Enantiopure β-hydroxysulfoxide derivatives as novel chiral auxiliaries in asymmetric biaryl suzuki reactions

Article abstract of DOI:10.1021/ol0351908

Highly diastereoselective biaryl Suzuki coupling reactions of (1R)-1-(2-iodo or bromophenyl)-2-(R)-(4-tolylsulfinyl)-1-ethanol derivatives with various aryl- or naphthylboronic acids (or esters) were performed with high yields (up to 99%) and an excellent control of the axial chirality (up to 98% de).

Full text of DOI:10.1021/ol0351908

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3281-3284
Enantiopure â-Hydroxysulfoxide
Derivatives as Novel Chiral Auxiliaries
in Asymmetric Biaryl Suzuki Reactions
Pierre-Emmanuel Broutin and Franc¸oise Colobert*
Laboratoire de ste´re´ochimie associe´ au CNRS, UMR 7008 UniVersite´ Louis Pasteur,
ECPM 25 rue Becquerel, 67087 Strasbourg Cedex 2, France
fcolober@chimie.u-strasbg.fr
Received June 26, 2003
ABSTRACT
Highly diastereoselective biaryl Suzuki coupling reactions of (1R)-1-(2-iodo or bromophenyl)-2-(R)-(4-tolylsulfinyl)-1-ethanol derivatives with
various aryl- or naphthylboronic acids (or esters) were performed with high yields (up to 99%) and an excellent control of the axial chirality
(up to 98% de).
Axially chiral biaryls are of importance not only as chiral
ligands1 in asymmetric reactions but also as biologically
active natural products, e.g., steganone,2 vancomycin,3 and
michellamine....4 A few successful methods using either
chiral ligands, stoichiometric chiral auxiliaries, or chiral
starting materials allow asymmetric synthesis of this biaryl
subunit.5 However, efficient examples of asymmetric Suzuki
reactions are relatively rare and have been reported only in
the past few years. The use of chiral ligands was first
explored by Nicolaou6 in the total synthesis of vancomycin.
Cammidge7 and Buchwald8 very recently reported atropo-
enantioselective Suzuki couplings induced by chiral ligands
for the synthesis of binaphthyl or phenylnaphthyl compounds.
We recently communicated asymmetric Suzuki coupling with
chiral phosphine ligands in the synthesis of 2,2′-dimethoxy-
1,1′-dinaphthalene. The results show that the ratio of BINAP
and Tol-BINAP to Pd(OAc)2 or (η3-allylPdCl)2 influences
the sense of the enantioselectivity.9 Another example of
(1) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525 and
references therein.
(2) Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Gilmore, C. J.;
Restivo, R. J.; Brian, R. F. J. Am. Chem. Soc. 1973, 95, 1335.
(3) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38, 1172.
(4) Bringmann, G.; Pokorny, F. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: New York, 1995; Vol. 46, p 127.
(5) (a) For a review, see: Bringmann, G.; Walter, R.; Weirich, R. Angew.
Chem., Int. Ed. 1990, 29, 977. (b) Meyers, A. I.; Lutomski, K. A. J. Am.
Chem. Soc. 1982, 104, 879. (c) Meyers, A. I.; Himmelsbach, R. J. J. Am.
Chem. Soc. 1985, 107, 682. (d) Wilson, J. M.; Cram, D. J. Org. Chem.
1984, 49, 4930. (e) Wilson, J. M.; Cram, D. J. J. Am. Chem. Soc. 1982,
104, 881. (f) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999,
38, 3530. (g) Feldmann, K. S.; Smith, R. S. J. Org. Chem. 1996, 61, 2606.
(h) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem.
Soc. 1999, 121, 8943. (i) Lin, G.-G.; Zhong, M. Tetrahedron: Asymmetry,
1997, 8, 1369. (j) Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem.
1996, 61, 1375. (k) Brusse, J.; Groenendijk, J. L. G.; te Copele, J. M.;
Jansen, A. C. A. Tetrahedron 1985, 41, 3313. (l) Hayashi, T.; Hayashizaki,
K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 10, 8153. (m) Hayashi, T.;
Hayashizaki, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 215. (n) Hayashi, T.;
Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc.
1995, 117, 9101. (o) Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55,
3455.
(6) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue,
T.-Y.; Natarajan, S.; Chu, X.-J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999,
5, 2584.
(7) Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723.
(8) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051.
10.1021/ol0351908 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/06/2003

