Highly enantioselective one-pot synthesis of chiral β-hydroxy sulfones via asymmetric transfer hydrogenation in an aqueous medium

Article abstract of DOI:10.1021/ol502832a

A mild transformation in an aqueous medium for the one-pot synthesis of optically active β-hydroxy sulfones is described. The intermediates of β-keto sulfones obtained via a nucleophilic substitution reaction of α-bromoketones and sodium sulfinates in H

Full text of DOI:10.1021/ol502832a

Letter
pubs.acs.org/OrgLett
Highly Enantioselective One-Pot Synthesis of Chiral β‑Hydroxy
Sulfones via Asymmetric Transfer Hydrogenation in an Aqueous
Medium
Dacheng Zhang, Tanyu Cheng,* Qiankun Zhao, Jianyou Xu, and Guohua Liu*
Key Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials,
Shanghai Normal University, Shanghai 200234, P. R. China
S
* Supporting Information
ABSTRACT: A mild transformation in an aqueous medium
for the one-pot synthesis of optically active β-hydroxy sulfones
is described. The intermediates of β-keto sulfones obtained via
a nucleophilic substitution reaction of α-bromoketones and
sodium sulfinates in H2O/MeOH (1:3, v/v) at 50 °C were
reduced through Ru-catalyzed asymmetric transfer hydro-
genation in one-pot using HCOONa as a hydrogen source providing a variety of chiral β-hydroxy sulfones with high yields
and excellent enantioselectivities.
ne-pot transformation, including one-pot tandem reac-
tion and one-pot sequential reaction, is an efficient
formed into the corresponding optically active O-acetyl
derivatives using a lipase promoted dynamic kinetic resolution.8
Carretero and colleagues recently obtained chiral β-hydroxy
sulfones though asymmetric conjugate boration of α,β-
unsaturated sulfones using nonracemic Cu(I)-diphosphine
complexes as a catalyst in the presence of the strong base t-
BuONa.9 Asymmetric reduction of β-keto sulfones is a
common way to obtain chiral β-hydroxy sulfones. The baker’s
yeast mediated reduction is a practical route. However, poor
yields and enantioselectivities were obtained when the
substrates were aryl ketones.10 Chemical methods for
asymmetric reduction of β-keto sulfones are one of the most
efficient ways to provide chiral β-hydroxy sulfones. Currently,
most of them are catalytic enantioselective hydrogenations.11
Although high yields and enantioselectivities were attained, the
high pressure of the reactions made them difficult to operate.
There are also some works synthesizing chiral β-hydroxy
sulfones via borane reduction in the organic solvent
tetrahydrofuran (THF).12 Despite ATH being an outstanding
procedure to enantioselectively reduce ketones, only a few
reports of chiral β-hydroxy sulfones synthesis employing this
method in DMF were published.13 Pure β-keto sulfones also
must be obtained for most of reported processes (Scheme 1),
which cause a long production cycle and high cost of products.
Herein, we report a novel catalytic procedure for the one-pot,
two-step synthesis of optically active β-hydroxy sulfones from
α-bromoketones and sodium sulfinates in an aqueous medium
(Scheme 1).
O
methodology for the construction of complex and high-value
compounds from relatively simple, inexpensive, and accessible
raw materials.1 The desired products could be obtained with
minimum workup and without the isolation of intermediates
through this method, which minimizes production cycles and
cost and decreases waste. So the increasing demands for
environmentally and economically friendly synthetic processes
have promoted the booming development of the one-pot
synthetic method.
The increasing demand for optically pure compounds for
pharmaceuticals, pesticides, and other fine chemicals has greatly
accelerated the development of asymmetric catalytic method-
ologies.2 Among these methods, asymmetric transfer hydro-
genation (ATH), utilizing transition metals including iridium,
rhodium, and ruthenium to enantioselectively reduce prochiral
ketones and imines, has become one of the most efficient
methods for constructing enantioenriched secondary alcohols
and amines.3 ATH has gained much attention and developed
rapidly in recent years because of its significant advantages such
as simple operation, mild reaction conditions, high yield, high
enantioselectivity, and so on.
