Design of chiral sulfoxide-olefins as a new class of sulfur-based olefin ligands for asymmetric catalysis

Article abstract of DOI:10.1021/ol201151r

The design and development of a novel class of chiral sulfur-olefin hybrid ligands with high synthetic feasibility are described. These new sulfoxide-olefin ligands showed excellent catalytic activities and enantioselectivities (up to 98% ee) in rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids to α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1021/ol201151r

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3410–3413
Design of Chiral SulfoxideÀOlefins as a
New Class of Sulfur-Based Olefin Ligands
for Asymmetric Catalysis
Wei-Yi Qi, Ting-Shun Zhu, and Ming-Hua Xu*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China
xumh@mail.shcnc.ac.cn
Received April 29, 2011
ABSTRACT
The design and development of a novel class of chiral sulfurÀolefin hybrid ligands with high synthetic feasibility are described. These new
sulfoxideÀolefin ligands showed excellent catalytic activities and enantioselectivities (up to 98% ee) in rhodium-catalyzed asymmetric 1,
4-addition reactions of aryl boronic acids to R,β-unsaturated carbonyl compounds.
In transition-metal-mediated asymmetric catalysis, chir-
al ligands play an essential role in efforts to achieve
excellent stereoselectivity. For this reason, design and dis-
covery of novel effective chiral ligands remain an impor-
tant focus of modern synthetic chemistry.1 Recently, chiral
olefins have attracted considerable attention as new steer-
ing ligands and have evoked great interest from the
chemical society.2À5 Nevertheless, despite the fact that
heteroatomÀolefin hybrid ligands generally exhibit in-
creased coordination ability to transition metals, their
development and use in asymmetric catalysis is far less
extensive than that of diene ligands; only rare examples of
pnictogen-based olefin analogues have been disclosed in
the literature.6 On the other hand, catalytic asymmetric
transformations applying sulfur-based ligands have been
more intensively investigated in recent years.7 Compared
to the phosphorus- or nitrogen-containing ligands, chiral
sulfur ligands present advantages of easy synthesis, high
stability, and special S-stereogenic control. Therefore, it is
reasoned that a structurally proper olefin containing het-
eroatomic sulfur could possibly act as a previously
unexplored sulfur-olefin hybrid class ligand, which should
offer new opportunities for asymmetric applications. Very
recently, we discovered that simple and readily available
chiral sulfinamide-olefins can display great catalytic
activities and enantioselectivities in rhodium-catalyzed
1,4-addition reactions.8
(4) For selected very recent examples on chiral dienes in asymmetric
catalysis, see: (a) Luo, Y.; Carnell, A. J. Angew. Chem., Int. Ed. 2010, 49,
2750. (b) Shintani, R.; Isobe, S.; Takeda, M.; Hayashi, T. Angew. Chem.,
Int. Ed. 2010, 49, 3795. (c) Shintani, R.; Takeda, M.; Nishimura, T.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 3969. (d) Nishimura, T.;
Wang, J.; Nagaosa, M.; Okamoto, K.; Shintani, R.; Kwong, F.; Yu, W.;
Chan, A. S. C.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 464. (e)
Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumanmoto, H.; Hayashi,
T. Angew.Chem., Int. Ed. 2010, 49, 1638. (f) Nishimura, T.; Maeda, Y.;
Hayashi, T. Angew. Chem., Int. Ed. 2010, 49, 7324. (g) Nishimura, T.;
Makino, H.; Nagaosa, M.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
12865. (h) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 13168. (i) Pattison, G.; Piraux, G.; Lam, H. W. J. Am.
Chem. Soc. 2010, 132, 14373. (j) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Feng, C.-
G.; Lin, G.-Q. Org. Lett. 2010, 12, 3820. (k) Nishimura, T.; Yasuhara, Y.;
Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7872. (l) Cao, Z.-P.;
Du, H.-F. Org. Lett. 2010, 12, 2602. (m) Shao, C.; Yu, H.-J.; Wu, N.-Y.;
Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Org. Lett. 2011, 13, 788. (n)
Li, Q.; Dong, Z.; Yu, Z.-X. Org. Lett. 2011, 13, 1122. (o)Wang, Y.-Z.; Hu,
X.-C.; Du, H.-F. Org. Lett. 2010, 12, 5482.
