The catalytic asymmetric 1,3-dipolar cycloaddition of ynones with azomethine ylides

Article abstract of DOI:10.1021/ol201898x

The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbon-carbon triple bonds with azomethine ylides has been established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in perfect enantioselectivities of up to >99% ee.

Full text of DOI:10.1021/ol201898x

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4680–4683
The Catalytic Asymmetric 1,3-Dipolar
Cycloaddition of Ynones with
Azomethine Ylides
Feng Shi,†,§ Shi-Wei Luo,‡ Zhong-Lin Tao,‡ Long He,‡ Jie Yu,‡ Shu-Jiang Tu,†,§ and
Liu-Zhu Gong*,‡
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou,
221116, China, Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry, University of Science and Technology of China, Hefei,
230026, China, and College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou, 215000, China
gonglz@ustc.edu.cn
Received July 13, 2011
ABSTRACT
The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbonꢀcarbon triple bonds with azomethine ylides has been
established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in
perfect enantioselectivities of up to >99% ee.
Recent decades have witnessed the great importance of
1,3-dipolar cycloaddition in organic chemistry.1 Particu-
larly, those of azomethine ylide dipoles with unsaturated
carbonꢀcarbon bonds represent important processes in
organic synthesis and their enantioselective versions have
offered a robust method to access chiral pyrrolidine struc-
tural motifs, which present frequently in natural alkaloids
and artificial molecules with vital bioactivities.2 Conse-
quently, elegant developments have been described in the
field of asymmetric 1,3-dipolar cycloadditions of azo-
methine ylides to electron-deficient olefins by using either
chiral metal-based catalysts3 or organocatalysts (eq 1).4
However, more than 40 years after Huisgen pioneered the
1,3-dipolar cycloaddition,5 no catalytic asymmetric var-
iants have been found for the electronically poor car-
bonꢀcarbon triple bond dipolarophiles (eq 2). More
surprisingly, even racemic 1,3-dipolar cycloadditions of
azomethine ylides with alkynes are rather limited with the
exception of a few intramolecular versions, which have
sporadically been described in past decades.2bꢀe,6 Thus,
this transformation, in particular, its enantioselective ver-
sion, has remained a formidable challenge.
The 2,5-dihydropyrrole skeleton, which can be con-
structed by 1,3-dipolar cycloaddition of azomethine ylides
with alkynes, not only constitutes the core structural
element of many natural alkaloids7 but also serves as a
key building block for a variety of natural products.8 More
importantly, a number of 2,5-dihydropyrrole derivatives
exhibit important bioactivities such as antioxidant,9
antitumor,10 anti-inflammatory,11 andquinone-dependent
amine oxidase inhibitory activity.12 The significance of 2,5-
dihydropyrrole motifs relevant to synthetic and medicinal
† Xuzhou Normal University.
§ Soochow University.
‡ University of Science and Technology of China.
r
10.1021/ol201898x
Published on Web 08/09/2011
2011 American Chemical Society

applications has led to a demand for efficient synthesis of
related compounds, especially those with high enantios-
electivity. We have recently established a series of 1,3-
dipolar cycloadditions between azomethine ylides and
electron-deficient olefins in excellent enantioselectivity
using chiral phosphoric acids as catalysts wherein a chiral
Brønsted acid bonded dipole is involved.13 Encouraged by
this success and in view of no enantioselective version of
the 1,3-dipolar cycloadditions of alkynes with azomethine
ylides as well as the importance of 2,5-dihydropyrroles, we
decided to use a chiral Brønsted acid14 to control the
stereoselectivity of the titled reaction. Herein, we report
the first asymmetric version of this reaction with exquisite
levels of enantioselectivity (up to >99% ee).
achieved in toluene (entry 8). More significantly, an ex-
quisite level of enantioselectivity of >99%eewas observed
for the reaction involving 1-phenylprop-2-yn-1-one (2b), but
the yield turned out to be moderate (entry 9). The presence of
excess amounts of 3a enabled the reaction to give a higher
yield with a maintained enantioselectivity (entry 10 vs 9).
