Highly enantioselective hydrogenation of α-oxy functionalized α,β-unsaturated acids catalyzed by a ChenPhos-Rh complex in CF3CH2OH

Article abstract of DOI:10.1039/c5cc09089j

Rhodium complexes coordinated by Chenphos are very effective catalysts for the enantioselective hydrogenation of α-aryloxy- and α-alkoxy-substituted α,β-unsaturated carboxylic acids under mild conditions in CF₃CH₂OH. The catalytic system could be successfully employed in building the core structure of a new FDA approved drug LCZ 696.

Full text of DOI:10.1039/c5cc09089j

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Highly Enantioselective Hydrogenation of α-oxy Functionalized α,
β-unsaturated Acids Catalyzed by a ChenPhos-Rh Complex In
CF CH OH
3
2
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
b
b
b
b
a
Lin Yao, Jialin Wen, Shaodong Liu, Renchang Tan, Noel Marie Wood, Weiping Chen,*
a
b
DOI: 10.1039/x0xx00000x
Shengyong Zhang,* and Xumu Zhang*
www.rsc.org/
The rhodium complexes coordinated by Chenphos are very
Enantioselective
hydrogenation
of
α,β-unsaturated
effective catalysts for the enantioselective hydrogenation of α- carboxylic acids by transition metal complexes represents a
aryloxy and α-alkoxy-substituted α, β-unsaturated carboxylic acids straightforward way to make these chiral carboxylic acids.
under mild conditions in CF
3 2
CH OH. The catalytic system could be Over the past decades, a variety of efficient chiral metal
successfully employed in building the core structure of a new FDA complexes have been developed for the hydrogenation of α-
approved drug LCZ 696.
aryl- or α-alkyl-substituted α,β-unsaturated acids with
4
excellent activities and enantioselectivities. However, highly
Enantiomerically pure α-oxy-functionalized carboxylic acids
are useful synthetic intermediates and have important
applications in the agrochemical field as crop protection
efficient catalysts for the asymmetric hydrogenation of α-
aryloxy- or α-alkoxy-substituted α,β-unsaturated acids are
limited. Ever since Maligres and Krska’s report on the first
highly enantioselective hydrogenation of α-aryloxy crotonic
1
reagents. In addition, they exhibit important pharmacological
5
properties, making them useful as nootropic, analgesic,
2
hypocholesterolemic and hyperlipidemic reagents. Many α-
acids using Ru-BINAP complexes as catalysts in 2004, several
other catalyst systems have been developed for asymmetric
hydrogenation of α-oxy-functionalized α,β-unsaturated
aryloxy and α-alkoxy cinnamic acid derivatives have attracted
considerable attention as potential agonists against
carboxylic acids. For examples, the Ru/diphosphine complexes
[
6
Ru(OAc) /SFDP] developed by Zhou for the hydrogenation of
peroxisome proliferator-activated receptors (PPARs) in the
3
diabetes, and several compounds of this
2
treatment of type
Ⅱ
α-aryloxy crotonic acids and Ru(OAc) /(S)-TMBTP system
2
7
reported by Puentener for the hydrogenation of α-methoxy
class are now in various stages of clinical development. Figure
shows selected examples of bioactive compounds containing
chiral α-oxy-functionalized carboxylic acids.
1
cinnamic acids. Rh/diphosphine catalysts such as the Rh-
8
Walphos complexes developed by Houspis and the Rh-Trifer
4
p
developed by Chen
were employed to asymmetric
hydrogenation of α-ethoxy cinnamic acids. The best results
9
were achieved by Zhou with high enantioselectivities in
asymmetric hydrogenation of various α-oxy-functionalized α,
β-unsaturated acids utilizing a chiral spiro Ir/phosphino-
oxazoline complex as catalyst, however, an external base is
needed to facilitate the reaction. Thus, considering the
importance of the α-oxy-functionalized carboxylic acids,
development of truly effective catalysts for this transformation
Fig. 1. Selected bioactive compounds derived from chiral α-aryloxy or is still highly desirable.
alkoxy carboxylic acids.
In our ongoing research in asymmetric hydrogenation, we
are always interested in developing a novel and highly efficient
catalyst to carry out useful transformations. Previously, we
reported ChenPhos as ligand in the Rh-catalysed highly
efficient asymmetric hydrogenation of α-alkyl-substituted
4
q
10
cinnamic acids and 2-substituted-2-alkenols. The key to our
success for ChenPhos is the activation of substrates through a
secondary interaction between the ligand and the substrates.
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Table 1. Screening of metal precursors and solvent in asymmetric
R1
O
R1
O
hydrogenation of α-methyloxy α, β-unsaturated acid by ChenPhos-
a
metal complex
H2, ChenPhos-Rh
*
R2
OH
R2
OH
O
O
R3
R3
Fe
Fe
Ph
NMe2
N
H
Ph
O
P
P
H
O
O
R3
Fe
Rh
Fe
b
c
P
R1
R2
Entry
Metal precursor
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
Conv. (%)
Ee (%)
PCy2
ChenPhos
Cy Cy
Substrate catalyst complex
1
2
3
4
5
[Rh(COD)
2
]BF
4
4
100
87
[Rh(NBD)
2
2
]BF
100
88
87
89
88
95
95
Scheme 1. Asymmetric hydrogenation of α-oxy functionalized α, β-
unsaturated acid catalysed by ChenPhos-Rh comple
[Rh(NBD)
]SbF
6
100
x
[Rh(NBD)Cl]
2
100
Following this idea, we envisioned that the metal complex of
this ligand should be suitable for the asymmetric
hydrogenation of α-oxy functionalized α,β-unsaturated acids
[Ir(COD)Cl]
2
100
d
6
[Rh(NBD)Cl]
2
2
CF
CF
3
3
CH
2
OH
OH
100
(
Scheme 1). Herein we document a Rh-ChenPhos complex
e
7
[Rh(NBD)Cl]
CH
2
97
catalyzed hydrogenation of α-aryloxy and α-alkyloxy α,β-
unsaturated acids, affording the corresponding saturated
