Chiral sulfoxide-olefin ligands: Tunable stereoselectivity in Rh-catalyzed asymmetric 1,4-additions

Article abstract of DOI:10.1016/j.tet.2012.02.038

A class of chiral sulfoxide-olefins were designed and synthesized through concise routes. Their applications as ligands in Hayashi-Miyaura reaction were studied, which found that vinyl substituents of the ligands vary in stereocontrolling ability. Particularly, either isomer of adducts with excellent ees could be readily obtained through changing the position of the substituents of olefins as well as changing the configuration of the CC bond of the ligands. Meanwhile, the substrate scope of arylboronic acids and alkenes was clearly shown.

Full text of DOI:10.1016/j.tet.2012.02.038

Tetrahedron 68 (2012) 3220e3224
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Tetrahedron
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Chiral sulfoxideeolefin ligands: tunable stereoselectivity in Rh-catalyzed
asymmetric 1,4-additions
,
b
,
,
b
,
,b,
*
Guihua Chen a c, Jiangyang Gui a c, Peng Cao b, Jian Liao a
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
c Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A class of chiral sulfoxideeolefins were designed and synthesized through concise routes. Their appli-
cations as ligands in HayashieMiyaura reaction were studied, which found that vinyl substituents of the
ligands vary in stereocontrolling ability. Particularly, either isomer of adducts with excellent ees could be
readily obtained through changing the position of the substituents of olefins as well as changing the
configuration of the C]C bond of the ligands. Meanwhile, the substrate scope of arylboronic acids and
alkenes was clearly shown.
Received 10 January 2012
Received in revised form 7 February 2012
Accepted 14 February 2012
Available online 3 March 2012
Keywords:
Sulfoxideeolefin
Rh-catalyzed
Ó 2012 Elsevier Ltd. All rights reserved.
Stereoselectivity reversal
1,4-Addition
1. Introduction
ligands. Very recently, Knochel,15 Du,16 Xu,17 Wan18 and our group19
simultaneously reported a new type of chiral hybrid sulfureolefin
Development of novel chiral ligands for an efficient asymmetric
transformation has become increasingly important in current
asymmetric catalysis,1 and particularly, catalytic asymmetric syn-
thesis of both enantiomers of a chiral compound is one of the hot
topics in the chemical community.2 Generally, in a catalytic asym-
metric protocol, to access each enantiomer of chiral compounds,
both isomers of a chiral ligand are required. Alternatives include:
using different central metals in the presence of identical ligand,3
changing reaction parameters (temperature, additives, and sol-
vents, etc.),4 and so on.5
As ligand, alkenes have a long history in organometallic chem-
istry.6 Since the pioneering work of Hayashi and Carreira,7 several
novel chiral cyclic8 and acyclic9 dienes have been successfully
exploited as chelating ligands in transition-metal-catalyzed asym-
metric reactions. Hybrid ligands combining alkenes with other
heteroatoms, such as phosphorus10 and nitrogen11 were also de-
veloped successfully. During the past few years, our interest was
focused on the design of chiral ligands utilizing sulfoxides as li-
gating entity and chiral source, directing to chiral bis-sulfoxides,12
PeSO,13 and SOeS14 ligands synthesized and applied in metal-
catalyzed reactions. Different properties of hybrid sulfoxides12d
shown in the asymmetric catalysis inspired us straightforward to
combine the alkene and sulfoxide moieties in the design of new
ligands and these ligands demonstrated excellent activity and
selectivity in rhodium-catalyzed asymmetric 1,4-additions.20
Interestingly, we found that the position of the substituents on
the C]C bond (branched and linear olefin) of the ligands has
a dramatic effect on the stereocontrol, which can lead to a complete
chirality inversion.19 Herein, we report our studies on the tunable
stereoselective rhodium-catalyzed 1,4-additions based on the
change of the geometry of C]C bonds (position of substitute,
Z- and E-isomer) of chiral sulfoxideeolefin ligands, whereas the
geometry of C]C bonds in some substrates have dramatic effects
on stereocontrol.21
2. Results and discussion
Compared with chiral dienes, chiral sulfoxideealkenes are less
challengeable to synthesize. Two concise synthetic routes, as out-
lined in Scheme 1, were developed. The first one started from
bromineelithium exchange of o-bromostyrenes, followed by chiral
sulfinates quenching, giving corresponding chiral sulfoxideeolefins
in reasonable yields (Scheme 1, a). For arylsulfinyl-containing
sulfoxideeolefin 5a and 5b, arylmagnesiums were used to avoid
racemization of the chiral sulfur.15
The other option was based on our previous procedure for
sulfoxideephosphine ligands synthesis.13a Commenced with chiral
tert-butyl phenyl sulfoxide 1, ortho-lithiation followed by addition
* Corresponding author. E-mail address: jliao@cib.ac.cn (J. Liao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.038

G. Chen et al. / Tetrahedron 68 (2012) 3220e3224
3221
Table 1
Rhodium-catalyzed asymmetric 1,4-addition of phenylboronic acid to cyclohex-2-
en-1-onea
Entry
L
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
3a
3b
4a
4b
5a
5b
6
98
98
98
27
80
98
97
98
98
98
99
Trace
98
>99 (R)
95 (R)
93 (R)
90 (R)
36 (R)
98 (S)
97 (S)
95 (R)
35 (R)
23 (R)
26 (R)
n.d.