With optimal conditions in hand, we then explored the
generality for aldehydes by reaction with 1-phenylprop-2-
yn-1-one (2b) and 2-aminomalonate (4a). As shown in
Table 2, the protocol is amenable to a wide scope of
aromatic aldehydes including electronically poor and rich
ones in excellent enantioselectivities (entries 1ꢀ9). Basi-
cally, benzaldehydes substituted with an electronically
withdrawing group at the para-position gave perfect
stereoselectivities (entries 1, 4, and 5, up to >99% ee).
The position of the substituent of benzaldehydes appeared
to exert some impact on the stereoselectivity (entries 1ꢀ3).
Importantly, even if electronically rich benzaldehydes
were applied, a high enantioselectivity could also be
delivered as exemplified by the reaction with 4-methox-
ylbenzaldehyde (entry 8). Moreover, disubstituted ben-
zaldehyde appeared to be an excellent substrate, offering a
perfect enantioselecitvity of >99% ee (entry 9). It is
noteworthy that heteroaromatic aldehyde and aliphatic
aldehyde can also be applied to this reaction with high
enantioselectivity (entries 10 and 11).
Table 1. Screening of Catalyst and Optimization of Conditionsa
The substrate scope with respect to ynones 2 was next
explored by reaction with either electronically poor or rich
benzaldehydes (Table 3). Both aliphatic and aromatic
ynones were capable of undergoing the reaction with
high to excellent enantioselectivities, while the former gave
a lower enantioselectivity (94% ee) than the aromatic
ones (entry 9 vs 1ꢀ4). When 4-nitrobenzaldehyde was
entry
5
1
solvent
yield (%)b
ee (%)c
1
2
5aaa
5aaa
5aaa
5aaa
5aaa
5aaa
5aaa
5aaa
5baa
5baa
1a
1b
1c
1d
1e
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
77
75
91
73
65
79
76
74
62
69
<5
7
3
<5
<5
<5
13
4
5
6
7
1f
26
ꢀ
(3) For highlights, see: (a) Najera, C.; Sansano, J. M. Angew. Chem.,
8
1f
toluene
toluene
toluene
94
Int. Ed. 2005, 44, 6272. Early reports:(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.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2002, 41, 4236. Selected examples:(d) Chen, C.; Li, X.; Schreiber, S. L.
9
1f
>99
>99d
10
1f
a The reaction was carried out in 0.1 mmol scale in solvent (1 mL)
€
J. Am. Chem. Soc. 2003, 125, 10174. (e) Knopfel, T. F.; Aschwanden, P.;
Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed.
ꢀ
˚
with 3 A MS (100 mg) for 12 h (2a) or 36 h (2b), and 2/3a/4a was
2.5/1.2/1. b Isolated yield. c Determined by HPLC. d 2b/3a/4a was 2.5/2/1.
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) Saito, S.; Tsubogo, T.; Kobayashi, S.
J. Am. Chem. Soc. 2007, 129, 5364. (j) Tsubogo, T.; Saito, S.; Seki, K.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (k)
Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130,
17250. (l) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H.
J. Am. Chem. Soc. 2010, 132, 5338. (m) Padilla, S.; Tejero, R.; Adrio, J.;
Carretero, J. C. Org. Lett. 2010, 12, 5608. (n) Zhang, C.; Yu, S.-B.; Hu,
X.-P.; Wang, D.-Y.; Zheng, Z. Org. Lett. 2010, 12, 5542. (o) Yamashita,
Y.; Guo, X.-X.; Takashita, R.; Kobayashi, S. J. Am. Chem. Soc. 2010,
132, 3262. (p) Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S. Org. Lett.
