Diastereoselective metal-catalyzed synthesis of C-aryl and C-vinyl glycosides

Article abstract of DOI:10.1002/anie.201204786

Cobalt, the catalyst of choice: The diastereoselective cobalt-catalyzed cross-coupling of 1-bromo glycosides and aryl or vinyl Grignard reagents is described. A convenient and inexpensive catalyst, [Co(acac)₃]/tmeda (acac=acetylacetonate, tmeda=N,N'-tetramethylethylenediamine), gives full α selectivity in the mannose and galactose series, and an α selectivity in the glucose series with α/β ratios of 1.3:1-3:1. Copyright

Full text of DOI:10.1002/anie.201204786

Angewandte
Chemie
DOI: 10.1002/anie.201204786
Synthetic Methods
Diastereoselective Metal-Catalyzed Synthesis of C-Aryl and C-Vinyl
Glycosides**
Lionel Nicolas, Patrick Angibaud, Ian Stansfield, Pascal Bonnet, Lieven Meerpoel,
Sꢀbastien Reymond,* and Janine Cossy*
C-glycosides are an important class of carbohydrate ana-
logues with applications as potent pharmaceutical com-
pounds.[1] As they are more resistant to metabolic processes
than O-glycosides, C-glycosides can be good drug candidates
for inhibitors of carbohydrate processing enzymes. Moreover,
C-aryl glycosides have been revealed to be of particular
biological importance, with some of them occurring natu-
rally.[1,2] Although numerous methods exist to prepare
C-glycosides,[1–4] the development of convergent and catalytic
methods is of the utmost importance. Metal-catalyzed cross-
coupling reactions between 1-halogeno glycosides and orga-
À
nometallics to form an anomeric C C bond are powerful and
versatile reactions to access C-glycosides. However, the major
Scheme 1. Recent developments in the coupling of 1-halogeno glyco-
drawback of these coupling reactions is a b-H elimination or
a b-elimination of the C2-substituent. Gagnꢀ et al. have
described a diastereoselective Negishi cross-coupling applied
to 1-halogeno glycosides, catalyzed by [Ni(cod)2]/tBu-Terpy,
(cod = 1,5-cyclooctadiene) leading to fully oxygenated C-aryl
and C-alkyl glycosides, with only traces of the corresponding
glucal (Scheme 1).[5,6] Recently, Lemaire et al. have reported
a metal-free coupling of Ar2Zn reagents with 1-bromo
glycosides with full b-selectivitiy in the glucose series and
full a selectivity in the mannose series, owing to the anchi-
meric assistance of the O-pivaloyl group at C2 (Scheme 1).[7]
Herein, we report the diastereoselective metal-catalyzed
cross-coupling between 1-bromo glycosides and easily acces-
sible or commercially available Grignard reagents, which
allows for the synthesis of an array of C-aryl and C-vinyl
glycosides with a selectivity when a cobalt- or iron-centered
catalytic system is used (Scheme 1).
sides and aryl organometallic reagents. Ac=acetate, acac=acetyl-
acetonate, cod=1,5-cyclooctadiene, dppe=1,2-bis(diphenylphos-
phino)ethane, tmeda=N,N’-tetramethylethylenediamine.
halides,[8,9] and considering the good compatibility of iron
catalysts with secondary alkyl halides possessing
b-hydrogen atoms,[10] the coupling reaction of O-acetyl-a-
bromo-d-mannose (1) with PhMgBr, which involved a combi-
nation of iron salts and ligands, was investigated (see the
Supporting Information). The best conditions for the cross-
coupling required three equivalents of PhMgBr to reach full
conversion of 1-bromo glycoside 1; however, coupling prod-
uct 2 was isolated in only 42% and glucal 3 was also produced
in 46% yield using FeCl3 (5 mol%)/Xantphos (10 mol%;
Xantphos
= 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene; Scheme 2). When the same conditions were applied
to O-acetyl-a-bromo-d-glucose (4), coupling product 5 was
isolated in 17% yield with a 3:1 a/b ratio, and the major
product obtained was glucal 3 (48%; Scheme 2). Interestingly,
1-bromo glycosides 1 and 4 both diastereoselectively led to
cross-products 2 and 5, respectively, with the a isomer being
the major product.
