Highly enantioselective synthesis of non-natural aliphatic α-amino acids via asymmetric hydrogenation

Article abstract of DOI:10.1039/c5ob01111f

By employing a rhodium-Duanphos complex as the catalyst, β-alkyl (Z)-N-acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed.

Full text of DOI:10.1039/c5ob01111f

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DOI: 10.1039/C5OB01111F
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Highly Enantioselective Synthesis of Non-natural
Aliphatic α-Amino Acids via Asymmetric
Hydrogenation†
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Jianjian Ji,‡ Caiyou Chen,‡ Jiayu Cai, Xinrui Wang, Kai Zhang, Liyang Shi,
Hui Lv* and Xumu Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
investigation on the asymmetric hydrogenation of the alkyl-
substituted α-dehydroamino acid derivatives remains rare. 15a As a
result, we are aiming at developing an efficient method for the
preparation of non-natural aliphatic chiral D-amino acids through
asymmetric hydrogenation. Herein, we report the highly
By employing rhodium-Duanphos complex as the catalyst, β-
alkyl
(Z)-N-acetyldehydroamino esters were smoothly
hydrogenated in a highly efficient and enantioselective way.
Excellent enantioselectivities together with excellent yields
were achieved for a series of substrates. An efficient approach
for the synthesis of the intermediate of the orally
administered anti-diabetic drug Alogliptin and Linagliptin in
the DPP-4 inhibitor class was also developed.
enantioselective hydrogenation of β-alkyl (Z)-N-acetyldehydroamino
esters by using Rh(I) and chiral bisphosphorus ligand as catalyst. A
series of non-natural aliphatic D-amino acid derivatives were
obtained with excellent enantioselectivities and very high yields.
Moreover, an efficient approach for the synthesis of the key
intermediate of the anti-diabetic drugs Alogliptin and Linagliptin in
the DPP-4 inhibitor class was also successfully developed.
Widely found as common intermediates for the preparation of
many chiral drugs,1 biologically active molecules,2 chiral axulliaries3
and some useful chiral building blocks,4 non-natural D-amino acids
have attracted intensive attention over the past decades regardless of
the fact that natural L-amino acids are readily available. Among all
the non-natural amino acids, aliphatic D-amino acids stand out as
elegant intermediates for the synthesis of many chiral drugs which
include the orally administered anti-diabetic drugs in the DPP-4
inhibitor class, among which, Alogliptin,5 Linagliptin,6 Sitagliptin,7
and Saxagliptin8 (Figure 1) are just to name a few. Moreover, due to
the significance of chiral aliphatic D-amino acids, the worldwide
market value of these valuable compounds is estimated at 2 billion
dollars annually.9
As a result, great efforts have been made for the preparation of
non-natural D-amino acids.10 Representative methods include
Strecker synthesis,11 enzymatic kinetic resolution of racemic amino
esters,12 enantioselective amination of carboxylic derivatives,13
amino enolate alkylations14 and the highly efficient transition-metal-
catalyzed asymmetric hydrogenation of α-dehydroamino acid
derivatives.15 However, for all of the former processes, they often
suffer from the drawbacks such as poor yields and
enantioselectivities, low conversion of starting materials, low
reaction rates, the need for multiple enzymes or long chemical
Figure 1. Examples of chiral drugs containing aliphatic amino acid moiety.
Initially, our attempts started from the hydrogenation of 1b
utilizing Rh(NBD)2BF4 as catalyst precursor under 100 psi hydrogen
pressure in methanol. A series of ligands were screened which were
summarized in Figure 2. As depicted in Table 1, ligand has a
substantial role in determining the enantioselectivity. Although all of
the ligands tested gave full conversion of the substrate, the
enantioselectivity excess (ee) varied in a large extend. With t-Bu-
Josiphos as the ligand, only 5.4% ee was obtained (Table 1, entry 1).
The same case went with BINAP which afforded only 9.4% ee
(Table 1, entry 5). Slightly higher ee was observed by using
Biphephos and C3-Tunephos as ligand, however, the results were
just moderate. In a big contrast, we were pleased to find that by
reaction steps. In
a sharp contrast, transition-metal-catalyzed
asymmetric hydrogenation overcomes all of these drawbacks giving
highly enantiomerically pure amino acid derivatives with very high
yields in a concise way and thus was certified as a powerful and
elegant methodology over the past decades.15a Although intensive
efforts have been made for the asymmetric hydrogenation of the
aryl-substituted α-dehydroamino acid derivatives, systematic
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DOI: 10.1039/C5OB01111F
Table 2. Solvent and temperature screening for the asymmetric hydrogenation of
using our previously developed chiral bisphosphorus ligands
Tangphos, Duanphos and Binapine, excellent ee was obtained (Table
1, entries 2-4). Remarkably, as high as 99.7% ee (Table 1, entry 3)
was obtained when using (Rc, Sp)-Duanphos as the ligand and the
desired D-configured product was obtained. As a consequence, (Rc,
Sp)-Duanphos was selected as the optimized ligand for the further
screening of the reaction conditions.
