Highly efficient synthesis of chiral aromatic ketones: Via Rh-catalyzed asymmetric hydrogenation of β,β-disubstituted enones

Article abstract of DOI:10.1039/c7cc04045h

A succinct and efficient protocol was developed for the synthesis of chiral aromatic ketones via asymmetric hydrogenation of β,β-disubstituted enones with rhodium catalysts based on chiral bisphosphine thiourea ligands. A series of substrates (17 examples) was smoothly catalyzed to afford the corresponding chiral aromatic ketones in high conversions (>99%) with excellent enantioselectivities (up to 96% ee).

Full text of DOI:10.1039/c7cc04045h

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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Highly Efficient Synthesis of Chiral Aromatic Ketones via Rh-
Catalyzed Asymmetric Hydrogenation of β, β-disubstituted
enones
Received 00th May 2017,
Accepted 00th January 2017
Tao Zhang,a,† Jun Jiang,b,† Lin Yao,c Huiling Geng,a,* Xumu Zhangd,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A succinct and efficient protocol was developed for the synthesis
of chiral aromatic ketones via asymmetric hydrogenation of β,β-
disubstituted enones with rhodium catalysts based on chiral
bisphosphine thiourea ligands. A series of substrates (17 examples)
was smoothly catalyzed to afford the corresponding chiral
aromatic ketones in high conversions（>99%）with excellent
enantioselectivities (up to 96% ee).
OH
O
OH
O
O
O
O
O
OH
N
O
A
C
B
O
Optically pure aromatic ketones are widely distributed in the
nature and play a significant role in the organic synthesis.
Chiral β,β-disubstituted ketones are key structural subunits of
many bioactive natural products and serve as prevalent
building blocks in many pharmaceuticals and agrochemicals.
HO
O
O
OH
O
O
D
F
E
For example, (S)-warfarin (
commonly used to prevent heart attack, stroke and the
formation of blood clot.1 Compound is an antifertility agent.2
is an
A), a well-known anticoagulant, is
OH
Fig. 1 Typically bioactive compounds containing chiral β,β-disubstituted ketones.
B
C
is used in the treatment of psoriasis,3 and
D
relay oxidative Heck reaction of acyclic alkenols,14
enantioselective β-arylation of ketones,15 as well as
asymmetric hydrogenation of β,β-disubstituted α,β-
unsaturated ketones. Among these approaches, transition-
metal catalyzed hydrogenation of C=C bond of enones
antihyperlipidemic constituent.4 Other bioactive compounds
are widely used as agrochemicals and fragrances, such as
carvone (E) and turmerone (F
) et al (Figure 1).5-6
Consequently, the research on efficient synthesis of chiral
β,β-disubstituted ketones has attracted increasingly
considerable attention. In this context, various approaches
have been developed in the last decades. Representative
examples of these methods are as follows: asymmetric 1,4-
represents
a promising strategy to access these chiral
compounds due to its high atom economy. However, the
chemoselective reduction of enones is still a stumbling block,
for both C=C bond and C=O bond could be reduced by H2. For
instance, a couple of catalytic systems would preferentially
reduce C=O bond of conjugated enone.16 Although several
chiral metal complexes have been developed for the
7
addition of boronic acids to enones catalyzed by Rh-Binap,
oxidation of C=C bond of chiral enols by Pd(II),8
enantioselective conjugate addition of organometallic
compounds to α,β-unsaturated enones,9-13 asymmetric redox-
hydrogenation
of
β-substituted
enones,17-25
their
enantioselectivities and reactivities still need to be further
improved.
a.School of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi
712100, China. E-mail: genghuiling@nwsuaf.edu.cn
Our group has developed the bisphosphine thiourea ligand
(ZhaoPhos) in 2013, wherein a covalent linker connected the
ferrocene-based bisphosphine unit with the thiourea moiety.26
The bifunctional ligand complexed with rhodium metal
precursor has successfully accomplished the hydrogenation of
β-amino nitroolefins,27 unprotected imines,28 isoquinolines and
b.College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei
430072, China.
c. School of Chemistry & Pharmacy, The Fourth Military Medical University, Xi’an,
Shaanxi 710032, China.
d.Department of chemistry, South University of Science and Technology, Shenzhen,
Guangzhou 518055, China. E-mail: zhangxm@sustc.edu.cn
† Tao Zhang and Jun Jiang contributed equally to this work.
Electronic Supplementary Information (ESI) available: Experimental procedures quinolones,29 carboxylic acid derivatives,30 and maleinimides31
and characterisation data for all products and substrates, NMR spectra and HPLC
spectra for all products. See DOI: 10.1039/x0xx00000x
with high reactivity and excellent enantioselectivity. Inspired
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O
O
by the previous exciting results, we wonder whether Rh-
ZhaoPhos could realize the asymmetric hydrogenation of β,β-
1 % [Rh(NBD)Cl]2/L, 60 atm H2, 48 h
MeOH:CF3CH2OH = 3:1, 25
C
4a
3a
disubstituted
α,β-unsaturated
ketones
with
high
CF3
CF3
chemoselectivity and enantioselectivity.
