Rh-Catalyzed Asymmetric Hydrogenation of α-Substituted Vinyl Sulfones: An Efficient Approach to Chiral Sulfones

Article abstract of DOI:10.1021/acs.orglett.6b03845

Rh/(S)-(+)-DTBM-Segphos complex catalyzed asymmetric hydrogenation of α-substituted vinyl sulfones has been achieved, furnishing the desired products in high yields and excellent enantioselectivities (>90% yield, up to 99% ee). This method provided an eff

Full text of DOI:10.1021/acs.orglett.6b03845

Letter
pubs.acs.org/OrgLett
Rh-Catalyzed Asymmetric Hydrogenation of α‑Substituted Vinyl
Sulfones: An Efficient Approach to Chiral Sulfones
Liyang Shi,‡,† Biao Wei,‡,† Xuguang Yin,† Peng Xue,† Hui Lv,*,† and Xumu Zhang*,§,†
†Key Laboratory of Biomedical Polymers of Ministry of Education & College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, Hubei 430072, China
§Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, P. R. China
S
* Supporting Information
ABSTRACT: Rh/(S)-(+)-DTBM-Segphos complex catalyzed
asymmetric hydrogenation of α-substituted vinyl sulfones has
been achieved, furnishing the desired products in high yields
and excellent enantioselectivities (>90% yield, up to 99% ee).
This method provided an efficient approach to α-substituted
chiral sulfones under mild conditions and has potential
applications in organic synthesis.
he chiral sulfones have been identified as valuable
Tmolecules that play an important role in organic
synthesis.1 For example, sulfones can be readily transformed
to acids,2 alcohols,3 carbohydrate derivatives,4 and other
functionalized compounds.5 In addition, chiral sulfones display
interesting biological properties as HIV-1 protease inhibitors,6
protein tyrosine phosphatase inhibitors,7 γ-secretase inhibitors,8
and antisepsis agents.9 Therefore, great efforts have been
devoted to the development of new methodologies for the
synthesis of chiral sulfones. Among them, the representative
methods include Ni-catalyzed Negishi arylations and alkenyla-
tions of α-bromosulfones,10 Rh-catalyzed asymmetric conjugate
addition to unsaturated sulfones,11 asymmetric Michael
addition of nucleophiles to vinyl sulfones employing organo-
catalysts,12 asymmetric catalytic radical additions,13 asymmetric
hydrogenation of functionalized sulfones,14 and others.15
However, most of the reported approaches are focused on
the synthesis of β-substituted chiral sulfones; α-substituted
chiral sulfones, an important chiral motif found in biologically
active molecules and drugs (Figure 1a), received far less
attention than β-substituted chiral sulfones. In fact, very few
synthetic routes to α-substituted chiral sulfones have been
reported.
Figure 1. Examples of biologically active compounds containing chiral
sulfone scaffolds and the synthesis of chiral sulfones involving
In the past decades, transition-metal-catalyzed asymmetric
hydrogenation has become a powerful route to chiral
compounds.16,17 In this context, asymmetric hydrogenation of
β-ketosulfones,14a β-amido acrylosulfones,14d and vinyl/allyl/
homoallylic sulfones14b,c have been reported by several groups,
and excellent enantioselectivities have been achieved (Figure
1b). However, the chiral center of these products is far away
from the sulfone groups. Highly enantioselective synthesis of
chiral α-substituted sulfones via asymmetric hydrogenation is
rarely reported. Herein, we disclose an efficient approach to
synthesize α-substituted chiral sulfones through Rh-catalyzed
asymmetric hydrogenation of α-substituted vinyl sulfones (Figure
1c).
asymmetric hydrogenation strategy.
Initially, α-Ts-substituted styrene 1a was selected as a model
substrate to optimize the reaction conditions. A variety of
diphosphine ligands were examined (Figure 2), and the results
are summarized in Table 1. When P-chiral ligands, such as Me-
DuPhos, Binapine, and TangPhos, were employed in this
reaction, all of them exhibited excellent activity and gave the
product with high yields, albeit with poor to moderate
Received: January 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03845
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Organic Letters
Letter
The substrate scope of asymmetric hydrogenation of α-
substituted vinyl sulfones was investigated under the optimal
reaction conditions. As shown in Scheme 1, this reaction
Scheme 1. Rh-Catalyzed Asymmetric Hydrogenation of α-
a
Substituted Vinyl Sulfones
Figure 2. Ligands screening in Rh-catalyzed hydrogenation of 1a.
Table 1. Ligand Screening for Rh-Catalyzed Asymmetric
a
Hydrogenation of 1a
b
c
entry
ligand
solvent
DCM
yield (%)
ee (%)
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
L9