(1) (a) New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens,
M., Eds.; Wiley: Hoboken, NJ, 2007. (b) Catalysis in Asymmetric Synth-
esis, 2nd ed.; Caprio, V., Williams, J. M. J., Eds.; Wiley: Hoboken, NJ, 2009.
(c) Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.; Wiley:
Hoboken, NJ, 2010. (d) Privileged Chiral Ligands and Catalysts; Zhou,
Q.-L., Ed.; Wiley-VCH: Weinheim, 2011.
(2) For two pioneering references, see: (a) Hayashi, T.; Ueyama, K.;
Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (b)
Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
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r
10.1021/ol201151r
Published on Web 06/02/2011
2011 American Chemical Society

Chiral sulfoxides are an intriguing class of molecules.9
During recent years, they have been successfully utilized as
chiral ligands in various kinds of transition-metal-cata-
lyzed asymmetric reactions.9a,b,10 The sulfinyl group is
perfectly featured with both an intrinsic stereogenic center
and binding site to metals. Inspired by these elegant works,
we envisioned probing sulfinyl-based olefin ligands.
To fulfill this idea, one simple design is to assemble molec-
ules that have both sulfinyl and olefin groups attached to a
benzene ring in a 1,2-fashion. As outlined in Scheme 1,
Initially, to examine whether the use of a designed ligand
could lead to catalysis in asymmetric reactions, compound
1a (R1 = R2 = H) was first prepared using 2-bromoben-
zaldehyde as the starting material in two steps,11 and we
evaluated it in Rh-catalyzed conjugate addition of phenyl
boronic acid to 2-cyclohexenone. The reaction proceeded
smoothly at 60 °C in the presence of 1a (3.3 mol %) under
aqueous K3PO4/dioxane and went to completion in
30 min,12 giving the corresponding product in 98%
yield, albeit with low enantioselectivity (8% ee).
When the corresponding sulfoxide ligand where the
vinyl group in 1a has been hydrogenated was used, the
reaction did not occur even after 6 h. This result clearly
indicates the necessity for the olefin donor to be present on
the ligand. Encouraged by these findings, we decided to
synthesize a series of new sulfoxideÀolefin ligands bearing
different R1 and R2 substitutents.
Scheme 1. Chiral SulfoxideÀOlefin Ligand Proposal
Scheme 2. Synthesis of SulfoxideÀOlefin Ligands 1
upon coordination to the metal, the sulfinyl function-
ality can be expected to serve as a nice stereodirecting
group, thus providing effective asymmetric inductions.
Herein, we disclose the first example of chiral sulfinyl-
based olefin ligands and their potential in asymmetric
catalysis.
(5) For our recent work involving on chiral diene ligands in asym-
metric catalysis, see: (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-
Q. J. Am. Chem. Soc. 2007, 129, 5336. (b) Feng, C.-G.; Wang, Z.-Q.;
Tian, P.; Xu, M.-H.; Lin, G.-Q. Chem. Asian J. 2008, 3, 1511. (c) Feng,
C.-G.; Wang, Z.-Q.; Shao, C.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2008, 10,
4101. (d) Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q.
Angew. Chem., Int. Ed. 2010, 49, 5780. (e) Wang, L.; Wang, Z.-Q.; Xu,
M.-H.; Lin, G.-Q. Synthesis 2010, 3263. (f) Zhang, S.-S.; Wang, Z.-Q.;
Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5546. (g) Yang, H.-Y.; Xu,
M.-H. Chem. Commun 2010, 46, 9223.
(6) For leading references, see: (a) Maire, P.; Deblon, S.; Breher, F.;
€
€
€
€
Geier, J.; Bohler, C.; Ruegger, H.; Schonberg, H.; Grutzmacher, H.
€
€
Chem.;Eur. J. 2004, 10, 4198. (b) Piras, E.; Lang, F.; Ruegger, H.;
€
€
Stein, D.; Worle, M.; Grutzmacher, H. Chem.;Eur. J. 2006, 12, 5849.
