Synthesis of pyrrolidine-3-carboxylic acid derivatives: Via asymmetric Michael addition reactions of carboxylate-substituted enones

Article abstract of DOI:10.1039/c7ob01484h

To concisely synthesize highly enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-carboxylic acids, organocatalytic enantioselective Michael addition reactions of 4-alkyl-substituted 4-oxo-2-enoates with nitroalkanes have been developed. Using the developed reaction method, 5-methylpyrrolidine-3-carboxylic acid with 97% ee was obtained in two steps.

Full text of DOI:10.1039/c7ob01484h

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DOI: 10.1039/C7OB01484H
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Synthesis of pyrrolidine-3-carboxylic acid derivatives via
asymmetric Michael addition reactions of carboxylate-substituted
enones
Received 00th January 20xx,
Accepted 00th January 20xx
Feng Yin,a Ainash Garifullina,a and Fujie Tanaka*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
To concisely synthesize highly enantiomerically enriched 5- addition reactions of 4-oxo-2-enoates bearing simple 4-alkyl
alkylsubstituted pyrrolidine-3-carboxylic acids, organocatalytic substitutions.
Scheme 1. Synthesis of 5-substituted pyrrolidine-3-carboxylic acid
enantioselective Michael addition reactions of 4-alkyl-substituted
4-oxo-2-enoates with nitroalkanes have been developed. Using
the developed reaction method, 5-methylpyrrolidine-3-carboxylic
acid with 97% ee was obtained in two steps.
derivatives and β2-amino acid derivatives.
NO2
NH2
CH3NO2
+
COOR2
O
O
O
catalyst
reduction
R1
R1
COOR2
R1
COOR2
COOH
*
*
*
Pyrrolidine-3-carboxylic acid (β-proline) derivatives and β2-
amino acids are important molecules as bioactives, catalysts for
chemical transformations, and their building blocks.1,2,3 For
example, (R)-pyrrolidine-3-carboxylic acid derivatives have
been reported as enzyme inhibitors and receptor agonists.1a,b
(3R,5R)-5-Methylpyrrolidine-3-carboxylic acid has been used
as a catalyst for diastereo- and enantioselective organocatalytic
reactions.2a,b Homochiral pyrrolidine-3-carboxylic acid
derivatives have often been synthesized from homochiral
starting materials.2a,b,4 Enantioselective methods that provide β-
proline and 2-, 3- and/or 4-substituted pyrrolidine-3-carboxylic
acid derivatives with or without substitutions at the 5-position
have also been reported;2c,5 however, the methods used for the
synthesis of these compounds cannot be used for the synthesis
of relatively simple 5-substituted pyrrolidine-3-carboxylic acid
derivatives. The 3-carboxylic acid group on the pyrrolidine ring
has also been introduced by late-stage transformations from
olefin, furan, and isooxazole precursor groups at the 3-position
on the pyrrolidine ring;6 but these methods are not atom-
economical. Similarly, β2-amino acid derivatives are difficult to
obtain.3 Here we report the development of concise, atom-
economical methods for the synthesis of highly
enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-
carboxylic acid derivatives and β2-amino acid derivatives via
Michael addition of nitroalkanes to 4-alkyl-substituted 4-oxo-2-
enoates (Scheme 1). To synthesize simple 5-substituted
pyrrolidine-3-carboxylic acid derivatives, such as 5-methyl-
substituted derivatives, we developed enantioselective Michael
1
*
NH2
X
Y
*
R1
N
H
R1
COOH
5-substituted-pyrrolidine-
3-carboxylic acids
β2-amino acids
In previously reported enantioselective Michael addition
reactions of nitroalkanes to acyclic enones, the enones were
mostly non-enolizable with one or two aryl-substitutions.7
Although all alkyl-substituted enones have been used as
reactants,7f,g,k the use of 4-oxopent-2-enoates and their
derivatives as Michael acceptors is rare.7d,m In addition, for the
reported reactions of 4-alkyl-substituted 4-oxo-2-enoates with
nitroalkanes, only substituted nitroalkanes (such as 2-
nitropropane) have been used;7d,m this is probably to avoid
potential polymerization and formation of byproducts via
Henry reactions8 of the products. In our design (Scheme 1),
carboxylic acid ester-substituted enones 1, such as 4-oxopent-2-
enoates (R1 = methyl) and 4-oxohex-2-enoates (R1 = ethyl),
were used. We reasoned that it would be possible to identify
catalyst systems and conditions that would accelerate
enantioselective Michael addition reactions of simple
nitromethane to the enones. These reactions would be used for
concise formation of 5-alkyl-substituted pyrrolidine-3-
carboxylic acids and functionalized β2-amino acids. With the
use of substituted nitromethanes,
β
2,3-amino acids and
pyrrolidine-3-carboxylic acids bearing substitutions at 2- and 5-
positions would also be accessed.