Chiral β-hydroxy sulfones are a type of important optically
active alcohol that is an essential building block for several
bioactive molecules. Because of the electron-withdrawing
property of the sulfonyl group at the β-position, the α-carbon
could be further functionalized and the sulfonyl group could be
removed without racemization.4 They have also been used for
the synthesis of optically active compounds such as γ-
butenolides,5 δ-valerolactone,6 etc. Because of the wide use of
chiral β-hydroxy sulfones, several methods were developed for
the synthesis of those compounds. Nageswar, Venkateswarlu
and co-workers synthesized racemic β-hydroxy sulfones via
opening of epoxides with sulfinates,7 which could be trans-
In the case of asymmetric synthesis, high enantioselectivity
should be one of the most important objectives. Therefore, we
started our studies with optimization of the conditions for
ATH. As we know, the complexes of transition metals, such as
Received: September 25, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502832a | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Chiral β-Hydroxy Sulfones from α-
Bromoketones and Sodium Sulfinate
Table 1. Screening of Catalysts for the Synthesis of (S)-1-
a
Phenyl-2-(phenylsulfonyl)ethanol via ATH
Figure 1. Kinetic investigation of the one-pot synthesis of β-hydroxy
sulfone.
b
entry
catalyst
conv (%)
ee (%)c
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
99
99
99
99
99
99
99
97
97
83
98
88
99
98
in aqueous solution and have done some work based on this
type of catalysts.15 Here, we chose the ATH of 1-phenyl-2-
(phenylsulfonyl)ethanone 2a for the synthesis of (S)-1-phenyl-
2-(phenylsulfonyl)ethanol 3a as a model reaction. The catalysts
Cp*MTsDPEN (Cp* = pentamethylcyclopentadiene, M = Ru,
Rh, and Ir) 4a−4c and AreneRuTsDPEN 4d−4g were
screened to catalyze the model reaction under the reported
conditions of H2O/i-PrOH (1:3, v/v) with HCOONa as a
hydrogen source.16 We found that 2a could be converted to 3a
smoothly in 4 h in the presence of all tested catalysts 4a−4g,
and 4f provided the best enantioselectivity (Table 1).
After catalyst 4f was designated, the conditions of a one-pot
synthesis of β-hydroxy sulfones were investigated next. Here,
we chose the reaction of 2-bromo-1-phenylethanone 1a and
sodium benzenesulfinate as a model reaction. As shown in
Table 2, the reaction was conducted in water first, and the
reaction rate was very slow (entry 1, Table 2). That was
probably due to the poor solubility of 2-bromo-1-phenyl-
ethanone in water. So cosolvent H2O−CH3OH (1:3, v/v) was
applied for this reaction, and the reaction rate significantly
increased (entry 2). When the reaction temperature was
increased from 20 to 50 °C, the reaction would be completed in
1 h (entry 3). However, the yield of the corresponding product
decreased when the reaction was carried out in organic
solvents, such as CH3OH and i-PrOH (entries 4 and 5). Then
the ratio of water and organic solvent was also evaluated
(entries 6−8), and it was found that H2O−CH3OH (1:3, v/v)
gave the best result. A decreased yield was obtained using
H2O−i-PrOH (1:3, v/v) as the solvent. Next, the optimal
reaction temperature was determined to be 50 °C (entries 9
and 10).
4g
a
Reaction conditions: 2a (0.1 mmol), 4 (5 mol %), HCOONa (0.3
mmol), 4 mL of H2O/i-PrOH (1:3, v/v). Determined by HPLC with
a Daicel Chiralpak column AD-H.
b
Table 2. Optimization of Reaction Conditions for the One-
Pot Synthesis of the Chiral β-Hydroxy Sulfones
a
b
c
entry
solvent
temp (°C) time (h) yield (%) ee (%)
1
2
H2O
20
20
50
50
50
50
50
50
40
60
24
9
78
89
93
85
82
86
90
88
85
80
95
98
99
96
96
95
97
98
97
95
H2O/CH3OH (1:3)
H2O/CH3OH (1:3)
CH3OH
3
1
4
1
5
i-PrOH
1
6
H2O/CH3OH (1:1)
H2O/CH3OH (1:5)
H2O/i-PrOH (1:3)
H2O/CH3OH (1:3)
H2O/CH3OH (1:3)
1
7
1
8
1
9
2
10
0.5
a
Reaction conditions: 2a (0.1 mmol), 4f (5 mol %), HCOONa (0.3
mmol), solvent (4 mL). Isolated yield. Determined by HPLC with a
Daicel Chiralpak column AD-H.
