Facile synthesis of enantioenriched Cγ-tetrasubstituted α-amino acid derivatives via an asymmetric nucleophilic addition/protonation cascade

Article abstract of DOI:10.1021/ol200550y

Chemical equations presented. An asymmetric nucleophilic addition/protonation reaction of 3-substituted oxindoles and ethyl 2-phthalimidoacrylate has been described. This strategy can give direct access to C^γ-tetrasubstituted α-amino acid derivatives bearing 1,3-nonadjacent stereocenters with up to 98% yield, 94:6 dr, and >99% ee. Dual activation is proposed in the transition state, and the opposite enantiomers can be obtained simply by changing cinchonidine-derived catalyst to the cinchonine analogue.

Full text of DOI:10.1021/ol200550y

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2290–2293
Facile Synthesis of Enantioenriched
Cγ-Tetrasubstituted r-Amino Acid
Derivatives via an Asymmetric Nucleophilic
Addition/Protonation Cascade
Shu-Wen Duan, Jing An, Jia-Rong Chen,* and Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
wxiao@mail.ccnu.edu.cn; jiarongchen2003@yahoo.com.cn
Received March 1, 2011
ABSTRACT
An asymmetric nucleophilic addition/protonation reaction of 3-substituted oxindoles and ethyl 2-phthalimidoacrylate has been described. This
strategy can give direct access to Cγ-tetrasubstituted R-amino acid derivatives bearing 1,3-nonadjacent stereocenters with up to 98% yield, 94:6
dr, and >99% ee. Dual activation is proposed in the transition state, and the opposite enantiomers can be obtained simply by changing
cinchonidine-derived catalyst to the cinchonine analogue.
Cγ-Tetrasubstituted R-amino acid derivatives are struc-
tural motifs often found in a number of natural products
and medicinally important agents.1 For instance, (þ)-
alantrypinone1d,e and (ꢀ)-serantrypinone1c,d have been
shown to be effective insecticidal reagents against green
peach aphids, while mollenine A1f has been proven to have
cytotoxic and antibacterial activity (Figure 1). As a result,
the development of methods for the catalytic asymmetric
construction of Cγ-tetrasubstituted R-amino acids and their
derivatives is of widespread interest in synthetic organic
chemistry.2 In contrast to the facile construction of CR- and
Cβ-tetrasubstituted R-amino acids,3,4 the de novo synthesis
of Cγ-tetrasubstituted R-amino acids is much more difficult,
especially the one bearing 1,3-nonadjacent stereocenters
with control of absolute stereochemistry.5 Very recently,
an elegant formal [3 þ 2] cycloaddition reaction of C(3)-
substituted indoles with 2-amidoacrylates was developed by
Reisman and co-workers representing, to our knowledge,
the first successful one-step strategy to pyrroloindolines
containing Cγ-tetrasubstituted R-amino acid motifs with
excellent stereoselectivities.6
(1) For selective examples, see: (a) Crich, D.; Banerjee, A. Acc. Chem.
Res. 2007, 40, 151. (b) Marti, M.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 11505. (c) Larsen, T. O.; Petersen, B. O.; Duus, J. Ø.;
Sørensen, D.; Frisvad, J. C.; Hansen, M. E. J. Nat. Prod. 2005, 68,
871. (d) Kuritama, T.; Kakemoto, E.; Takehashi, N.; Imamura, K.-I.;
Oyama, K.; Suzuki, E.; Harimaya, K.; Yaguchi, T.; Ozoe, Y. J. Agric.
Food Chem. 2004, 52, 3884. (e) Hart, D. J.; Magomedov, N. A. J. Am.
Chem. Soc. 2001, 123, 5892. (f) Wang, H.-J.; Gloer, J. B.; Wicklow,
D. T.; Dowd, P. F. J. Nat. Prod. 1998, 61, 804.
(2) Selected examples for the stereoselective synthesis of Cγ tetra-
substituted R-amino acid derivatives: (a) Takiguchi, S.; Iizuka, T.;
Kumakura, Y.; Murasaki, K.; Ban, N.; Higuchi, K.; Kawasaki, T. J.
Org. Chem. 2010, 75, 1126. (b) Trzupek, J. D.; Lee, D.; Crowley, B. M.;
Marathias, V. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 8506.
(c) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008,
10, 4009. (d) Goundry, W. R. F.; Lee, V.; Baldwin, J. E. Synlett 2006, 15,
2407. (e) Lam, H. W.; Murray, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743.
Figure 1. Examples of biologically important molecules con-
taining Cγ-tetrasubstituted R-amino acid motifs.
r
10.1021/ol200550y
Published on Web 04/06/2011
2011 American Chemical Society