2010, 12, 1752. (q) Robles-Machin, R.; Gonzalez-Esguevillas, M.;
Adrio, J.; Carretero, J. C. J. Org. Chem. 2010, 75, 233. (r) Robles-
Machin, R.; Alonso, I.; Adrio, J.; Carretero, J. C. Chem.;Eur. J. 2010,
16, 5286. (s) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.;
Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897. (t) Yamashita, Y.;
Imaizumi, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2011, 50, 4893.
At the outset of our study, we conducted a reaction of
3-butynone (2a) and diethyl 2-aminomalonate (4a) with
4-nitrobenzaldehyde (3a) in dichloromethane at room
temperature in the presence of 10 mol % of chiral phos-
phoric acids 1. However, the preliminary screening of the
catalysts led to disappointing results (Table 1, entries 1ꢀ6).
To our delight, the screening of solvents revealed that
nonpolar solvents appeared to be more suitable for the
reaction and a high enantioselectivity of 94% ee could be
(1) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products;
John Wiley & Sons, Inc.: New York, 2002.
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J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. (d)
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Org. Lett., Vol. 13, No. 17, 2011
4681

Table 2. Scope of Aldehydesa
Scheme 1. Reaction Using R-Aryl Amino Ester As Substrate
and Absolute Configuration of Products
entry
5
R (3)
yield (%)b
ee (%)c
1
5baa
5bba
5bca
5bda
5bea
5bfa
5bga
5bha
5bia
5bja
5bka
4-NO2C6H4 (3a)
3-NO2C6H4 (3b)
2-NO2C6H4 (3c)
4-BrC6H4 (3d)
4-CNC6H4 (3e)
Ph (3f)
69
57
80
79
78
76
43
73
67
82
41d
>99
>99
91
2
3
4
99
5
98
6
97
7
2-Naphthyl (3g)
4-MeOC6H4 (3h)
3,4-Cl2C6H3 (3i)
2-Thiophenyl (3j)
Isopropyl (3k)
98
8
94
9
>99
86
81d
configuration of products 5 was assigned to be 5S by X-ray
structures of compounds 5aaa and 6 (>99% ee’s after
recrystallization),15 which was derived from benzoylation
of 5bab in 79% yield (Scheme 1).
To understand the stereochemistry experimentally ob-
served, theoretical calculations were performed on the
transition state (TS) of the 1f-catalyzed 1,3-dipolar cy-
cloaddition of ynone 2b to the azomethine ylide by the
hybrid density functional theory (DFT) method.16 The
10
11
a The reaction was carried out in 0.1 mmol scale in toluene (1 mL)
with 3 A MS (100 mg) for 36 h, and 2b/3/4a was 2.5/2/1. b Isolated yield.
ꢀ
˚
c Determined by HPLC. d Performed for 72 h.
employed, the substitution pattern on the aryl group of 2
has very little impact on the stereoselectivity (entries 1ꢀ4).
Electronically poor, neutral, rich or heteroaromatic ynones
(2cꢀ2f) gave perfect enantioselectivities (entries 1ꢀ4,
>99% ee’s). When 4-methoxybenzaldehyde was used as
the reaction component, the diminished ee’s were observed
for different 1-arylprop-2-yn-1-ones 2 in comparison with
those obtained in cases involving 4-nitrobenzaldehyde, but
still reached high levels of enantioselectivity of up to 94%
ee (entries 5ꢀ8).
(5) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(6) For closely related intramolecular 1,3-dipolar addition of carbon-
carbon triple bonds with imine azomethine ylides: (a) Bashiardes, G.;
Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2003, 44, 8417. (b)
Armstrong, P.; Grigg, R.; Jordan, M. W.; Malone, J. F. Tetrahedron
1985, 41, 3547. (c) Tsuge, O.; Ueno, K.; Oe, K. Chem. Lett. 1979, 1407.