First, catalysts and conditions for the Michael reaction step
were screened in the reaction of enone 1a with nitromethane to
afford 2a. We tested amine derivatives as the catalyst to
accelerate the reaction through an iminium activation
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mechanism. Selected results are shown in Table 1. Of catalysts reaction was deduced from 3. A plausible transition state of the
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and conditions tested, the best results were obtained with the Michael addition reaction to afford 2g isDaOlsI:o10s.h10o3w9n/Ci7nOBS0c1h4e8m4He
use of catalyst F or G in CH2Cl2 either with or without acetic 3. This route required only two steps to provide 3 from
acid additive.
commonly accessible starting materials. Note that 3 was
Table 1. Catalyst and condition screening in the Michael previously synthesized form 4-hydroxy-proline via more than
reactiona
10 steps.2a From 2h and 2a, pyrrolidine-3-carboxylic acid
NO2
catalyst
(0.2 equiv)
derivatives were also obtained (Scheme 4).
Table 2. Scope of the Michael reaction to afford 2.
O
O
+
CH3NO2
COOEt
solvent
rt
*
COOEt
R3
catalyst F
(0.2 equiv)
NO2
O
1a
2a
O
R4
R3R4CHNO2
+
R1
COOR2
CF3
CH2Cl2
rt, 48 h
*
COOEt
1
COOH
2
N
H
S
A
N
NO2
NO2
COOEt
NO2
N
H
N
H
CF3
N
O
O
O
N
N
NH2
NH2
NH2
F
N
H
F
F
COOEt
N
H
COOEt
N
D
2a
2b
B
F
F
F
2c
with imidazolec
90%, 92% ee
S
with CH3COOHb
0 °C, 5 days
76%, 94% ee
99%, dr 1:1,
90% ee, 93% ee
NH2
Ph
Ph
OTMS
N
H
N
H
N
NH2
H
C
G
E
O
NO2
O
NO2
COOEt
COOEt
2e
85%, 93% ee
NO2
entry
1
2
3
4
catalyst
additive
solvent
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
yield (%)
0
ee (%)
-
-
2d
45 °C, 65%, 92% ee
NO2
A
B
C
D
E
F
F
F
F
F
-
-
-
-
-
-
-
-
NO2
0
7
O
O
O
nd
21
-20
82
85
91
89
94
96
93
94
COOBn
COOtBu
COOiPr
2g
2h
79%, 93% ee
14
10
51
70
63
50
76
40
61
70
2f
72%, 94% ee
(with CH3COOHb 4days,
75%, 97% eed)
with CH3COOHb
75%, 94% ee
5
6
7
NO2
COOEt
NO2
O
O
O
8b
NO2
9b
CH3COOHc
CH3COOHc
CH3COOHc
-
COOBn
COOBn
2i
2j
2k
72%, 90% ee
10b,d
11b,e
12b
13b,d
with CH3COOHb
70%, 96% ee
with CH3COOHb
60%, 95% ee
F
G
G
CH2Cl2
CH2Cl2
a
Conditions: Enone (0.2 mmol), nitroalkane (1.0 mmol), and catalyst F (0.04 mmol) in
CH3COOHc
b
c
d
CH2Cl2 (0.2 mL) at 24 °C for 48 h. CH3COOH (0.04 mmol). Imidazole (0.04 mmol).
a Conditions: Enone (0.2 mmol), nitromethane (1.0 mmol), and catalyst (0.04 mmol) in
b
c
d
Enone 6.4 mmol-scale reaction; ee was determined after transformation to 3.
solvent (0.5 mL) at rt (24 °C) for 48 h. Solvent (0.2 mL). CH3COOH (0.04 mmol).
10 °C for 5 days. e 0 °C for 5 days.
Scheme 2. Expanded scope of the Michael reaction to afford 2.
Next, the scope of the reaction catalyzed by catalyst F was
analyzed (Table 2 and Scheme 2). Various products 2a-2m
were obtained. Although we designed the reactions to work
with simple nitromethame, reactions with various nitroalkanes
also afforded the Michael products. In addition to the 4-
NO2
catalyst F (0.2 equiv)
CH3COOH (0.2 equiv)
O
O
COOEt
+
CH3NO2
COOEt
CH2Cl2
0 °C, 5 days
2a
70%, 94% ee
NO2
catalyst F
O
O
O
O
(0.2 equiv)
oxopent-2-enoates,
4-oxohex-2-enoates
were
effective
+
CH3NO2
CH2Cl2
COOEt
COOEt
COOEt
substrates resulting in formation of 2i and 2j. The ester groups
of the substrates worked in the reaction system included ethyl,
isopropyl, benzyl, and tert-butyl esters (Table 2).9
When the (Z)-isomer of enone 1a was used, product 2 was
obtained with the same degrees of reactivity and
enantioselectivity as in the reaction of the corresponding (E)-
isomer substrate 1a (Scheme 2). During the reaction, the (Z)-
enone was isomerixed to (E)-enone 1a. The resulting (E)-enone
may have reacted to give the product. Products 2l and 2m were
also obtained, but as racemic forms (<5% ee).