1b a
Table 1. Ligand screening for the asymmetric hydrogenation of 1b a
Entry
Solvent
MeOH
DCM
Conv (%)c
> 99
Ee (%)d
99.7
1
2
> 99
99.0
3
Toluene
i-PrOH
EtOH
EA
> 99
99.1
4
> 99
99.3
Entry
Ligand
Conv (%)b
> 99
Ee (%)c
5.4
Configurationd
5
> 99
99.0
1
2
3
4
5
6
7
t-Bu-Josiphos
(S, R)-Tangphos
(Rc-Sp)-Duanphos
(S)-Binapine
D
D
D
L
6
> 99
99.0
> 99
99.0
99.7
95.1
9.4
7
TFE
> 99
97.4
8b
MeOH
>99
99.6
> 99
> 99
[a] Unless otherwise mentioned, all reactions were carried out with
a
[Rh(NBD)2]BF4/ligand/substrate ratio of 1:1.1:100, at room temperature, under
hydrogen (100 psi) for 2 h, all the configuration of the products was D, NBD =
(S)-BINAP
> 99
L
2,5-norbornadiene, DCM
= dichloromethane, EA = ethyl acetate, TFE =
(R)-MeO-BIPHEP
(S)-C3-Tunephos
> 99
46.8
68.7
D
L
trifluoroethanol; [b] Temperature was increased to 50 °C; [c] Determined by 1H
NMR spectroscopy; [d] Determined by HPLC analysis using a chiral stationary
phase.
> 99
[a] Unless otherwise mentioned, all reactions were carried out with
a
[Rh(NBD)2]BF4/ligand/substrate ratio of 1:1.1:100, in MeOH, at room temperature,
under hydrogen (100 psi) for 2 h, NBD = 2,5-norbornadiene; [b] Determined by
1H NMR spectroscopy; [c] Determined by HPLC analysis using a chiral stationary
phase; [d] Absolute configuration was determined by comparing the optical
rotation data with those reported by literature16.
Table 3. Rh-catalyzed asymmetric hydrogenation of β-alkyl (Z)-N-
acetyldehydroamino esters a
O
O
O
NH
NH
NH
O
O
O
O
O
O
2c, Conv.%> 99
ee% = 99.5
2a, Conv.%> 99
ee% = 99.0
2b, Conv.%> 99
ee% = 99.7
O
O
NH
HN
O
O
O
O
2e, Conv.%> 99
ee% = 99.5
2d, Conv.%> 99
ee% = 99.2
O
O
O
HN
O
HN
O
HN
Cl
O
O
O
O
2f, Conv.%> 99
ee% = 99.7
2g, Conv.%> 99
ee% = 98.5
2h, Conv.%> 99
ee% = 96.5
Figure 2.Ligands screened for the asymmetric hydrogenation of 1b
O
O
O
O
In order to further screen the reaction conditions, solvent and
temperature effect were also investigated (Table 2). It was found that
solvent had little influence on the enantioselectivity and the substrate
conversion. Except for TFE (Table 2, entry 7), all of the solvents
tested gave satisfactory results (>99% conversion, >99% ee, Table 2,
entries 2-6). Methanol was selected as the best solvent for the
slightly higher enantioselectivity obtained. It was observed that
increasing the reaction temperature to 50 °C had little influence on
the enantioselectivity (Table 2, entry 8). For optimal results, the
temperature was kept at 25 °C as a result.
