Asymmetric hydrogenation of maleic anhydrides catalyzed by Rh/bisphosphine-thiourea: efficient construction of chiral succinic anhydrides

Article abstract of DOI:10.1039/c7cc01626c

Asymmetric hydrogenation of various 3-substituted maleic anhydrides catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos) under mild conditions was successfully developed. A wide range of 3-alkyl and 3-aryl maleic anhydrides were hydrogenated well to provide the desired products 3-substituted succinic anhydrides in one hour with excellent results (full conversions, up to 99% yield, 99% ee, 3000 TON). Importantly, we developed a creative and efficient synthetic route to construct the key intermediate of the hypoglycemic drug mitiglinide through our catalytic system.

Full text of DOI:10.1039/c7cc01626c

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DOI: 10.1039/C7CC01626C
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Asymmetric Hydrogenation of Maleic Anhydrides Catalyzed by
Rh/Bisphosphine-Thiourea: Efficient Construction of Chiral
Succinic Anhydrides
Received 00th January 20xx,
Accepted 00th January 20xx
Zhengyu Han,a Rui Wang,a Guoxian Gu,b Xiu-Qin Dong,*a Xumu Zhang*b,a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Asymmetric hydrogenation of various 3-substituted maleic Coates and co-workers reported catalytic double carbonylation of
anhydrides catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos) several chiral alkyl-substituted epoxides to construct chiral succinic
under mild conditions was successfully developed. A wide range of anhydrides, which involved chiral substrate induction and toxic CO in
3-alkyl and 3-aryl maleic anhydrides was hydrogenated well to high pressure (scheme 1b).8b In 2014, Pfaltz and co-workers
provide the desired products 3-substituted succinic anhydrides in developed asymmetric hydrogenation of 3-methyl, 3-isopropyl maleic
one hour with excellent results (full conversions, up to 99% yield, 99% anhydrides catalyzed by Ir/NeoPHOX with good conversions and
ee, 3 000 TON). Importantly, we developed a creative and efficient enantioselectivities, but other maleic anhydrides weren’t employed
synthetic route to construct the key intermediate of hypoglycemic
drug mitiglinide through our catalytic system.
Chiral succinic anhydrides are useful synthetic intermediates and
owned wide applications in the field of organic chemistry,1 which can
be readily ring opened to prepare chiral diacids,2 diesters3 and other
succinate derivatives4. In addition, chiral succinic anhydrides and their
derivatives are important structural skeletons in many biologically
active natural products,5 pharmaceuticals6 and metalloprotease
inhibitors,7a such as caspase 1 inhibitor, mupircocin H and mitiglinide
(Figure 1).
Figure 1. Examples of drugs and natural products containing chiral succinic anhydrides
and derivatives.
Owing to the great importance, much effort has been devoted to
develop efficient catalytic methodologies to approach chiral succinic
anhydrides and derivatives in the last few decades.7 In 2004, Shimoda
and co-workers made use of the p68 reductase enzyme isolating from
M. polymorpha to reduce citraconic anhydride, and (R)-methyl
succinic anhydride product was obtained (scheme 1a).8a In 2007,
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei,
430072, P. R. China
b Department of Chemistry, South University of Science and Technology of China,
Shenzhen, Guangdong, 518055, P. R. China.
E-mail address: xumu@whu.edu.cn; xiuqindong@whu.edu.cn.
‡ Electronic supplementary information (ESI) available: Experimental procedures, NMR
Scheme 1. Representative methods for the preparation of chiral succinic anhydrides.
spectra of compounds. See DOI: 10.1039/x0xx00000x.
