First Iridium-Catalyzed Highly Enantioselective Hydrogenation of β-Nitroacrylates

Article abstract of DOI:10.1021/acs.orglett.5b01758

The first highly chemo- and enantioselective hydrogenation of β-nitroacrylates was accomplished with an iridium catalyst (Ir-4) with yields and enantioselectivities of up to 96% and 98% ee, respectively. The resulting α-chiral β-nitro propionates are attractive building blocks for the synthesis of chiral β²-amino acids, which are the core scaffolds of bioactive natural products, pharmaceuticals, and β-peptides.

Full text of DOI:10.1021/acs.orglett.5b01758

Letter
pubs.acs.org/OrgLett
First Iridium-Catalyzed Highly Enantioselective Hydrogenation of
β‑Nitroacrylates
Shengkun Li,*,† Taifeng Xiao,†,§ Dangdang Li,†,§ and Xumu Zhang*,‡
†Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District, Nanjing
210095, P.R. China
‡Department of Chemistry and Chemical Biology and Department of Pharmaceutical Chemistry, Rutgers, the State University of New
Jersey, Piscataway, New Jersey 08854, United States
S
* Supporting Information
ABSTRACT: The first highly chemo- and enantioselective
hydrogenation of β-nitroacrylates was accomplished with an
iridium catalyst (Ir-4) with yields and enantioselectivities of up
to 96% and 98% ee, respectively. The resulting α-chiral β-nitro
propionates are attractive building blocks for the synthesis of
chiral β2-amino acids, which are the core scaffolds of bioactive
natural products, pharmaceuticals, and β-peptides.
ncreasing attention has been devoted to the efficient
construction of β-amino acids because of their wide
occurrence in pharmacologically and biologically interesting
molecules1 such as the well-known β-lactam drugs and paclitaxel.
β2-Amino acids are particularly attractive among different β-
amino acids and are embedded in many bioactive natural
products and pharmaceuticals (Figure 1). For example,
catalytic enantioselective aminomethylation of aldehydes (Man-
nich reaction) is another elegant tactic to this end.10 We envision
that asymmetric reduction of the prochiral β-nitroacrylates will
be an alternative approach but not limited to the valuable β2-
amino acids since the resulting β-nitroesters can also serve as a
masked functionality to many interesting molecules through
simple transformation11 (Figure 2).
I
Figure 2. Multifunctionalities of chiral β2-nitro acids.
Compared with the asymmetric reduction of the simple β,β-
disubstituted nitroalkenes, the similar transformation of β-
nitroacrylates was relatively underdeveloped. The List group
developed the first highly organocatalytic enantioselective-
transfer hydrogenation of β-nitroacrylates with Jacobsen-type
thiourea catalyst and commercially available Hantzsch ester.12
Subsequently, a similar transformation was reported by
Paradies.13 Asymmetric bioreductions by Saccharomyces carlsber-
gensis old yellow enzyme14 and enoate reductase15 were disclosed
by Stewart and Wu, respectively. These approaches suffer from
high catalyst loading, a complex reaction system, or tedious
workup. Development of a new methodology of asymmetric
reduction of β-nitroacrylates to furnish the chiral β2-amino acids
is of high significance. Considering the atom economy and
environmental compatibility, we envisage that direct asymmetric
hydrogenation will be a compelling approach. Herein, we
Figure 1. Drugs and bioactive natural products.
cryptophycin-1 was reported by Merck for the treatment of
AIDS and cancers and can also be used as a fungicide;2 β2-amino
acids derived β-lactam 4AA are the core unit of the eminent
antibiotic drug carbapenem;3 and pyridine alkaloids nakinadines
B and C have been demonstrated to show cytotoxicity.1,4 More
importantly, the pioneering works by Seebach and Gellmann
demonstrated that β2 -amino acid residues are essential for the
formation of most interesting and specific β-peptide secondary
structures, which are necessary for versatile functionalities.5,6
Versatile and efficient synthesis of chiral β2-amino acids will be
of great interest, while only limited progress was achieved
compared with the β3-amino acid counterparts. Asymmetric
hydrogenation of protected or functionalized prochiral amino-
substrates is documented by Zheng, Chan, and Qiu, including β-
phthalimide acrylates7 and α-amino- methyl acrylates.8,9 Organo-
Received: June 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01758
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Letter
document our efforts in the enantioselective hydrogenation of β-
nitroacrylates catalyzed by transition metals (Figure 3).
