Efficient synthesis of chiral β-hydroxy sulfones: Via iridium-catalyzed hydrogenation

Article abstract of DOI:10.1039/c8ob02923g

A highly efficient Ir/f-Amphol-catalyzed asymmetric hydrogenation of prochiral β-keto sulfones was successfully developed to prepare a series of chiral β-hydroxy sulfones with good to excellent results (62%->99% conversions, 35%-99% yields and 86%->99% ee). Our Ir/f-Amphol L4 catalytic system exhibited very high activity; the gram-scale asymmetric hydrogenation was performed well with just 0.005 mol% catalyst loading (S/C = 20,000) to afford the desired product 2a with >99% conversion, 99% yield and 93% ee.

Full text of DOI:10.1039/c8ob02923g

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Efficient synthesis of chiral β-hydroxy sulfones via
iridium-catalyzed hydrogenation†
Cite this: DOI: 10.1039/c8ob02923g
a,b
Lin Tao,‡a Congcong Yin,‡a Xiu-Qin Dong *a and Xumu Zhang
*
Received 23rd November 2018,
Accepted 28th December 2018
DOI: 10.1039/c8ob02923g
rsc.li/obc
A highly efficient Ir/f-Amphol-catalyzed asymmetric hydrogenation reduction,6 polymer-supported sulfonamide/prolinol-catalyzed
of prochiral β-keto sulfones was successfully developed to prepare borane reduction,7 transition metal-catalyzed asymmetric hyrdo-
a series of chiral β-hydroxy sulfones with good to excellent results genation8 and asymmetric transfer hydrogenation.9 Transition
(62%–>99% conversions, 35%–99% yields and 86%–>99% ee). Our metal-catalyzed asymmetric hydrogenation has been regarded as
Ir/f-Amphol L4 catalytic system exhibited very high activity; the a powerful synthetic method to generate various chiral β-hydroxy
gram-scale asymmetric hydrogenation was performed well with just sulfones with atom-economy and eco-friendly advantages. Genêt
0.005 mol% catalyst loading (S/C = 20 000) to afford the desired and coworkers reported an enantioselective hydrogenation of
product 2a with >99% conversion, 99% yield and 93% ee.
β-keto sulfones with a chiral Ru(II) catalyst.1i,j Hou and co-workers
realized Rh-catalyzed enantioselective hydrogenation of β-keto
sulfones by using a bisferrocenyl diphosphine ligand with planar
chirality.8a Zhang and coworkers developed Ru-SUNPHOS-cata-
lyzed asymmetric hydrogenation of a variety of sulfonyl ketones
in the presence of iodine with excellent enantioselectivities.8b
However, there are seldom powerful catalytic systems developed
for the asymmetric hydrogenation of β-keto sulfones to afford
high reactivities and enantioselectivities. The turnover number
(TON) of most catalytic systems is less than 2000, which limited
their practical applications. Therefore, it is important to develop
a highly efficient catalytic system for the asymmetric hydrogen-
ation of β-keto sulfones to access enantioenriched β-hydroxy sul-
fones. As our efforts have been directed towards developing privi-
liged chiral phosphine ligands for asymmetric hydrogenation, we
successfully developed a series of tridentate ferrocene-based
aminophosphoxazoline (f-amphox) ligands10 and ferrorence-
based amino-phosphine-alcohol (f-Amphol) ligands,11 which
achieved excellent results in the iridium-catalyzed asymmetric
hydrogenation of prochiral ketones and derivatives recently.
Encouraged by these results, we herein successfully realized
Ir-catalyzed asymmetric hydrogenation of prochiral β-keto sul-
fones, affording a series of chiral β-hydroxy sulfones with high
reactivities and excellent enantioselectivities (Scheme 1, up to
>99% conversion, 99% yield, >99% ee, and 20 000 TON).
Introduction
Chiral β-hydroxy sulfones are important and useful chiral syn-
thons for the construction of a variety of chiral organic com-
pounds in organic synthesis.1 The α-carbon atom of these
compounds can be easily further functionalized, and the sulfo-
nyl group always works as a synthetically useful functional
group.2 They can be efficiently converted to other important
chiral organic molecules, such as chiral β-hydroxy-
α-substituted sulfones, γ-butenolides, γ-butyrolactones,
δ-valeroactones, and 2,5-disubstituted tetrahydrofurans.1
Taking into account the great importance of chiral β-hydroxy
sulfones, their preparation has attracted considerable attention.