S
O
Initially, β,β-disubstituted conjugated enones were prepared
through Horner-Wadsworth-Emmons reaction using aromatic
ketones as starting material according to the reported
procedure (see supplementary information).20
F3C
N
H
N
F3C
N
H
N
H
H
Ph2P Fe
Ph2P Fe
Con.: 99%
94%
Con.: 93%
7%
ee:
Ph2P
Ph2P
ee:
L1
L2
CH3
CF3
Then (E)-1,3-diphenylbut-2-en-1-one 3a was chosen as a
model substrate. The hydrogenation of 3a in the presence of
the ZhaoPhos-Rh complex, generated in situ from [Rh(NBD)Cl]2
(1.0 mol%; NBD = 2,5-norbornadiene) and ZhaoPhos (1.0
equivalent of Rh), in trifluoroethanol under 30 atm of
hydrogen pressure at room temperature for 24 h, gave (S)-4a
with 75% conversion and 65% ee (Table 1, entry 1). When the
pressure of hydrogen was increased to 60 atm, full conversion
and 65% ee was afforded (entry 2). With this encouraging
result, we examined the catalytic activity of ZhaoPhos with
different metal sources (entries 3-5). [Rh(COD)Cl]2 and
[Rh(NBD)2]BF4 provided higher conversion (>99%) with lower
enantioselectivity. On the contrary, [Rh(COD)2]BF4 showed
both lower conversion and enantioselectivity. In most cases,
solvent played a crucial role in the Rh-ZhaoPhos system.
Consequently, various types of solvents were screened, using
methol, ethanol and isopropanol as solvent gave 4a with 92%
ee (entries 6-8), while trifluoroethanol afforded the highest
S
S
H3C
N
H
N
F3C
N
H
N
H
Ph2P Fe
Ph2P Fe
Con.: 49%
Con.: 99%
Ph2P
Ph2P
L3
L4
35%
88%
ee:
ee:
F3C
CF3
S
S
N
H
N
H
F3C
N
H
N
H
Ph2P Fe
Ph2P Fe
Con.: 10%
33%
Con.: 76%
65%
Ph2P
L6
ee:
ee:
L5
CF3
S
S
N
N
N
F3C
N
N
H
H
H
H
Ph2P Fe
(Me2Ph)2P Fe
(Me2Ph)2P
Con.: 20%
57%
Con.: 10%
70%
Ph2P
L7
ee:
ee:
L8
CF3
O
O
N
F3C
N
H
H
Ph2P Fe
Con.: >99%
ee: 2%
Table 1 Optimization of the reaction conditions a
L9
Ph2P
a
All reactions were carried out with a substrate/catalyst ratio of 100:1 at room
b
temperature under 60 atm of hydrogen for 48 h. Determined by 1H NMR
spectroscopy. c The ee value was determined by HPLC on a chiral phase.
Scheme 1 Screening ligands for Rh-catalyzed asymmetric hydrogenation of 3a a, b, c
Entry
Precursors
Solvent
Con.
(%)b
75
Ee
(%)c
65
65
15
45
56
92
92
92
85
81
89
23
88
85
94
93
93
93
conversion (>99%). When we turned our eyes to a mixture
solution of methanol and trifluoroethanol (V:V = 3:1), the best
result, full conversion and 94% ee could be obtained (entry
15). The pressure of hydrogen was also tuned and the
conversion was proportionate to the pressure without erosion
of the enantioselectivity (entries 15, 17 and 18). The absolute
configuration of 4a was confirmed as S by comparison of the
observed optical rotation with reported data.
1d
2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(COD)Cl] 2
[Rh(NBD)2] BF4
[Rh(COD)2] BF4
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
[Rh(NBD)Cl] 2
CF3CH2OH
CF3CH2OH
>99
>99
>99
66
3
CF3CH2OH
4
CF3CH2OH
5
CF3CH2OH
6
MeOH
97
7
EtOH
iPrOH
87
8
77
Moreover, other eight species of ZhaoPhos analogues
developed by our group were also screened with [Rh(NBD)Cl]2
as metal precursor. In contrast with the result of ZhaoPhos
9
EtOAc
40
10
11
12
13
14
15
16
17e
18f
CH2Cl2
30
toluene
36
(
L1), bisphosphine ureas L2 and L9 only gave 7% and 2% ee,
dioxane
10
respectively. This sharp contrast implied that thiourea was an
inevitably active moiety to the series of ligands. Compared to
L3 with 3, 5-dimethyl on the phenyl ring, L5 with electron-
acetone
43
MeOH: CF3CH2OH =1:1
MeOH: CF3CH2OH =3:1
MeOH: CF3CH2OH =9:1
MeOH: CF3CH2OH =3:1
MeOH: CF3CH2OH =3:1
>99
>99
98
withdrawing
group,
trifluoromethyl,
increased
the
95
enantioselectivity to 65%. After the 3,5-bis(trifluoro-methyl)
phenyl group was replaced by a pyridyl ring, L7 showed lower
yield (20%) and ee value (57%). Furthermore, whether
monophosphine ligand L6 or bisphosphine thiourea ligand with
a bulky group L8 resulted in lower reactivity. However, L4
bearing very similar structure as L1, provided 99% conversion
and 88% ee. These results revealed that bisphosphine moiety,
91
a Unless otherwise mentioned, all reactions were carried out with a Rh/L/3a ratio
b
of 1/1.1/100 in 1.0 mL of solvent at 25 °C under 60 atm of hydrogen for 48 h.
