Phosphine-free suzuki-miyaura cross-coupling in aqueous media enables access to 2-C-aryl-glycosides

Article abstract of DOI:10.1021/ol3003139

A general strategy for the synthesis of 2-aryl-glycals and their elaboration to 2-C-aryl-α-glycosides and 1,5-anhydro-2-C-aryl-2-deoxy alditols are described. The use of reliable, efficient phosphine-free Suzuki-Miyaura cross-coupling of 2-iodoglycals in

Full text of DOI:10.1021/ol3003139

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1728–1731
Phosphine-Free SuzukiÀMiyaura
Cross-Coupling in Aqueous Media
Enables Access to 2-C-Aryl-Glycosides
‡
‡
Isidro Cobo,†,‡ M. Isabel Matheu, Sergio Castillon, Omar Boutureira,*,†,‡ and
ꢀ
Benjamin G. Davis*,†
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
´ ´
12 Mansfield Road, Oxford OX1 3TA, U.K., and Departament de Quımica Analıtica i
´
Quımica Organica, Universitat Rovira i Virgili, C/Marcel lı Domingo s/n,
43007 Tarragona, Spain
ꢁ
´
3
omar.boutureira@urv.cat; ben.davis@chem.ox.ac.uk
Received February 7, 2012
ABSTRACT
A general strategy for the synthesis of 2-aryl-glycals and their elaboration to 2-C-aryl-R-glycosides and 1,5-anhydro-2-C-aryl-2-deoxy alditols are
described. The use of reliable, efficient phosphine-free SuzukiÀMiyaura cross-coupling of 2-iodoglycals in aqueous media as a key step proceeds
with complete regioselectivity at C-2 and enables access to 2-aryl-glycals with different configurations in excellent yields.
C-Arylglycosides are members of the C-glycosides1 fam-
ily of carbohydrate mimetics, and their synthesis has
attracted considerable interest due to the presence of such
motifs in several naturally occurring bioactive products.2
Many methods have been developed for the synthesis of
1-C-arylglycosides where a carbon atom substitutes the
anomeric glycosidic oxygen.3 The most common method
for 1-C-arylglycosides synthesis involves the use of transi-
tion-metal-catalyzed reactions, in particular, the addition
of organometallic species to the sp2-hybridized anomeric
center of glycals.4 Regioselectivity may be efficiently con-
trolled using a directing halogen atom at the anomeric
position5 (e.g., 1-haloglycals). However, and when this re-
giocontrol element is missing, reactions often lead to the
formation of Ferrier and other 2,3-unsaturated products
due to β-elimination processes.4À7 Although the high
demand for functionalized 1-C-arylglycosides has stimulated
† University of Oxford.
‡ Universitat Rovira i Virgili.
ꢂ
ꢀ
ꢂ
ꢀ
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109, 6729. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier: Oxford, 1995. (c) Yuan, X.; Linhardt, R. J. Curr. Top. Med. Chem.
2005, 5, 1393. (d) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron
1998, 54, 9913. (e) Beau, J.-M.; Gallagher, T. Top. Curr. Chem. 1997,
187, 1. (f) Sinay, P. Pure Appl. Chem. 1997, 69, 459. (g) Postema,
M. H. D. Tetrahedron 1992, 48, 8545.
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4608. (b) Bai, Y.; Leow, M.; Zeng, J.; Liu, X.-W. Org. Lett. 2011, 13,
5648. (c) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S. Org. Lett. 2009, 11, 1709.
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r
10.1021/ol3003139
Published on Web 03/13/2012
2012 American Chemical Society

