Biomimetic asymmetric 1,3-dioplar cycloaddition: Amino acid precursors in biosynthesis serve as latent azomethine ylides

Article abstract of DOI:10.1021/ol400983j

The first asymmetric catalytic biomimetic three-component 1,3-dipolar cycloaddition of α-keto esters and benzylamine with electron-deficient olefins, inspired by the transamination of α-keto acids involving pyridoxal phosphate (PLP)-dependent enzymes in biological systems, giving several families of structurally diverse pyrrolidine derivatives in high yields and excellent enantioselectivities (up to 99% ee) under mild conditions is described.

Full text of DOI:10.1021/ol400983j

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Biomimetic Asymmetric 1,3-Dioplar
Cycloaddition: Amino Acid Precursors
in Biosynthesis Serve as Latent
Azomethine Ylides
Chang Guo, Jin Song, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, University of Science and Technology of China, Hefei 230026, China
gonglz@ustc.edu.cn
Received April 9, 2013
ABSTRACT
The first asymmetric catalytic biomimetic three-component 1,3-dipolar cycloaddition of R-keto esters and benzylamine with electron-deficient
olefins, inspired by the transamination of R-keto acids involving pyridoxal phosphate (PLP)-dependent enzymes in biological systems, giving several
families of structurally diverse pyrrolidine derivatives in high yields and excellent enantioselectivities (up to 99% ee) under mild conditions is described.
Five-membered nitrogenous heterocycles, in particular,
pyrrolidines and spirooxindoles, are key structural motifs
prevalent in numerous biologically significant molecules
and natural alkaloids.1 The asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylides with electronically defi-
cient olefins has been accepted as the most straightforward
access to optically active pyrrolidine derivative. The past
decade has witnessed the explosive emergence of excellent
chiral ligands and catalysts capable of affording a highly
enantioselective 1,3-dipolar cycloaddition.2,3 In these re-
actions, the azomethines, serving as the dipole compo-
nents, were exclusively generated from the classical
condensation reaction of amino esters with either alde-
hydes or ketones (Scheme 1a).4 In nature, the biosynthesis
of R-amino acids from R-keto acids via transamination
reactions catalyzed by pyridoxamine phosphate (PLP)-
dependent enzymes suggests that the aldimine intermediates,
analogues of azomethine ylides, could be smoothly gener-
ated from a 1,3-proton shift reaction of ketimines formed
from R-keto acids and corresponding amines (Scheme 1b).5
The recent biomimetic transaminations have led to an
(2) Early reports on chiral metal complex catalyzed 1,3-dipolar cycload-
ditions: (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400. (b) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 4236. Selected examples: (c) Chen,
€
C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (d) Knopfel,
T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew.
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Chem., Int. Ed. 2004, 43, 5971. (e) Cabrera, S.; Arrayas, R. G.; Carretero,
J. C. J. Am. Chem. Soc. 2005, 127, 16394. (f) Yan, X.-X.; Peng, Q.; Zhang,
Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed.
2006, 45, 1979. (g) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am.
Chem. Soc. 2007, 129, 750. (h) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am.
Chem. Soc. 2007, 129, 5364. (i) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita,
Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (j) Wang, C.-J.;
Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250. (k)
Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem.
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Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50, 4893. (q) Hernandez-
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(1) (a) Pearson, W. H. In Studies in Natural Product Chemistry;
Rahman, A., Eds.; Elsevier: New York, 1988, Vol. 1, pp 323ꢀ358. (b)
Bindra, J. S. In The Alkaloids; Manske, R. H. F., Eds.; AcademicPress: New
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r
10.1021/ol400983j
XXXX American Chemical Society