9
10
11
12
13d
4a
95 (R)
a
Reaction condition: 7a (30 mL, 0.3 mmol), 8a (73.0 mg, 0.6 mmol), [Rh(C2H4)2Cl]2
(1.2 mg, 0.003 mmol, 2.0 mol % of Rh), L (0.0072 mmol, 2.4 mol %), MeOH (0.6 mL),
KF (0.15 mL, 1.0 M in H2O).
b
Yield of 9aa isolated after flash chromatography.
Determined by chiral HPLC analysis using a Chiralpak IA column and the ab-
c
solute configuration of products is assigned by comparison of optical rotation and
retention time on HPLC.
d
[Rh(C2H4)2Cl]2 (0.5 mol %) and 1.1 equiv of PhB(OH)2 were used and MeOH/H2O
is 3:1.
We then went on to investigate the substrate scope for the
stereoselectivity inversion employing the new olefin 4a. As shown
in Table 2, a variety of arylboronic acids were evaluated. And
the electronic properties of aryl p-substituents have little effect.
Adducts with excellent yields and ees could be obtained with
completely opposite absolute configurations of those employing
ligand 3a (Table 2, entries 1, 2, 4, 7, and 11e13). o-Methox-
ylphenylboronic acid also could show 79% yield and 87% ee (Table 2,
entry 6). Although the stereocontrol of the 2-naphenyl adduct was
successful (Table 2, entry 10), the 1-naphenylboronic acid was not
suitable (Table 2, entry 9). The Michael acceptor, in addition to
cyclohex-2-en-1-one, could be cyclopent-2-enone 7b with 84%
yield and 92% ee. But, other Michael acceptors, such as linear
Scheme 1.
of amides or esters to generate chiral o-acyl sulfoxides in good
yields, the target ligands could then be obtained in good yields via
Wittig or HornereWadswortheEmmons (HWE) reaction (Scheme
1, b). In addition, cis-olefin 4a was separated from 3a through
HPLC resolution, 4b from 3b via fractional recrystallization.
With chiral sulfoxideeolefins 2e6 in hand, we first investigated
the efficacy of these ligands in rhodium-catalyzed asymmetric 1,4-
addition (Table 1). Treating cyclohex-2-en-1-one 7a with phenyl-
boronic acid 8a in the presence of 2 mol % rhodium/2a complex and
0.5 equiv of KF in MeOH/H2O (4/1) at 40 ꢀC for 3 h,19 the desired
adduct 9aa was readily delivered with 98% yield and single isomer.
Aromatic substituted 2b and 2c also showed high activities and
enantioselectivities, whereas ligands 2d and 2e provided low yield
or ee, which indicates the enormous effect of electronic and steric
properties of olefin moieties to the reaction. Furthermore, the de-
rived trisubstituted olefin ligand 6 was obviously harmful for the
reaction and only trace of product was afforded, which might result
from steric hindrance of vinyl moiety (Table 1, entry 12). In term of
the enantiocontrol of chiral sulfinyl moieties, tert-butylsulfoxide
provided much better chiral environment than arylsulfinyl moiety.
For example, the replacement of the tert-butyl of 2a or 2b with
para-tolyl significantly decreased ees (Table 1, entries 1, 2, 10, and
11). Considering the absolute configuration of product, it is note-
worthy that not only substituent’s position (branched and linear)
on olefin but also the E/Z geometry of olefin can lead to a complete
stereoselectivity inversion, >99% ee of (R)-isomer, 98% ee of (S)-
isomer, and 95% ee of (R)-isomer were obtained when ligands 2a,
3a, and 4a were utilized, respectively (Table 1, entries 1, 6, and 8).