extensive studies on metal-catalyzed CÀC bond-forming
reactions,8 the development of more efficient methods that
involve arylation at other positions is highly desirable.
C-Functionalizations at other positions of the sugar ring
leading to C-branched sugars are by far less explored because
they usually require many steps,9 the use of strongly basic
organolithium and Grignard reagents,10 or the use of toxic
reagents such as tin or mercury.11 Particularly, the synthesis
of 2-C-aryl-modified-carbohydrates12 is rare, even though
they are of potential interest for the development of new
biologically active carbohydrate mimetics.
Scheme 1. General Strategy towards the Preparation of 2-Ar-
ylglycals 9
We envisaged a general strategy for accessing 2-arylgly-
cals (Scheme 1) as key intermediates for synthesizing 2-C-
arylglycosides. We anticipated that this could be achieved
through the use of 2-haloglycals as privileged starting
materials for this transformation featuring a regiocontrol
element at the desired C-2 position.13À15 Herein we report
a general and efficient method for the synthesis of 2-aryl-
glycals 9 with different configurations under relatively
mild conditions by an aqueous, phosphine-free SuzukiÀ
Miyaura cross-coupling of 2-iodoglycals 5À8 with aryl
boronic acids in the presence of an inexpensive Pd
complex16 (Scheme 1).
Although iodo-derivates are preferable over chlorine or
bromine for these reactions17 they are less used, probably
due to the lack of a general method for their preparation.18
Thus, starting 2-iodoglycals 5À8 were prepared by treating
alkenyl sulfanyl derivatives 1 or commercially available
glycals 2 with iodonium reagents in aqueous media to
provide the corresponding 2-deoxy-2-iodopyranoses 3
which were then eliminated with Ph2SO/Tf2O and TTBP.
Importantly, the optimization of original reaction condi-
tions by driving the reaction under thermodynamic control
allowed the selective preparation of otherwise elusive
2-iodoglycals 5 and 6 (see Supporting Information (SI)
for details). Under kinetic control, 2-deoxy-2-iodo-trehaloses
4 were principally obtained.18,19
The feasibility of the SuzukiÀMiyaura cross-coupling
reaction was initially examined by using our recently
developed Pd catalyst16 (Table 1). Treatment of 2-iodoga-
lactal 5 and phenylboronic acid 10a with 2 mol % catalyst
and Na2HPO4 in 1:3 CH3CN/H2O afforded 2-phenylga-
lactal 11a in 82% yield with complete selectivity at C-2
after 300 min at 100 °C (entry 1). Attempts to decrease the
catalyst loading proved ineffective (entry 2). Changing the
solvent ratio from 1:3 to 1:1 CH3CN/H2O to increase the
solubility of 5 improved the yield of 11a to 90% after only
30 min at 100 °C (entry 3). Next, the effect of reaction
temperature was evaluated (entries 4À6), 125 °C being
optimal. The best yield for 11a (95%) was finally obtained
with 2 mol % catalyst in 1:1 CH3CN/H2O at 125 °C for
only 5 min (entry 6). Globally, the use of this cheap and
environmentally friendly catalyst provides several advan-
tages; carrying out the reaction under aqueous condi-
tions is key since the use of nonpolar solvents accelerates
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Sridhar, P. R.; Kumar, P. V.; Seshadri, K.; Satyavathi, R. Chem.;Eur.
J. 2009, 15, 7526. (d) Elamparuthi, E.; Kim, B. G.; Yin, J.; Maurer, M.;
Linker, T. Tetrahedron 2008, 64, 11925. (e) Bouisset, T.; Gosselin, G.;
Griffe, L.; Meillon, J.-C.; Storer, R. Tetrahedron 2008, 64, 6657. (f)
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Lett. 2004, 45, 3077.
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Ed. Engl. 1984, 23, 69.
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S. Tetrahedron Lett. 2006, 47, 3307. (c) Willson, M.; Perie, J. Spectrochim.
Acta Part A 1999, 55, 911. (d) Sugimura, H.; Osumi, K.; Koyama, T.
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Chem. Lett. 1991, 20, 1379. (e) Auge, C.; Gautheron, C.; David, S.;
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J. B.; Scalon, B. J. Chem. Soc. D 1969, 17, 955.
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Tetrahedron 1999, 55, 12287. (b) Hayashi, M.; Amano, K.; Tsukada, K.;
Lamberth, C. J. Chem. Soc., Perkin Trans. 1 1999, 239. (c) Lamberth, C.;
Bednarski, M. Carbohydr. Lett. 1995, 1, 369.
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Chem.;Eur. J. 2011, 17, 9888. (b) Leibeling, M.; Koester, D. C.;
Pawliczek, M.; Schild, S. C.; Werz, D. B. Nat. Chem. Biol. 2010, 6,
199. (c) Leibeling, M.; Koester, D. C.; Pawliczek, M.; Kratzert, D;
Dittrich, B.; Werz, D. B. Bioorg. Med. Chem. 2010, 18, 3656.
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(b) Chalker, J. M.; Wood, C. S. C.; Davis, B. G. J. Am. Chem. Soc. 2009,
131, 16346.
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Tetrahedron Lett. 2003, 44, 6111. (b) Gomez, A. M.; Danelon, G. O.;
Pedregosa, A.; Valverde, S.; Lopez, J. C. Chem. Commun. 2002, 2024.
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Patel, M. K.; D’Hooge, F.; Lee, S. S.; Via, L. E.; Tahlan, K.; Barry,
C. E.; Davis, B. G. Nat. Chem. Biol. 2011, 7, 228.
´
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Castillon, S.; Seeberger, P. H. J. Org. Chem. 2007, 72, 8998.
Org. Lett., Vol. 14, No. 7, 2012
1729

