Organocatalytic Asymmetric Decarboxylative Amination of β-Keto Acids: Access to Optically Active α-Amino Ketones and 1,2-Amino Alcohols

Article abstract of DOI:10.1021/acs.orglett.7b00797

An organocatalytic asymmetric decarboxylative amination reaction of β-keto acids is described. Under mild reaction conditions, a series of chiral α-amino ketones were obtained in good to high yields (up to 99%) and enantioselectivities (up to 95% ee). A chiral 1,2-amino alcohol was synthesized from the corresponding decarboxylative amination product in several steps without loss of enantioselectivity.

Full text of DOI:10.1021/acs.orglett.7b00797

Letter
pubs.acs.org/OrgLett
Organocatalytic Asymmetric Decarboxylative Amination of β‑Keto
Acids: Access to Optically Active α‑Amino Ketones and 1,2-Amino
Alcohols
Yi Wei, Heng-Xia Zhang, Jun-Liang Zeng, Jing Nie, and Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Tianjin University, and Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: An organocatalytic asymmetric decarboxylative amination reaction of β-keto acids is described. Under mild
reaction conditions, a series of chiral α-amino ketones were obtained in good to high yields (up to 99%) and enantioselectivities
(up to 95% ee). A chiral 1,2-amino alcohol was synthesized from the corresponding decarboxylative amination product in several
steps without loss of enantioselectivity.
Scheme 1. Catalytic Asymmetric Synthesis of β-Amino
Ketones and α-Amino Ketones
ptically active α-amino ketones are a very important class
Oof compounds in synthetic chemistry, which can be
readily converted into other useful building blocks, such as
amines, 1,2-amino alcohols, and α-amino acid derivatives
(Figure 1a).1 Furthermore, a very large number of natural
products and active pharmaceutical molecules contain the α-
amino ketones and its derivatives (Figure 1b).2 The catalytic
asymmetric α-amination of various carbonyl substrates
represents a most attractive route to this important class of
products, and many practical enantioselective methods have
been enabled by the identification of various chiral metal and
organic catalysts.3 Despite the impressive advances made in this
subarea, it is still highly desirable to develop new catalytic
enantioselective amination reactions of carbonyl compounds
and to broaden the diversity of α-amino ketones.
The utility of β-keto acids to generate highly reactive ketone
enolate equivalents has emerged as a very useful platform in
asymmetric catalysis.4,5 In this context, three groups of Tian,6
Lu,7 and Ma8 described the asymmetric decarboxylative
Mannich reactions of β-keto acids with imines under the
catalysis of chiral metal complexes or small organic molecules
for the synthesis of optically active β-amino ketones (Scheme
1a). On the basis of this behavior, we considered whether
Figure 1. Synthetic transformation and selected bioactive compounds
of α-amino ketones.
Received: March 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00797
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Letter
Table 1. Optimization of Conditions for the Asymmetric
Decarboxylative Amination Reaction
Scheme 2. Scope for the Organocatalytic Asymmetric
Decarboxylative Amination of β-Keto Acids
a
solvent/temp (°C)/time
yield
b
c
entry catalyst (mol %)
(h)
(%)
ee (%)
1
I (10)
THF/25/24
99
86
89
89
92
97
99
99
99
99
75
88
90
88
92
90
90
90
92
92
85
90
30
57
43
66
25
47
32
65
44
4
2
II (10)
III (10)
IV (10)
V (10)
THF/25/24
3
THF/25/12
4
THF/25/12
5
THF/25/12
6
VI (10)
VII (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (10)
IV (5)
THF/25/12
7
THF/25/12
8
CH2Cl2/25/12
Et2O/25/12
9
10
11
12
13
14
15
16
17
18
19
20
21
22
toluene/25/12
CH3CN/25/24
CH3OH/25/24
EtOH/25/12
n-PrOH/25/12
i-PrOH/25/12
t-BuOH/25/12
i-PrOH/0/12
i-PrOH/−20/12
i-PrOH/0/1
80
70
90
90
92
92
94
93
94
95
92
88
i-PrOH/0/0.5
i-PrOH/0/0.25
i-PrOH/0/0.5
a
The reaction was carried out with β-keto acid 1a (0.2 mmol),
diisopropyl azodicarboxylate 2a (0.4 mmol), and organocatalyst I−VII
b
(5−10 mol %) in solvent. Yields of isolated product averaged over
c
two runs. Enantiomeric excess (ee) was determined by chiral HPLC
analysis.
the desired enantioenriched α-amino ketones. Herein, we
describe the successful implementation of this process to
provide α-amino ketone derivatives and significant opportu-
nities for structural diversification.
In the initial studies, we conducted the asymmetric