Motivated by our previous results with iron-catalyzed
cross-coupling between vinyl Grignard reagents and alkyl
[*] Dr. L. Nicolas, Dr. S. Reymond, Prof. Dr. J. Cossy
Laboratoire de Chimie Organique
ESPCI ParisTech, UMR CNRS 7084
10 Rue Vauquelin—75231 Paris Cedex 05 (France)
E-mail: sebastien.reymond@espci.fr
janine.cossy@espci.fr
Dr. P. Angibaud, Dr. I. Stansfield
Janssen Research & Development, Oncology Medicinal Chemistry
Campus de Maigremont—BP615–27106
Val de Reuil Cedex (France)
Dr. P. Bonnet, Dr. L. Meerpoel
Janssen Research & Development, Janssen Pharmaceutica N.V.
Turnhoutsweg 30, 2340 Beerse (Belgium)
[**] Janssen Research & Development (grant to L.N.) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204786.
Scheme 2. Iron-catalyzed cross-coupling of PhMgBr and 1-bromo
glycosides 1 and 4.
Angew. Chem. Int. Ed. 2012, 51, 11101 –11104
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11101

.
Angewandte
Communications
Iron-catalyzed cross-coupling reactions have been sug-
gested to proceed by an oxidative addition of a low-valent
affecting the yield of 2 (Table 1, entry 6). However, the
replacement of [Co(acac)3] by [Co(acac)2] decreased the yield
of 2 (54%) (Table 1, entry 7). On the basis of these results, we
selected [Co(acac)3] as the cobalt source, as it is less
hygroscopic than CoCl2, and tmeda, which is cheaper than
N,N’-tetramethyl-trans-cyclohexanediamine or dppe, as the
additive.
À
iron intermediate into the C1 Br bond, a process which
involves the formation of a carbon-centered radical.[8,11] As
a carbon-centered anomeric radical intermediate can be
hypothesized to account for the observed a selectivity
(Scheme 2),[4b,6,12] and as carbon-centered radical intermedi-
ates were also suggested to occur in cobalt-catalyzed cross-
coupling reactions between alkyl halides and Grignard
reagents,[13,14] we turned our attention to the cobalt-catalyzed
coupling of O-acetyl-a-bromo-d-mannose (1) with PhMgBr
(Table 1). Moreover, as cobalt-catalyzed cross-coupling reac-
tions between aryl Grignard reagents and alkyl halides do not
suffer from b-H elimination,[13] and tolerate a-oxygenated
substituents on alkyl halides,[14a,c–g,i–l] the formation of glucal 3
should be decreased.
The optimized conditions were applied to evaluate the
scope and limitations of the cobalt-catalyzed cross-coupling
of aryl Grignard reagents with 1-bromo glycosides 1, 4, and 6;
the results are reported in Table 2. With 1-bromo mannose
derivative 1 (Table 2, entries 1–8), the cross-coupling was
diastereoselective, as only the a isomer was detected. Elec-
tron-rich or electron-poor Grignard reagents led to similar
results (70–83% yield of isolated product; Table 2, entries 1–
5); however, bulkier Grignard reagents induced lower yields
(Table 2, entries 6 and 7). The cross-coupling was also
possible with an N-methylindole Grignard reagent, which
afforded the corresponding coupling product in 53% yield
(Table 2, entry 8). On the other hand, with o-CF3-PhMgCl, 2-
thienylmagnesium bromide, and an N-methylpyrazole
derived Grignard reagent, no cross-coupling products were
observed, and 1 was recovered (Table 2, entries 9–11). With
1-bromo glycoside 4, which is derived from glucose, the
coupling with aryl Grignard reagents was still diastereo-
selective in favor of the a isomers, which were obtained in
good yields, but with a lower a/b ratio (1.3:1–3:1; Table 2,
entries 12–16). When O-acetyl-a-bromo-d-galactose (6) was
used as the electrophile, the cross-coupling was diastereo-
selective (only the a isomer was detected) and the C-aryl
glycosides were obtained in moderate to good yields (Table 2,
entries 17–21).
