Highly regio- And enantioselective synthesis of g,d-unsaturated amido esters by catalytic hydrogenation of conjugated enamides

Article abstract of DOI:10.1002/anie.201410213

An efficient and highly regio- and enantioselective catalytic asymmetric hydrogenation of a,γ-dienamido esters to g,d-unsaturated amido esters has been achieved using Rh/ TangPhos as the catalyst. A series of γ,δ-unsaturated amido acids were furnished in excellent yields with up to 99%ee. This effective methodology was applied in the asymmetric synthesis of key intermediate of Ramipril, an ACE inhibitor.

Full text of DOI:10.1002/anie.201410213

Angewandte
Chemie
DOI: 10.1002/anie.201410213
Synthetic Methods
Highly Regio- and Enantioselective Synthesis of g,d-Unsaturated
Amido Esters by Catalytic Hydrogenation of Conjugated Enamides**
Min Gao, Jing-jing Meng, Hui Lv,* and Xumu Zhang*
Abstract: An efficient and highly regio- and enantioselective
catalytic asymmetric hydrogenation of a,g-dienamido esters to
g,d-unsaturated amido esters has been achieved using Rh/
TangPhos as the catalyst. A series of g,d-unsaturated amido
acids were furnished in excellent yields with up to 99% ee. This
effective methodology was applied in the asymmetric synthesis
of key intermediate of Ramipril, an ACE inhibitor.
Phos-catalyzed asymmetric hydrogenation, but failed to
achieve the goal. Recently, some advances in the synthesis
E
nantiomerically pure g,d-unsaturated amido acids and
their derivatives are versatile intermediates in organic syn-
thesis. They can be readily converted into a variety of useful
building blocks in nonproteinogenic amino acids, antibiotics,
and other biologically active molecules, such as trapoxin A,[1]
Ramipril,[2] isostatine,[3] 7-epicylindrospermopsin,[4] pin1
inhibitors,[5] barmumycin,[6] etc. (Figure 1). In addition to
their catalytic application,[7] transformation of the enantio-
merically pure g,d-unsaturated amido esters derivatives led to
diversity in combinatorial chemistry.[8] However, the cost of
enantiomerically pure g,d-unsaturated amino acids is too high
(such as allylglycine, 1500 $gÀ1, Sigma–Aldrich) and greatly
limited their applications. Therefore, to develop an efficient
method to synthesis of g,d-unsaturated amino acids is highly
desired.
In the past decades, asymmetric hydrogenation of enam-
ides using chiral ligands (Figure 2) on either rhodium or
iridium has proven to be a robust and readily accessible route
for synthesis of chiral amines.[9,10] However, in the case of
asymmetric synthesis of g,d-unsaturated amino acid deriva-
tives,[3,11] little progress has been made. In 1998, Burk and co-
workers reported their pioneering work on Rh/DuPhos-
catalyzed asymmetric hydrogenation of a,g-dienamido
esters,[12] thus affording g,d-unsaturated amido esters in
good yields and excellent enantioselectivities. However,
over-reduction products were unavoidable in their catalytic
system even with reduction of the catalyst loading and
shortening of the reaction time. Later, Jiang and co-work-
ers[13] tried to improve the results through RhI/(R)-H8-Mono-
Figure 1. Selected examples of biologically active products derived
from amido acid moiety.
[*] M. Gao,[+] Dr. J. Meng,[+] Dr. H. Lv, Prof. Dr. X. Zhang
Key Laboratory of Biomedical Polymers of Ministry of Education &
College of Chemistry and Molecular Sciences
Wuhan University, Wuhan, Hubei 430072 (China)
E-mail: huilv@whu.edu.cn
xumu@whu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful for the financial support by a grant from Wuhan
University (203273463), “111” Project of the Ministry of Education
of China, and the National Natural Science Foundation of China
(Grant No. 21372179, 21432007, 21402145).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410213.
Figure 2. Structures of the phosphine ligands for hydrogenation of a,g-
dienamide esters.