98
99
15
65
20
27
93
94
95
93
97
2
DCM
a
Unless otherwise noted, all reactions were carried out with a
3
DCM
99
Rh(COD)2BF4/ligand/substrate(0.1 mmol) ratio of 1:1.1:100 in 1.5
mL DCM at room temperature under H2 (10 bar) for 2−5 h. Isolated
yields. Enantiomeric excesses were determined by HPLC analysis
using a chiral stationary phase.
4
DCM
99
5
DCM
95
6
DCM
95
7
DCM
97
8
DCM
99
9
DCM
99
exhibited good substrate tolerance. When R2 was substituted
with different aryl groups, α-substituted vinyl sulfones were
efficiently hydrogenated and gave the desired products with
excellent yields (>95%) and enantioselectivities (97−99% ee,
Scheme 1, 2a−f) regardless of whether the substituents on the
phenyl ring were electron donating (Scheme 1, 2b−d) or
electron withdrawing (Scheme 1, 2e and 2f). Moreover, the
substitution positions on the phenyl ring did not influence the
reaction activity and enantioselectivity (Scheme 1, 2b and 2c).
Heteroaromatic groups, such as α-thienyl vinyl sulfone, were
also well tolerated in this reaction (Scheme 1, 2g). Excellent
yields and good enantioselectivities were obtained when R2 was
replaced by alkyl groups (>90% yields, 88−95% ee; Scheme 1,
2h−j). In addition, when R1 was changed to a p-
acetamidophenyl or 2-naphthalenyl group, this reaction also
worked smoothly. It is worth noting that α-substituted
sulfonate 1m was a good substrate for this reaction and
afforded chiral sulfonic acid esters with 96% yield and 94% ee,
which can be readily transferred to chiral phenylethanesulfonic
acid ((−)-PES), an efficient resolving agent for the optical
resolution of DL-leucine.18
10
11
12
13
14
MeOH
THF
trace
trace
trace
trace
trace
1,4-dioxane
CF3CH2OH
CH3CN
a
Unless otherwise noted, all reactions were carried out with a
Rh(COD)2BF4/ligand/substrate(0.1 mmol) ratio of 1:1.1:100 in 1.5
mL of solvent at room temperature under H2 (10 bar) for 5 h. Yield
of purified product. Determined by HPLC analysis using a chiral
stationary phase.
b
c
enantioselectivities (Table 1, entries 1−3). Josiphos, a typical
planar chiral ligand, also afforded excellent yield but with a poor
ee (Table 1, entry 4). To our delight, excellent yield and
enantioselectivity were obtained when (S)-BINAP was used as
the ligand (Table 1, entry 5). Therefore, a series of chiral
biphosphine ligands with axial chirality were screened to further
improve the yield and enantioselectivity. It was found that
substrate 1a can be hydrogenated smoothly by Rh/(S)-
(+)-DTBM-SegPhos complex, affording the desired product
with the best yield and ee (Table 1, entry 9). Subsequently, the
exploration of various solvents showed that DCM is the best
solvent for this reaction.
To further illustrate the potential utility of this method, the
asymmetric hydrogenation of α-Ts substituted styrene 1a was
carried out on a 0.88 g scale with 0.3% catalyst loading,
B
DOI: 10.1021/acs.orglett.6b03845
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furnishing the desired product with 97% yield and 95% ee
(Scheme 2).
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Scheme 2. Gram-Scale Reaction for AH of 1a
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In summary, we have developed an efficient strategy for
highly enantioselective synthesis of α-substituted chiral sulfones
through Rh-catalyzed asymmetric hydrogenation. This reaction
features high reaction activity (>90% yield), excellent
enantioselectivity (up to 99% ee), wide substrate scope, mild
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03845.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
(15) (a) Velazquez, F.; Arasappan, A.; Chen, K.; Sannigrahi, M.;
*E-mail: huilv@whu.edu.cn.
*E-mail: zhangxm@sustc.edu.cn.
ORCID
Venkatraman, S.; McPhail, A. T.; Chan, T. M.; Shih, N. Y.; Njoroge, F.
G. Org. Lett. 2006, 8, 789−792. (b) Nakamura, S.; Hirata, N.; Kita, T.;
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2007, 46, 7648−7650. (c) Ueda, M.; Hartwig, J. F. Org. Lett. 2010, 12,
92−94. (d) Jin, Z.; Xu, J.; Yang, S.; Song, B.-A.; Chi, Y. R. Angew.
Chem., Int. Ed. 2013, 52, 12354−12358.
Xumu Zhang: 0000-0001-5700-0608
Author Contributions
‡L.S. and B.W. contributed equally to this work.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21402145,
21432007, and 21372179), the Youth Chen-Guang Science
and Technology Project of Wuhan City (2015071704011640),
the Natural Science Foundation of Hubei Province
(2014CFB181), and the “111” Project of the Ministry of
Education of China.
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configuration follows that of 2m.
D
DOI: 10.1021/acs.orglett.6b03845
Org. Lett. XXXX, XXX, XXX−XXX