Therefore, many synthetic methods have been developed so far
for the enantioselective synthesis of chiral β-hydroxy sulfones in
the past few decades,3–9 such as kinetic resolution of racemic
β-hydroxy sulfones,3 kinetically controlled oxidation of racemic
β-hydroxy sulfoxides4 and asymmetric reduction of β-keto
sulfones,5–9 including bioreduction,5 CBS-catalyzed borane
aKey Laboratory of Biomedical Polymers, Engineering Research Centre of
Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry
and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R. China.
E-mail: zhangxm@sustc.edu.cn, xiuqindong@whu.edu.cn
bDepartment of Chemistry and Shenzhen Grubbs Institute, Southern University of
Science and Technology, Shenzhen, Guangdong, 518055, P. R. China
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, and NMR spectra of compounds. See DOI: 10.1039/c8ob02923g
‡These authors contributed equally to this work.
Results and discussion
We began our initial research by investigating the Ir-cata-
lyzed asymmetric hydrogenation of 1-phenyl-2-(phenylsulfo-
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Table 1 Screening of ligands and solvents for the Ir-catalyzed asym-
metric hydrogenation of 1-phenyl-2-(phenylsulfonyl)ethan-1-one 1a a
Conv.b (%)
eec (%)
Scheme 1 Ir-Catalyzed asymmetric hydrogenation of β-keto sulfones.
Entry
Ligand
Solvent
1d
2d
3d
4
5
6
7
8
9
10
11
12
13
14
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
iPrOH
9
17
>99
68
93
33
98
58
NR
89
8
37
40
94
94
93
83
88
95
NA
90
>99
94
94
94
iPrOH
iPrOH
nyl)ethan-1-one 1a 12 as a model substrate at room tempera-
ture with the catalyst generated in situ by mixing [Ir(COD)Cl]2
with ligands L1–L3 (Fig. 1) in iPrOH (S/C = 100). Full
conversion and excellent enantioselectivity were achieved
with f-Amphol L3 as the ligand (>99% conversion, 94% ee,
Table 1, entry 3). When the catalyst loading was decreased
from 1.0 mol% (S/C = 100) to 0.1 mol% (S/C = 1000), moderate
conversion and excellent enantioselectivity can be obtained
(68% conversion, 94% ee, Table 1, entry 4). Good to excellent
enantioselectivities can be obtained, but poor reactivities were
observed in CF3CH2OH/iPrOH, MeOH/iPrOH, CHCl3/iPrOH,
THF/iPrOH, 1,4-dioxane/iPrOH and hexane/iPrOH (v/v = 10 : 1)
(8%–58% conversions, 83%–>99% ee, Table 1, entries 6, 8,
11–14). The mixture of PhMe/iPrOH (10 : 1) gave the best reac-
tion result (93% conversion, 93% ee, Table 1, entry 5).
iPrOH
PhMe/iPrOH = 10 : 1
CF3CH2OH/iPrOH = 10 : 1
CH2Cl2/iPrOH = 10 : 1
MeOH/iPrOH = 10 : 1
EtOH/iPrOH = 10 : 1
DCE/iPrOH = 10 : 1
CHCl3/iPrOH = 10 : 1
THF/iPrOH = 10 : 1
1,4-Dioxane/iPrOH = 10 : 1
Hexane/iPrOH = 10 : 1
32
13
24
a Reaction conditions: 0.2 mmol 1a, 0.0001 mmol [Ir(COD)Cl]2,
0.00021 mmol ligand, 1.0 mL solvent. The catalyst was preformed in
iPrOH (0.1 mL for each reaction vial), solvent/iPrOH (v/v) = 10 : 1.
DCE = dichloroethane, THF = tetrahydrofuran. NR = no reaction, NA =
not available. b Determined by 1H NMR analysis. c Determined by
HPLC analysis. d S/C = 100.