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Table 2: Solvent screening for rhodium-catalyzed asymmetric hydro-
of g, d-unsaturated amido esters have been achieved and the
synthesis of vinylglycine analogues with high diastereoselec-
tivities and high yields has been reported. Unfortunately, the
reaction turnover number (TON) is very low, and greatly
hinders their use in practical applications.[14] Herein we report
an efficient approach to the synthesis of g,d-unsaturated
amido acid derivatives with high yields and excellent enan-
tioselectivities as well as high TONs.
genation of conjugated enamides.[a]
Entry
Solvent
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1,4-dioxane
ethyl acetate
oxolane
propan-2-ol
ethanol
toluene
1,2-dichloroethane
trifluoroethanol
dichloromethane
dichloromethane
>99 (99)
>99 (99)
>99 (99)
>99 (98)
>99 (23)
>99 (99)
92.8 (91)
95.2 (93)
>99 (99)
>99 (99)
99.2
99.5
99
99
99.4
99
92
95
99.9
99.9
Initially, the conjugated enamide (Z)-7a was chosen as
a model substrate for optimization of the reaction conditions
for the hydrogenation. When [Rh(cod)2]BF4/(R,S)-DuanPhos
was employed as the catalyst, we were delighted to find that
the reaction was complete in 1 hour under 1–2 atm H2
pressure at room temperature and gave the product 8a with
full conversion and 99% ee (Table 1, entry 1). Further screen-
ing of ligands indicated that highly electron-donating bisphos-
phine ligands, such as (S)-Binapine, (R,S)-JosiPhos, (S,S)-Me-
DuPhos, (S,S)-Et-DuPhos, and (S,S,R,R)-TangPhos led to
quantitative conversion and good ee values (86–99.3%;
entries 2–6). When Rh/TangPhos was employed, the reaction
provided the target product in 99.3% ee, which is slightly
better than that of the Rh/DuPhos catalytic system reported
by Burk and co-workers.[13] When (R,R)-Quinoxp was used, it
was found that an over-reduction process occurred even
under low H2 pressure over a shorter reaction time (entry 7).
Meanwhile, chiral biaryl bisphosphorus ligands such as (R)-
MeO-Biphep, (S)-SegPhos, and (S)-Binap were also
employed and gave high conversions but poor ee values
(20–52%; entries 8–10). In addition, the complexes with
chiral ferrocene ligands, such as Rh/WalPos, Rh/TaniPhos,
and Rh/f-Binaphane, were also evaluated and afforded the
g,d-unsaturated amido ester with good conversions and low
enantioselectivities (entries 11–13).
9
10[d]
[a] Unless otherwise mentioned, all reactions were carried out with
a [Rh(cod)2]BF4/(S,S,R,R)-TangPhos/substrate ratio of 1:1.1:100, at room
temperature under hydrogen (1–2 atm) for 1 h. [b] Determined by
1H NMR spectroscopy. Data in parentheses are the yields of the isolated
products based on starting material. [c] Determined by HPLC analysis
using a chiral stationary phase. [d] S/C=3000, 1 h.
appears that the conversion is not sensitive to the solvent
when the Rh/TangPhos complex is employed as catalyst, but
a very low yield of the isolated product was obtained with
ethanol because of the over-reduction of 7a. (entry 5). When
dichloromethane was used as the solvent, the reaction
proceeded smoothly and an excellent results were achieved
in terms of both yield and enantioselectivity under mild
reaction conditions (99% yield and 99.9% ee; entry 9).
Increasing the ratio of substrate to catalyst (S/C = 3000) had
no effect on the reaction and afforded 8a with the same
conversion and ee value (entry 10).