This is the first example of the ligand E/Z geometry controlling the
absolute configuration of the product. In addition, it is pleased to
find that the reactivity and enantioselectivity were still excellent
when reducing the catalyst loading (1.0 mol %) and phenylboronic
acid usage (1.1 equiv) for ligand 4a (Table 1, entry 13).
enones and a,b-unsaturated lactone failed in this transformation.
Furthermore, we explored the Rh/sulfoxideeolefin complex on
a gram-scale model reaction, in the presence of the complex of
0.1 mol % [Rh(C2H4)2Cl]2 and 0.24 mol % 2a (S/C¼500), the reaction
could smoothly proceed at 40 ꢀC in 3 h to give 9aa with 75% yield and
99% eewhen 1.5 equiv of phenylboronic acid 8awas used (Scheme 2).
The stereochemical pathways with Rh/2a, Rh/3a, and Rh/4a were
rationalized in Fig. 1. Thus, the initial coordination of the rhodium
species might resultin a transrelationshipbetweenthe phenyl group
and the olefin moiety of the ligands, and the substrate 2-cyclohexen-
1-one binds to the rhodium center at the position cis to the olefin
moieties of ligands. Due to the steric repulsion between the methyl
group of the ligands and the carbonyl moiety of the enone, the C]C
bond of the substrate binds to the rhodium center with its re-face in
the case chiral sulfoxide-branched-alkene 2a and chiral sulfoxide-Z-
alkene 4a was used as ligand, respectively. But for chiral sulfoxide-E-
alkene 3a, the enantioface of cyclohexanone got close to the rhodium
center favorably to give the products with opposite configuration.
3. Conclusion
In conclusion, we have synthesized a new type of chiral sul-
foxideeolefin ligands with various vinyl moieties, which readily

3222
G. Chen et al. / Tetrahedron 68 (2012) 3220e3224
Table 2
bind to rhodium(I) with their sulfur atoms and the carbonecarbon
double bonds. The formed Rh-complexes could efficiently catalyze
1,4-addition of arylboronic acids to a,b-unsaturated ketones. Vinyl
Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to
a,b-unsaturated
ketonesa
substituents of the ligands varied in stereocontrolling ability as well
as the substrate scope. Either isomer of the product with good to
excellent ees was easily obtained employing either olefinic isomer
of the ligand.
4. Experimental section
4.1. General method
Entry
R
9
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
H (8a)
9aa
9ab
9ac
9ad
9ae
9af
9ag
9ah
9ai
9aj
9ak
9al
9am
9ba
98
98
97
86
90
79
95
99
74
96
93
90
92
84
95(ꢁ98)
94(ꢁ97)
94(ꢁ96)
88(ꢁ98)
86(ꢁ97)
87(ꢁ66)
88(ꢁ97)
91(ꢁ97)
29(ꢁ92)
93(ꢁ64)
89(ꢁ95)
91(ꢁ96)
86(ꢁ85)
92(ꢁ26)
p-Me (8b)
m-Me (8c)
p-MeO (8d)
m-MeO (8e)
o-MeO (8f)
p-tBu (8g)
3,5-Me (8h)
1-Naph (8i)
2-Naph (8j)
p-Cl (8k)
Unless otherwise noted, all commercially available reagents
were used as received without further purification. Solvents used in
catalysis were distilled from appropriate drying agents and bubbled
with argon for 30 min prior to use. Solutions used in the catalysis
were made by dissolving the salt in distilled water then bubbled
with argon for 30 min prior to use. Flash column chromatography
was performed on silica gel H (HG/T2354-92, Qingdao Haiyang
Chemical Co. Ltd.); analytical TLC was performed on HSGF 254 glass
plates precoated with 0.15e0.20 mm thickness of silica gel (Yantai
Jiangyou Silica Gel Development Co. Ltd). 1H NMR and 13C NMR
spectra were recorded on a Bruker 300 spectrometer (300 MHz for
1H and 75 MHz for 13C) in CDCl3 or acetone-d6. Chemical shifts were
9
10
11
12
13
14
p-F (8l)
p-CF3 (8m)
H (8a)
a
All the reactions were performed with 0.6 mmol of enones, 0.66 mmol of
arylboronic acids, 1.2 mg [Rh(C2H4)2Cl]2 (0.003 mmol, 1.0 mol % of Rh), 1.2 mg
(0.0072 mmol, 1.2 mol %) 4a, 1.0 mL of MeOH, 0.3 mL of KF (1.0 M in H2O), 40 ꢀC, 3 h.
recorded in parts per million (d
) relative to CHCl3 at 7.26 for 1H NMR
b
and 77.0 for 13C NMR or to acetone at 2.05 for 1H NMR and 29.8 for
13C NMR. Infrared spectra were recorded on a Nicolet 560 FTIR
spectrometer. Electrospray ionization high-resolution mass spectra
(ESI-HRMS) were recorded on a Bruke P-SIMS-Gly FT-ICR mass
spectrometer. Optical rotation was recorded on PE polarimeter 341.
