Enantioselective Synthesis of Chiral 3-Substituted-3-silylpropionic Esters via Rhodium/Bisphosphine-Thiourea-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1002/adsc.201700355

We have successfully developed the asymmetric hydrogenation of β-silyl-α,β-unsaturated esters to prepare chiral 3-substituted-3-silylpropionic ester products catalyzed by rhodium/bisphosphine-thiourea (ZhaoPhos) with excellent results (up to 97% yield, >99% ee, 1500 TON). Moreover, our hydrogenation products can be efficiently converted to other important organic molecules, such as chiral ethyl (R)-3-hydroxy-3-phenylpropanoate or (R)-3-[dimethyl(phenyl)silyl]-3-phenylpropanoic acid. (Figure presented.).

Full text of DOI:10.1002/adsc.201700355

Title: Enantioselective Synthesis of Chiral 3-Substituted-3-silylpropionic
Esters via Rhodium/Bisphosphine-Thiourea-Catalyzed
Asymmetric Hydrogenation
Authors: Zongpeng Zhang, Zhengyu Han, Guoxian Gu, Xiu-Qin Dong,
and Xumu Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700355
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10.1002/adsc.201700355
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Synthesis of Chiral 3-Substituted-3-
silylpropionic Esters via Rhodium/Bisphosphine-Thiourea-
Catalyzed Asymmetric Hydrogenation
Zongpeng Zhang,a Zhengyu Han,a Guoxian Gu,b Xiu-Qin Dong,*a Xumu Zhang*b,a
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R. China.
Department of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong, 518055, P. R.
b
China.
E-mail address: xumu@whu.edu.cn; xiuqindong@whu.edu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Herein, we successfully developed asymmetric
hydrogenation of β-silyl-α,β-unsaturated esters for
the synthesis of various chiral 3-substituted-3-
silylpropionic esters catalyzed by Rh/bisphosphine-
thiourea (ZhaoPhos) with high yields and excellent ee
(Scheme 1c). Thiourea motif of ZhaoPhos worked as
hydrogen bond donors, which successfully activated
some substrates, such as nitroolefins, [7] unprotected
Abstract. We successfully developed asymmetric
hydrogenation of β-silyl-α,β-unsaturated esters to prepare
chiral
3-substituted-3-silylpropionic
ester
products
catalyzed by rhodium/bisphosphine-thiourea (ZhaoPhos)
with excellent results (up to 97% yield, >99% ee, 1 500
TON). Moreover, our hydrogenation product can be
efficiently converted to other important organic molecules,
such as chiral ethyl (R)-3-hydroxy-3-phenylpropanoate,
(R)-3-(dimethyl(phenyl)silyl)-3-phenylpropanoic acid.
imines,[8]
(iso)quinolines,[9]
and
carbonyl
compounds[10] through forming hydrogen-bonding
interaction in the asymmetric hydrogenations. And
the successful asymmetric hydrogenation of β-silyl-
α,β-unsaturated esters is another excellent example of
our powerful catalytic system.
Keywords: Asymmetric hydrogenation; Bisphosphine-
thiourea
ligand;
β-Silyl-α,β-unsaturated
esters;
Enantioselectivity; Chiral silicon compounds
Chiral organic silicon compounds are important
intermediates due to their wide application in the
field of organic synthesis.[1] Silyl groups are well
established protective groups, which not only worked
as hydroxyl surrogates via Tamao[2] or Fleming[3]
oxidation but also took part in the asymmetric
carbon-carbon bond formations.[4] Asymmetric
catalysis represented several synthetic approaches for
the preparation of chiral organic silicon compounds. [5]
In 2005, Hayashi and coworkers reported Rh-
catalyzed asymmetric 1,4-addition of arylboronic
acids to β-silylated-α,β-carbonyl compounds using
chiral diene (R, R)-Bn-bod* ligand with excellent
results (Scheme 1a).[5d] In 2006, Lipshutz and
coworkers reported CuH-catalyzed asymmetric
conjugate reduction of α-silyl-α,β-unsaturated esters
with polymethylhydrosiloxane (PMHS) as
a
stoichiometric source of hydride and in situ generated
CuH ligated by (R, S)-PPF-P(t-Bu)2 (Scheme 1b).[5e]
Owing to the great importance of chiral organic
silicon compounds, it is still significant to develop
efficient and attractive catalytic methodologies to
construct them. Catalytic asymmetric hydrogenation
of functionalized olefins is recognized as a powerful
synthetic strategy to access chiral molecules.[6]
Scheme 1. Synthesis of chiral 3-substituted-3-
silylpropionic ester.