(c) Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T.
Angew. Chem., Int. Ed. 2005, 44, 4611. (d) Defieber, C.; Ariger, M. A.;
Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (e)
€
Hahn, B. T.; Tewes, F.; Frohlich, R.; Glorius, F. Angew. Chem., Int. Ed.
2010, 49, 1143. (f) Minuth, T.; Boysen, M. M. K. Org. Lett. 2009, 11,
4212. (g) Liu, Z.-Q.; Du, H.-F. Org. Lett. 2010, 12, 3054. (h) Drinkel, E.;
~
Briceno, A.; Dorta, R.; Dorta, R. Organometallics 2010, 29, 2503.
(7) (a) Organosulfur Chemistry in Asymmetric Synthesis; Toru, T.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008. (b) Chiral Sulfur Ligands:
Asymmetric Catalysis; Pellissier, H., Ed.; Royal Society of Chemistry:
Cambridge, U.K., 2009. (c) Mellah, M.; Voituriez, A.; Schulz, E. Chem.
Rev. 2007, 107, 5133. (d) Pellissier, H. Tetrahedron 2007, 63, 1297.
(8) Jin, S.-S.; Wang, H.; Xu, M.-H. Chem. Commun. 2011, 47, DOI:
10.1039/c1cc12322j.
ꢀ
(9) (a) Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. (b) Hiroi,
K.; Sone, T. Curr. Org. Synth. 2008, 5, 305. (c) Pellissier, H. Tetrahedron
~
ꢀ
2006, 62, 5559. (d) Carreno, M. C.; Hernandez-Torres, G.; Ribagorda,
M.; Urbano, A. Chem. Commun. 2009, 6129.
Figure 1. SulfoxideÀolefin ligands with diverse structures.
(10) For recent leading examples, see: (a) Mariz, R.; Luan, X. J.;
Gatti, M.; Linden, A.; Dorta, R. J. Am. Chem. Soc. 2008, 130, 2172. (b)
Burgi, J. J.; Mariz, R.; Gatti, M.; Drinkel, E.; Luan, X.-J.; Blumentritt,
S.; Linden, A.; Dorta, R. Angew. Chem., Int. Ed. 2009, 48, 2768. (c)
Mariz, R.; Poater, A.; Gatti, M.; Drinkel, E.; Buergi, J.; Luan, X.-J.;
Blumentritt, S.; Linden, A.; Cavallo, L.; Dorta, R. Chem.;Eur. J. 2010,
16, 14335. (d) Chen, J.; Chen, J.-M.; Lang, F.; Zhang, X.-Y.; Cun, L.-F.;
Zhu, J.; Deng, J.-G.; Liao, J. J. Am. Chem. Soc. 2010, 132, 4552. (e)
Chen, Q.-A.; Dong, X.; Chen, M.-W.; Wang, D.-S.; Zhou, Y.-G.; Li, Y.-
X. Org .lett. 2010, 12, 1928. (f) Lang, F.; Li, D.; Chen, J.-M.; Chen, J.; Li,
L.-C.; Cun, L.-F.; Zhu, J.; Deng, J.-G.; Liao, J. Adv. Synth. Catal. 2010,
352, 843.
As illustrated in Scheme 2, the synthesis of structurally
diverse sulfoxide-olefin ligands can generally be accomplished
in three concise steps. HornerÀWadsworthÀEmmons reac-
tion of the resulting phosphonate 3 with the corresponding
(11) See the Supporting Information for details.
(12) The reaction was found to be slow at room temperature or 40 °C.
Org. Lett., Vol. 13, No. 13, 2011
3411

aldehyde under microwave irridation for 30 min afforded
mainly trans-stilbene derivatives 4 in good yields. Treat-
ment of 4 with nBuLi at À78 °C, followed by addition of
(S)-thiosulfinate 5, led to the desired molecules13 (see
Figure 1 for representative structures).
ligands 1m and 1n derived from benzophenone and piva-
laldehyde respectively were examined.14 As a result, the use
of these two ligands seriously hampered the reaction,
giving no or only trace amount of products (entries 13
and 14). We also investigated the substitution effect (R1)
on the central benzene ring moiety (1oÀs, entries 15À19),
to our delight, the introduction of multimethoxy groups
(1p, 1q, and 1r) was beneficial (entries 16À18), the best
selectivity of 95% ee was obtained when ligand 1p was
employed (entry 16). Notably, replacing the tert-butyl
sulfinyl group in 1b with p-tolylsulfinyl led to a much lower
reaction stereocontrol (entry 20).