carboxylic acids in high enantioselectivities. There are several
advantages of this catalyst system: 1) no external base is
needed to achieve high activities and enantioselectivities,
comparing to Zhou’s Ir catalyst system; 2) high
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.1 mol/L, solvent = 2
mL, 1.0 mol% of catalyst. Determined by H NMR analysis. Determined
by chiral HPLC analysis on a chiral stationary phase. S/C=1000.
b
1
c
d
e
S/C=5000.
enantioselectivities (up to 99% ee) and high TONs (up to 5000) solvent, up to 95% ee was realized. Interestingly, the ee drops
have been achieved; 3) solvent effect plays a critical role in dramatically with the increase of the bulkiness and the PKa
achieving high ees and a strong ionic interaction can dictate value of the alcohols. It seems that the alcohol is possibly
enantioselectivities in an appropriate solvent, such as involved in the ionic interaction. Using an alcohol with proper
CF
3
CH
2
OH.
steric, electronic factors and PKa value, this secondary
Initially, the (Z)-2-methoxy-3-phenylacrylic acid 1a was interaction could be stabilized to dictate the high efficiency of
chosen as a model substrate. To our delight, hydrogenation of the catalyst; otherwise, unsatisfactory results were obtained.
1a
in the presence of ChenPhos-Rh complex, generated in situ Other solvents, such as nonpolar solvent and polar aprotic
from [Rh(COD) ]BF (1.0 mol%; NBD = 2,5-norbornadiene) and solvent tested all gave low catalytic efficiencies and poor ee
ChenPhos (1.1 equivalent with respect to Rh), in methanol values (see ESI†). With CF CH OH as the solvent, complete
under 20 atm of hydrogen pressure at room temperature, gave conversion and up to 95% ee were obtained with 0.1 mol% of
S)-2a with full conversion and 87% ee (Table 1, entry 1). With [Rh(Chenphos)Cl] catalyst. In further test, up to 5000
2
4
3
2
(
2
this encouraging result, various metal precursors were turnovers were achieved while enantioselectivities remained
screened. All of other Rh precursors gave similar results, and (entries 6 and 7).
[
Rh(NBD)Cl]
2
offered up to 89% ee (entries 1-4). Although an Ir
2 3 2
Under an optimal condition with 20 atm of H in CF CH OH
precursor [Ir(COD)Cl]
2
gave similar ee value (entry 5), it with 0.1 mol% of ChenPhos-Rh complex, hydrogenation of a
showed less activities comparing with the Rh species (see ESI†). series of α-oxy functionalized α, β-unsaturated acids were
Solvent effect plays an important role in asymmetric examined at r.t. for 20 h. As shown in Table 2, all the α-aryloxy
catalysis, especially for the Rh-catalyzed asymmetric and α-alkoxy cinnamic acid derivatives were hydrogenated
1
1
hydrogenation. Firstly, several polar protic solvents MeOH, with full conversions. In all these cases, high to excellent
EtOH, CF CH OH, i-PrOH and t-BuOH were tested in this enantioselectivities were achieved. The hydrogenation appears
3
2
transformation (Scheme 2). Employing CF
3
CH
2
OH as the
to be insensitive to the position and the steric properties of
the substituent on the aromatic ring, and both the α-aryloxy
and α-alkyloxy α, β-unsaturated acids tested were all
successfully hydrogenated to afford the corresponding
products with high ees (Table 2, 2a-2d). Especially, using a 2-
naphthaldehyde derived unsaturated acid as the substrate, up
to 99% ee was realized (2m). Importantly, the heteroaromatic
ring substituted substrates also gave excellent ees (2n, 2o).
Moreover, the obtained chiral products 2d and 2r could serve
Scheme 2. Solvent effect in the reaction
2
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Table 2. Asymmetric hydrogenation of α-substituted α, β-Unsaturated the anticipated ionic interaction between the dimethylamino
a,b
acid by ChenPhos-Rh complex
group of the ligand and the carboxylate unit of the substrate.
On one hand, using the corresponding unsaturated ester as
the substrate, no reaction was detected and all the substrate
was recovered under the optimized hydrogenation conditions
(Scheme 3, Eq 1); On the other hand, when 50 mol% of NEt
3
was added as additive, while all the substrate was consumed,
the enantioselectivity was decreased dramatically to only 46%
ee (Eq 2). These results have elucidated our original proposal
about the critical role of ionic interaction in this catalyst
system to achieve high enantioselectivities.
The application of the highly enantioselective hydrogenation
was demonstrated in the synthesis of the core structure of
neprilysin inhibitor Sacubitril (AHU 377), which is one of the
compositions in a new FDA approved drug LCZ 696 (see ESI†).
In summary, this work demonstrates that the Chenphos/Rh
complex could serve as a highly efficient catalyst system for
the asymmetric hydrogenation of α-oxy functionalized α, β-
unsaturated acids. Control experiment indicated the ionic
interaction between the ligand and substrate plays a vital role
for achieving high enantioselectivities in a proper solvent. The
potential application of this catalyst system was demonstrated
in the model reaction to prepare the core motif of a new drug
LCZ 696. Further study of the Chenphos-Rh catalysts for other
substrates is under investigation and will be reported in a due
course.
We appreciate the National Science Foundation (NSF CHE
0
956784), the China Scholarship Council and the National
Natural Science Foundation of China (No. 21172262,
1272271) for finantial support.
2
Notes and references
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