O
HN
HN
O
HN
O
N
O
O
O
O
2i, Conv.%> 99
ee% = 99.7
2j, Conv.%> 99
ee% = 99.5
2k, Conv.%> 99
ee% = 99.8
[a] Unless otherwise mentioned, all reactions were carried out with
[Rh(NBD)2]BF4/Duanphos/substrate ratio of 1:1.1:100, in MeOH, at room
temperature, under hydrogen (100 psi) for 2 h, conversion was determined by H
NMR spectroscopy, ee was determined by HPLC analysis using a chiral stationary
phase, for all cases, D-configured products were obtained, NBD
norbornadiene.
a
1
= 2,5-
2 | J. Name., 2012, 00, 1-3
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excellent yield. By treating 2k with aluminium and sodium
hydroxide followed by reduction with lithium aluminium hydride,
the key intermediate of Alogliptin and Linagliptin 7k was efficiently
obtained in good yield. Starting from the key intermediate 7k,
Alogliptin and Linagliptin can be readily synthesized following
literature procedure.5, 6
Delighted by the prelimary results, a series of β-alkyl (Z)-N-
acetyldehydroamino esters, 1a-1k, were synthesized and were
subsequenty subjected to the optimal reaction conditions. These
compounds were easily prepared in one step from readily available
α
-alkyl aldehydes utilizing an Horner-Wadsworth-Emmons
protocol,17 owing to its high yield and operational simplicity (See
supporting information).
The newly synthesized Z-configured
β-alkyl (Z)-N-
acetyldehydroamino esters were subjected to the optimal reaction
conditions as a consequence. As shown in Table 3, these Z-
configured compounds proved to be good substrates affording a
series of chiral aliphatic α-amino esters. Linear alkyl substitued
dehydroamino substrates were all smoothly converted giving
excellent ee higher that 99% (Table 3, 2a-2e). However, for the
branched alkyl substituted substrates, the ee value was slightly lower
(Table 3, 2g, 2h), probably due to the steric hindrance of these
substrates. Cyclic alkyl substituted dehydroamino esters also proved
to be good substrates giving excellent enantioselectivity (Table 3, 2i,
2j). Intrestingly, halogenated substrate was also tolerated affording
high conversion and excellent ee (Table 3, 2f). Remarkbaly, the
protected amine substituted substrate 1k was also smoothly
hydrogenated with ee value higher than 99% (Table 3, 2k).
Figure 3. Highly Enantioselective Synthesis of Alogliptin and Linagliptin.
Inspired by the above results, we intended to conduct the
hydrogenation reaction with lower catalyst loading employing 1k
(Table 4) as the model substrate. When the reaction was conducted
with 0.2 mol% (S/C = 500) catalyst loading under 50 atm hydrogen
pressure at room temperature, the reaction proceeded smoothly with
full conversion and excellent ee (Table 4, entry 1). However, further
lowering the catalyst loading to 0.1 mol% (S/C = 1, 000) led to a
disappointing result that almost all of the substrate remained
untouched (Table 4, entry 2). In order to promote the conversion of
the substrate, the temperature was increaed to 50 °C which to our
delight led to full conversion of the substrate and the ee remained the
same when the catalyst loading was 0.1 mol% (Table 4, entry 3).
Excellent ee and substrate conversion were also observed when the
catalyst loading was lowered to 0.02 mol% while further lowering
the catalyst loading to 0.001 mol% gave a substrate conversion of
only 67% although the ee remained high.
Conclusions
In summary, a new type of β-alkyl (Z)-N-acetyldehydroamino
esters were prepared by Horner-Wordwoths-Emmons reaction in
high yields and were hydrogenated with excellent enantioselectivity,
which provides an efficient method for the synthesis of the
enantiomerically pure non-natural amino acids that are important in
synthetic, medicinal, and bioorganic chemistry. More importantly,
the key intermidiate 7k was synthesized providing a highly
enantioselective route for the synthesis of the DPP-4 inhibitor
Alogliptin and Linagliptin.
We are grateful for the financial support by the 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).
Table 4. Asymmetric Hydrogenation of 1k with lower catalyst loading a
Notes and references
Key Laboratory of Biomedical Polymers of Ministry of Education & coll
ge of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hu
bei 430072, China.
Email: xumu@whu.edu.cn, huilv@whu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/c000000x/
Entry
S/C
500
Temp. (°C)
Conv (%)b
> 99
Ee (%)c
99.6
1
2
3
4
5
25
25
50
50
50
1, 000
1, 000
5, 000
10, 000
< 5
ND
> 99
99.6
‡ Both authors contributed equally to this work.
> 99
99.6
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DOI: 10.1039/C5OB01111F
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By employing rhodium-DuanPhos as catalyst,
β-alkyl (Z)-N-acetyldihydroamino esters were smoothly hydrogenated in a highly
efficient and enantioselective way. Excellent enantioselectivities together with good yields were achieved for a series of substrates. An
efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drug Alogliptin and Linagliptin in the
DPP-4 inhibitor class was also developed.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5