Enantiomeric excess was determined by HPLC analysis on Chiralpak
AD-H, IA column (Daicel Chemical Industries, LTD) using UV
detector.
Isolated yield.
c
Determined by chiral HPLC analysis and the absolute configuration of products
are R by comparison of optical rotation and retention time on HPLC.
d
The ee values in parentheses, which were obtained when 3a was used, are cited
from our previous report19 for comparison.
4.2. General procedure A: for ligands synthesis from o-
bromostyrenes (Scheme 1, a)
n-BuLi (1.2 equiv, 2.5 M in hexane) was added to the solution of
o-bromostyrenes (1.1 equiv) in THF (styrenes, 0.2 mmol/mL) slowly
at ꢁ78 ꢀC, after that, stirring was continued at the same tempera-
ture for 0.5 h, then the solution of chiral sulfinate (1.0 equiv) in THF
(sulfinate, 0.5 mmol/mL) was added dropwise at ꢁ78 ꢀC. After
addition, the mixture was warmed to rt slowly. About 1.5 h later, to
the solution was added satd NH4Cl (aq), then diluted with EtOAc.
Layers were separated and the aqueous layer was extracted with
EtOAc, the combined organic layer was dried over anhydrous
Na2SO4. After removing the solvent in vacuo, the residues were
purified by chromatography with petroleum/EtOAc as eluent to
afford chiral sulfoxide-enes.
Scheme 2.
4.3. General procedure B: for ligands synthesis from tert-
butylphenylsulfoxide (Scheme 1, b)
To the mixture of tert-butylphenylsulfoxide (1.0 equiv) and
TMEDA (1.2 equiv) in THF (tert-butylphenylsulfoxide, 0.2 mmol/mL)
was added n-BuLi (1.2 equiv, 2.5 M in hexane) slowly at ꢁ78 ꢀC,
after stirring at this temperature for 30 min, ester or amide
(1.5 equiv) was added slowly. Stirring was continued overnight, and
then satd NH4Cl (aq) was added to quench the reaction. After
concentrating in vacuo, the residues were dissolved in dichloro-
methane, layers were separated, and the aqueous layer was
extracted with dichloromethane, the combined organic layer was
washed with brine and dried over anhydrous Na2SO4. After re-
moving the solvent in vacuo, the residues were purified by chro-
matography to afford o-acylaryl tert-butylsulfoxides.
Fig. 1. Proposed stereochemical pathway.

G. Chen et al. / Tetrahedron 68 (2012) 3220e3224
3223
To the mixture of phosphonium halide (1.5 equiv) and t-BuOK
(2.0 equiv) was added anhydrous THF (phosphonium halide,
0.5 mmol/mL) (for phosphonate, the solution of phosphonate in
THF was slowly added to the mixture of t-BuOK in THF) and stirred
at rt for 30 min under argon, then the solution of ketone or alde-
hyde (1.0 equiv) in THF (ketone or aldehyde, 0.2 mmol/mL) was
added slowly, the resulting solution was allowed to stir at rt over-
night. To the mixture was added satd NH4Cl (aq), then diluted with
EtOAc (50 mL). The aqueous layer was extracted with EtOAc, the
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4. After removing the solvents, the residue was purified
by chromatography with petroleum/EtOAc as eluent to afford chiral
sulfoxide-enes.
5, 0.8 mL/min, 254 nm, retention time: 8.63 min (minor), 9.09 min
(major).
Acknowledgements
We thank the NSFC (Nos. 21072186 and 20872139), the West
Light Foundation of CAS, Chengdu Institute of Biology of CAS
(Y0B1051100), the Major State Basic Research Development Pro-
gram (973 program, 2010CB833300) for financial support. Prof.
Wanbin Zhang in Shanghai Jiao Tong University is appreciated for
preparative HPLC separation.
Supplementary data
4.3.1. (R,Z)-1-(tert-Butylsulfinyl)-2-(prop-1-enyl)benzene
(4a). Following general method A starting from the Z/E-isomer
mixture of 1-bromo-2-(prop-1-enyl)-benzene and (R)-tert-butyl
tert-butanethiosulfinate, the mixture of 3a, 4a was separated
by preparative HPLC using Daicel Chiralcel AD-H column
(2 cm øꢂ25 cm) with n-hexane/i-propanol¼100/8, flow¼9 mL/min.