Under the optimized reaction conditions, the scope of g,d-
unsaturated enamides was examined (Table 3). It was found
that a broad range of conjugated enamides could be hydro-
genated smoothly. More importantly, the position and elec-
tronic properties of the substituents on the phenyl rings had
no effect on the reaction and gave products in high yields with
excellent regio- and enantioselectivities in all the cases(8b–
h). The g-substituted dienamide was also a good substrate for
this reaction (8i). Replacement of the aryl groups with
a heteroaryl group also worked very well (8j). Notably, d-
alkyl-substituted dienamides could also readily participate in
this reaction and all the examined d-alkyl-dienamides gave
the desired products (8k–m) in high yields and excellent
enantioselectivities (99% ee).
To demonstrate the practical utility of the current
methodology, we cooperated with Chiral Quest Inc. to
achieved the highly enatioselective synthesis of the key
intermediate 11 [precursor to Ramipril (2)] by employing
asymmetric hydrogenation of 10 on a ton scale with up to
80000 for a TON (Scheme 1). The process was patented by
Chiral Quest Inc.[2] To the best of our knowledge, this process
represents one of the most concise and economical routes for
synthesis of Ramipril, and the turnover number is also the
best one for hydrogenation of conjugated enamides for
synthesis of chiral g,d-unsaturated amino acid derivatives.
Subsequently, we evaluated the solvent effect on the
transformation and the results are summarized in Table 2. It
Table 1: Ligand screening for rhodium-catalyzed asymmetric hydroge-
nation of conjugated enamides.[a]
Entry
Ligand
Conversion [%][b]
ee[%][c]
1
2
3
4
5
6
7
8
(R,S)-DuanPhos
(S)-Binapine
>99 (99)
>99 (99)
>99 (98)
>99 (99)
>99 (99)
>99 (99)
>99 (23)
>99 (99)
94 (94)
99
86
(R,S)-JosiPhos
(S,S)-Me-DuPhos
(S,S)-Et-DuPhos
(S,S,R,R)-TangPhos
(R,R)-Quinoxp
(R)-MeO-Biphep
(S)-SegPhos
93.5
97.5
96.2
99.3
13
51
71
9
10
11
12
13
(S)-Binap
(S)-WalPhos
TaniPhos
(S,S)-f-Binaphane
>99 (99)
>99 (99)
>99 (99)
93 (93)
20
9
78
41
[a] Unless otherwise mentioned, all reactions were carried out with
a [Rh(cod)2]BF4/ligand/substrate ratio of 1:1.1:100, in methanol at room
temperature under hydrogen (1–2 atm) for 1 h. [b] Determined by
1H NMR spectroscopy. Data within parentheses are the yields of the
isolated product based on starting material. [c] Determined by HPLC
analysis using a chiral stationary phase. cod=1,5-cyclooctadiene.
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Table 3: Rhodium-catalyzed enantioselective hydrogenation of a,g-
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[a] Unless otherwise mentioned, all reactions were carried out with
a [Rh(cod)2]BF4/(S,S,R,R)-TangPhos/substrate ratio of 1:1.1:3000, at
room temperature under hydrogen (1–2 atm) for 1 h. Yields of isolated
products are given. The enantioselectivities were determined by HPLC
using a chiral stationary phase. Chiral assignment was determined by
comparison of sign of optical rotation and order of elution, from an
HPLC using a chiral stationary phase, with configurationally defined
sample. [b] 1 atm.
Scheme 1. An environmentally friendly route to a Ramipril intermediate
by an asymmetric hydrogenation protocol.
In summary, we developed a Rh/TangPhos-catalyzed
asymmetric hydrogenation of a,g-dienamido esters to afford
g,d-unsaturated amido esters in high yield with good regio-
selectivities and excellent enantioselectivities. More impor-
tantly, the methodology exhibits excellent TONs, which made
it successful for making a key intermediate in Ramipril
synthesis. Further investigation into catalytic asymmetric
hydrogenation for synthesis of high bioactivity and value-
added compounds are in progress.
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Received: October 17, 2014
Published online: December 15, 2014
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Keywords: amino acids · asymmetric synthesis · hydrogenation ·
regioselectivity · rhodium
.
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