Table 1: Optimization of the cobalt-catalyzed cross-coupling of PhMgBr
and 1-bromo glycoside 1.[a]
Entry
Cobalt source
(mol%)
Ligand
(mol%)
Yield of 2
3[c]
[%][b]
1
2
[Co(acac)3] (5)
CoCl2 (5)
–
–
10%
13%
trace
–
3
CoCl2 (5)
74%
–
4
5
CoCl2 (5)
dppe (5)
73%
76%
75%
54%
–
–
–
–
[Co(acac)3] (5)
[Co(acac)3] (1)
[Co(acac)2] (5)
tmeda (5)
tmeda (1)
tmeda (5)
6
As an extension of this study, and owing to the synthetic
value of C-vinyl glycosides, the reactivity of bromides 1, 4, and
6 with alkenyl Grignard reagents was evaluated (Table 3). We
were delighted to isolate the expected C-vinyl glycosides with
full a selectivity for bromides 1 and 6 (Table 3, entries 1, 2, 5,
and 6). In the case of 1-bromo glycoside 4, a moderate a/b
selectivity (1.5:1) was observed (Table 3, entry 4). Unexpect-
edly, vinylMgBr failed to react, and the starting bromide was
recovered (Table 3, entry 3).
7[d]
[a] Conditions: 1 (0.1m in THF), PhMgBr (1m in THF; 1.5 equiv) was
added at a rate of 2 mLminÀ1; once the addition was complete, the
reaction medium was warmed to RT. [b] Yield of isolated product.
[c] Detected by GC-MS. [d] 2.2 equiv of PhMgBr were used. acac=
acetylacetonate, dppe=1,2-bis(diphenylphosphino)ethane, tmeda =
N,N’-tetramethylethylenediamine.
The cobalt-centered catalytic system in the cross-coupling
of O-acetyl-a-bromo-d-mannose (1) and PhMgBr (1.5 equiv)
in THF was examined, and the results are reported in Table 1.
The use of [Co(acac)3] (5 mol%) in the absence of any ligand
led to product 2 in only 10% yield with traces of glucal 3
(Table 1, entry 1), and the use of CoCl2 (5 mol%) led to 2 in
only 13% yield (Table 1, entry 2). With the combination of
CoCl2 and N,N’-tetramethyl-trans-cyclohexanediamine as
a ligand, (5 and 6 mol%, respectively),[14f] the expected
product 2 was obtained in 74% yield as a single a isomer
(Table 1, entry 3). Replacing N,N’-tetramethyl-trans-cyclo-
From a mechanistic point of view, the stereochemical
outcome of this cobalt-catalyzed cross-coupling seems to
support a radical pathway, as suggested in the literature.[13,14]
In our case, the formation of an anomeric radical intermediate
at C1 during the oxidative addition of low-valent cobalt
species would induce an a-selective cross-coupling.[4b,6,12] To
verify if a radical pathway is operational in the cobalt-
catalyzed cross-coupling of 1-bromo glycosides with aryl
Grignard reagents, the reactivity of d-olefinic 1-bromo glyco-
side 7 was examined (Scheme 3). Treatment of 7 with
PhMgBr under our reaction conditions [PhMgBr
(1.5 equiv), [Co(acac)3] (5 mol%), tmeda (5 mol%)] pro-
duced an epimeric mixture of bicyclic compound 8 (d.r. = 1:1),
which was isolated in 88% yield. This product results from the
formation of an anomeric radical that leads to a 5-exo-trig
cyclization followed by cross-coupling with PhMgBr, which
suggests that the cyclization is faster than the direct cross-
coupling.[16]
hexanediamine
with
1,2-bis(diphenylphosphino)ethane
(dppe; 5 mol%)[14l] led to a similar result (73% yield of 2;
Table 1, entry 4), and the use of [Co(acac)3] (5 mol%) and