decarboxylative amination reaction of 1-oxo-1,2,3,4-tetrahydro-
naphthalene-2-carboxylic acid 1a with diisopropyl azodicar
boxylate 2a by employing a series of commercially available
cinchona alkaloids I−VII (Figure 2) as chiral organocatalysts in
tetrahydrofuran (THF) at room temperature. We discovered
that the amination product 3a could be obtained in high yield
and variable enantioselectivity (Table 1, entries 1−7), with the
catalyst (DHQD)2PYR (IV) giving the best performance (entry
4). Subsequently, the solvent was found to have an important
effect on the reactivity (entries 8−16). Among the solvents
tested, isopropanol (i-PrOH) was found to be the best with
respect to the asymmetric induction. The reaction temperature
and time were also found to exert profound effects on
enantioselectivity (entries 17−21). Optimal results were
obtained in i-PrOH at 0 °C within 0.5 h (entry 20). In
addition, the reduction of the catalyst loading had a deleterious
effect on both yield and ee (entry 22).
Figure 2. Structures of cinchona alkaloids tested.
azodicarboxylates could be engaged in the catalytic asymmetric
amination reaction with β-keto acids (Scheme 1b). In this
scenario, the use of chiral amine organocatalysts may generate
and position an enolate species for nucleophilic addition to give
B
DOI: 10.1021/acs.orglett.7b00797
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recrystallization in MeOH/ethyl acetate provided the single
stereoisomer 5 with excellent optical purity, and its absolute
configuration was determined to be (S,S) from the X-ray
structural analysis.12
Scheme 3. Scaled-up Decarboxylative Amination, Further
Synthetic Transformation, and X-ray Crystallographic
Structure of the Product 5 (Thermal Ellipsoids Shown at
50% Probability)
In summary, we have developed an efficient organocatalytic
asymmetric decarboxylative amination reaction of β-keto acids
by using dialkyl azodicarboxylates as amination reagents. In the
presence of biscinchona alkaloids, a series of chiral α-amino
ketone derivatives were obtained in good to high yields (up to
99%) and enantioselectivities (up to 95% ee) under mild
reaction conditions. Moreover, the synthetic potential of this
methodology was also demonstrated to access an optically
active 1,2-amino alcohol. Further application of α-amino
ketones and related products is currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00797.
1
Experimental details, H and 13C NMR spectra, and
HPLC analytic results for 3a−r and 4 (PDF)
Crystallographic data for compound 5 (CIF)
AUTHOR INFORMATION
With the optimized conditions in hand, the scope of this
organocatalytic asymmetric decarboxylative amination reaction
was probed by varying both azodicarboxylates and β-keto acids.
The results are summarized in Scheme 2. A series of
azodicarboxylates were found to participate in enantioselective
amination reactions with β-keto acid 1a catalyzed by
(DHQD)2PYR (IV), and the desired products 3a−d were
obtained in good to high yields and enantioselectivities.
Subsequently, a variety of 1-oxo-1,2,3,4-tetrahydro-
naphthalene-2-carboxylic acids were tested. Most of the α-
amino ketones (3e−n) could be produced in 75−99% yields
with high enantioselectivities (88−95% ee). However, the
strong electron-withdrawing substituent at the phenyl ring has
little effect on the enantioselectivity. These reactants gave the
amination products 3o and 3p with 75% ee. Indanone- and 1-
benzosuberanone-derived β-keto acids are also viable sub-
strates, affording the desired product 3q and 3r with 57% ee
and 72% ee, respectively. In addition, we investigated the
amination reactions of diisopropyl azodicarboxylate 2a with 2-
oxocyclopentanecarboxylic acid, 2-oxocyclohexanecarboxylic
acid, and 2-oxocycloheptanecarboxylic acid. These β-keto
acids were found to be unsuitable for this asymmetric
transformation, and no expected products were observed.
Acyclic 2-benzoylbutanoic acid gave the corresponding
amination product in 56% yield with poor enantioselectivity
(15% ee).9
■
Corresponding Author
*E-mail: majun_an68@tju.edu.cn.
ORCID
Jun-An Ma: 0000-0002-3902-6799
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21225208, 21472137, and
21532008), the National Basic Research Program of China
(973 Program, 2014CB745100), and Tianjin Municipal Science
& Technology Commission (14JCZDJC33400).
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