(d) Tsuge, O.; Ueno, K. Heterocycles 1983, 20, 2133. For related
reactions involving iminium azomethine ylides:(e) Vedejs, E.; Grissom,
J. W. J. Am. Chem. Soc. 1988, 110, 3238. (f) Vedejs, E.; Dax, S.;
Martinez, G. R.; McClure, C. K. J. Org. Chem. 1987, 52, 3470. (g)
Huisgen, R.; Niklas, K. Heterocycles 1984, 22, 21. (h) Katritzky, A. R.;
Yeung, W. K.; Patel, R. C.; Burgess, K. Heterocycles 1983, 20, 623.
(7) (a) Fattorusso, E.; Taglialatela-Scafati, O. Modern alkaloids:
structure, isolation, synthesis and biology; WILEY-VCH Verlag GmbH &
Co. KGaA: Weinheim, 2008. (b) Carmeli, S.; Moore, R. E.; Patterson,
G. M. L. Tetrahedron 1991, 47, 2087.
Table 3. Scope of Ynonesa
€
(8) (a) Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (b)
Ritthiwigrom, T.; Willis, A. C.; Pyne, S. G. J. Org. Chem. 2010, 75,
815. (c) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731. (d)
Cinquin, C.; Bortolussi, M.; Bloch, R. Tetrahedron 1996, 52, 6943.
(9) Krishna, M. C.; DeGraff, W.; Hankovszky, O. H.; Sar, C. P.;
Kalai, T.; Jeko, J.; Russo, A.; Mitchell, J. B.; Hideg, K. J. Med. Chem.
1998, 41, 3477.
(10) Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1987, 30, 2144.
(11) Sugden, J. K.; Tavakoli Saberi, M. R. Eur. J. Med. Chem. 1979,
14, 189.
(12) Lee, Y.; Ling, K.-Q.; Lu, X.; Silverman, R. B.; Shepard, E. M.;
Dooley, D. M.; Sayre, L. M. J. Am. Chem. Soc. 2002, 124, 12135.
(13) (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.
(14) For a Brønsted acid catalyzed 1,3-diploar addition of nitrones:
(a) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed.
2008, 47, 2411. For reviews:(b) Akiyama, T. Chem. Rev. 2007, 107, 5744.
(c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (d) Terada,
M. Chem. Commun. 2008, 4097. (e) Terada, M. Synthesis 2010, 1929.
(15) CCDC 824305 for compound 5aaa, CCDC 824305 for com-
pound 6. See the Supporting Information for details.
entry
5
R1
3
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
5caa
5daa
5eaa
5faa
5cha
5dha
5eha
5fha
5aaa
4-FC6H4 (2c)
3a
3a
3a
3a
3h
3h
3h
3h
3a
64d
61e
50
>99d
>99e
>99
>99
90
4-MeOC6H4 (2d)
2-Naphthyl (2e)
2-Thiophenyl (2f)
4-FC6H4 (2c)
69
72
4-MeOC6H4 (2d)
2-Naphthyl (2e)
2-Thiophenyl (2f)
CH3 (2a)
78
94
55
91
88
74f
83
94f
a The reaction was carried out in 0.1 mmol scale in toluene (1 mL)
with 3 A MS (100 mg) at rt for 36 h, and 2/3/4a was 2.5/2/1. b Isolated
ꢀ
˚
yield. c Determined by HPLC. d Performed at 50 °C for 58 h. e Performed
at 50 °C for 84 h. f Performed for 12 h and 2a/3a/4a was 2.5/1.2/1.
(16) The calculations were performed with the Gaussian 03 program:
Frisch, M. J. et al. Gaussian 03, revision D.01; Gaussian, Inc.: Wallingford,
CT, 2004 (for complete ref 16, see Supporting Information)
More interestingly, R-aryl amino esters proved to be a
reactivecomponent and affordedhigh enantioselectivity as
exemplified by 4b (Scheme 1). In addition, the absolute
(17) The details on bioscreen of 5 are in the Supporting Information.