45 °C, 48 h
2l 43%
NO2
catalyst F
(0.2 equiv)
+
CH3NO2
CH2Cl2
rt, 48 h
H
H
COOEt
2m 47%
Acyclic β2-amino acid derivatives were also obtained from
the Michael products (Scheme 5). Acetal protection of the
ketone carbonyl group of 2a afforded 6. Using the reported
reduction7h of the nitro group of 6, β2-amino acid derivative 7
can be obtained. Tosylhydrazone derivative 8 was also
Michael products
2 were transformed to pyrrolidine
synthesized. This compound is
a precursor of amino-
derivatives (Schemes 3 and 4). When 2g was treated with Pd/C
under hydrogen, (3R,5R)-5-methylpyrrolidine-3-carboxylic acid
(3)2a was directly obtained in 90% yield with 97% ee (Scheme
3). The absolute configuration of 2g obtained by the Michael
functionalized β2-amino acid derivatives.
Further, the Michal products were transformed to lactam
derivatives 9 (Scheme 6a). From the Michal product of the
2 | J. Name., 2012, 00, 1-3
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reaction of a cyclic nitroalkane, spiropyrrolidine-3-carboxylic
acid derivative 10 was obtained (Scheme 6b).
In conclusion, we have developed organocatalytic
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enatioselective Michael reactions of 4-aDlkOyIl:-1s0u.1b0s3t9it/uCt7eOdB041-4o8x4oH-
2-enoates with nitroalkanes that are useful for the synthesis of
pyrrolidine-3-carboxylic acid derivatives and β2-amino acid
derivatives. Using the Michael reaction method, highly
enantiomerically enriched 5-methylpyrrolidine-3-carboxylic
acid was synthesized in two steps from easily accessible
starting materials.
We thank Dr. Michael Chandro Roy, Research Support
Division, Okinawa Institute of Science and Technology
Graduate University for mass analyses. This study was
supported by the Okinawa Institute of Science and Technology
Graduate University and by the MEXT/JSPS (Japan) Grant-in-
Aid for Scientific Research on Innovative Areas “Advanced
Molecular Transformations by Organocatalysts” (No.
26105757).
Scheme 3. Synthesis of (3R,5R)-5-methylpyrrolidine-3-carboxylic
acid via the Michael reaction to afford 2g.
NO2
catalyst F (0.2 equiv)
CH3COOH (0.2 equiv)
O
O
+
CH3NO2
COOBn
CH2Cl2
COOBn
rt, 4 days
2g 75%
COOH
+
N
HO
CH2
10% Pd/C, H2
-
O
N
H
MeOH
rt
H
N
H
N
3
90%, 97% ee
Ar
COOBn
+
N
H
S
plausible transition state
Scheme 4. Transformation of Michael products 2 to pyrrolidine-3-
carboxylic acid derivatives.
There are no conflicts of interest to declare.
(a)
O
NO2
NO2
COOH
10% Pd/C
H2
O
CF3COOH
Notes and references
1
MeOH
COOtBu
2h 93% ee
COOH
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N
H
3
4
85% (2 steps)
COOEt
1) CbzCl, Et3N, CH2Cl2
2) SOCl2, EtOH
N
5 91%ee
Cbz
(b)
COOEt
NO2
O
1) 10% Pd/C, TsOH, H2, MeOH
2) CbzCl, Et3N, CH2Cl2
COOEt
2a 95% ee
N
5 92%ee
Cbz
(c)
COOEt
COOH
COOH
10% Pd/C
NaOH
EtOH-H2O
H2
MeOH
N
N
N
H
Cbz
Cbz
2
3
3 90% (2 steps)
5 91%ee
Scheme 5. Transformation of 2 to acyclic β2-amino acid derivatives.
OH
NO2
NO2
NH2
HO
O
O
O
O
O
[H]
TsOH
COOEt
COOEt
COOEt
benzene
2a
6 90%
7
TsNH
NO2
COOEt
N
TsNHNH2
MeOH
8 99%
Scheme 6. Transformation of 2 to lactam and spirooyrrolidine
derivatives.
(a)
NO2
NO2
NO2
O
BnNH2
+
O
O
N
N
NaBH(OAc)3
CH2Cl2
COOEt
Bn
Bn
2a
2e
9a 24%
9b 34%
(b)
COOEt
NO2
O
1) 10% Pd/C, TsOH, H2, MeOH
2) CbzCl, Et3N, CH2Cl2
4
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The configuration of 2g generated using catalyst F was
determined to be (R) based on that trans-5-methylpyrrolidine-
3-carboxylic acid (3) synthesized from 2g had a (3R,5R)
configuration (comparison of the [α]D value with that of
previously reported (3R,5R)-32a). Compounds 2a and 2h also
had a (R) configuration; this was confirmed after
transformation to 3 and 5. For compounds 2b, 2c, 2d, 2e, 2i,
2j, and 2k shown in Table 2, the stereochemistry was
tentatively assigned by analogy.
4 | J. Name., 2012, 00, 1-3
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