) were first examined (Table 1, entries
1-3). When 1b,c and 2a were catalyzed by Pd(OAc)2 in
the presence of benzoquinone (BQ), ketone type C-glycosides
3a and 3b were isolated in moderate to good yield,
respectively (entries 2 and 3). The coupling products 3a and
3b resulted from ꢀ-hydride elimination of the intermediate
σ-adducts and cleavage of the benzyl and silyl group.
However, when 1a was used as the starting material, no
ꢀ-hydride elimination product was obtained. In accord with
Daves’ conclusion5b that conformational rigidity and poor
leaving property at the C-3-O-substituent facilitate syn-ꢀ-
hydride elimination of the intermediate σ-adduct, we chose
TBS (tert-butyldimethylsilyl)-protected glycals as our sub-
strates.
Table 1. Coupling Reactions of 1a-c and 2a To Form
C-Glycosidesa
entry substrate
oxidant (equiv)
BQ (2.0)
BQ (2.0)
BQ (2.0)
DMSO (6.0)/O2
Cu(OAc)2 (2.0)
Cu(OAc)2 (2.0)/O2
O2
DDQ (2.0)
IBX (2.0)
PhI(OAc)2 (2.0)
oxone (2.0)
H2O2 (2.0)
TEMPO (2.0)
CAN (2.0)
product yieldb (%)
1
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
2
3
4
5
6
7
8
9
3a
3b
3b/4a
4a
4a
4a
5a
3b
3b/4a
3b
32
84
68/7
50
94
trace
69
39
10/78
11
10
10
11
12
13
14
15
3b
3b
3b
trace
70
BQ (2.0)/AcOH(2.0)
a Reaction conditions: Pd(OAc)2 (0.1 equiv), PhB(OH)2 (2.0 equiv),
oxidant, CH3CN, 30-40 °C. b Isolated yield.
O2 was the best terminal oxidant to produce enol ether 4a,
and DDQ was the best terminal oxidant to form enone 5a.
Encouraged by these results, the scope of the reaction was
investigated by varying both the arylboronic acids and the
glycals in the presence of BQ (Table 2). A variety of
arylboronic acids containing electron-donating, electron-
withdrawing, and sterically congested groups were employed,
giving ketone-type coupling products in moderate to good
isolated yields. A series of glycals were also examined, and
all provided the desired products as single anomers. Interest-
ingly, the cross-coupling of galactal 1d and phenylboronic
acid (2a) must be carried out under O2 atmosphere, and enol
ether 4e was also obtained as a side product in 19% yield
(entry 5). Mechanistic considerations suggest that the steric
configuration of newly introduced aryl group at anomeric
position will be on the face opposite the C3-O-substituent
of the starting glycals. Indeed, the anomeric configuration
of the coupling product was unambiguously identified by
its 1H and 13C NMR analyses as described in the literature.4
As shown in Table 3, under the optimized reaction
conditions, the palladium-catalyzed coupling reactions of a
series of arylboronic acids and glycals were also performed
Subsequently, we checked the palladium-catalyzed reac-
tions of 1c and 2a utilizing various oxidants (Table 1, entries
4-15). When the combination of Cu(OAc)2 and O2 was used
as the oxidant, enol ether type C-glycoside 4a was obtained
in high yield (94%) (entry 6). Interestingly, enone-type
C-glycoside 5a was generated in moderate yield (69%) when
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was used
as the terminal oxidant (entry 8). Strong oxidants were also
used to explore a PdII/PdIV process,10 but with no success
(entries 9-14). We also failed in the protonolysis process11
(entry 15). Thus, we found that BQ was the best terminal
oxidant to generate ketone 3b, the combination of Cu(OAc)2/
(5) (a) Czernecki, S.; Dechavanne, V. Can. J. Chem. 1983, 61, 533–
540. (b) Cheng, J. C.-Y.; Daves, G. D., Jr. J. Org. Chem. 1987, 52, 3083–
3090. (c) Daves, G. D., Jr. Acc. Chem. Res. 1990, 23, 201–206.
(6) Arai, I.; Daves, G. D., Jr. J. Am. Chem. Soc. 1981, 103, 7683.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(8) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–
9695.
(9) de la Figuera, N.; Forns, P.; Ferna`ndez, J.-C.; Fiol, S.; Ferna´ndez-
Forner, D.; Albericio, F. Tetrahedron Lett. 2005, 46, 7271–7274.