On the other hand, asymmetric cascades or domino
reactions, which combine two or more reactions together,
are highly efficient pathways that allow the synthesis of
complex molecules from simple substrates.7 Different from
a stepwise strategy toward a target molecule, this process
represents an advance of synthetic efficiency, operational
simplicity, and atom economy. As part of our recent research
program to develop new cascade methodologies,8 we envi-
saged that the enantioselective nucleophilic addition/diaster-
eoselective protonation between prochiral trisubstituted
nucleophiles and R-aminoacrylates would probably be a
potential method to achieve Cγ-tetrasubstituted R-amino acid
derivatives.9ꢀ11 However, there are two problems that possi-
bly counteract the success of this process, including: (1) the
steric hindrance for the formation of the quaternary stereo-
center and (2) the difficulty in diastereoselectivity control
during asymmetric protonation. Owing to the significance of
Cγ-tetrasubstituted R-amino acid derivatives and in continua-
tion from our recent investigation on unnatural amino
acids,12 we present herein an enantioselective nucleophilic
addition/diastereoselective protonation cascade between a
wide range of C(3)-substituted oxindoles13 and ethyl 2-phtha-
limidoacrylate, affording Cγ-tetrasubstituted R-amino acid
derivatives bearing 1,3-nonadjacent stereocenters in one pot.
By giving high stereoselectivities (up to 94:6 dr and >99% ee)
with easily accessible thiourea as the catalyst under opera-
tionally simple conditions, the current reaction provides a
complementary method to a series of unnatural amino acids
with excellent structural diversity. Notably, the procedure
allows the construction of the opposite enantiomers by
changing the cinchonidine-derived thiourea catalyst to its
cinchonine analogue.
In view of the fact that the reaction of 3-phenyloxindole
1a and ethyl 2-phthalimidoacrylate 2 catalyzed by tetra-
methylguanidine (TMG) proceeded very quickly at room
temperature to give the racemic compounds, our investiga-
tion started with the screening of various kinds of chiral
tertiary amine catalysts. Although only trace amounts of the
Michael adduct were obtained using Takemoto’s catalyst or
the cinchonine-derived catalyst II after 5 days on the basis of
TLC analysis (Table 1, entries 1 and 2), the chiral multi-
hydrogen bonding catalyst III could give the desired product
in moderate yield with moderate stereoselectivities (Table 1,
entry 3). Encouraged by these results, we surveyed the more
basic cinchona-derived thioureas for this reaction.
ꢀ
(3) Forareview, see:(a)Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107,
4584. For recent examples, see: (b) Arai, T.; Mishiro, A.; Yokoyama, N.;
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Jautze, S.; Frey, W.; Peters, R. J. Am. Chem. Soc. 2010, 132, 12222. (d) Alba,
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A.-N. R.; Companyo, X.; Valero, G.; Moyano, A.; Rios, R. Chem.;Eur. J.
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Liu, X.-F.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (c) Wang, Y.; Liu,
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As shown in Table 1, IV was found to be the best catalyst
to give the Cγ-tetrasubstituted R-amino acid derivative 3a
with good stereoselectivity and yield after 10 h at room
temperature (Table 1, entry 4). These results indicated that
a cinchona alkaloid proved suitably basic to enolize the
3-phenyloxindole; the thiourea moiety was indispensable to
activate the ethyl 2-phthalimidoacrylate. Significantly, sim-
ply by changing catalyst from cinchonidine-derived thiourea
to its cinchonine analogue, the opposite enantiomer could
be produced with even slightly better diastereoselectivity
(Table 1, entry 5, 94:6 dr, 93% ee). Further optimization of
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Org. Lett., Vol. 13, No. 9, 2011
2291