enantioselective Suzuki coupling was described by Baudoin
in the synthesis of an axially chiral antimitotic biaryl.10
Diastereoselective Suzuki couplings were only reported by
Uemura5j using chiral arene(chromium)halide complexes.
tosulfoxide 1a in 80% yield. Diastereoselective reduction
with DIBAL in the presence of ZnCl2 is known to provide
the desired [2(R),S(R)]-â-hydroxy sulfoxide 2a in which the
OH group is syn to the bulky substituant of the sulfoxide
(Scheme 1.).13
It is surprising that the chiral auxiliary approach, presum-
ably less substrate dependent, has been rarely investigated.
Although sulfoxides have proved to be efficient chiral
auxiliaries in asymmetric synthesis11 especially in C-C bond
formation such as Diels-Alder cycloadditions or nucleophilic
additions, only a few examples are known in asymmetric
transition-metal-catalyzed reactions.12 In connection with our
interest in the synthesis of biaryls with axial chirality, we
report here the first examples of asymmetric biaryl Suzuki
coupling reactions using enantiopure â-hydroxy- and â-meth-
oxysulfoxides as chiral auxiliaries with a powerful control
of the axial chirality.
Scheme 1. Synthesis of the â-Hydroxysulfoxide 2a
Table 1 summarizes the results obtained in the palladium-
catalyzed Suzuki coupling of 2-methoxy-1-naphthylboronic
acid 3a and the enantiopure (1R)-1-(2-iodophenyl)-2(R)-(4-
tolylsulfinyl)-1-ethanol 2a.
We have reported efficient conditions for sterically
hindered Suzuki cross-couplings,9 e.g., DME and cesium
fluoride in the presence of Pd(OAc)2 and triphenylphosphine.
Therefore, we studied the Suzuki coupling reaction between
2-methoxy-1-naphthyl boronic acid 3a and the readily
available enantiopure (1R)-1-(2-iodophenyl)-2-(R)-(4-tolyl-
sulfinyl)-1-ethanol 2a as a model reaction (Table 1.).
Dppf with Pd(OAc)2 in dioxane or THF was found to give
remarkable stereocontrol (de 94-96%)14 with a yield of 70%
in dioxane at reflux (Table 1, entries 1 and 2). However, we
observed the hydrodehalogenation of the aryl iodide (20%
in the case of the coupling reaction performed in dioxane).
Use of the racemic BINAP or 2-(di-tert-butylphosphino)-
biphenyl (ligand A) did not provide any coupling product.
Surprisingly, 1,3-bis-(2,6-diisopropylphenyl)imidazolidine
(ligand B) and its imidazolium salt (ligand C) gave the
coupling product with opposite axial chirality (de 70%), a
surprising result probably due to the Pd complexes (Table
1, entries 5 and 6). In this case, mono crystals of the major
diastereomer 5a were obtained from ethyl acetate at 20 °C.
Analysis by X-ray crystallography15 revealed that the con-
figuration of the chiral axis was aS (Figure 1).
Table 1. Suzuki Reactions of 2a with
2-Methoxy-1-naphthylboronic Acid 3aa
biaryl
yieldb
starting reduction
material product
drc
entry
ligand
dppf
dppf
solvent
(%) 4a /5a yield (%) yield (%)
1
2
3
4
5
6
dioxane
THF
70
50
0
97/3
98/2
9
33
85
20
17
<15
rac BINAP dioxane
A
B
C
dioxane
dioxane
dioxane
0
50
20
>85
50
80
15/85
15/85
0
a Reaction conditions: 2a (1 equiv), 2-methoxy-1-naphthyl boronic acid
3a (2 equiv), Pd(OAc)2 (10 mol %), bidentate ligand (15 mol %),
monodentate ligand (30 mol %), CsF (4 equiv), 70 °C, 3-5 h. b Isolated
product after chromatography. c Determined by 1H NMR on the crude
mixtures.
Figure 1. Crystal structure of 5a.
We performed the asymmetric Suzuki reaction on other
coupling partners using Pd(OAc)2 with dppf in dioxane
(Table 2.). The various â-hydroxysulfoxides 2 were obtained
using the same methodology as for the synthesis of the
Condensation of the lithiated anion of (+)-(R)-methyl-p-tolyl
sulfoxide to the 2-iodo-1-methylbenzoate afforded the â-ke-
(11) (a) Solladie´, G.; Carren˜o, M. C. in Organosulfur Chemistry:
Synthetic Aspects; Page, P. C. B., Ed.; Academic Press: New York, 1995;
pp 1-47. (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.
Tetrahedron: Asymmetry 1997, 8, 1339. (c) Carren˜o, M. C. Chem. ReV.
1995, 95, 1717.
(9) Castanet, A.-S.; Colobert, F.; Broutin, P.-E.; Obringer, M. Tetrahe-
dron: Asymmetry 2002, 13, 659.
(10) Herrbach, A.; Marinetti, A.; Baudoin, O.; Gue´nard, D.; Gue´ritte, F.
J. Org. Chem. 2003, 68, 4897.
3282
Org. Lett., Vol. 5, No. 18, 2003