The Ir/f-Amphol L3-catalyzed asymmetric hydrogenation of
1-phenyl-2-(phenylsulfonyl)ethan-1-one 1a was further studied
with different bases in PhMe/iPrOH (10 : 1). Poor to high con-
versions and excellent enantioselectivities were afforded in the
Table 2 Screening of bases and ligands for the Ir-catalyzed asymmetric
hydrogenation of 1-phenyl-2-(phenylsulfonyl)ethan-1-one 1a a
t
t
presence of KOMe, Cs2CO3, BuONa, BuOLi and NaOH (37%–
92% conversions, 92%–94% ee, Table 2, entries 2–6). Full con-
version and 96% ee were provided with Na2CO3 (Table 2,
entry 7). We found that ligand f-Amphol L4 also can provide
the same result (Table 2, entry 8). When the H2 pressure was
decreased from 50 atm to 20 atm, ligand f-Amphol L4 provided
better enantioselectivity than ligand L3, which was selected as
the best ligand (>99% conversion, 96% ee, Table 2, entry 10 vs.
entry 9).
We then focused on the investigation of the substrate gener-
ality of this Ir/f-Amphol L4-catalyzed asymmetric hydrogen-
ation under the optimized reaction conditions, and the results
are summarized in Table 3. A series of prochiral aryl substi-
tuted β-keto sulfones (1a–1p) were hydrogenated smoothly in
this catalytic system, and the desired hydrogenation products
(2a–2p) were obtained with excellent results (>99% conversion,
Entry
Ligand
Base
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
L3
L3
L3
L3
L3
L3
L3
L4
L3
L4
tBuOK
KOMe
93
79
92
51
37
93
94
93
92
92
93
96
96
90
96
Cs2CO3
tBuONa
tBuOLi
NaOH
Na2CO3
Na2CO3
Na2CO3
Na2CO3
53
>99
>99
98
8
9d
10d
>99
a Unless otherwise noted, reaction conditions: 0.2 mmol 1a,
0.0001 mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL toluene. The
catalyst was preformed in iPrOH (0.1 mL for each reaction vial),
toluene/iPrOH (v/v)
=
10 : 1. b Determined by 1H NMR analysis.
c Determined by HPLC analysis. d 20 atm H2.
96%–99% yields, 90%–>99% ee). The electronic properties and
position of the substituted groups on the phenyl ring of β-keto
sulfones have little influence on the reactivity and enantio-
selectivity. In addition, whether the sulfone is phenyl or
methyl substituted, these substrates worked well in this asym-
metric hydrogenation. Furthermore, the heterocyclic aromatic
substrate 1-(furan-2-yl)-2-(phenylsulfonyl)ethan-1-one 1q also
Fig. 1 The structure of chiral phosphine ligands in this asymmetric
hydrogenation.
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Table 3 Scope study for the Ir/F-Amphol L4-catalyzed asymmetric
hydrogenation of β-keto sulfonesa
Scheme 2 Asymmetric hydrogenation with high TON under mild reac-
tion conditions.
(Scheme 2a). In addition, the asymmetric reduction of the
model substrate 1a was conducted in the presence of 1 atm
H2 under mild reaction conditions, and it afforded 98%
yield and 96% ee (Scheme 2b). These reaction results
showed that our Ir/f-Amphol L4 catalytic system has very
high activity.
Conclusions
In summary, we successfully developed a highly efficient
asymmetric hydrogenation of prochiral β-keto sulfones,
affording various chiral β-hydroxy sulfones with excellent
results (up to >99% conversion, 99% yield and >99% ee). Our
Ir/f-Amphol L4 catalytic system showed very high activity; this
gram-scale asymmetric hydrogenation proceeded smoothly in
the presence of only 0.005 mol% catalyst loading (S/C =
20 000) with 99% yield and 93% ee. Moreover, this asym-
metric hydrogenation can be conducted under mild reaction
conditions.
a Unless otherwise noted, reaction conditions: 0.2 mmol substrate 1,
0.0001 mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL toluene. The
catalyst was preformed in iPrOH (0.1 mL for each reaction vial),
PhMe/iPrOH (v/v) = 10 : 1, Na2CO3 (5 mol%). Conversion was deter-
mined by 1H NMR analysis, the yield reported is the isolated yield, ee
was determined by HPLC analysis. b S/C = 500, 0.1 mmol substrate,
Na2CO3 (10 mol%). c S/C = 500, 0.2 mmol substrate, Na2CO3 (5 mol%).
Conflicts of interest
The authors declare no competing financial interest.
proceeded smoothly, affording the desired hydrogenation
product with >99% conversion, 96% yield and 86% ee.