b
c
A kinetic investigation of this model reaction was also carried
out, and the result is shown in Figure 1. This reaction can be
accomplished via two alternative routes. Nucleophilic sub-
stitution takes place in one pathway first involving the
intermediate B followed by ATH. Another pathway includes
ruthenium, rhodium, and iridium, with the ligand of N-(p-
toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) are
efficient catalysts for the asymmetric reduction of ketones and
imines.3b,14 We are interested in the ATH of aromatic ketones
B
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Organic Letters
Letter
a
constant, which indicates that the route of this reaction is
through the nucleophilic substitution−ATH pathway. The
resuling kinetic curves also demonstrate that the reaction is
totally finished in 60 min.
Scheme 2. One-Pot Synthesis of Chiral β-Hydroxy Sulfones
Encouraged by the above good results, the scope of the one-
pot synthetic reaction was investigated with a variety of α-
bromoketones and sodium sulfinates, and the results are
summarized in Scheme 2. It was found that all 4′-substituted α-
bromoacetophenones, regardless of the electron-donating or
-withdrawing property of the substituent, provided correspond-
ing optically active β-hydroxy sulfones 3b−3i in high yields and
excellent enantioselectivities reacting with sodium benzenesul-
finate. Very similar results were obtained using 3′-substituted α-
bromoacetophenones as substrates 1j−1l. When the reactions
of 2′-substituted α-bromoacetophenones (1m and 1n) and
sodium benzenesulfinate were carried out, 3m and 3n were
obtained with slighly decreased enantioselectivities (95% and
90% ee, respectively). That was probably due to the steric
hindrance of the substituents. 2-Bromo-1-(2-naphthyl)-
ethanone 1o was also tested for the one-pot synthesis, and it
afforded 3o in 92% yield with 98% ee. The aliphatic α-
bromoketones, 1p and 1q, were investigated for this trans-
formation as well, which furnished the desired products in good
yields (85% and 86%) with slightly declined enantioselectivities
(91% and 80% ee). In addition, the one-pot transformations
were successfully accomplished using sodium p-toluenesulfinate
and sodium methanesulfinate providing 3r−3x with high yields
and enantioselectivities. To demonstrate the practicality of this
reaction, a scale-up one-pot reaction with 1 mmol of 2-bromo-
1-phenylethanone 1a was carried out. The result showed that a
longer reaction time (2 h) was needed and the same ee value
with a slightly reduced yield (83%) was observed compared to
the small-scale reaction. Furthermore, almost the same result
(85% yield, 98% ee) was observed in this reaction with a lower
catalyst loading (2 mol %), which demonstrated the high
catalytic effectivity of catalyst 4f for this one-pot procedure.
In summary, we have described a mild, ATH-based
procedure for the one-pot synthesis of optically active β-
hydroxy sulfones in an aqueous medium from α-bromoketones
and sodium sulfinates. This reaction is carried out in a
cosolvent of H2O and CH3OH at 50 °C, catalyzed with
RuCl[(S,S)-TsDPEN)](mesitylene) using HCOONa as a
hydrogen source. This transformation affords desired products
in high yields with excellent enantioselectivities using a variety
of α-bromoketones and sodium sulfinates as substrates.
ASSOCIATED CONTENT
■
a
S
* Supporting Information
Reactions were performed with 0.1 mmol of α-bromoketone, 0.11
mmol of sodium sulfinate, 5 mol % of 4f, and 0.3 mmol of HCOONa
in 4 mL of H2O/CH3OH (1:3, v/v) at 50 °C for 1 h; isolated yield; ee
values were determined by HPLC with a Daicel Chiralpak column AD-
H or Daicel Chiralcel column OJ-H.
General information, typical experimental procedures, charac-
terization, and HPLC spectra of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
ATH which provides the intermediate C followed by
nucleophilic substitution. As shown in the kinetic curve plot,
2-bromo-1-phenylethanone A decreases rapidly and 1-phenyl-2-
(phenylsulfonyl)ethanone B increases quickly within the first 5
min. Then the ratio of product D increases gradually, and both
A and B slowly disappear. In the process of this reaction, the
concentration of 2-bromo-1-phenylethanol C is essentially
Corresponding Authors
*E-mail: tycheng@shnu.edu.cn.
*E-mail: ghliu@shnu.edu.cn.
Notes
The authors declare no competing financial interest.