(10) Yin, G.; Liu, G. Angew. Chem., Int. Ed. 2008, 47, 5442–5445, and
references therein.
(11) Lu, X. Top. Catal. 2005, 35, 73–86.
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Org. Lett., Vol. 11, No. 8, 2009

Table 2. The Preparation of Ketone Type C-Glycosides 3c-m
Table 3. Preparation of Enol Ether Type C-Glycosides 4b-h
with BQ as the Oxidanta
with Cu(OAc)2/O2 as the Oxidanta
a Reaction conditions: Pd(OAc)2 (0.1 equiv), Cu(OAc)2 (2.0 equiv)/O2,
ArB(OH)2 (2.0 equiv), CH3CN, 30-40 °C, 12-24 h. b Isolated yield.
c Cu(OAc)2 (0.4 equiv) was used, 48 h.
anomer was detected. However, for the cross-coupling of
1c with 2c, a catalytic amount of Cu(OAc)2 had to be used
to reduce the formation of homocoupling byproduct of
4-(trifluoromethyl)phenylboronic acid (2c) (entry 2, Table
3). The anomeric stereochemistry of the product followed
the same rule as that for the above-mentioned ketone product
and was confirmed by its 13C NMR and NOESY spectra.12
Finally, the coupling reactions of 1c and other arylboronic
acids in the presence of DDQ were examined. Although the
a Reaction conditions: Pd(OAc)2 (0.1 equiv), BQ (2.0 equiv), ArB(OH)2
(2.0 equiv), CH3CN, 30-40 °C, 4-48 h. b Isolated yield. c Conditions a
under O2 atmosphere and enol ether: 4e was obtained in 19% yield.
(12) Brakta, M.; Farr, R. N.; Chaguir, B.; Massiot, G.; Lavaud, C.;
Anderson, W. R., Jr.; Sinou, D.; Daves, G. D., Jr. J. Org. Chem. 1993, 58,
2992–2998.
(13) (a) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin
Trans. 1 1992, 2997–2998. (b) Tanemura, K.; Suzuki, T.; Horaguchi, T.
Bull. Chem. Soc. Jpn. 1994, 67, 290–292.
in the presence of Cu(OAc)2/O2. In all cases, the desired enol
ether product was obtained in good yield, and only a single
Org. Lett., Vol. 11, No. 8, 2009
1711

enone-type C-glycoside was obtained, the isolated yield was
low (Scheme 1). Presumably under the reaction conditions,
the TBS group of the reactant is easily cleaved.13
Scheme 1
.
Preparation of Enone-Type C-Glycosides 5b-c with
DDQ as the Oxidant
Although the details are not yet known, we propose the
possible mechanism shown in Figure 1. As delineated in
cycle I, a Heck-type C-glycosylation first occurs to give enol
ether type product under all conditions. When BQ or DDQ
is used as the oxidant, like the Saegusa oxidation, the
palladium adducts (A, B) are formed.14 The subsequent
hydrolysis (cycle II) or ꢀ-H elimination (cycle III) of the
palladium adducts generates the ketone- or enone-type
product. Cycle III may be also a radical process.15
In conclusion, a simple, mild, and oxidant-controlled Heck-
type C-glycosylation of glycals with various arylboronic
acids has been developed. Different types of C-glycosides
(ketones, enol ethers, and enones) were predictably obtained
by just adjusting the oxidants. The cross-coupling reactions
proceeded with high regioselectivity and stereoselectivity.
To the best of our knowledge, this is the first Heck-type
C-glycosylation by using Pd(OAc)2 as catalyst in the presence
of oxidant. Given all the advantages associated with aryl-
boronic acids, the disclosed methodology may find wide
applications in the preparation of many biologically important
C-glycosides. Further investigations into protonolysis and the
Figure 1. Proposed mechanistic rationale.
PdII/PdIV processes of the reaction in the presence of oxidant
are in progress.
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China and
“973” and “863” grants from the Ministry of Science and
Technology of China.
Supporting Information Available: Experimental pro-
cedures and data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900273D
(14) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013. (b) Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew.
Chem., Int. Ed. 1999, 38, 2015–2016.
(15) Evans, P. A; Longmire, J. M; Modi, D. P. Tetrahedron Lett. 1995,
36, 3985–3988.
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