competing elimination reactions20 and also avoids the use
of degassed solvents combined with expensive, easily oxi-
dized phosphines that are particularly detrimental for the
success of this reaction. For example, we observed 40%
hydrodehalogenation of 2-iodogalactal 5 when reacted
with PBu3 (see SI for details).
Table 2. Scope of SuzukiÀMiyaura Cross-Coupling of 2-Iodo-
galactal 5 with Arylboronic Acids 10bÀha
Table 1. Optimization of Reaction Conditions for the SuzukiÀ
Miyaura Cross-Coupling of 2-Iodogalactal 5 with Phenylboro-
nic Acid 10aa
boronic
acid
t
yieldb
(%)
entry
Ar
4-CN
product
(min)
1
2
3
4
5
6
7
10b
10c
10d
10e
10f
11b
11c
11d
11e
11f
5
5
95
95
90c
90
89
94
95
4-OMe
4-F
5
2-Me
40
40
5
3-Py
10g
10h
1-Naph
3,5-(CF3)2
11g
11h
5
a Conditions: a mixture of 2-I-galactal 5 (1 equiv), ArB(OH)2 10bÀh
(1.5 equiv), L2Pd(OAc)2 (2 mol %), and Na2HPO4 (5 equiv) in 1:1
CH3CN/H2O (0.02 M) was microwave irradiated (125 °C, 300 W) unless
otherwise indicated. b Isolated yield. c Traces of 3,4,6-tri-O-benzyl-D-
galactal were also detected (see Supporting Information for a mecha-
nistic investigation).
[Pd]
CH3CN/H2O
(v/v)
temp
t
yieldb
(%)
entry
(mol %)
(°C)
(min)
1
2
1:3
1:3
1:1
1:1
1:1
1:1
100
100
100
40
300
30
82
NRc
2
0.1
2
3
30
90
4
2
720
190
5
NRc
84
5
6d
5
80
2
125
95
a Reactions were performed in a sealed vessel under single-mode
microwave irradiation (65 W) with 2-I-galactal 5 (1 equiv), PhB(OH)2
10a (1.5 equiv), L2Pd(OAc)2 (up to 5 mol %), and Na2HPO4 (5 equiv) in
solvent (0.02 M) unless otherwise indicated. b Isolated yield. c NR = no
reaction (>98% starting material was recovered). d Microwave power
(300 W).
Table 3. Scope of SuzukiÀMiyaura Cross-Coupling of 2-Iodo-
glycals 6À8 with Phenylboronic Acida
Encouraged by these results, a variety of arylboronic
acids 10bÀh containing representative groups with poten-
tial in different imaging modalities21 (e.g., PET, MRI, and
fluorescence) were examined to expand the scope of the
SuzukiÀMiyaura cross-coupling of 2-iodogalactal 5
(Table 2). Phenylboronic acids with electron-withdrawing
groups (entries 1, 3, and 7) or electron-donating groups
(entry 2) afforded excellent results. Similarly, the use of
sterically hindered boronic acids (entries 4 and 6), or
heterocyclic derivatives (entry 5), also afforded excellent
results although longer reaction times were required. Next,
2-iodoglycals 6À8were reacted with phenylboronic acid 10a
under the optimized reaction conditions (Table 1, entry 6)
and 2-phenylglycals 12À14 were efficiently obtained in
excellent yields (up to 95%) confirming that different con-
figurations are compatible with this procedure (Table 3).
Having demonstrated the success of the SuzukiÀ
Miyaura cross-coupling reaction with 2-iodoglycals,
the potential of the resulting 2-arylglycals as intermediates
for the preparation of 2-C-arylglycoconjugates was
a Conditions: a mixture of 2-I-glycal 6À8 (1 equiv), PhB(OH)2 10a
(1.5 equiv), L2Pd(OAc)2 (2 mol %), and Na2HPO4 (5 equiv) in 1:1
CH3CN/H2O (0.02 M) was microwave irradiated (125 °C, 300 W) for
5 min unless otherwise indicated. b Isolated yield. c Traces of 3,4,6-tri-O-
benzyl-D-glucal were also detected (see Supporting Information for full
details).
ꢀ
(20) Gong, H.; Sinisi, R.; Gagne, M. R. J. Am. Chem. Soc. 2007, 129,
1908.
(21) Spicer, C. D.; Triemer, T.; Davis, B. G. J. Am. Chem. Soc. 2012,
134, 800.
1730
Org. Lett., Vol. 14, No. 7, 2012