tmeda (N,N’-tetramethylethylenediamine)[14a] (5 mol%)
afforded 2 in 75% yield as a single a isomer (Table 1,
entry 5).[15] The catalytic loading could be decreased to
1 mol% of [Co(acac)3] and tmeda without significantly
11102 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11101 –11104

Angewandte
Chemie
Table 2: Scope of the cobalt-catalyzed cross-coupling of ArMgX and
1-bromo glycosides 1, 4, and 6.[a]
Table 3: Scope of the cobalt-catalyzed cross-coupling of alkenyl Grignard
reagents and 1-bromo glycosides 1, 4, and 6.[a]
Entry
1
Substrate
ArMgX
Yield [%][b]
70
a/b[c]
>9:1
Entry
Substrate
AlkenylMgBr
Yield [%][b]
66
a/b[c]
>9:1
>9:1
1
1
2
1
1
2
3
4
1
1
1
82
83
72
>9:1
>9:1
>9:1
62[d]
3
4
1
4
–
–
79
1.5:1
5
6
6
6
77
>9:1
>9:1
70[d]
5
6
1
1
77
37
>9:1
>9:1
[a] AlkenylMgBr (1.5 equiv) was added at a rate of 2 mLminÀ1; once the
addition was complete, the reaction medium was warmed to RT. [b] Yield
of isolated product. [c] Determined by 1H NMR spectroscopy. [d] Alke-
nylMgBr (2 equiv).
7
1
39
53
>9:1
8
9
1
1
>9:1
[d]
–
–
Scheme 3. Cross-coupling of 1-bromo glycoside 7 with PhMgBr.
[d]
10
11
1
1
–
–
–
[d]
–
catalytic system is convenient (both the catalyst and the
ligand are commercially available), inexpensive, and air-
stable. When O-acetyl-a-bromo-d-glucose (4) was used, good
diastereoselectivities were obtained with moderate a/b ratios
of 1.5:1–3:1. The cross-coupling is fully a-selective in the case
of O-acetyl-a-bromo-d-mannose (1), and O-acetyl-a-bromo-
d-galactose (6). The observed diastereoselectivities with
1-bromo glycosides 1, 4, and 6, as well as the cyclization of
olefinic 1-bromo glycoside 7 strongly support a radical path-
way for the oxidative addition step of the cross-coupling,
which involves the formation of an anomeric radical.
12
13
4
4
PhMgBr
96
83
3:1
2.4:1
14
15
4
4
85
81
2.3:1
2:1
16
17
4
34
61
1.3:1
PhMgBr
>9:1
Received: June 16, 2012
Published online: September 28, 2012
18
19
20
6
6
6
82
73
75
>9:1
>9:1
>9:1
Keywords: C-glycosides · cobalt · cross-coupling ·
.
diastereoselectivity · Grignard reagent
21
6
53
>9:1
[1] a) J. Stanbasky, M. Hocek, P. Kosovsky, Chem. Rev. 2009, 109,
6729 – 6764; b) Q. Wu, C. Simons, Synthesis 2004, 1533 – 1553;
c) P. G. Hultin, Curr. Top. Med. Chem. 2005, 5, 1299 – 1331; d) W.
Zou, Curr. Top. Med. Chem. 2005, 5, 1363 – 1391; e) P. Compain,
O. R. Martin, Bioorg. Med. Chem. 2001, 9, 3077 – 3092; f) F.
Nicotra, Top. Curr. Chem. 1997, 187, 55 – 83.
[2] a) T. Bililign, B. R. Griffith, J. S. Thorson, Nat. Prod. Rep. 2005,
22, 742 – 760; b) K. W. Wellington, S. A. Benner, Nucleosides
Nucleotides Nucleic Acids 2006, 25, 1309 – 1333.
[a] ArMgBr (1.5 equiv) was added at a rate of 2 mLminÀ1; once the
addition was complete, the reaction medium was warmed to RT. [b] Yield
of isolated product. [c] Determined by 1H NMR spectroscopy. [d] 1 was
recovered.
In conclusion, we have described the diastereoselective
cobalt-catalyzed cross-coupling of 1-bromo glycosides with
aryl and vinyl Grignard reagents. The [Co(acac)3]/tmeda
[3] For examples, see: a) D. Y. W. Lee, M. He, Curr. Top. Med.