Figure 4. Representative chiral ligands and catalysts.
The asymmetric hydrogenation of 1a was initially carried out
with 5% catalyst under 50 atm of H2 atmosphere in DCM. Since
rhodium catalysts with chiral ferrocene ligands furnished efficient
reactivity and enantioselectivity in our previous studies, the
rh(cod)2BF4/JosiPhos catalytic system was originally tested;
however, it only gave 5.3% ee (Table 1, entry 1). Parameter
screening demonstrated that temperature is crucial for the
reactivity (Table 1, entry 1 vs 6) and the nonpolar toluene is
beneficial for the conversion (Table 1, entries 6−10), while the
erosion of enantioselectivity was emitted (Table 1, entry 10). A
parallel execution of combination of the subspecies of ferrocene
ligands with rhodium salts did not reveal any satisfactory
improvement in the enantioselectivities (Table 1, entries 11−
13).
Other chiral bidentate ligands were also evaluated with
disappointing outputs, including planar chiral ligand, atropiso-
meric biaryl ligand, and rigid P-chiral ligand (Table 1, entries 2−
5). Ruthenium catalysts were evaluated and seemed to be inert
for this chiral transformation (Table 1, entries 14−16). Based on
the chiral toolbox developed by our group22 and the elegant
performance of iridium catalysts in transfer hydrogenation of
nitroalkenes,23 we turned our attention to the iridium−PN
ligands catalyst for the hydrogenation of 1a. Versatile conforma-
tionally rigid phosphino-oxazolines were tested under standard
conditions. To our delight, the phospholane−oxazoline ligands
(Table 1, entries 19−21) furnished good to excellent
enantioselectivities (82−94% ee), which are already very high
for this type of asymmetric hydrogenation. In order to
counterbalance the reaction efficiency and enantioselectivity
(the ee value) appropriately for identifying a potentially useful
catalytic system, enantioselectivity was highlighted as a more
important parameter to optimize in comparison with the
conversion. A mathematical function of conversion and square
of the enantioselectivity was established. Such a mathematical
formula together with careful scanning of different solvents and
mixed solvents indicated Ir-4 in DCM as a promising system
(Table 1, note e).
Figure 3. First enantioselective hydrogenation of β-nitroacrylates.
The inspiration of asymmetric hydrogenation to β2-amino
acids was triggered not only by the current limited progress in
asymmetric reduction of β-nitroacrylates but also by our
continuing efforts in the asymmetric hydrogenation of nitro-
alkenes. In our previous works, we developed the first highly
enantioselective rhodium-catalyzed hydrogenation of β, β-
disubstituted nitroalkenes16 and α,β-disubstituted nitroalkenes17
and a modified practical hydrogenation assisted by basic
additives.18 A novel bifunctional catalyst was also designed,
synthesized, and applied for the rhodium-catalyzed hydro-
genation.19 β-Amino nitroalkenes were hydrogenated enantio-
selectively by Rh/TangPhos;20 subsequently, an elegant iridium
catalytic system was developed for this process.21 Encouraged by
these exciting results, we switched our attention to the
asymmetric hydrogenation of β-nitroacrylates and envisioned
that any progress in this topic will be of both fundamental and
practical importance.
The β-nitroacrylates required in this proposal were prepared
typically starting from α-ketoesters, which are commercially
available or can be synthesized efficiently from Grignard reagents
and oxalate.12,14 A series of β-nitroacrylates were synthesized
with Z-isomers predominantly through Henry reaction of α-
ketoesters followed by NEt3-assisted dehydration of mesylates
(Scheme 1).