Table 2. Suzuki Coupling Reactions between
â-Hydroxysulfoxides 2 and Boronic Acids 3a
Table 3. Suzuki Coupling Reactions between
â-Methoxysulfoxides 6 and Boronic Acids 3 or Boronic Esters
7a
starting
reduction
product
biaryl
yield (%)b
material
yield (%)
entry
2
3
drc
yield (%)
1
2
3
4
5
6
2b
2b
2b
2c
2c
2c
3b
3c
3d
3b
3c
3d
0
0
60
27
0
99
>90
30
62
88
70/30
90/10
entry
6
3 or 7
ligand
Dppfb
PPh3
Dppfb
Dppfb
biaryl yieldd (%)
dre
61
93/7
23
1
2
3
4
5
6
7
8
9
10f
11
12
13
14
15
6a
6a
6a
6d
6b
6b
6b
6c
6c
6c
6f
3a
3a
3e
3a
7b
7c
7d
7b
7c
3d
7b
7c
7d
3a
3e
99
93
99
98
88
78
89
86
86
80
87
70
75
93
84
>99/1
>99/1
>99/1
>99/1
90/10
75/25
80/20
95/5
90/10
85/15
85/15
75/25
80/20
>99/1
>99/1
a Reaction conditions: 2 (1 equiv), 3 (2 equiv), Pd(OAc)2 (10 mol %),
dppf (15 mol %), CsF (4 equiv), 70 °C, 3-5 h. b Isolated product after
c
chromatography. c Determined by H NMR on the crude mixtures.
1
c
PPh3
PPh3
PPh3
PPh3
c
c
â-hydroxysulfoxide 2a with good yields and diastereoselec-
tivities (Scheme 1).
c
c
PPh3
The o-methoxyphenyl iodide 2c in coupling reaction with
o-methoxyphenylboronic acid 3d gave good yield and
diastereoselectivity (Table 2, entry 6). However, with the
other coupling partners major hydrodehalogenation of the
aryl halide occurred.
Either the free hydroxy group or the acidic protons of the
boronic acid might be responsible for the reduction of the
aryl halide. Therefore, we decided to protect the hydroxy
group of the â-hydroxysulfoxides 2 (as a methoxy) in the
presence of NaH and methyliodide in DMF at -20 °C.
Excellent yields were obtained for the formation of the
corresponding â-methoxysulfoxides 6a-f.
Furthermore, we synthesized in good yields the boronic
esters 7a-e by condensation of ethylene glycol with the
boronic acids 3a-e in the presence of CaH2 in refluxing
THF.
Table 3 summarizes the results obtained in the palladium-
catalyzed Suzuki coupling of various boronic acids 3 or esters
7 with various â-methoxysulfoxides 6.
Dppfb
Dppfb
c
6f
6f
6e
6e
PPh3
PPh3
PPh3
PPh3
c
c
c
a Reaction conditions: 6 (1 equiv), 3 or 7 (2 equiv), CsF (4 equiv), reflux
dioxane, 1 h. b Pd(OAc)2 (10 mol %), dppf (15 mol %). c Pd(OAc)2 (3 mol
%), PPh3 (9 mol %). d Isolated product after chromatography. e Determined
1
by H NMR on the crude mixtures. f 70 °C.
in only 1 h the coupling product with an excellent yield
(>99%) and a complete control of the diastereoselectivity
(>98% de) (Table 3, entry 1).
No trace of the other diastereomer was detected by 13C
and 1H NMR.16 Furthermore, using PPh3 (9 mol %) as ligand
with 3 mol % of Pd(OAc)2 afforded the coupling product
with the same diastereoselectivity and slightly lower yield
(Table 3, entry 2). With the bromide 6d instead of the iodide
the results are identical (Table 3, entry 3). In the same way,
a coupling reaction of 6a with 2-methyl-1-naphthyl boronic
acid 3e occurred with excellent yield and diastereoselectivity
(Table 3, entry 4). Starting from the bromide 6e with a nitro
group in the para position and 2-methoxy-1-naphthylboronic
acid 3a or 2-methyl-1-naphthylboronic acid 3e, the coupling
products were obtained very efficiently (Table 3, entries 14
and 15). â-Methoxysulfoxide bearing a naphthyl moiety 6f
The first attempt between the iodide 6a and 2-methoxy-
1-naphthylboronic acid 3a using Pd(OAc)2 and dppf gave
(12) Recent references: (a) Buezo, N. D.; De la Rosa, J. C.; Priego, J.;
Alonso, I.; Carretero, J. C. Chem. Eur. J. 2001, 7, 3890 and references
therein. (b) Henrich, M.; Delgado, A.; Molins, E.; Roig, A.; Llebaria, A.
Tetrahedron Lett. 1999, 40, 4259. (c) Paley, R. S.; Estroff, L. A.; McCulley,
D. J.; Martinez-Cruz, L. A.; Jimenez Sanchez, A.; Cano, F. H. Organo-
metallics 1998, 17, 1841.
(13) Solladie´-Cavallo, A.; Suffert, J.; Adib, A.; Solladie´, G. Tetrahedron
Lett. 1990, 31, 6649.
(14) The diastereomeric ratio was established by H NMR studies: the
1
chemical shifts of the methoxy and the methyl(p-tolyl) groups were
significantly different.
(15) We thank Dr. Nathalie Gruber for assistance with the analysis of
the crystal structure (Service commun Rayons X, 4 rue Blaise Pascal, 67070
Strasbourg cedex, e-mail: sercomrx@chimie.u-strasbg.fr).
(16) We did the synthesis of the other diastereomer with opposite axial
chirality by synthesis of the methyl ether of the coupling biaryl product
obtained with ligand B, and we noticed by 1H and 13C NMR studies the
different chemical shifts for the two axial diastereomers (cf. the Supporting
Information).
Org. Lett., Vol. 5, No. 18, 2003
3283