C
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Organic Letters
Letter
40, 3175−3178. (d) Wan, X.; Meng, Q.; Zhang, H.; Sun, Y.; Fan, W.;
Zhang, Z. Org. Lett. 2007, 9, 5613−5616. (e) Zhang, H. L.; Hou, X. L.;
Dai, L. X.; Luo, Z. B. Tetrahedron: Asymmetry 2007, 18, 224−228.
(f) Huang, X. F.; Zhang, S. Y.; Geng, Z. C.; Kwok, C. Y.; Liu, P.; Li, H.
Y.; Wang, X. W. Adv. Synth. Catal. 2013, 355, 2860−2872.
ACKNOWLEDGMENTS
■
We are grateful to the Shanghai Sciences and Technologies
Development Fund (13ZR1458700 and 12 nm0500500), the
Shanghai Municipal Education Commission (14YZ074,
12ZZ135, Young Teacher Training Project), Specialized
Research Fund for the Doctoral Program of Higher Education
(20133127120006), and Shanghai Key Laboratory of Chemical
Biology Fund Project for financial support.
(12) (a) Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12,
2043−2047. (b) Zhao, G.; Hu, J. B.; Qian, Z. S.; Yin, W.-x.
Tetrahedron: Asymmetry 2002, 13, 2095−2098.
(13) Ding, Z.; Yang, J.; Wang, T.; Shen, Z.; Zhang, Y. Chem.
Commun. 2009, 571−573.
(14) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521−2522. (b) Hashiguchi, S.; Fujii, A.;
Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
7562−7563. (c) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M.
J. Am. Chem. Soc. 2005, 127, 7318−7319. (d) Li, X.; Wu, X.; Chen, W.;
Hancock, F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321−3324.
(e) Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Y. Q. Org. Lett. 2003, 6, 169−
172. (f) Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori, R.;
Ikariya, T. Org. Lett. 1999, 1, 1119−1121. (g) Wu, X.; Li, X.; Hems,
W.; King, F.; Xiao, J. Org. Biomol. Chem. 2004, 2, 1818−1821.
(15) (a) Liu, R.; Jin, R.; Kong, L.; Wang, J.; Chen, C.; Cheng, T.; Liu,
G. Chem.Asian J. 2013, 8, 3108−3115. (b) Sun, Y.; Liu, G.; Gu, H.;
Huang, T.; Zhang, Y.; Li, H. Chem. Commun. 2011, 47, 2583−2585.
(c) Liu, R.; Cheng, T.; Kong, L.; Chen, C.; Liu, G.; Li, H. J. Catal.
2013, 307, 55−61. (d) Xiao, W.; Jin, R.; Cheng, T.; Xia, D.; Yao, H.;
Gao, F.; Deng, B.; Liu, G. Chem. Commun. 2012, 48, 11898−11900.
(16) Zhang, D.; Gao, X.; Cheng, T.; Liu, G. Sci. Rep. 2014, 4, 5091.
REFERENCES
■
(1) (a) Ramachary, D. B.; Jain, S. Org. Biomol. Chem. 2011, 9, 1277−
1300. (b) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2011, 50, 8492−8509. (c) Climent, M. J.; Corma, A.; Iborra, S.
Chem. Rev. 2010, 111, 1072−1133. (d) Zhu, Y.; Sun, L.; Lu, P.; Wang,
Y. ACS Catal. 2014, 4, 1911−1925. (e) Filice, M.; Palomo, J. M. ACS
Catal. 2014, 4, 1588−1598. (f) Cheng, D.; Ishihara, Y.; Tan, B.;
Barbas, C. F. ACS Catal. 2014, 4, 743−762. (g) Simon, R. C.; Richter,
N.; Busto, E.; Kroutil, W. ACS Catal. 2014, 4, 129−143. (h) Xia, Y.;
Zhang, Y.; Wang, J. ACS Catal. 2014, 4, 2586−2598. (i) Lin, J.-L.;
Palomec, L.; Wheeldon, I. ACS Catal. 2014, 4, 505−511. (j) Climent,
M. J.; Corma, A.; Iborra, S.; Sabater, M. J. ACS Catal. 2014, 4, 870−
891.
(2) (a) Boersma, A. J.; Megens, R. P.; Feringa, B. L.; Roelfes, G.