Retention times: 13.3e18.4 min for 4a and 18.9e22.9 min for 3a.
Full experimental details for all compounds, as well spectral
data can be found in the Supplementary data. Supplementary data
related to this article can be found online at doi:10.1016/
j.tet.2012.02.038.
References and notes
a 25
Compound 4a, 45% yield, pale yellow oil, ½ ꢃD þ11 (c 0.192,
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, NY,
1994; (b) Jacqueline, S. P. Chiral Auxiliaries and Ligands in Asymmetric Synthesis;
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Catalytic Asymmetric Synthesis, 2nd ed.; Wiley: New York, NY, 2000; (e) Mikami,
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New York, NY, 2009.
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼1.14 (s, 9H), 1.74e1.77 (dd,
J¼1.80, 7.11 Hz, 3H), 5.80e5.91 (dq, J¼7.09, 11.58 Hz, 1H), 6.60e6.64
(dd, J¼1.56, 11.52 Hz, 1H), 7.25e7.28 (m, 1H), 7.41e7.44 (m, 2H),
7.86e7.89 (m, 1H). 13C NMR (75 MHz, CDCl3):
d¼14.5, 23.0, 57.8,
126.2, 127.0, 127.1, 128.9, 129.5, 130.4, 137.4, 139.0. IR (neat):
n
3057,
3018, 2973, 2865, 1644, 1465, 1466, 1364, 1171, 1061, 1033, 770,
564 cmꢁ1. HRMS: calcd for [C13H18OSþNa]: 245.0976, found:
245.0971.
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4.3.2. (R,Z)-1-(tert-Butylsulfinyl)-2-styrylbenzene (4b). Following
general method B starting from (R)-tert-butylsulfinylbenzene, first
with DMF and then with benzyl triphenylphosphonium bromide.
Compound 4b can be enriched by fractional recrystallizing the
mixture of 3b/4b from hexane/ethyl acetate at ꢁ20 ꢀC. 20% yield for
two steps, colorless solid, mp. 110e112 ꢀC, ½a D25
ꢁ116 (c 0.160,
ꢃ
CHCl3). 1H NMR (300 MHz, CDCl3):
d
¼1.27 (s, 9H), 6.64 (d,
J¼12.39 Hz, 1H), 6.80 (d, J¼12.39 Hz, 1H), 7.21e7.45 (m, 8H), 7.92 (d,
J¼7.95 Hz, 1H). 13C NMR (75 MHz, CDCl3):
¼23.2, 57.7, 126.1, 126.5,
d
127.7, 128.3, 128.6, 129.3, 130.4, 131.6, 135.9, 137.4, 139.3. IR (neat):
n
3063, 2922, 2856, 1665, 1578, 1485, 1296, 1241, 1152, 1104, 1062,
1020, 868, 776, 701, 561 cmꢁ1. HRMS: calcd for [C18H20OSþNa]:
307.1133, found: 307.1127.
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4.4. General procedure for the catalytic asymmetric 1,4-
additions
Under argon atmosphere, to a 10-mL Schlenk tube was added
[Rh(C2H4)2Cl]2 (1.2 mg, 0.003 mmol), sulfoxide-ene ligand
(0.0072 mmol), followed by 1.00 mL dichloromethane, the mix-
ture was stirred at rt for 30 min, then solvent was removed and
arylboronic acid (0.66 mmol) was added, after purging with ar-
gon, enone (0.60 mmol), methanol (1.00 mL), and KF (0.30 mL,
1.0 M in H2O, 0.30 mmol) were added sequentially. The mixture
was stirred at 40 ꢀC for 3 h, then the solvent was removed in
vacuo and the residue was purified by flash chromatography on
silica gel with petroleum ether/ethyl acetate 10/1 as eluent to
afford the adducts.
4.4.1. (R)-3-Phenyl-cyclohexanone19 (9aa). Yield 98%, colorless oil,
½
a 2D5
ꢃ
þ16 (c 0.194, CHCl3) for 95.4% ee. 1H NMR (300 MHz, CDCl3):
d¼1.70e1.88 (m, 2H), 2.06e2.17 (m, 2H), 2.37e2.63 (m, 4H),
2.96e3.06 (m, 1H), 7.21e7.26 (m, 3H), 7.32e7.36 (m, 2H). 13C NMR
(75 MHz, CDCl3):
¼25.4, 32.6, 41.0, 44.6, 48.8, 126.4, 126.5, 128.5,
144.2, 210.8. HPLC: Daicel Chiralpak, IA, n-hexane/i-propanol¼95/
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d

3224
G. Chen et al. / Tetrahedron 68 (2012) 3220e3224
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