Table 1. Ligand Screeninga
entry
ligand
yieldb (%)
eec (%)
Table 2. Optimization of the Reaction Conditionsa
1
2
1a
1b
1c
1d
1e
1f
98
99
99
93
99
93
90
99
99
95
98
4
8 (S)
90 (R)
83 (R)
86 (R)
90 (R)
80 (R)
86 (R)
87 (R)
85 (R)
89 (R)
90 (R)
48 (R)
3
4
5
6
7
1g
1h
1i
entry
ligand
base
solvent
yieldb (%)
eec (%)
8
9
1
2
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1p
1q
1r
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KOH
dioxane
CH2Cl2
toluene
MeOH
THF
99
98
98
89
93
90
94
91
97
96
97
97
99
99
99
90
75
67
88
91
88
92
92
92
93
93
94
97
94
93
10
11
12
13
14
15
16
17
18
19
20
1j
1k
1l
3
4
1m
1n
1o
1p
1q
1r
1s
6e
5
trace
81
N.Dd
6
dioxane
dioxane
dioxane
dioxane
dioxane
THF
70 (R)
95 (R)
93 (R)
91 (R)
88 (R)
12f (R)
7
KF
99
8
Na2CO3
K2CO3
K2HPO4
K2CO3
K2HPO4
K2HPO4
K2HPO4
K2HPO4
99
9
99
10
11
12
13
14
15
99
99
THF
THF
a Reaction conditions: PhB(OH)2 (0.5 mmol), 2-cyclohexenone
(0.25 mmol), [Rh(C2H4)2Cl]2 (3 mol %, 1.5 mg), ligand (3.3 mol %),
and K3PO4 (1.5 M aq, 83 μL, 0.5 equiv) in dioxane (0.5 mL) at 60 °C for
0.5 h. b Isolated yield. c Determined by HPLC analysis on a Daicel
Chiralcel OJ-H column; the absolute configuration was determined by
comparison with known data. d Not determined. e The optical purity of
this ligand was low (48% ee). f A retained 25% ee can be obtained if a
optically pure 6 could be used.
THF
THF
a Reaction conditions: PhB(OH)2 (0.5 mmol), 2-cyclohexenone
(0.25 mmol), [Rh(C2H4)2Cl]2 (3 mol %, 1.5 mg), ligand (3.3 mol %),
and base (1.5 M aq, 83 μL, 0.5 equiv) in the indicated solvent (0.5 mL)
at 60 °C for 0.5 h. b Isolated yield. c Determined by HPLC analysis on a
Daicel Chiralcel OJ-H column.
With various sulfoxideÀolefin ligands in hand, we then
turned our attention to survey their catalytic performance
(Table 1). In comparison with 1a bearing a terminal olefin,
most of ligands (1bÀk) with an R2 substitutent attached to
the double bond showed dramatically improved enantios-
electivities while maintaining the same high catalytic activ-
ity (entries 2À11). Among them, ligands 1b, 1e, and 1k
performed equally well and gave a promising 90% ee
(entries 2, 5, and 11). When 1l was applied to the reaction,
the yield became very low, and the ee value decreased to
only 48% (entry 12), suggesting that a sterically very bulky
R2 would disfavor the coordination and induction. To
understand whether the trans-stilbene structure is crucial,
Given the encouraging results, the reaction conditions
were further explored (Table 2). The easily available
sulfoxideÀolefin 1b was first chosen as a model ligand
(entries 1À11). The use of a noncoordinating solvent such
as CH2Cl2 or toluene provided low enantioselectivities
(entries 2 and 3). When THF was used, a slightly better
enantioselectivity was observed (entry 5). A careful survey
of inorganic bases led to the identification of K2HPO4 as
the best additive, affording the addition product with 94%
ee in THF (entry 12). Gratifyingly, an excellent enantios-
electivity of 97% ee was obtained by using the previously
recognized optimal ligand 1p (entry 13).