Chem. Soc. Rev. 2010, 39, 2083−2092. (b) Fernan
P.; Panossian, A.; Vidal-Ferran, A. Chem. Rev. 2011, 111, 2119−2176.
(c) Leeuwen, P. W. N. M. V.; Kamer, P. C. J.; Claver, C.; Pamies, O.;
Dieguez, M. Chem. Rev. 2010, 111, 2077−2118. (d) Liu, Y.; Xuan, W.;
́ ́
dez-Perez, H.; Etayo,
̀
́
Cui, Y. Adv. Mater. 2010, 22, 4112−4135. (e) Mahlau, M.; List, B.
Angew. Chem., Int. Ed. 2013, 52, 518−533. (f) Phipps, R. J.; Hamilton,
G. L.; Toste, F. D. Nat. Chem. 2012, 4, 603−614. (g) Rueping, M.;
Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed.
2011, 50, 6706−6720. (h) Teichert, J. F.; Feringa, B. L. Angew. Chem.,
Int. Ed. 2010, 49, 2486−2528. (i) Wang, F.; Liu, L.; Wang, W.; Li, S.;
Shi, M. Coord. Chem. Rev. 2012, 256, 804−853. (j) Yoon, M.;
Srirambalaji, R.; Kim, K. Chem. Rev. 2011, 112, 1196−1231.
(3) (a) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226−236.
(b) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300−1308.
(c) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282−2291. (d) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97−102. (e) Wang, C.;
Wu, X.; Xiao, J. Chem.Asian J. 2008, 3, 1750−1770. (f) You, S. L.
Chem.Asian J. 2007, 2, 820−827. (g) Zassinovich, G.; Mestroni, G.;
Gladiali, S. Chem. Rev. 1992, 92, 1051−1069.
(4) (a) Gais, H. J.; von der Weiden, I.; Fleischhauer, J.; Esser, J.;
Raabe, G. Tetrahedron: Asymmetry 1997, 8, 3111−3123. (b) Fuchs, P.
L.; Braish, T. F. Chem. Rev. 1986, 86, 903−917.
(5) (a) Solladie, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org.
Chem. 1986, 51, 1912−1914. (b) Sato, T.; Okumura, Y.; Itai, J.;
Fujisawa, T. Chem. Lett. 1988, 17, 1537−1540. (c) Robin, S.; Huet, F.;
Fauve, A.; Veschambre, H. Tetrahedron: Asymmetry 1993, 4, 239−246.
(6) Kozikowski, A. P.; Mugrage, B. B.; Li, C. S.; Felder, L.
Tetrahedron Lett. 1986, 27, 4817−4820.
(7) (a) Narayana Murthy, S.; Madhav, B.; Prakash Reddy, V.; Rama
Rao, K.; Nageswar, Y. V. D. Tetrahedron Lett. 2009, 50, 5009−5011.
(b) Suryakiran, N.; Reddy, T. S.; Venkateswarlu, Y. J. Sulfur Chem.
2007, 28, 513−518. (c) Deeming, A. S.; Russell, C. J.; Hennessy, A. J.;
Willis, M. C. Org. Lett. 2013, 16, 150−153.
́
(8) Kiełbasinski, P.; Rachwalski, M.; Mikołajczyk, M.; Moelands, M.
A. H.; Zwanenburg, B.; Rutjes, F. P. J. T. Tetrahedron: Asymmetry
2005, 16, 2157−2160.
(9) Moure, A. L.; Gomez Arrayas, R.; Carretero, J. C. Chem.
Commun. 2011, 47, 6701−6703.
(10) Csuk, R.; Glaenzer, B. I. Chem. Rev. 1991, 91, 49−97.
(11) (a) Bernabeu, M. C.; Bonete, P.; Caturla, F.; Chinchilla, R.;
Naj
P.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet
R.; Homri, T.; Hassine, B. B. Tetrahedron: Asymmetry 1999, 10, 1369−
1380. (c) Bertus, P.; Phansavath, P.; Ratovelomanana-Vidal, V.; Genet
J. P.; Touati, A. R.; Homri, T.; Hassine, B. B. Tetrahedron Lett. 1999,
́
era, C. Tetrahedron: Asymmetry 1996, 7, 2475−2478. (b) Bertus,
̂
, J. P.; Touati, A.
̂
,
D
dx.doi.org/10.1021/ol502832a | Org. Lett. XXXX, XXX, XXX−XXX