in Suzuki coupling with various boronic esters 7b-d gave
good yields but control of the axial chirality was slightly
lower (up to 70% de) (Table 3, entries 11-13). The coupling
reaction between aryl iodides bearing a methoxy group in
an ortho′ position 6c or a methyl group in an ortho′ position
6b and phenyl or naphthylboronic acid or ester afforded the
coupling products in very good yields and selectivity up to
90% de (Table 3, entries 5-10).
Scheme 3. Suzuki Coupling between 11 and
2-Methoxy-1-naphthylboronic Acid 3a
To determine the relative contribution of both stereogenic
centers to the asymmetric induction of the coupling reaction,
we oxidized the sulfoxide to the corresponding sulfone with
m-CPBA in CH2Cl2 and we performed the coupling reaction
of sulfone 8 with 2-methoxy-1-naphthylboronic acid 3a. The
corresponding biaryl product 9 was obtained in 82% yield
and 70% diastereomeric excess. Therefore, the presence of
the sulfinyl group is essential for total control of the axial
chirality (98% de). However, this result indicates that the
diastereoselectivity of the coupling reaction is mainly
controlled by the stereogenic carbon atom which is closer
to the biaryl C-C bond formed (Scheme 2.).
to act as an efficient stereochemical controller in Suzuki
cross-coupling reactions between aryl and naphthyl moieties
giving either binaphthyl or biphenyl or phenylnaphthyl
compounds. The coupling products were obtained with
excellent yields. Another interesting result is the dependence
of the stereoselectivity with the ligand (dppf or imidazoli-
dine).
Further studies on the coupling reaction with some specific
substrates are ongoing in order to propose a model to
understand this high diastereoselectivity.
Scheme 2. Suzuki Coupling between the Sulfone 8 and
2-Methoxy-1-naphthylboronic Acid 3a
Given our interest in total synthesis, these asymmetric
cross-coupling reactions are promising because of the pos-
sible transformation of the chiral sulfoxide group in other
functions (by desulfurization, Pummerer reaction, etc.).17
Acknowledgment. This work was supported by the
CNRS and Ministe`re de la Recherche. P.-E.B. thanks la
re´gion Alsace for a fellowship.
We also synthesized the [2(S),S(R)]-â-hydroxy sulfoxide
10, the epimer of 6a at the stereogenic carbon atom by
diastereoselective reduction of the â-ketosulfoxide 1a with
DIBAL. Hence, the hydroxy group is anti to the bulky
substituent of the sulfoxide. After protection of the hydroxy-
group as methoxy 11, we performed the coupling reaction
of 11 with 2-methoxy-1-naphthylboronic acid 3a. The
coupling product 12 was obtained in 89% yield but only 10%
diastereomeric excess (Scheme 3.).
Supporting Information Available: General experimen-
tal procedure for the biaryl Suzuki cross-coupling reaction.
1H and 13C NMR chemical shifts of the enantiopure biaryl
compound formed by coupling reaction of 6a and 3a and its
axial diastereomer obtained with ligand B. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0351908
In conclusion, we have shown that the â-methoxysulfinyl
group with the methoxy syn to the p-tolyl substituant is able
(17) (a) De Lucchi, O.; Mioti, U.; Modena, G. Org. React. 1991, 40,
157. (b) Zasshi, Y. J. Pharm. Soc Jpn 1997, 117, 282.
3284
Org. Lett., Vol. 5, No. 18, 2003