Determined by 1H NMR spectroscopy, no side product was observed. c The ee
value was determined by HPLC on a chiral phase. d Under 30 atm of H2 for 24 h. e
Under 50 atm of H2. f Under 30 atm of H2.
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R2
O
R2
O
80% yield and 90% ee (4l) were obtained. However, when the
phenyl group was substituted by 1-naphthyl group, 4m was
achieved only in 44% yield with 80% ee. The diverse results
Rh/ZhaoPhos, 60 atm H2
R1
R3
R1
R3
MeOH/CF3CH2OH = 3:1, rt, 48 h
4
3
Me
*
O
Me
O
Me
*
O
between 4d and 4c
& 4e as well as between 4l and 4m might
be attributed to the sterically hindered effects related to the
cooperation of catalyst and substrates. The hetero aromatic
ring substituted substrate 3k afforded excellent ee value as
well. Substrates with different R2 and R3 were also
hydrogenated via the catalytic system. If the R2 were methyl,
ethyl or propyl group, the yields and enantioselectives were
4b
4a
4c
Cl
F
yield: 95 %
ee: 95 %
yield: 95 %
ee: 96 %
yield: 96 %
ee: 94 %
Cl
Me
*
O
Me
*
O
Me
*
O
4e
4f
4d
Br
Cl
yield : 91 %
ee: 91 %
yield: 89 %
ee: 93 %
yield: 94 %
ee: 95 %
almost identical (4a vs. 4n-
4o). But both R1 and R3 were all
Me
O
Me
*
O
Me
O
alkyl groups, significant changes of the conversion and
enantioselectivity were observed. For example, when R1 was
changed to phenyl ethyl group, full conversion and only 63%
ee were observed (4p); and R3 was replaced by methyl group,
93% yield and 86% ee were obtained (4q). These outcomes
implied that the catalytic system was not applicable to the
substrates with alkyl substituents at α- or β-position.
*
*
4g
4i
Me
4h
F3
C
yield: 93 %
ee: 96 %
yield: 91%
ee: 94%
yield: 95 %
ee: 91 %
Me
Me
O
Me
*
O
Me
O
*
S
4k
4j
4l
MeO
yield: 93 %
ee: 86 %
yield: 64 %
ee: 88 %
yield: 80 %
ee: 90 %
In conclusion, we have developed a succinct and efficient
protocol for the synthesis of chiral aromatic ketones via
asymmetric hydrogenation of β,β-disubstituted α,β-
unsaturated ketones catalyzed by Rh-ZhaoPhos under mild
conditions. In most cases, the enantiomerically pure products,
versatile precursors in chemical synthesis, were achieved with
high conversion and excellent enantioselectivity. This catalytic
system is compatible with various functional groups. A further
study is in progress with the aim of exploring the mechanism
of this novel catalytic system and expanding substrate scope.
This research was financially supported by State Scholarship
Fund (201406305057 and 201506270049) of the China
Scholarship Council and the National Natural Science
Foundation of China (Nos. 31301712 and 31572038).
nPr
O
Et
O
O
Me
*
4o
4n
yield: 44 %
ee: 80 %
4m
yield: 96 %
ee: 89 %
yield: 96 %
ee: 93 %
Me
O
Me
O
*
*
O
4q
4p
4r
yield: 96 %
ee: 63 %
yield: 93 %
ee: 86 %
yield: NA
ee: NA
a
All reactions were carried out with a substrate/catalyst ratio of 100:1 at
room temperature under 60 atm of hydrogen for 48 h. b The yield of the
isolated product was calculated by deduction the consumed starting
material. c Determined by chiral HPLC analysis. d The hydrogenated product
3r didn’t detect at all; NA referred to “not available”.
Scheme 2 Asymmetric hydrogenation of β,β-disubstituted α,β-unsaturated
ketones by the Rh-ZhaoPhos complex a, b, c
Notes and references
thiourea subunit and trifluoromethyl group at the 3- and 5-
positions on the phenyl ring were the three key elements of
the effective catalyst, which promoted the coordination of the
ligand with substrates, facilitated the reaction, maintained the
geometry of intermediates, and hampered the racemization.
The chemo- and enantioselective hydrogenation of conjugated
enones was therefore catalyzed by 1 mol% L1 in the mixture
solvent of MeOH and CF3CH2OH (V:V = 3:1) under 60 atm of H2
at 25 °C for 48 h.
1
2
3
4
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conditions (Scheme 2). In most cases, whether electron-
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-3j were hydrogenated with high yields and
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-
4j). Substrates with
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substituted compound (4c and 4e vs. 4d). Unexpectedly, the
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Tables of Contents
A series of chiral aromatic ketones were achieved with excellent enantioselectivities
via Rh‐ZhaoPhos catalyzed asymmetric hydrogenation of β,β‐disubstituted enones.