Acknowledgements
Moderate reactivity and excellent enantioselectivity can be We are grateful for the financial support from the National
obtained, when the alkyl substrate 1-cyclohexyl-2-(phenylsulfo- Natural Science Foundation of China (Grant No. 21432007,
nyl)ethan-1-one 1r was applied in this reaction (62% conver- 21502145), the Wuhan Morning Light Plan of Youth Science
sion, 35% yield, 90% ee).
and Technology (Grant No. 2017050304010307), the Shenzhen
The gram-scale Ir/f-Amphol L4-catalyzed asymmetric Nobel Prize Scientists Laboratory Project (Grant No.
hydrogenation of the model substrate 1-phenyl-2-(phenylsul- C17783101) and the Fundamental Research Funds for Central
fonyl)ethan-1-one 1a was performed successfully with just Universities (Grant No. 2042018kf0202). The Program of
0.005 mol% catalyst loading (S/C = 20 000). The product 2a Introducing Talents of Discipline to Universities of China (111
was afforded with >99% conversion, 99% yield and 93% ee Project) is also appreciated.
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Tetrahedron Lett., 1984, 25, 3979; (g) V. Gotor, F. Rebollelo
and R. Liz, Tetrahedron: Asymmetry, 2001, 12, 513.
Notes and references
1 (a) G. Solladié, C. Frechou, G. Demailly and C. Greck,
J. Org. Chem., 1986, 51, 1912; (b) S. Robin, F. Huet,
A. Fauve and H. Veschambre, Tetrahedron: Asymmetry,
1993, 4, 239; (c) A. P. Kozikowski, B. B. Mugrage, C. S. Li
and L. Felder, Tetrahedron Lett., 1986, 27, 4817;
(d) R. Tanikaga, K. Hosoya and A. Kaji, Synthesis, 1987,
389; (e) R. Tanikaga, K. Hosoya and A. Kaji, J. Chem.
Soc., Perkin Trans. 1, 1987, 1799; (f) G. Sarakinos and
E. J. Corey, Org. Lett., 1999, 1, 1741; (g) P. Metzner and
A. Thuillier, Sulfur Reagents in Organic Synthesis,
Academic Press, New York, 1994; (h) T. Sato,
Y. Okumura, J. Itai and T. Fujisawa, Chem. Lett., 1988,
1537; (i) P. B. Phansavath, V. Ratovelomanana-Vidal,
J.-P. Genêt, A. R. Touati, T. Hornri and B. B. Hassine,
Tetrahedron: Asymmetry, 1999, 10, 1369; ( j) P. Bertus,
P. Phansavath, V. Ratovelomanana-Vidal and J.-P. Genêt,
Tetrahedron Lett., 1999, 40, 3175; (k) J. Rojo, M. Garcia
and J. C. Carretero, Tetrahedron, 1993, 49, 9787.
6 (a) B. T. Cho and D. J. Kim, Tetrahedron: Asymmetry, 2001,
12, 2043; (b) O. K. Choi and B. T. Cho, Org. Prep. Proced.
Int., 2000, 32, 493.
7 (a) G. Zhao, J. B. Hu, Z. S. Qian and W. X. Yin, Tetrahedron:
Asymmetry, 2002, 13, 2095; (b) G.-Y. Wang, X.-Y. Liu and
G. Zhao, Synlett, 2006, 1150.
8 (a) H.-L. Zhang, X.-L. Hou, L.-X. Dai and Z.-B. Luo,
Tetrahedron: Asymmetry, 2007, 18, 224; (b) X.-B. Wan,
Q.-H. Meng, H.-W. Zhang, Y.-H. Sun, W.-Z. Fan and
Z.-G. Zhang, Org. Lett., 2007, 9, 5613; (c) X.-F. Huang,
S.-Y. Zhang, Z.-C. Geng, C.-Y. Kwok, P. Liu, H.-Y. Li and
X.-W. Wang, Adv. Synth. Catal., 2013, 355, 2860.
