Rhodium-catalyzed Asymmetric Hydrogenation of α-Dehydroamino Ketones: A General Approach to Chiral α-amino Ketones

Article abstract of DOI:10.1002/asia.201500892

Rhodium/DuanPhos-catalyzed asymmetric hydrogenation of aliphatic α-dehydroamino ketones has been achieved and afforded chiral α-amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β-amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α-amino ketones and chiral β-amino alcohols. Taking a different route: Rh/DuanPhos is shown to be an effective catalyst for the asymmetric hydrogenation of α-dehydroamino ketones, affording aliphatic α-amino ketones in high yields and excellent enantioselectivities. This method provides an efficient and general route to the synthesis of chiral aliphatic α-amino ketones and α-amino alcohols.

Full text of DOI:10.1002/asia.201500892

DOI: 10.1002/asia.201500892
Communication
Hydrogenation
Rhodium-catalyzed Asymmetric Hydrogenation of a-Dehydro-
amino Ketones: A General Approach to Chiral a-amino Ketones
Wenchao Gao, Qingli Wang, Yun Xie, Hui Lv,* and Xumu Zhang*[a]
tions by Candida species and Aspergillus species in severely im-
Abstract: Rhodium/DuanPhos-catalyzed asymmetric hy-
munocompromised patients. Considerable efforts have been
drogenation of aliphatic a-dehydroamino ketones has
devoted to developing new methodologies for the synthesis
been achieved and afforded chiral a-amino ketones in
a-amino ketones. Typical methods include the reaction of or-
high yields and excellent enantioselectives (up to 99% ee),
ganometallic reagents with a-amino acids and a-amino acids
which could be reduced further to chiral b-amino alcohols
derivatives,[5] aza-benzoin reaction,[6] Friedel–Crafts-type reac-
by LiAlH(tBuO)3 with good yields. This protocol provides
tion,[7] cross-coupling reaction[5e] as well as Dakin–West reac-
a readily accessible route for the synthesis of chiral a-
tion[8]. However, most of these approaches suffer from draw-
amino ketones and chiral b-amino alcohols.
backs such as high catalyst loading and limited substrate
scope. In addition, methods relating to the asymmetric synthe-
sis of chiral aliphatic a-amino ketones remain underexploited.
Chiral a-amino ketones as a versatile building block widely
exist in natural products, drugs, and synthetic biologically
active molecules.[1] Enantiopure b-amino alcohols can be ob-
tained from chiral a-amino ketones, and this provides a direct
route to the preparation of natural and pharmacologically
active products (Figure 1).[2–4] For example, posaconazole is
a triazole antifungal drug that is used to treat invasive infec-
Therefore, it is highly desirable to develop new methods for
the synthesis of chiral aliphatic a-amino ketones.
In the past decades, asymmetric hydrogenation[9] has
become one of the most powerful strategies to obtain chiral
compounds, especially for the synthesis of chiral amines and
chiral alcohols.[10] In this context, our group has developed
some efficient chiral diphosphine ligands which have been suc-
cessfully used in the asymmetric hydrogenation of enamides,
and developed a series of highly efficient methods for the
asymmetric synthesis of chiral amines and their analogues.[11]
However, asymmetric hydrogenation is rarely used in the
highly enantioselective synthesis of chiral aliphatic a-amino ke-
tones despite obvious advantages in the synthesis of chiral
amines. The possible reason lies in that it is difficult to control
the regioselectivities of hydrogenation of a-dehydroamino ke-
tones. In addition, the enantioselectivities of asymmetric hy-
drogenation of aliphatic enamides is poor. Regioselective hy-
drogenation of a-dehydroamino ketones with high enantiose-
lectivities remains a significant challenge. Herein, we report the
asymmetric hydrogenation of aliphatic a-dehydroamino ke-
tones to give a-amino ketones in high enantioselectivities and
their applications in the synthesis of chiral b-amino alcohols
(Scheme 1).
Figure 1. Representative drugs containing a-amino ketones and b-amino al-
We began our experiments with 2-(benzylamino)pent-1-en-
3-one (2c) as a model substrate, and various chiral diphos-
phine ligands were evaluated. As shown in Table 1, (S)-Binap
exhibited good activity for this reaction but poor enantioselec-
tivites (Table 1, entry 1). On the contrary, when Quinoxp was
used as a ligand, it gave the desired product with poor yield
but excellent enantioselectivity. When Tangphos, Josiphos, and
C3-Tunephos were employed (Figure 2), the results were im-
proved dramatically, but it remained difficult to obtain high
yields and high enantioselectivites simultaneously (Table 1, en-
tries 2, 5, 6). To our delight, when (S,S’,R,R’)-DuanPhos devel-
oped in our lab was employed, it afforded the aliphatic a-
cohols.
[a] W. Gao,+ Q. Wang,+ Y. Xie, 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.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500892.
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Communication
the optimal solvent as it gave
desired products with slightly
higher ee value (Table 2).
Under the optimized reaction
conditions, a variety of aliphatic
a-dehydroamino ketones were
tested. As shown in Table 3, all
substrates tested here could
Scheme 1. Design and synthesis of a-amino ketones and b-amino alcohols.
Table 1. Ligand screening for Rh-catalyzed asymmetric hydrogenation.[a]
convert smoothly into the corre-
sponding products with high
yields and excellent ee values in a short time (3a–3i). Generally,