This journal is © The Royal Society of Chemistry 20xx
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a
Unless otherwise noted, all reactions were carried out with
a
b
as substrates because of their poor solubility in this catalytic system
(scheme 2c).8c Therefore, it remains an important goal to develop
highly efficient catalytic system to prepare chiral succinic anhydrides
with great tolerance of wide range of substrates and excellent
enantioselectivity. It was well known that catalytic asymmetric
hydrogenation of functionalized olefins was regarded as a powerful
methodology for the construction of chiral compounds.9 Recently, our
group developed chiral bifunctional bisphosphine-thiourea ligands
(ZhaoPhos) based on the synergistic activations strategy via combing
catalytic modes of transition metal-catalysis and organo-catalysis,
which has been successfully applied in some asymmetric
hydrogenations.10 Thiourea motif serving as a hydrogen-bond donor
can activate the carbonyl group of substrates through hydrogen-
bonding interaction.10e-g Herein, we successfully developed
asymmetric hydrogenation of 3-substituted maleic anhydrides
catalyzed by Rh/Zhaophos to afford chiral succinic anhydrides in one
hour with excellent results (full conversions, 90%-99% ee, TON up to
3 000). The hydrogen bonds between the thiourea motif of ZhaoPhos
and the carbonyl group of maleic anhydrides were greatly contributed
to high reactivity and excellent enantioselectivity of this
transformation.
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DOI: 10.1039/C7CC01626C
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ration of 1:1.1:100 in 1.0 mL CH2Cl2.
Determined by 1H NMR analysis. Determined by HPLC analysis using a chiral
stationary phase. Configuration of 2a was determined by comparing the optical
rotation data with those reported by the literature.8c NR = No Reation, NA = Not
Available.
c
We began our study by evaluating several chiral diphosphine
ligands (Figure 2) for the asymmetric hydrogenation of 3-phenyl
maleic anhydride (1a)11 as the model substrate at room temperature
with the catalyst generated in situ by mixing Rh(NBD)2BF4 and ligands
(S/C = 100). As shown in Table 1, (S)-Segphos, JosiPhos, (S)-BINAP,
Binapine, (RC, SP)-DuanPhos, Walphos and (S, S)-Me-DuPhos exhibited
poor reacticities and enantioselectivities (Table 1, entries 1-7). The
reaction system catalyzed by Rh/Walphos was in mess, and there was
no desired product (Table 1, entry 6). To our delight, ZhaoPhos
afforded >99% conversion and 92% ee (Table 1, entry 8). When the
reaction time was reduced from 12 h to 1 h, the same result was still
obtained (>99% conversion, 92% ee, Table 1, entry 9).
Figure 2. Chiral diphosphine ligands for the asymmetric hydrogenation of 3-phenyl
maleic anhydride (1a).
Subsequently, this asymmetric hydrogenation was explored in
various solvents catalyzed by Rh(NBD)2BF4/ZhaoPhos. These
results were summarized in Table 2. The reaction proceeded well
in CH2Cl2, 1,4-dioxane, ClCH2CH2Cl, CHCl3 and ethyl acetate (EA)
with high conversions and excellent enantioselectivities
(98%->99% conversions, 92%-96% ee, Table 2, entries 1-3, 5-6).
Moderate results were observed in THF (91% conversion, 81% ee,
Table 2, entry 4). The ethyl acetate was chosen as the best
solvent by considering both reactivity and enantioselectivity
(>99% conversion, 96% ee, Table 2, entry 6). When the hydrogen
pressure was reduced from 30 atm to 1 atm, we can obtain the
same result (>99% conversion, 96% ee, Table 2, entry 7). We
found that this asymmetric hydrogenation can be finished in 0.5
h with full conversion and 97% ee (Table 2, entry 8).