We began our initial study by investigating the
effect of several chiral biphosphine ligands for the
asymmetric hydrogenation of ethyl (Z)-3-phenyl-3-
(trimethylsilyl)acrylate (1a)[11] as the model substrate
1
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10.1002/adsc.201700355
Advanced Synthesis & Catalysis
at 40 oC with the catalyst generated in situ by mixing
Rh(NBD)2BF4 with ligands (S/C = 100). As shown in
Table 1, (S)-BINAP, (S)-Segphos, (S)-DTBM-
Segphos and (Rc, Sp)-DuanPhos exhibited poor
reactivities and enantioselectivities in this asymmetric
hydrogenation (10%-30% conversions, 5%-56% ee,
Table 1, entries 1-4). We obtained moderate result
when Binapine was applied to this transformation (83%
conversion, 71% ee, Table 1, entry 5). To our delight,
ZhaoPhos with a thiourea motif can provide excellent
enantioselectivity (97% ee, Table 1, entry 6), which is
mainly due to the activation between the ester group
of substrate 1a and the thiourea motif through
forming hydrogen bonds.
Table 2. Screening solvents for Rh-catalyzed asymmetric
hydrogenation
of
ethyl
(Z)-3-phenyl-3-
(trimethylsilyl)acrylate (1a).a
Entry
Solvent
iPrOH
CH2Cl2
CH3CH2OH
CF3CH2OH
Toluene
THF
Conv.(%) [b]
Ee (%)[c]
97
1
2
3
4
5
6
80
NR
61
>99
94
NA
97
97
96
96
91
Table 1. Screening ligands for Rh-catalyzed asymmetric
[a]All
reactions
were
carried
out
with
a
hydrogenation
of
ethyl
(Z)-3-phenyl-3-
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ratio of 1:1.1:100 in
1.0 mL solvent under 50 atm H2 at 40 oC for 24 h.
[b] Determined by 1H NMR analysis.
(trimethylsilyl)acrylate (1a).[a]
[c] Determined by HPLC analysis. TMS = trimethylsilyl
group. The configuration of 2a was determined as (R) by
comparing the optical rotation data by the literature. [5d] NR
is no reaction. NA is not available.
Entry
Ligand
(S)-BINAP
(S)-Segphos
Conv.(%)[b] Ee (%)[c]
1
2
3
4
5
6
23
10
22
30
83
80
56
5
7
23
71
97
After we optimized the reaction conditions, we
focused on the investigation of the generality of the
asymmetric hydrogenation of β-silyl-α,β-unsaturated
esters. These results were summarized in Table 3.
The Si-protecting group of the substrates (1a-1d) has
(S)-DTBM-Segphos
(Rc, Sp)-Duanphos
Binapine
ZhaoPhos
little
impact
on
the
reactivities
and
enantioselectivities. When the Si-protecting group
[a] All reactions were carried out with
a
[Rh(NBD)2BF4]/ligand/1a (0.1 mmol) ratio of 1:1.1:100 in
1.0 mL iPrOH under 50 atm H2 at 40 oC for 24 h.
[b] Determined by 1H NMR analysis.
Table 3. Scope study of Rh-catalyzed asymmetric
hydrogenation of β-silyl-α,β-unsaturated esters. [a]
[c] Determined by HPLC analysis. TMS = trimethylsilyl
group. The configuration of 2a was determined as (R) by
comparing the optical rotation data by the literature.[5d]
The solvents had a great effect in this asymmetric
transformation, and we screened various solvents
(Table 2). Moderate to good conversions were
i
provided in PrOH and EtOH, albeit with excellent
enantioselectivities (61%-80% conversions, 97% ee,
Table 2, entries 1, 3). No reaction was observed in
CH2Cl2 (Table 2, entry 2). The asymmetric
hydrogenation proceeded well in CF3CH2OH,
toluene, THF with high conversions and excellent
enantioselectivities (91%->99% conversions, 96%-
97% ee, Table 1, entries 4-6). The CF3CH2OH was
identified as the best solvent in terms of both high
reactivity and excellent enantioselectivity (>99%
conversion, 97% ee, Table 2, entry 4).
2
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10.1002/adsc.201700355
Advanced Synthesis & Catalysis
[a] The yield was isolated yield. Ee was determined by
HPLC analysis. TMS = trimethylsilyl group. TES =
triethylsilyl group. The configuration of products 2 were
determined as (R) by comparing the optical rotation data
by the literature. [5d]
In addition, our Rh-ZhaoPhos catalytic system is
very efficient in the asymmetric hydrogenation of
ethyl
(Z)-3-(methyldiphenylsilyl)-3-phenylacrylate
1d. When the catalyst loading was reduced to 0.067
mol% (S/C = 1 500), the asymmetric hydrogenation
of substrate 1d with 0.56 g scale proceeded smoothly
with 93% yield and 98% ee (Scheme 3).
[b] Asymmetric hydrogenation of (E)-substrate.
was changed from trimethylsilyl (1a) to triethylsilyl
(1b),
dimethylphenylsilyl
(1c)
and
diphenylmethylsilyl (1d) group, the corresponding
hydrogenation products (2a-2d) were obtained with
high yields (95%-97% yields) and excellent
enantioselectivities (97%-99% ee). The substrates β-
silyl-α,β-unsaturated esters bearing electron-rich (1e-
1g), electron-deficient (1h-1k) groups on the phenyl
ring were hydrogenated efficiently to afford the
hydrogenation products (2e-2k) with excellent results
(60%-97% yields, 95->99% ee). The position of the
substituents on the phenyl ring (1e-1l) have little
effect on the reactivities and enantioselectivities. To
our delight, the alkyl substrates, such as ethyl (Z)-3-
(dimethyl(phenyl)silyl)but-2-enoate (Z)-1m and (Z)-
ethyl 3-(dimethyl(phenyl)silyl)pent-2-enoate (Z)-1n
also proceeded well with moderate results (67%-95%
yields, 81%-89% ee). In addition, we also
investigated the (E)-substrates in this asymmetric
Scheme 3. Rh-catalyzed asymmetric hydrogenation of
ethyl (Z)-3-(methyldiphenylsilyl)-3-phenylacrylate 1d with
high TON.
In order to explore the synthetic utility of our
catalytic methodology, further applications were
carried out for the construction of other important
organic molecules (Scheme 4). The hydrogenation
product 2c can be converted to ethyl (R)-3-hydroxy-
3-phenylpropanoate 3c without loss of ee value via
Tamao oxidation.[5d] On the other hand, compound 2c
also can be transformed efficiently to the
corresponding chiral (R)-3-(dimethyl(phenyl)silyl)-3-
phenylpropanoic acid 4c through the hydrolysis of
ester group with high yield.[5e]
hydrogenation.
The
ethyl
(E)-3-
(dimethyl(phenyl)silyl)but-2-enoate (E)-1m and (E)-
ethyl 3-(dimethyl(phenyl)silyl)pent-2-enoate (E)-1n
can work
and afford the corresponding
hydrogenation products ent-2m and ent-2n with
opposite configuration (53%-62% yields, 77%-78%
ee). However, (E)-ethyl 3-(dimethyl(phenyl)silyl)-4-
phenylbut-2-enoate (E)-1o and (E)-ethyl 3-(4-
chlorophenyl)-3-(triethylsilyl)acrylate (E)-1k with
relatively hindered groups showed very poor
reactivity, and no reactions were observed.
Scheme 4. Synthetic transformations of the hydrogenation
product 2c.
In summary, we have successfully developed
Rh/ZhaoPhos catalyzed asymmetric hydrogenation of
various β-silyl-α,β-unsaturated esters to access
enantio-enriched 3-substituted-3-silylpropionic esters
with excellent results (up to 97% yield, >99% ee).
Our catalytic system is very efficient, and the TON is
up to 1 500. In addition, the hydrogenation product 2c
can be efficiently converted to other important
organic molecules through Tamao oxidation and the
hydrolysis of ester group, providing chiral ethyl (R)-
In order to investigate the important role of
thiourea motif of ZhaoPhos, control experiments
were conducted. We applied ligands L1 and L2
without thiourea motif into the asymmetric
hydrogenation of β-triethylsilyl-α,β-unsaturated ethyl
ester 1b under the optimized reaction conditions. As
shown in Scheme 2, no reaction was observed when
ligand L1 was used in this reaction, and ligand L2
provided poor conversion and enantioselectivity
(50% conversion, 42% ee). These results displayed
that the thiourea motif can activate our substrate and
contribute to afford excellent enantioselectivity
through forming hydrogen bonding between substrate
and ligand.
3-hydroxy-3-phenylpropanoate
3c,
(R)-3-
(dimethyl(phenyl)silyl)-3-phenylpropanoic acid 4c.
Further investigations of this efficient catalytic
system are ongoing in our laboratory.
Experimental Section
General procedure for the asymmetric hydrogenation
of variousβ-silyl-α,β-unsaturated esters:
A
stock
solution was made by mixing [Rh(NBD)2]BF4 with
Zhaophos in a 1:1.1 molar ratio in trifluoroethanol at room
temperature for 30 min in a nitrogen-filled glovebox. An
aliquot of the catalyst solution (0.1 mL, 0.001 mmol) was
transferred by syringe into the vials charged with different
substrates (0.1 mmol for each) in anhydrous
trifluoroethanol (1.0 mL). The vials were subsequently
transferred into an autoclave into which hydrogen gas was
Scheme 2. Control experiments.
3
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10.1002/adsc.201700355
Advanced Synthesis & Catalysis
charged. The reaction was then stirred under H2 (50 atm) at
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carefully. The solution was concentrated and passed
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to get hydrogenation products. The ee values of all
products 2 were determined by HPLC analysis on a chiral
stationary phase.
Acknowledgements
We thank the grant from Wuhan University (203273463,
203600400006), the support of the Important Sci-Tech Innovative
Project of Hubei Province (2015ACA058), and “111” Project of
the Ministry of Education of China for financial support and the
National Natural Science Foundation of China (Grant No.
21372179, 21432007, 21502145). Natural Science Foundation of
Hubei Province (Grant No. 2016CFB449).
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4
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10.1002/adsc.201700355
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Synthesis of 3-Substituted-3-
silylpropionic Esters via Rhodium/Bisphosphine-
Thiourea-Catalyzed Asymmetric Hydrogenation
Adv. Synth. Catal. 2017, Volume, Page – Page
Zongpeng Zhang,a Zhengyu Han,a Guoxian Gu,b
Xiu-Qin Dong,*a Xumu Zhang*a,b
5
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