(13) During the addition reaction, a small degree of S-stereogenic
racemization was observed; fortunately, in most cases, the ee’s of ligands
were >98%. See the Supporting Information for detailed ee values. For
a similar racemization discussion, see: Cogan, D. A.; Liu, G.; Kim, K.;
Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011.
(14) An attempt to synthesize the corresponding ligand 1b with cis-
stilbene structure was also carried out, and the product was obtained in a
cis/trans ratio of 3:1. However, this cis-dominating ligand only gave the
reaction in 50% yield and 35% ee, also suggesting the important effect of
trans-stilbene structure on both yield and enantioselectivity.
3412
Org. Lett., Vol. 13, No. 13, 2011

electronic and steric demands were successfully reacted
with R,β-unsaturated carbonyl compounds such as 2-cy-
clohexenone (7a), 2-cyclopentenone (7b), and 5,6-dihydro-
2-pyranone (7c), giving the corresponding addition pro-
ducts 8 with excellent enantioselectivities (94À98% ee)
in all cases. The nature of the substituent on the phenyl
ring of the arylboronic acid had very little effect on the
reaction stereoselectivity. Unlike in the previous obser-
vations with chiral olefin or related ligands,15 it is
worthy of note that the current catalytic system proved
equally suitable for both six- and five-membered
cyclic substrates. Unfortunately, when linear enone
(E)-2-heptenone was subjected to react with phenyl-
boronic acid, both low yield (34%) and selectivity
(21% ee) were afforded.
In summary, we have developed an unprecedented new
exciting class of sulfinyl-based olefin ligands for asym-
metric catalysis. By taking advantage of inherent stereo-
genic elements in the scaffold of the sulfoxide, readily
available chiral sulfoxideÀolefins with simple molecular
framwork have shown great catalytic activities and enan-
tioselectivities as in rhodium-catalyzed asymmetric con-
jugate additions. This study revealed that the innovative S-
stereogenic olefin ligands can also be as useful as other
classical asymmetricligands. Furtherdevelopmentofmore
effective chiral sulfurÀolefin hybrid ligands and their
applications in other asymmetric reactions is currently
underway in our laboratory.
Table 3. [RhCl(C2H4)2]2/1p-Catalyzed Asymmetric Conjugated
Additiona
entry
7
Ar
C6H5
8
yieldb (%)
eec (%)
1
2
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
7b
7c
8a
8b
8c
8d
8e
8f
99
99
99
94
97
96
85
99
31
53
99
97
98
99
95
91
97
96
95
98
96
97
97
97
94
96
97
98
96
96
95
96
4-MeC6H4
4-MeOC6H4
4-FC6H4
3
4
5
4-ClC6H4
3-MeC6H4
3-ClC6H4
3-MeOC6H4
2-MeC6H4
2-MeOC6H4
2-naphthyl
1-naphthyl
C6H5
6
7
8g
8h
8i
8
9
10
11
12
13
14
15
16
8j
8k
8l
8m
8n
8o
8p
4-MeC6H4
4-ClC6H4
C6H5
a The reaction was carried out with 0.25 mmol of enone/ester 7,
0.5 mmol of arylboronic acid in the presence of 3 mol % of
[RhCl(C2H4)2]2, 3.3 mol % of ligand 1p, and 1.5 M aq K2HPO4
(0.1 mL) in THF (1 mL) at 60 °C for 0.5À2 h. b Isolated yield.
c Determined by HPLC analysis on Daicel chiral columns.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20972172,
21021063), theChinese Academy of Sciences, and National
Science & Technology Major Project is greatly acknowl-
edged.
With the best ligand 1p, we next examined the substrate
scope of this rhodium-catalyzed asymmetric 1,4-addition
under the above optimized conditions. As presented in
Table 3, a wide range of arylboronic acids with varying
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR and
HPLC spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) For selected examples, see refs 4k, 5b, 5c, 6h, and 10f.
Org. Lett., Vol. 13, No. 13, 2011
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