di- and trisubstituted a-dehydroamino ketones could be used
Table 2. Solvent screening for Rh-catalyzed asymmetric hydrogenation.[a]
Entry
Ligand
Conversion[b] [%]
ee[c] [%]
1
(S)-Binap
98
9
2
3
4
5
6
7
8[e]
9[f]
(R,S)-JosiPhos
(R,R)-Quinoxp
(S)-SegPhos
(S)-C3-TunePhos
(S,S,R,R)-TangPhos
(S,S,R,R)-DuanPhos
(S,S,R,R)-DuanPhos
(S,S,R,R)-DuanPhos
94
23
–
77
88
93
–
98
63
>99
>99
93
Entry
Solvent
Conversion[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
THF
EtOH
>99
>99
>99
>99
>99
85
99.8
99.4
99.5
98.2
99.1
99.7
96.9
91
iPrOH
MeOH
CH2Cl2
Toluene
Dioxane
>99
>99
>99
5
[a] All reactions were carried out with a substrate/Rh-L catalyst ratio of
100:1 in 1 mL THF at room temperature under 1 atm H2 for 0.5 h. [b] De-
termined by 1H NMR spectroscopy. [c] Determined by HPLC on a chiral
phase. [d] Determined by H NMR spectroscopy, the data in parenthesis is
the ratio of 3c and byproduct. [e] 0.5 h. [f] Substrate (1 mmol), cat.
[a] All reactions were carried out with a substrate/Rh-DuanPhos catalyst
ratio of 100:1 in 1 mL solvent at room temperature under 1 atm H2 for
0.5 h. [b] Determined by 1H NMR spectroscopy. [c] Determined by HPLC
or GC on a chiral phase.
1
(0.1 mol%), THF (1 mL) at room temperature under 20 atm H2 for 24 h.
Table 3. Asymmetric hydrogenation of a-dehydroamino ketone by Rh/
(S,S’,R,R’)-DuanPhos.[a]
3a
3b
3c
2 h
2 h
0.5 h
(93% yield, >99% ee)
(98% yield, >99% ee)
(98% yield, >99% ee)
Figure 2. Structures of the phosphine ligands for hydrogenation of 2.
3d
3e
3 f
1.5 h
1.5 h
2 h
(98% yield, >99% ee)
(97% yield, >99% ee)
(97% yield, >99% ee)
amino ketone with 99.8% ee, although a large amount of by-
product (amino alcohol) was obtained (Table 1, entry 7). Short-
ening of the reaction time to 0.5 h, 2c was completely trans-
formed to the a-amino ketone with high yield and excellent
enantioselectivity (Table 1, entry 8). When we reduced the cata-
lyst loading to 0.1 mol%, the reaction still proceeded smoothly
but with a slightly loss in enantioselectivity (Table 1, entry 9).
Solvent screening revealed that excellent enantioselectivities
could be observed in all solvents examined, but that the sol-
vent had a large influence on the conversion. Generally, excel-
lent conversion was obtained when THF, dichloromethane, and
alcohols were employed as solvents. At last, we chose THF as
3g
2 h
3h
2 h
3i
2 h
(97% yield, >99% ee)
(99% yield, >99% ee)
(99% yield, 98% ee)
[a] Reaction conditions: 2 (0.1 mmol), Rh(cod)-DuanPhos (0.001 mmol),
THF (1 mL), under 1 atm H2 at room temperature. Yields of isolated prod-
ucts are given. The enantioselectivities were determined by HPLC or GC
using a chiral stationary phase.
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Communication
in this reaction, and they gave
the corresponding a-amino ke-
tones with satisfactory results.
With regard to the R1 and R2
groups, the length of the alkyl
chain had no obvious influence
Scheme 2. Synthesis of N-((2S,3R)-2-hydroxypentan-3-yl)benzamide 4.
on the yields and ee values of
the products. Besides, when we
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ence on the result was observed (3b, 3c).
To illustrate the potential usefulness of this approach, a con-
cise synthetic route to chiral 3-aminopentan-2-ol, a key chiral
intermediate in the synthesis of posaconzole, an important an-
tibacterial drug, has been developed. Using LiAlH(tBuO)3 as re-
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In summary, we found Rh/DuanPhos to be an effective cata-
lyst for the asymmetric hydrogenation of a-dehydroamino ke-
tones, affording aliphatic a-amino ketones in high yields and
excellent enantioselectivities. This method is applied under
mild conditions and has a broad substrate scope, providing
a very efficient and general route to the synthesis of chiral ali-
phatic a-amino ketones and a-amino alcohols. This protocol
may find important applications for synthesizing chiral phar-
maceutical products containing a-amino ketones and b-amino
alcohols. Further studies on expanding the substrate scope
and applications are undergoing in our lab.
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Experimental Section
General hydrogenation procedure: In a nitrogen-filled glovebox,
the Rh complex (0.001 mmol) was dissolved in anhydrous THF
(0.1 mL), and the solution was equally divided into 10 vials charged
with a-dehydroamino ketones (0.1 mmol) in anhydrous THF solu-
tion (1.0 mL). The resulting vials were transferred to an autoclave,
which was charged with 1 atm of H2, and the reaction mixtures
were stirred at room temperature for a specified time. The hydro-
gen gas was then released slowly, and the solution was concentrat-
ed and passed through a short column of silica gel to remove the
metal complex. The chiral a-amino ketones were then analyzed by
HPLC or GC on a chiral stationary phase to determine the enantio-
meric excesses.
Acknowledgements
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 Founda-
tion of China (Grant No. 21372179, 21432007, 21402145).
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[13] The product’s absolute configuration was confirmed as (R) by compar-
ing the specific rotation and the NMR spectrum of 4 with data reported
in the literature (see ref. 12b).
Keywords: asymmetric catalysis · hydrogenation · P ligands ·
rhodium · a-amino ketones
Manuscript received: August 25, 2015
Accepted Article published: October 1, 2015
Final Article published: October 15, 2015
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