9 (a) V. K. Vyas, P. Srivastava, P. Bhatt, V. Shende, P. Ghosh and
B. M. Bhanage, ACS Omega, 2018, 3, 12737; (b) J. Wang, L. Wu,
X. Hu, R. Liu, R. Jin and G. Liu, Catal. Sci. Technol., 2017, 7,
4444; (c) Z. Xu, S. Zhu, Y. Liu, L. He, Z. Geng and Y. Zhang,
Synthesis, 2010, 811; (d) Z. Xiong, C. Pei, P. Xue, H. Lv and
X. Zhang, Chem. Commun., 2018, 54, 3883; (e) D. C. Zhang,
T. Y. Cheng, Q. K. Zhao, J. Y. Xu and G. H. Liu, Org. Lett.,
2014, 16, 5764; (f) X. Hu, K. Zhang, F. Chang, R. Liu, G. Liu
and T. Cheng, Mol. Catal., 2018, 452, 271.
2 (a) The Chemistry of Sulfur-Containing Functional Groups, ed.
S. Patai and Z. Rappoport, Wiley-Interscience, New York,
1993; (b) S. Oae, Organic Sulfur Chemistry, CRC Press, Boca
Raton, FL, 1991; (c) L. I. Belenkii, Chemistry of Organosulfur 10 (a) S. Wang, Y. Yu, J. Wen and X. Zhang, Synlett, 2018, 29,
Compounds,
Ellis
Horwood,
New
York,
1990;
2203; (b) Y. Hu, X. Yin, Z. Chen, X.-Q. Dong and X. Zhang,
Org. Chem. Front., 2018, 5, 2000; (c) C. Yin, W. Wu, Y. Hu,
X. Tan, C. You, Y. Liu, Z. Chen, X.-Q. Dong and X. Zhang,
Adv. Synth. Catal., 2018, 360, 2119; (d) Y. Hu, W. Wu,
X.-Q. Dong and X. Zhang, Org. Chem. Front., 2017, 4, 1499;
(e) W. Wu, C. You, C. Yin, Y. Liu, X.-Q. Dong and
X. Zhang, Org. Lett., 2017, 19, 2548; (f) W. Wu, Y. Xie,
P. Li, X. Li, Y. Liu, X.-Q. Dong and X. Zhang, Org. Chem.
Front., 2017, 4, 555; (g) W. Wu, S. Liu, M. Duan, X. Tan,
C. Chen, Y. Xie, Y. Lan, X.-Q. Dong and X. Zhang, Org.
Lett., 2016, 18, 2938.
(d) N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon
Press, New York, 1993; (e) B. M. Trost, Bull. Chem. Soc. Jpn.,
1988, 61, 107; (f) P. L. Fuchs and T. F. Breish, Chem. Rev.,
1986, 86, 903.
3 (a) R. Chinchilla, C. Nájera, J. Pardo and M. Yus,
Tetrahedron: Asymmetry, 1990, 1, 575; (b) P. Kiełbasiński,
M. Rachwalski, M. Mikołajczyk, M. A. H. Moelands,
B. Zwanenburg and F. P. J. T. Rutjes, Tetrahedron:
Asymmetry, 2005, 16, 2157.
4 H. Ohta, Y. Kato and G. Tsuchihashi, J. Org. Chem., 1987,
52, 2735.
5 (a) S. Servi, Synthesis, 1990, 1; (b) R. Csuk and B. I. Glänzer,
Chem. Rev., 1991, 91, 49; (c) R. L. Crumble, B. S. Deol,
J. E. Nemorin and D. D. Ridley, Aust. J. Chem., 1978, 31,
1965; (d) S. M. Roberts, J. Chem. Soc., Perkin Trans. 1, 1999,
11 (a) C. Yin, X.-Q. Dong and X. Zhang, Adv. Synth. Catal.,
2018, 360, 4319; (b) G. Gu, J. Lu, O. Yu, J. Wen, Q. Yin and
X. Zhang, Org. Lett., 2018, 20, 1888; (c) J. Yu, M. Duan,
W. Wu, X. Qi, P. Xue, Y. Lan, X.-Q. Dong and X. Zhang,
Chem. – Eur. J., 2017, 23, 970.
1; (e) S. Iriuchijima and N. Kojima, Agric. Biol. Chem., 1978, 12 N. Suryakiran, T. S. Reddy, K. Ashalatha, M. Lakshman and
42, 451; (f) K. Nakamura, K. Ushio, S. Oka and A. Ohno,
Y. Venkateswarlu, Tetrahedron Lett., 2006, 47, 3853.
Org. Biomol. Chem.
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