attractive synthesis of optically active amino acids, wherein
the imino esters, precursors of azomethine ylides, existed
as key intermediates.6ꢀ9 Inspired by the biosynthetic
mechanism10 and biomimetic procedures, we proposed
a biomimetic 1,3-dipolar cycloaddition, rendering assem-
bly of R-keto esters, amines and electron-deficient olefins
into pyrrolidine derivatives in a structurally diverse man-
ner (Scheme 1c).
esters with amine turned out to be key element of the
proposed biomimetic 1,3-dipolar cycloaddition (Scheme 1c).
Previously, we demonstrated that chiral phosphoric acids
are excellent catalysts for 1,3-dipolar cycloaddition;11
therefore, we initially investigated if the phosphoric acid
was able to catalyze the transamination of keto esters. The
1H NMR studies on the measurement of a mixture of
diethyl 2-oxomalonate (1a) and 4-nitrobenzylamine (2a)
with 10 mol % of 5a in toluene-d8 indicated that the
transamination proceeded smoothly to give azomethine
ylide at room temperature (Scheme 2).12 These findings
essentially permit the direct use of R-keto esters, the amino
acid precursors, as latent azomethine ylides to participate
in the enantioselective 1,3-dipolar cycloaddition with di-
polarophiles 3 under the catalysis of chiral phosphoric
acids. However, the use of either chiralLewis acids orother
organocatalysts that were typically applied to asymmetric
1,3-dipolar cycloaddition2,3 failed to afford smooth trans-
amination, and thus they are impossible to catalyze the
three-component biomimetic 1,3-dipolar cycloaddition
reaction.
Scheme 1. Design of Bio-mimetic Cycloaddition Reaction
Scheme 2. Brønsted Acid Catalyzed Transamination
As long as azomethine ylides are formed, the 1,3-dipolar
cycloaddition with electronically deficient olefins could
occur in the presence of either organocatalysts or Lewis
acids.2,3 Thus, the identification of an appropriate chiral
catalyst for the efficient transamination process of keto
Consequently, the feasibility of the three-component
biomimetic 1,3-dipolar cycloaddition was explored by
evaluating a reaction of diethyl 2-oxomalonate (1a), 4-nitro-
benzylamine (2a), and dimethyl maleate (3a) in the
presence of 10 mol % of BINOL-derived phosphoric
acids13 at room temperature (Table 1). As expected, the enan-
tioselective cycloaddtion reaction proceeded smoothly to
furnish the desired product 4a in a 62% yield, but with a
low ee value (Table 1, entry 1). As reported previously,11
the structure of the chiral phosphoric acids derived from
BINOL still exerted great impact on the enantioselectivity
(entries 1ꢀ8) and the bisphosphoric acid 6 turned out to be
the best catalyst in terms of the stereochemical outcomes,
capable of delivering 95% ee (Table 1, entry 8). Further
optimization of reaction conditions revealed that the high-
est level of enantioselectivity (98% ee) could be achieved in
DCM at 50 °C (Table 1, entry 11).
ꢀ
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Substituted Benzylamines and the
Electron-Deficient Olefins of the Bio-mimetic
Asymmetric Three-Component 1,3-Dipolar Cycloadditiona
entry
4
R1
R2
R3
R4
yieldb (%) eec (%)
1
4b 3-NO2 COOMe
4c 2-NO2 COOMe
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
80
92
2e
3
76
92
4d 4-CN
4e 4-Br
4f 4-Cl
4g 4-F
COOMe
COOMe
COOMe
COOMe
COOMe
69 (93e)
73
94 (92e)
98
entry
catalyst
conditions
yieldb (%)
eec (%)
4
5e
6
82
99
1
5a
5b
5c
5d
5e
5f
5g
6
toluene, rt, 3 days
toluene, rt, 3 days
toluene, rt, 8 days
toluene, rt, 3 days
toluene, rt, 3 days
toluene, rt, 3 days
toluene, rt, 3 days
toluene, rt, 3 days
toluene, 0 °C, 8 days
CH2Cl2, rt, 8 days
CH2Cl2, 50 °C, 8 days
62
68
93
68
88
69
59
71
-
8
4
2
64
97
7e
8e
9e
10e
11
4h
H
83
92
3
13
10
6
4
4i 4-MeO COOMe
79
96
5
4j 4-NO2
4k 4-NO2
4l 4-NO2
H
H
H
60
94
6
8
OMe
76
93
7
5
Ph OMe
71
94
8
95
-
a
˚
Reactions were carried out on a 0.2 mmol scale with 3 A MS
(300 mg) in the presence of phosphoric acid 6 at 50 °C for 8 days, and the
ratio of 1a/2/3 was 2.0/2.0/10.0. b Isolated yields. c Determined by chiral
high-performance liquid chromatography (HPLC) and the absolute
configuration was determined by comparison with literature data.11
e In toluene.
9
6
10
11
6
70
90
98
98
6
a
˚
Reactions were carried out on a 0.2 mmol scale with 3 A MS
(300 mg) in the presence of phosphoric acid 5 or 6, and the ratio of 1a/2a/3a
was 2.0/2.0/10.0. b Isolated yields. c Determined by chiral high-perfor-
mance liquid chromatography (HPLC), and the absolute configuration
was determined by comparison with literature data.11 rt = room
temperature.
Table 3. Scope of R-Phenyl Keto Esters of the Bio-mimetic
Asymmetric Three-Component 1,3-Dipolar Cycloadditiona
With the optimal conditions in hand, we investigated the
generality for the scope of primary amines and electron-
deficient olefins (Table 2). Significantly, the biomimetic
enantioselective 1,3-dipolar cycloaddition showed excel-
lent substrate generality, which is basically required for the
diversity-oriented synthesis. For example, a wide spectrum
of benzylamine derivatives including those bearing either
electron-withdrawing or electron-donating substituents
could be nicely tolerated and afforded pyrrolidine deriva-
tives with 92ꢀ99% ee (Table 2, entries 1ꢀ8). Moreover,
the exploration of the substrate scope focused on di-
polarophiles revealed that a structurally diverse range
of electronically deficient functionalized olefins, such as
methyl vinyl ketone (MVK, 3j), methyl acrylate (3k) and
2-substituted methyl acrylate (3l) were all able to undergo
the 1,3-dipolar cycloaddition, furnishing the desired pro-
ducts with excellent levels of stereoselectivity (Table 2,
entries 9ꢀ11).
entry
4
R1
C6H5
yieldb (%)
eec (%)
1
4m
4n
4o
4p
4q
4r
90
75
74
78
86
67
91
92
99
90
93
94
2d
3d
4d
5d
6d
4-BrC6H4
4-ClC6H4
4-FC6H4
4-CF3C6H4
3-BrC6H4
a
˚
Reactions were carried out on a 0.1 mmol scale with 3 A MS
(150 mg) in the presence of phosphoric acid 6 at 50 °C for 6 days, and the
ratio of 1/2a/3a was 6.0/4.0/1.0. b Isolated yields. c Determined by chiral
high-performance liquid chromatography (HPLC), and the absolute
configuration was determined by comparison with literature data.11
d Performed at 70 °C.
We next turned our attention to explore the scope and
generality of R-keto esters (Table 3). Although the aryl
R-keto esters 1 are basically less reactive toward the amine
and the corresponding imines are much more difficult to
undergo the transamination than 2-oxomalonate and its
imines, they could also participate in the enantioselective
1,3-dipolar cycloaddition. The variation of the substituent
on phenyl group in the aryl R-keto esters 1 could be
tolerated to give the corresponding pyrrolidine derivatives 4
in high yields and with very high levels of enantioselectivity
(up to 99% ee). It is worth mentioning that the protocol
was amenable to the phenyl R-keto esters bearing either a
bromo or a trifluoromethyl substituent on the benzene ring
to give the corresponding pyrrolidines, which were not
available from previous methods,11 in part due to the
unavailability of the related amino acids (Table 3, entries
2, 5, and 6). In this regard, the current approach presents
some intrinsic advantages over the methods developed
Org. Lett., Vol. XX, No. XX, XXXX
C