Chem. 2005, 5, 1333 – 1350; b) L. Somsꢁk, Chem. Rev. 2001, 101,
Angew. Chem. Int. Ed. 2012, 51, 11101 –11104
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11103

.
Angewandte
Communications
81 – 135; c) Y. Du, R. J. Linharrdt, Tetrahedron 1998, 54, 9913 –
9959; d) C. Jaramillo, S. Knapp, Synthesis 1994, 1 – 20; e) D. E.
Levy, C. Tang in The Chemistry of C-glycosides (Tetrahedron
Organic Chemistry Series, Vol. 13), Elsevier, Oxford, 1995;
f) J. M. Beau, T. Gallagher, Top. Curr. Chem. 1997, 187, 1 – 54;
g) M. Choumane, A. Banchet, N. Probst, S. Gꢀrard, K. Plꢀ, A.
Haudrechy, C. R. Chim. 2011, 14, 235 – 273.
Commun. 2005, 4161 – 4163; d) R. Martin, A. Fꢃrstner, Angew.
Chem. 2004, 116, 4045 – 4047; Angew. Chem. Int. Ed. 2004, 43,
3955 – 3957; e) Y. Hayashi, H. Shinokubo, K. Oshima, Tetrahe-
dron Lett. 1998, 39, 63 – 66.
[12] a) N. Miquel, G. Doisneau, J. M. Beau, Angew. Chem. 2000, 112,
4277 – 4280; Angew. Chem. Int. Ed. 2000, 39, 4111 – 4114;
b) H. G. Korth, J. Dupuis, B. Giese, J. Chem. Soc. Perkin Trans.
2 1986, 1453 – 1459; c) J. Dupuis, B. Giese, J. Am. Chem. Soc.
1985, 107, 4332 – 4333; d) J. Dupuis, B. Giese, D. Rꢃegge, H.
Fischer, H. G. Korth, R. Sustmann, Angew. Chem. 1984, 96, 887 –
888; Angew. Chem. Int. Ed. Engl. 1984, 23, 896 – 898; e) B. Giese,
J. Dupuis, Angew. Chem. 1983, 95, 633 – 634; Angew. Chem. Int.
Ed. Engl. 1983, 22, 622 – 623; f) R. M. Adlington, J. E. Baldwin,
A. Basak, R. P. Kozyrod, J. Chem. Soc. Chem. Commun. 1983,
944 – 945.
[4] For recent methods, see: a) J. Zheng, S. Vedachalam, S. Xiang,
X. W. Liu, Org. Lett. 2011, 13, 42 – 45; b) G. Li, D. C. Xiong, X. S.
Ye, Synlett 2011, 2410 – 2414; c) R. S. Andrews, J. J. Becker,
M. R. Gagnꢀ, Angew. Chem. 2010, 122, 7432 – 7434; Angew.
Chem. Int. Ed. 2010, 49, 7274 – 7276; d) H. Gong, R. S. Andrews,
J. L. Zuccarello, S. J. Lee, M. R. Gagnꢀ, Org. Lett. 2009, 11, 879 –
882; e) K. P. Kaliappan, A. V. Subrahmanyam, Org. Lett. 2007, 9,
1121 – 1124; f) S. F. Martin, Pure Appl. Chem. 2003, 75, 63 – 70.
[5] H. Gong, R. Sinisi, M. R. Gagnꢀ, J. Am. Chem. Soc. 2007, 129,
1908 – 1909.
[13] For a recent review, see: G. Cahiez, A. Moyeux, Chem. Rev.
2010, 110, 1435 – 1462.
[6] H. Gong, M. R. Gagnꢀ, J. Am. Chem. Soc. 2008, 130, 12177 –
12183.
[7] S. Lemaire, I. N. Houpis, T. Xiao, J. Li, E. Digard, C. Gozlan, R.
Liu, A. Gavryushin, C. Diꢂne, Y. Wang, V. Farina, P. Knochel,
Org. Lett. 2012, 14, 1480 – 1483.