Scheme 1. Synthesis of β-Nitroacrylates
Our study started by exploring the asymmetric hydrogenation
of 1a as the model substrate. The previously established catalytic
systems16−19 were initially tested since they have been proven to
be efficient for enantioselective hydrogenation of different
nitroalkenes. Unfortunately, neither of them gave satisfying
enantioselectivity and conversion for 1a. In an effort to overcome
the “untouched problem”, the evaluation of a large and diverse
set of catalysts was carried out (Figure 4), including rhodium
catalysts, ruthenium catalysts, and iridium catalysts; representa-
tive results are shown in Table 1.
In light of the limited efficacy with Ir-3 as catalyst for
hydrogenation of 1a, a large, diverse set of additives was
evaluated (see the Supporting Information for details). These
additives are typically used in iridium-catalyzed hydrogenation
(iodine, chiral, and nonchiral acids and bases) or specifically
added in the asymmetric reduction of nitroalkenes (CH3NO2
and KF). Unfortunately, no synergistic effect was detected; both
acidic and basic additives can deactivate the catalyst execrably.
Fine tuning and detailed optimization of the reaction
parameters showed that the thermal effect is more remarkable,
B
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Table 1. Selected Catalytic Systems for Hydrogenation of 1a
Table 2. Optimization for Hydrogenation of 1a with Ir-4
a
b
c
entry
cat. (%)
conditions
conv (%)
ee (%)
1
2
3
4
5
6
5
70 °C; 80 atm; 24 h
70 °C; 80 atm; 24 h
70 °C; 80 atm; 24 h
60 °C; 80 atm; 24 h
70 °C; 50 atm; 24 h
70 °C; 50 atm; 48 h
> 95
55
92
93
93
94
93
93
2.5
1.25
2.5
2.5
2.5
21
a
b
c
32
entry
conditions (cat.; solv; temp)
conv (%)
ee (%)
54
1
2
Rh/(R)-JosiPhos
Rh/(R, R)-Ph-BPE
90
<5
<5
36
15
<5
32
<5
30
74
>95
>95
>95
10
6
5.3
95
NA
NA
0.4
8.2
NA
5.6
NA
1.5
2.3
1.5
5.2
4.2
3
a
Unless otherwise mentioned, all reactions were carried out with Ir-4
as catalyst, X% = molar ratio. Conversion was determined by H
NMR of the crude product of hydrogenation. Enantiomeric excess
was determined by HPLC on a chiral phase.
3
Rh/(S)-C3-Tunephos
Rh/Tangphos
b
1
4
c
5
Rh/(S)-Phanephos
6
Rh/(R)-JosiPhos; DCM; rt
Rh/(R)-JosiPhos; EA; rt
7
With the optimized reaction conditions, the scope of this
iridium-catalyzed enantioselective hydrogenation was explored
with an array of β-nitroacrylates (Figure 5). To our delight, all
types of substrates 1a−k underwent hydrogenation to furnish the
chiral β-nitroesters in good to excellent enantioselectivities (92−
98% ee).
8
Rh/(R)-JosiPhos; MeOH; rt
Rh/(R)-JosiPhos; THF; rt
Rh/(R)-JosiPhos; tol; rt
Rh/Mandyphos; tol; rt
Rh/Chenphos; tol; rt
Rh/(S)-f-Binaphane; tol; rt
Ru/(S)-C3-tunephos
Ru/Duanphos
Ru/MeO-Biphep
Ir-1
9
10
11
12
13
d
14
d
15
20
d
16
9
20
17
18
19
20
21
22
23
24
25
26
27
5
11
Ir-2
7
8
Ir-3
38
34
25
16
17
43
41
44
42
82 (−) (S)
Ir-4
94 (−) (S)
84 (−) (S)
13 (−) (S)
50 (−) (S)
82 (−) (S)
87 (−) (S)
79 (−) (S)
91 (−) (S)
Ir-5
Ir-4; MeOH
Ir-4; EA
Ir-4; toluene
Ir-4; THF
Ir-4; DCM/tol = 1:1
Ir-4; DCM/THF = 1:1
a
Unless otherwise mentioned, all reactions were carried out with a
catalyst/substrate molar ratio of 1:20 under 50 atm of H2 in DCM at
50 °C (solvent = DCM; temperature = 50 °C). Metal precursors: Rh =
b
Rh(cod)2BF4, Ru = [RuCl2(p-cymene)]2. Conversion was deter-
c
mined by 1HNMR of the crude product of hydrogenation. The ee was
determined by HPLC on a chiral phase; the configuration was assigned
d
by comparison with the reported data. [RuCl2(p-cymene)]2/ligand/
substrate = 1:2:40. Key: NA, not available; DCM, dichloromethane,
EA, ethyl acetate, THF, tetrahydrofuran, Tol, toluene; rt = room
temperature (25 °C).
Figure 5. β-Nitroacrylates scope in Ir-4-catalyzed hydrogenation.
Remarkably, the β-nitroacrylate 1b, with an o-chloro
substituent on the benzene ring, can be hydrogenated with an
enantioselectivity of up to 98% ee, albeit with modest yield,
which can be improved either by temperature elevation or higher
catalyst loading. Though excellent enantioselectivities were
detected when the nitroacrylates 1c (93% ee) and 1d (95% ee)
were submitted, the reaction efficiency seems to be suppressed
by the introduction of substituents to the meta-position of
benzene ring, regardless of whether it was electrondonating or
electron-withdrawing. Surprisingly, the MeO substituent appears
to be unamiable and acts as an “ugly factor”; a sharp decrease in
the reaction efficiency was observed in the hydrogenation of 3-
methoxyphenyl-substituted and 4-methoxyphenyl-substituted
nitroacrylates (Figure 5, 1c and 1e), but a high level of
enantioselectivity was retained.
and elevation in the reaction temperature will accelerate the
desired catalytic cycle and lead to a decrease in catalyst loading
without an obvious reduction in the enantioselectivity (Table 2).
More importantly, a higher temperature possibly decelerate the
formation of the hydride-bridged Ir trimer, which will result in
catalyst deactivation.24 Systematic optimization furnished 2a in
95% yield with up to 93% ee through iridium-catalyzed
enantioselective hydrogenation (Table 2, entry 6).
C
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Notes
In addition, the other nitroacrylates, with either electron-
donating or electron-withdrawing groups at the para position of
the benzene ring, were well tolerated. Compound 1h was
hydrogenated with excellent stereocontrol in nearly quantitative
yields (94% yield and 96% ee). The alkyl-substituted β-
nitroacrylates (E)-1l and (Z)-1l were also tested and hydro-
genated smoothly with useful enantioselectivity (Figure 5, 1l).
The effect of different ester groups was also taken into
consideration, and the ester group can be varied significantly as
probed with α-phenyl substituted β-nitroacrylates (1a, 1i−k),
while prolongation is necessary for full conversion. The
enantioselectivity increased slightly with size and bulkiness of
the ester moiety and followed the trend CH3 < Et < Bn < iPr.
Gratifyingly, nitroacrylate 1j was successfully hydrogenated in
high yield with almost complete stereocontrol; this is the highest
enantioselectivity achieved among different reduction tactics of
nitroacrylates.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (No. 31401777), the Natural
Science Foundation of Jiangsu Province (No.BK20140684), and
the Fundamental Research Funds for the Central Universities
(No. KJQN201510). We also thank Dr. Kexuan Huang of
Rutgers University for helpful discussions.
DEDICATION
■
This paper is dedicated to Prof. Wenjun Wu of Northwest A&F
University on the occasion of his 70th birthday.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01758.
■
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: saintkun001@njau.edu.cn.
*E-mail: xumu@rci.rutgers.edu.
Author Contributions
§T.X. and D.L. contributed equally to this work.
D
DOI: 10.1021/acs.orglett.5b01758
Org. Lett. XXXX, XXX, XXX−XXX