potential of this transformation as a privileged tool, a
biomimetic enantioselective organocatalytic approach to
rapidly access spirooxindole derivatives was described.
The catalyst screening and optimization of conditions were
carried out again for the three-component 1,3-dipolar
cycloaddition reaction of R-keto esters, benzylamine, and
methyleneindolinones 7. The highest enatioselectivity of
spirooxindole derivatives was obtained from the reaction
conducted in the presence of 3,30-β-naphthyl phosphoric
acid 5a. A structurally diverse collection of spiro-
[pyrrolidin-3,30-oxindole] derivatives 8 were obtained in
excellent yields and enantioselectivities (Figure 1).11b In-
deed, the protocol provides a significant opportunity for
the diversity-oriented synthesis of oxindoles containing
quaternary stereogenic centers.
In conclusion, we have developed a highly efficient, so
far unique, biomimetic diversity-oriented synthesis of a
pyrrolidinederivativecollection. This relieson thestrategic
use of phosphoric acid catalyzed biomimetic transamina-
tion of keto esters and amines, the precursors of amino
acids, to in situ generate azomethine ylides, which readily
participated in a highly enantioselective 1,3-dipolar cy-
cloaddition with a structurally diverse range of dipolaro-
philes. As a result, highly functionalized pyrrolidines and
spirooxindole derivatives were obtained with excellent
enantioselectivities. Considering the easier accessibility of
R-keto esters than the corresponding amino esters, the
unique biomimetic protocol will be more promising for
the synthesis of pyrrolidine derivatives in structural
diversity than the traditional 1,3-dipolar cycloaddition
reactions. In addition, these findings also open a win-
dow for the development of new Brønsted acid-catalyzed
stereoselective cycloaddition reactions involving ketimine
intermediates.
Figure 1. Biomimetic asymmetric three-component 1,3-dipolar
cycloaddition for the synthesis of spirooxindole derivatives. (a)
˚
Reactions were carried out on a 0.1 mmol scale with 3 A MS
(150 mg) in the presence of phosphoric acid 5a at room
temperature for 2ꢀ3 days, and the ratio of 1a/2/7 was 1.2/1.0/2.0.
(b) Isolated yields. (c) Determined by chiral high-performance
liquid chromatography (HPLC), and the absolute configura-
tion was determined by comparison with literature data.11
(d) Performed at 50 °C.
Acknowledgment. We are grateful for financial support
from NSFC (21232007), MOST (973 program 2009CB-
825300), and the Ministry of Education.
Supporting Information Available. Detailed experimen-
tal details, compound characterization data, and spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
previously for constructing five-membered heterocyclic
rings from R-phenylglycine esters.
To demonstrate the pivotal influence of various phos-
phoric acids on catalytic activity and to further expand the
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX