Asymmetic organocatalytic 1,3-dipolar cycloaddition of azomethine ylide to methyl 2-(2-nitrophenyl)acrylate for the synthesis of diastereoisomers of spirotryprostatin A

Article abstract of DOI:10.1021/ol200652j

Chemical equations presented. The total synthesis of two diastereomers of spirotryprostatin A has been established starting with an asymmetric 1,3-dipolar cycloaddition of methyl 2-(2-nitrophenyl)acrylate with azomethine ylides catalyzed by a Bronsted aci

Full text of DOI:10.1021/ol200652j

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2418–2421
Asymmetic Organocatalytic 1,3-Dipolar
Cycloaddition of Azomethine Ylide to
Methyl 2-(2-Nitrophenyl)acrylate for the
Synthesis of Diastereoisomers of
Spirotryprostatin A
Mou-Nuo Cheng, Hao Wang, 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 March 11, 2011
ABSTRACT
The total synthesis of two diastereomers of spirotryprostatin A has been established starting with an asymmetric 1,3-dipolar cycloaddition of
methyl 2-(2-nitrophenyl)acrylate with azomethine ylides catalyzed by a Brønsted acid.
The spiro[pyrrolidin-3,30-oxindole] unit constitutes a
core structural element prevalent in a large family of
alkaloid natural products exhibiting important bioactivity
profiles and having interesting structural properties.1,2
Spirotryprostatins A and B (Figure 1) were isolated from
the fermentation broth of Aspergillus fumigatus and have
proven to completely inhibit the G2/M progression of cell
division in mammalian tsFT210 cells.3 The unique struc-
ture of these natural compounds has attracted much
attention from synthetic chemists.4 In 2000, Williams
reported the first total synthesis of spirotryprostatin B by
using a chiral auxiliary-induced asymmetric synthesis of
the spiro[pyrrolidin-3,30-oxindole] core skeleton.4c On the
other hand, the significant biological activity has intrigued
intense interest in the development of biologically promis-
ing analogues with improved efficiency and selectivity.5
Danishefsky has found that the configuration of the
stereogenic center of the spirooxindole (C3) moiety
(1) Bindra, J. S. In The Alkaloids, Vol. 14; Manske, R. H. F., Ed.;
Academic Press: New York, 1973; p 84.
(2) For reviews, see: (a) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (b) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209.
(3) (a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651. (b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832.
(4) (a) Edmondson, S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
1998, 37, 1138. (b) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino,
L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147. (c) Sebahar, P. R.;
Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666. (d) Sebahar, P. R.;
Osada, H.; Usui, T.; Williams, R. M. Tetrahedron 2002, 58, 6311. (e) von
Nussbaum, F.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000, 39, 2175.
(f) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685. (g) Overman,
L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39, 4596. (h) Meyers,
C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694. (i) Miyake,
F. Y.; Yakushijin, K.; Horne, D. A. Angew. Chem., Int. Ed. 2004, 43,
5357. (j) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505.
(k) Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763. (l) Onishi, T.;
Sebahar, P. R.; Williams, R. M. Org. Lett. 2003, 5, 3135.
Figure 1. Structures of spirotryprostatin A and B.
r
10.1021/ol200652j
Published on Web 04/12/2011
2011 American Chemical Society

appears to be less important, given the spirotryprostatin
analogies.4b It would be appealing to prepare the diaster-
eoisomers of spirotryprostatin alkaloids to clarify the
effects of the configuration on biological activities.
Scheme 1. Strategy for the Synthesis of Spiro[pyrrolidin-3,
30-oxindole]
Figure 2. Brønsted acids used in this study.
(Figure 2) in dichloromethane at 0 °C (Table 1). However,
none of them afforded a satisfactory cyclization reaction
(entries 1ꢀ4). Encouragingly, the bisphosphoric acid 1e
enabled the reaction to give an excellent enantioselectivity
of 93% ee albeit with a low yield. Elevating the reaction
temperature from 0 to 30 °C rendered the reaction pro-
ceeding in 92% yield and with maintained stereoselectivity
(entry 6). The solvent screening revealed that toluene was
the best media in terms of enantioselectivity (entries 6ꢀ9),
although the yield was slightly lower than that obtained in
dichloromethane. Lowering the catalyst loading resulted
in a slow reaction with a diminished enantioselectivity
(entry 11).
Recently, we established a series of chiral Brønsted acid
catalyzed 1,3-dipolar cycloaddition reactions of azomethine
ylides.6 Encouraged by these achievements, we proposed to
expand the protocol to use methyl 2-(2-nitrophenyl)acrylate
as a substrate, resulting in the generation of pyrrolidines
that are able to undergo a nitro reductive lactamization
reaction7 to afford the spiro[pyrrolidin-3,30-oxindole] unit
that appeared in the spirotryprostatin alkaloids (Scheme 1).
It is noteworthy that although elegant reports describe
catalytic asymmetric 1,3-dipolar cycloaddition reactions of
azomethine ylides to electron-deficient olefins that yield
chiral pyrrolidines,6,8 methyl 2-(2-nitrophenyl)acrylate and
its anologues were seldom successfully involved in highly
enantioselective catalytic variants. Herein we report a chiral
Brønsted acid catalyzed 1,3-dipolar cycloaddition reaction of
methyl 2-(2-nitrophenyl)acrylate with azomethine ylides and
the applications to the enantioselective synthesis of the
diasteromers of spirotryprostatin A.
Table 1. Screening Catalysts and Optimization of Reaction
Conditionsa
At the outset of the study, we examined a reaction
of methyl 2-(2-nitrophenyl)acrylate (4a) with benzalde-
hyde and diethyl 2-aminomalonate in the presence of
structurally diverse binol-based phosphoric acids 1aꢀd
yield
(%)b
ee
entry
catalyst
solvent
CH2Cl2
drc
nd
(%)d
1
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
9e
0
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
12e
tracee
8e
nd
ꢀ2
nd
ꢀ20
93
92
93
92
97
98f
92g
(5) (a) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.;
Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish,
D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130.
(b) Lo, M. M. C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077. (c) Antonchick,
3
nd
4
nd
5
24e
92
nd
6
>50:1
>50:1
>50:1
97:3
nd
€
A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.;
7
73
Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735.
8
ClCH2CH2Cl
toluene
toluene
toluene
65
(6) (a) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem. Soc.
2008, 130, 5652. (b) Liu, W.-J.; Chen, X.-H.; Gong, L.-Z. Org. Lett.
2008, 10, 5357. (c) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-
Z. J. Am. Chem. Soc. 2009, 131, 13819. (d) Yu, J.; He, L.; Chen, X.-H.;
Song, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2009, 11, 4946. (e) Wang,
C.; Chen, X.-H.; Zhou, S.-M.; Gong, L.-Z. Chem. Commun. 2010, 46,
1275. (f) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2010, 12, 4050.
(7) Lawrence, N. J.; Davies, C. A.; Gray, M. Org. Lett. 2004, 6, 4957.
9
85
10
11
87
80
nd
a The reaction was carried out in 0.1 mmol scale in solvent (1 mL)
with 3 A MS (100 mg) at 30 °C for 72 h, and the ratio of 2a/3/4a was 1.2/
1/2. b Isolated yield based on 3. c Determined by 1HNMR. d Ee values
were determined by HPLC analysis. e The reaction was carried at 0 °C.
f 15 mol % of catalyst was used. g 5 mol % of catalyst was used.
ꢀ
(8) For highlights, see: (a) Najera, C.; Sansano, J. M. Angew. Chem.,
Int. Ed. 2005, 44, 6272. For examples, see: (b) Longmire, J. M.; Wang,
B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (c) Gothelf, A. S.;
Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2002, 41, 4236. (d) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc.
€
2003, 125, 10174. (e) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.;
Having the optimized conditions in hand, we next
investigated the scope of aldehydes. As shown in Table 2,
the protocol tolerated a wide range of aldehyde substrates.
Basically, aromatic aldehydes gave higher levels of enan-
tioselectivity than aliphatic ones. The electronic feature of the
substituent on the aryl ring seemingly exerted little effect on
the stereoselectivity. Thus, high levels of enantioselectivity
Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (f)
ꢀ
Cabrera, S.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005,
127, 16394. (g) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.;
Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. (h) Zeng,
W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129,
750. (i) Vicario, J. L.; Reboredo, S.; Badıa, D.; Carrillo, L. Angew.
Chem., Int. Ed. 2007, 46, 5168. (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. Soc. 2010, 132, 5338.
Org. Lett., Vol. 13, No. 9, 2011
2419

Table 2. Scope of Aldehydes of the Asymmetric Three-Com-
ponent 1,3-Dipolar Cycloaddition Reactiona
yield
(%)b
ee
(%)d
entry
5
R
drc
1
5b
5c
5d
5e
5f
4-FC6H4
88
86
81
96
73
80
82
97
80
95
73
77
86
88
75
25
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
>99:1
99:1
99:1
>99:1
99:1
99:1
99:1
99:1
20:1
ꢀ
98
95
97
95
97
97
98
96
97
98
91
96
93
93
>99
74
2
4-MeC6H4
4-CNC6H4
4-MeOC6H4
4-CF3C6H4
4-ClC6H4
3
4
5
6
5g
5h
5i
7
4-BrC6H4
8
2-ClC6H4
9
5j
3-ClC6H4
Figure 3. X-ray structure of 5h.
10
11
12
13
14
15
16
5k
5l
2-Cl, 3-ClC6H4
2-furan
5m
5n
5o
5p
5q
2-thiophene
1-naphthyl
2-naphthyl
2-MeOPhCHdCH
c-C6H11
Table 3. Scope of Olefins of the Asymmetric Three-Component
1,3-Dipolar Cycloaddition Reactionsa
a The reaction was carried out in 0.1 mmol scale in toluene (1 mL)
with 3 A MS (100 mg) at 30 °C for 72 h, and the ratio of 2/3/4a was 1.2/1/
2. b Isolated yield based on 3. c Determined by 1H NMR. d Determined
by HPLC.
were observed for either of the electronically rich, neutral, or
poor aromatic aldehydes (entries 1ꢀ10). Heterocyclic aro-
matic aldehydes such as 2-furancarbaldehyde and 2-thiophe-
nealdehyde participated in smooth cycloaddition reactions in
fairly good yields and excellent enantioselectivities (entries
11ꢀ12). Either R- or β-naphthaldehyde served as a good
substrate to yield 5n or 5o with 93% ee (entries 13ꢀ14).
Significantly, an azomethine ylide generated from an R,
β-unsaturated aldehyde also successfully reacted with 4a in
an excellent enantioselectivity of >99% ee (entriy 15). An
attempt to use an aliphatic aldehyde as the reaction compo-
nent led to a sluggish reaction with moderate enantioselec-
tivity (entry 16). The relative and absolute configurations of 5h
were assigned by X-ray analysis (Figure 3), and the stereo-
chemistry of the other products was assigned by analogy.
The generality for the scope with respect to the substituent
on the phenyl ring of methyl 2-(2-nitrophenyl)acrylates was
finally explored (Table 3). The presence of electronically
withdrawing or donating substituents on the phenyl ring
was nicely tolerated, giving the desired products in high
yields and with excellent levels of stereoselectivity.
yield
(%)b
ee
entry
6
R1
R2
drc
(%)d
1
2
3
4
6a
6b
6c
6d
F
H
96
91
95
80
47:1
48:1
99:1
99:1
93
92
93
95
H
Br
Cl
H
H
MeO
a The reaction was carried out in 0.1 mmol scale in toluene (1 mL)
with 3 A MS (100 mg) at 30 °C for 72 h, and the ratio of 2a/3/4 was 1.2/1/
2. b Isolated yield based on 3. c Determined by 1H NMR. d Determined
by HPLC.
optimized conditions only afforded the desired 9 in a low
yield.9 Interestingly, conducting the reaction under an argon
atmosphere at 40 °C with 5 equiv of 8 gave 9 in 94% yield
and with >99:1 dr and >99% ee. An attempt to perform
reductive lactamization of compound 9 with Zn/HOAc
failed to directly give the spiro[pyrrolidin-3,30-oxindole]
11. On the contrary, the major product revealed that the
hydroxylamine intermediate easily underwent a cyclization
reaction, but it was difficult to cleave the NꢀO bond under
the same reduction conditions. Alternatively, a stepwise
approach to the target molecule 11 ultimately proved
successful. Thus, the reduction of 9 with Zn/HOAc, fol-
lowed by protection of the resultant N-hydroxyoxindole
with BnBr/TEA, and then cleavage of the NꢀO bond with
SmI2 in the presence of water in THF provided 11 in a good
The synthetic potential of the 1,3-dipolar cycloaddition
presented currently is demonstrated in the synthesis of
spirotryprostatin alkaloid derivatives (Scheme 2). Unfor-
tunately, the initial trial in the three-component 1,3-dipolar
cycloaddition of prenyl aldehyde (7), diethyl 2-aminomalo-
nate (3), and methyl 2-(4-methoxy-2-nitrophenyl)acrylate
(8) catalyzed by the bisphosphoric acid (1e) under the
(9) Less than 15% yield was obtained.
2420
Org. Lett., Vol. 13, No. 9, 2011

moiety followed by a subsequent lactamization gave
18-epispirotryprostatin A and 9,18-bis-epispirotryprostatin
A, respectively. The chiral center of 18-epispirotryprostatin
A was assigned the R configuration on the basis of the
observation of a strong NOE interaction between H3 and
H4. However, for the product 9,18-bis-epispirotryprostatin
A, nearly no NOE interaction was observed, thus suggesting
that the corresponding H1 and H2 are in anti-positions.
The biological investigation revealed that the diastereoi-
somers showed similar efficiency in inhibiting MDA MB-
468 cells, but a little lower than natural product, which
suggested that the configuration of C9 and C18 of the
molecule was not the key element in the structureꢀactivity
relationships among spirotryprostatin A.10
Scheme 2. Total Synthesis of 18-Epispirotryprostatin A and
9,18-Bis-epispirotryprostatin A
In summary, we have disclosed a 1,3-dipolar cycloaddi-
tion reaction of azomethine ylides with methyl 2-(2-nitro-
phenyl)acrylate, yielding highly enantioenriched pyrroli-
dine derivatives, which can be readily transformed to the
spiro[pyrrolidin-3,30-oxindole] unit by easily operative re-
actions. The methodology holds great potenial in total
synthesis as demonstrated by its applications to the synth-
esis of diastereoisomers of spirotryprostatin A. Moreover,
the biological evaluation suggested that the configuration
of the stereogenic center of spirooxindole (C9 and C18)
was not the key element affecting the anticancer biological
activity of spirotryprostatin alkaloids.
Acknowledgment. We are grateful for financial support
from NSFC (20732006), the Ministry of Education, and
the Ministry of Health (2009ZX09501-017). We also thank
Min-Zhi Fan at the National Center for Drug Screening
(NCDS) for the biological assay.
overall yield. Ba(OH)2 8H2O performed better than KOH
3
or NaOH in the hydrolysis of 11. Decarboxylation followed
by esterification with SOCl2 in methanol gave 12 with a dr of
1.2:1, which was treated with the acid chloride derived from
N-Boc-L-proline to give 13. Deprotection of the proline
Supporting Information Available. Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) For biological activities, see Supporting Information.
Org. Lett., Vol. 13, No. 9, 2011
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