investigated. Thus, 2-phenylglucal 12 was efficiently hy-
drogenated with Pd/C in methanol to afford 1,5-anhydro-
2-C-aryl-2-deoxy alditols 15 and 16 in 95% yield and dr
10:1 as indicated by the analysis of diagnostic coupling
constants and key NOE signals in15and 16both present in
their 4C1 conformation (Scheme 2).
To the best of our knowledge this transformation repre-
sents the first transition-metal-catalyzed 2-C-arylation of
2-haloglycals. The simplicity and relative mildness of this
method allow the regioselective preparation of various
2-arylglycals with different configurations in excellent
yields with no Ferrier or 2,3-unsaturated byproduct de-
tected. Notably, the 2-iodoglycal substrates proved un-
stable in the presence of phosphines, necessitating systems
that avoid their use. The elaboration of the 2-C-arylglycal
moiety gives access to both 1,5-anhydro-2-C-aryl-2-deoxy
alditols and challenging quaternary 2-C-aryl-R-glycosides
which will broaden the plethora of 2-C-aryl branched
glycosides at positions different than C-1. Further
application of this methodology to the synthesis of
more complex 2-C-aryl branched glycosides is currently
under investigation.
Scheme 2. Synthesis and Conformational Analysis of 1,5-An-
hydro-2-C-aryl-2-deoxy Alditols 15 and 16
Scheme 3. Synthesis and Conformational Analysis of Branched
2-C-Phenylglycosides 18 and 19
The preparation of challenging quaternary 2-C-aryl
moieties was next studied using our two-step approach,
which involves the epoxidation of starting 2-arylglycals
followed by ring opening of resulting 2-C-aryl branched
1,2-anhydropyranosides.22 Thus, treatment of 2-phenyl-
glucal 12 with Oxone and acetone afforded epoxide 17 in
quantitative yield23,24 (Scheme 3). Next, 2-C-phenyloxir-
ane 17 was subjected to an acid-promoted glycosylation
with EtOH or BnOH. Under such conditions, 2-C-phe-
nylglycosides 18 and 19 were obtained in good yields
(85À90%) with exclusive R-selectivity (Scheme 3). The
stereochemistry of compounds 18 and 19 was initially
deduced by analysis of diagnostic 3J3,4 = 9.5 Hz coupling
constants that account for a 4C1 conformation. Moreover,
1
the anomeric JC1ÀH1 = 174.8 Hz coupling constant is
Acknowledgment. We thank the European Commis-
sion (Marie Curie Intra European Fellowship, O.B.),
DGI (CTQ2008-01569-BQU), and Ministerio de Cien-
cia y Tecnologıa, Spain (CSD2006-0003, Consolider
´
Ingenio 2010) for generous financial support. We also
indicative of an R-configuration.25 Finally, selective NOE
irradiation of the aromatic Ph protons at C-2 caused an
enhancement of signals corresponding to H-1 and H-4,
which confirmed the axial disposition of the Ph group at
C-2 in both 18 and 19.
ꢀ
thank the Ministerio de Ciencia e Innovacion, Spain
In conclusion, we have developed a general catalytic
strategy for the efficient synthesis of 2-arylglycals by
phosphine-free SuzukiÀMiyaura cross-coupling of 2-iodo-
glycals in aqueous media using an inexpensive Pd catalyst.
(Juan de la Cierva Fellowship to O.B. and predoctoral
fellowship to I.C.). B.G.D. is a recipient of a Royal Society
Wolfson Merit Award and is supported by an EPSRC LSI
Platform grant.
(22) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380.
(23) Initial attempts using Gin’s epoxidation conditions were unsuc-
cessful, see: (a) Honda, E.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 7343
and references therein. (b) Kim, J.-Y.; Di Bussolo, V.; Gin, D. Y. Org.
Lett. 2001, 3, 303.
Supporting Information Available. Experimental pro-
cedures, additional experiments, characterization data,
and copies of 1H, 13C and 19F NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Cheshev, P.; Marra, A.; Dondoni, A. Carbohydr. Res. 2006, 341,
2714.
(25) Tvaroska, I.; Taravel, F. R. Adv. Carbohydr. Chem. Biochem.
1995, 51, 15.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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