[14] For examples of cobalt-catalyzed cross-coupling reactions
involving secondary alkyl halides, see: a) G. Cahiez, C. Cha-
boche, C. Duplais, A. Moyeux, Org. Lett. 2009, 11, 277 – 280;
b) M. Amatore, C. Gosmini, Chem. Commun. 2008, 5019 – 5021;
c) H. Someya, H. Ohmiya, H. Yorimitsu, K. Oshima, Org. Lett.
2007, 9, 1565 – 1567; d) H. Someya, H. Ohmiya, H. Yorimitsu, K.
Oshima, Tetrahedron 2007, 63, 8609 – 8618; e) H. Ohmiya, H.
Yorimitsu, K. Oshima, Org. Lett. 2006, 8, 3093 – 3096; f) H.
Ohmiya, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2006, 128,
1886 – 1889; g) H. Ohmiya, K. Wakabayashi, H. Yorimitsu, K.
Oshima, Tetrahedron 2006, 62, 2207 – 2213; h) H. Yorimitsu, K.
Oshima, Pure Appl. Chem. 2006, 78, 441 – 449; i) H. Someya, A.
Kondoh, A. Sato, H. Ohmiya, H. Yorimitsu, K. Oshima, Synlett
2006, 3061 – 3062; j) H. Ohmiya, T. Tsuji, H. Yorimitsu, K.
Oshima, Chem. Eur. J. 2004, 10, 5640 – 5648; k) T. Tsuji, H.
Yorimitsu, K. Oshima, Angew. Chem. 2002, 114, 4311 – 4313;
Angew. Chem. Int. Ed. 2002, 41, 4137 – 4139; l) K. Wakabayashi,
H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2001, 123, 5374 –
5375.
[8] A. Guꢀrinot, S. Reymond, J. Cossy, Angew. Chem. 2007, 119,
6641 – 6644; Angew. Chem. Int. Ed. 2007, 46, 6521 – 6524.
[9] For a review on cross-coupling reactions involving secondary
alkyl halides, see: A. Rudolph, M. Lautens, Angew. Chem. 2009,
121, 2694 – 2708; Angew. Chem. Int. Ed. 2009, 48, 2656 – 2670.
[10] For recent reviews on iron-catalyzed cross-coupling reactions,
see: a) Iron Catalysis in Organic Chemistry (Ed.: B. Plietker),
Wiley-VCH, Weinheim, 2008; b) R. Jana, T. P. Pathak, M. S.
Sigman, Chem. Rev. 2011, 111, 1417 – 1492; c) E. Nakamura, N.
Yoshikai, J. Org. Chem. 2010, 75, 6061 – 6067; d) B. Plietker,
Synlett 2010, 2049 – 2058; e) W. M. Czaplik, M. Mayer, J.
Cvengros, A. J. von Wangelin, ChemSusChem 2009, 2, 396 –
417; f) B. D. Sherry, A. Fꢃrstner, Acc. Chem. Res. 2008, 41,
1500 – 1511; g) S. Enthaler, K. Junge, M. Beller, Angew. Chem.
2008, 120, 3363 – 3367; Angew. Chem. Int. Ed. 2008, 47, 3317 –
3321; h) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev. 2004,
104, 6217 – 6254.
[15] The cross-coupling of 1 and PhMgBr is not possible in Et2O.
However, when the cross-coupling was performed in THF using
a solution of PhMgBr in Et2O (3m), the yield of 2 remained
76%.
[16] The use of TEMPO (20 mol%) partially inhibits the coupling of
1 and PhMgBr (2 was isolated in 14%); whereas, with one
equivalent of TEMPO, the cross-coupling is fully inhibited.
[11] a) X. Lin, F. Zheng, F. L. Qing, Organometallics 2012, 31, 1578 –
1582; b) T. Hatakeyama, Y. Okada, Y. Yoshimoto, M. Naka-
mura, Angew. Chem. 2011, 123, 11165 – 11168; Angew. Chem.
Int. Ed. 2011, 50, 10973 – 10976; c) R. B. Bedford, M. Betham,
D. W. Bruce, A. A. Danopoulos, R. M. Frost, M. Hird, Chem.
11104 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11101 –11104