Table 1. Conditions Optimizationa
Table 2. Substrate Scope Examinationa
entry
R
R1
yieldb (%)
3a
drc
eec (%)
1
2
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
93
95
90
93
96
96
94
96
95
94
93
98
94
95
95
96
94
95
94
92
94
93
90
91:9
94
93
93
95
96
97
97
98
97
98
97
97
96
97
95
>99
>99
95
94
93
>99
98
87
ent-3a
3b
94:6
3
5-Me
5-F
5-Br
5-OCF3
6-Cl
6-Br
7-F
H
89:11
93:7
4
ent-3b
3c
entry
cat.
solvent
time
yieldb (%)
drc
eec (%)
5
91:9
6
ent-3c
3d
90:10
89:11
93:7
91:9d
93:7d
92:8
1
2
I
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
Et2O
5 d
trace
trace
79
7
II
5 d
8
ent-3d
3e
3
III
IV
V
3 d
67:33
91:9
75
95
ꢀ93
84
95
94
0
9
4
10 h
10 h
3 d
93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
ent-3e
3f
5
95
94:6
6
IV
IV
IV
IV
IV
IV
IV
63
64:36
74:26
89:11
54:46
58:42
92:8
ent-3f
3g
93:7
7
16 h
16 h
24 h
10 h
16 h
16 h
92
90:10
94:6
8
xylenes
DMF
93
ent-3g
3h
9
94
93:7
10
11d
12e
DMSO
PhMe
PhMe
99
0
ent-3 h
3i
93:7
88
92
97
4-FPh
4-MePh
2-naphth
Bn
90:10
93:7
92
85:15
ent-3i
3j
a The reaction was carried out with 1a (0.24 mmol), 2 (0.2 mmol), and
H
89:11
92:8
91:9d
91:9d
52:48
cat. (0.02 mmol) in solvent (1.0 mL) at rt. b Isolated yield. c Determined by
ent-3j
3k
chiral HPLC. d 10 equiv of H2O was added. e 30 mg of 4 A MS was added.
˚
H
ent-3k
ent-3 L
H
the reaction medium revealed that less polar solvents, such as
toluene and xylenes, were superior to polar solvents which
dramatically depressed the selectivity (Table 1, entries 9ꢀ10).
Water had little effect on this asymmetric procedure, since
a The reaction was carried out with 1 (0.24 mmol), 2 (0.2 mmol), and
IV or V (0.02 mmol) in PhMe (1.0 mL) at rt. b Isolated yield. c Deter-
mined by chiral HPLC analysis unless noted. d Determined by 1H NMR.
˚
using H2O or 4 A MS as an additive gave comparable results
regarding the yields and stereoselectivities (Table 1, entries 11
and 12).
could also provide the desired product 3l in 90% yield with
good enantioselectivity, although with a prolonged reac-
tion time (Table 2, entry 23). Furthermore, the absolute
configuration of the 1,3-nonadjacent stereocenters was
confirmed to be (S,R) by X-ray crystallographic analysis
of 3d (Figure 2). On the basis of this observation, we
proposed a dual activation model for the transition state,
wherein the Michael donor was enolized by a tertiary
amine and the thiourea motif directed the Michael accep-
tor through a hydrogen bonding interaction.14 The enolic
Michael donor approached the acceptor with its Si face
The scope of this cascade reaction was then investigated
with IV and V as the catalysts under optimized conditions.
As summarized in Table 2, this procedure provided a facile
approach to a range of Cγ-tetrasubstituted R-amino acid
derivatives with the generation of 1,3-nonadjacent stereo-
centers in high enantiomeric excess. The stereoselectivity
was found to be nearly independent of the electronic
properties of the oxindoles. Consistently high diastereos-
electivities (89:11 to 94:6 dr) and enantioselectivities (93 to
>99% ee) were observed for both the electron-rich and
electron-deficient 3-aryl oxindoles. The reactions com-
pleted within 2 h for a series of oxindoles substituted with
electron-withdrawing groups at the C5ꢀC7 positions
(Table 2, entries 3ꢀ16). Importantly, different aryl groups
at the C3 position, including the 4-Me phenyl, 4-F phenyl,
and 2-naphthyl groups, could be well tolerated, and ex-
cellent enantioselectivities (93 to >99% ee) for both
enantiomers were achieved in the presence of IV or V
(Table 2, entries 17ꢀ22). Notably, the 3-benzyloxindole
(14) For reviews, see: (a) Connon, S. J. Synlett 2009, 354. (b) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (c) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (d) Connon, S. J.
Chem.;Eur. J. 2006, 12, 5418. (e) Tian, S.-K.; Chen, Y.; Hang, J.; Tang,
L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. For selected
examples, see:(f) Zu, L.-S.; Wang, J.; Li, H.; Xie, H.-X.; Jiang, W.;
Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (g) Berkessel, A.;
€
Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem.,
Int. Ed. 2005, 44, 807. (h) McCooey, S. H.; Connon, S. J. Angew. Chem.,
ꢀ
ꢀ
Int. Ed. 2005, 44, 6367. (i) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T.
Org. Lett. 2005, 7, 1967. (j) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.;
Ding, L.-S.; Wu, Y. Synlett 2005, 603. (k) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun 2005, 4481.
2292
Org. Lett., Vol. 13, No. 9, 2011