Table 1. Screening diphosphine ligands for the asymmetric hydrogenation of 3-phenyl
maleic anhydride (1a). a
Table 2. Screening solvents, hydrogen pressure and reaction time for the asymmetric
hydrogenation of 3-phenyl maleic anhydride (1a). a
Entry
Ligand
(S)-Segphos
JosiPhos
Time (h)
12
Conv. (%)b
Ee (%)c
1
2
3
4
5
<5
7
7
12
49
4
(S)-BINAP
Binapine
12
6.5
13
<5
Entry
Solvent
CH2Cl2
1,4-dioxane
ClCH2CH2Cl
THF
H2 (atm)
Time (h)
Conv. (%)b
>99
Ee (%)c
92
12
10
23
1
2
3
4
5
6
7
30
30
30
30
30
30
1
1
1
1
1
1
1
1
(Rc, Sp)-
Duanphos
12
>99
93
>99
95
6
7
Walphos
12
12
40
NA
NA
91
81
(S,S)-Me-
DuPhos
NR
CHCl3
98
96
8
9
ZhaoPhos
ZhaoPhos
12
1
>99
>99
92
92
EA
>99
96
EA
>99
96
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Moreover, our Rh-ZhaoPhos catalytic system iVsievweArryticelefOfincliineent
8
EA
1
0.5
>99
97
DOI: 10.1039/C7CC01626C
in this asymmetric hydrogenation of 3-phenyl maleic anhydride
1a). When the catalyst loading was reduced to 0.0333 mol% (S/C
a
Unless otherwise noted, all reactions were carried out with
a
b
(
[Rh(NBD)2BF4]/ZhaoPhos/1a (0.1 mmol) ration of 1:1.1:100 in 1.0 mL solvent.
= 3 000), this transformation was hydrogenated smoothly in 24
h with excellent result (Scheme 2, >99% conversion, 96% yield,
97% ee).
Determined by 1H NMR analysis. Determined by HPLC analysis using a chiral
stationary phase. Configuration of 2a was determined by comparing the optical
rotation data with those reported by the literature.8c EA is ethyl acetate.
c
With the optimized reaction conditions in hand, we explored
the scope of the asymmetric hydrogenation of 3-substituted
maleic anhydrides (Table 3). A series of 3-substituted maleic
anhydrides were hydrogenated smoothly, and the desired
hydrogenation products chiral succinic anhydrides were
provided with full conversions, high yields and excellent
enantioselectivities (94%-99% yields, 90%-99% ee). The
substrates (1a-1i) containing different substitution patterns
(ortho-, meta-, para-) on the phenyl ring were proceeded
efficiently, regardless of their properties (electron-neutral,
electron-rich, electron-deficient). In addition, the alkyl
substrates 3-methyl (1j), 3-isopropyl (1k) and 3-benzyl (1l) maleic
anhydrides also performed well with excellent results (full
conversions, 96%-99% yields, 90%-96% ee). To our delight, the
3-benzyl succinic anhydride (2l) is solid, and the enantioenriched
prodcut (99% ee) can be easily obtained by simple
recrystallization in hexane/ethyl acetate.
Scheme 2. Asymmetric hydrogenation of 3-phenyl maleic anhydride (1a) with high TON.
Our highly enantioenriched hydrogenation products can be
transformed to prepare other optically active drug molecules. As
shown in Scheme 3, the 3-benzyl succinic anhydride (2l) can be easily
obtained through our asymmetric catalytic hydrogenation system (0.2
mmol, 0.1 mol% catalyst, S/C = 1 000), which is the key intermediate
for the construction of hypoglycemic drug mitiglinide.13 Compared
with previous methods through racemic resolution,13 our asymmetric
catalytic hydrogenation is highly efficient with low cost.
Table 3. Asymmetric hydrogenation of various 3-substituted maleic anhydrides with
Rh/ZhaoPhos.a
Scheme 3. Synthesis of mitiglinide.
In summary, we successfully reported a highly efficient asymmetric
hydrogenation of 3-substituted maleic anhydrides catalyzed by
Rh/bisphosphine-thiourea (ZhaoPhos) under mild reaction conditions,
the desired products 3-substituted succinic anhydrides were obtained
in one hour with excellent results (full conversions, up to 99% yield,
99% ee and 3 000 TON). Moreover, we made use of this catalytic
system to develop a creative and efficient route for the synthesis of
the key intermediate of hypoglycemic drug mitiglinide. Further
investigations on the extension of our catalytic system are currently
underway in the laboratory.
We are grateful for financial support by the grant from Wuhan
University (203273463, 203600400006), the support of the Important
Sci-Tech Innovative Project of Hubei Province (2015ACA058), the
National Natural Science Foundation of China (Grant No. 21372179,
21432007, 21502145) and Natural Science Foundation of Hubei
Province (Grant No. 2016CFB449).
Notes and references
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