Scheme 1. Derivatization of the Cascade Adduct 3a
Figure 2. Absolute configuration of 3d and proposed transition
state.
In conclusion, we have developed a novel procedure to
achieve both enantiomers of Cγ-tetrasubstituted R-amino
acid derivatives with high stereoselectivities and yields.
This strategy allows for rapid and facile access to a series
of unnatural amino acids bearing 1,3-nonadjacent stereo-
centers through an enantioselective nucleophilic addition/
distereoselective protonation cascade under operationally
simple conditions.
followed by diastereoselective protonation to give the
corresponding chiral product.
The significance of this nucleophilic addition/asym-
metric protonation cascade reaction was demonstrated in
the synthesis of Cγ-tetrasubstituted R-amino acids from
the adducts. As shown in Scheme 1, a gram-scale reaction
of tert-butyl 2-oxo-3-phenylindoline-1-carboxylate 1a
with ethyl 2-phthalimidoacrylate 2 was accomplished in
90% yield with 89:11 dr and 95% ee using IV within 10 h.
The major diastereoisomer was then separated by SiO2
chromatography. The deprotection of of the adduct 3a
afforded 4 in 97% yield, which was directly converted to 5
through a sequential hydrazinolysis and acylation in order
to avoid unnecessary purification. The hydrolysis of 5
provided 6 in high yield without loss in optical purity,
which was confirmed by HPLC analysis of its correspond-
ing ester 7. In addition, the synthesis of pyrroloindoline
natural product 8 starting from this kind of Cγ-tetrasub-
stituted R-amino acid derivatives is currently underway.
Acknowledgment. We are grateful to the National
Science Foundation of China (NO. 20872043, 21072069
and 21002036), the National Basic Research Program of
China (2011CB808600), and the Program for Changjiang
Scholars and Inovation Research Team in University
(IRT0953) for support of this research.
Supporting Information Available. Experimental pro-
cedures and compound characterization data including
X-ray crystal data (CIF) for 3d. This material is available
free of charge via the Internet at http://pubs.acs.org
Org. Lett., Vol. 13, No. 9, 2011
2293