4682
Org. Lett., Vol. 13, No. 17, 2011

BINOL-derived phosphoric acid 1f again served as a
Brønsted acid/Lewis base bifunctional catalyst13c to accel-
erate the cycloaddition between the ynone and the azo-
methine ylide by H-bonding interactions. Basically, the
located TS structures (Figure 1) indicated that the triple
bond of ynones would become more electron-deficientby a
H-bond formed between the carbonyl oxygen of the ynone
and the phosphoric OH of the catalyst to render the
β-carbon more electrophilic and, simultaneously, the car-
bon anion of the dipole of azomethine ylide would become
more reactive due to the H-bonding interaction between
the HꢀN of the ylide and the Lewis basic phosphoryl
oxygen.13c Such a dual activation mode facilitates a
smooth conjugate addition of the azomethines to the
ynones as shown in Ts-I, wherein the predicted forming
bond distances indicated this conjugate addition step
occurs much earlier than the Mannich-type reaction.
Therefore, the 1,3-dipolar cycloaddition proceeded via a
sequential Michael addition and Mannich-type cyclization
rather than a concerted pathway.
Moreover, comparison of the located transition struc-
tures Ts-I-S and Ts-I-R indicated that even in the con-
jugate addition step, the stereodiscrimination already
occurred because Ts-I-S is predicted to be more stable
than Ts-I-R. Further calculaztions on the subsequent
Mannich reaction revealed that the stereochemistry of the
products were controlled by the steric interactions between
the reaction substrates and 3,30-substituents of the catalyst
1f. In detail, the 9-anthracenyl rings at the 3,30-positions of
1f were oriented paralleling toward the substrates in Ts-II-S,
and this geometry is more suitable for establishing
interactions between 1f and the substrates to stabilize
the transition state. In contrast, the 3,30-bulky substi-
tuents of 1f are directed perpendicularly to the sub-
strates in Ts-II-R, resulting in the disfavored orientation
of the substrates and thereby destabilizing Ts-II-R
structure. The Ts-II-S was predicted to be more stable
than Ts-II-R by ∼7 kcal/mol in favor of the generation
of the S-enantiomer, which is in accordance with the
experimentally observed stereochemistry.
Figure 1. B3LYP/6-31G* optimized transition state structures
and partial crucial bond length parameters in angstrom, relative
energies in enthalpy (blue) and Gibbs free energy (red), and
reaction mechanism.
chiral phosphoric acid catalyzed reaction tolerates a wide
range of substrates to furnish novel 2,5-dihydropyrrole
derivatives with potential bioactivities17 in perfect enan-
tioselectivities of up to >99% ee. DFT studies on the
reaction mechanism suggested that the reaction underwent
a sequential conjugate addition and Mannich reaction
rather than a concerted pathway, distinct from most
variants between electron-deficient olefins and azomethine
yildes.3dꢀr,13 This reaction not only represents the first
enantioselective catalytic 1,3-dipolar cycloaddition invol-
ving carbonꢀcarbon triple bond dipolarophiles but also
provides a facile approach to access chiral 2,5-dihydropyr-
role architecture, which holds great potential in synthetic
and medicinal chemistry.
Acknowledgment. We are grateful for financial support
from MOST (973 Project 2009CB82530), Ministry of
Education, and NSFC (20732006, 21002083).
Finally, in order to identify potential bioactivity of these
novel chiral compounds, some selected 2,5-dihydropyr-
roles 5 were subjected to an in vitro cytotoxicity test to
mammary carcinoma cell line MCF7. The preliminary
results reveal that compound 5aaa exhibits cytotoxicity
to the MCF7 cell with an IC50 value of 166.92 μg/mL,17
which indicates this type of 2,5-dihydropyrrole derivatives
may find medicinal applications after further structural
modulation and biological studies.
Supporting Information Available. Experimental de-
tails, characterization of new compounds, and crystal
data of 5aaa and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.(16) The
calculations were performed with the Gaussian 03 pro-
gram: Frisch, M. J. et al. Gaussian 03, revision D.01;
Gaussian, Inc.: Wallingford, CT, 2004 (for complete ref
16, see Supporting Information)
In summary, we have established the first asymmetric
catalytic 1,3-dipolar cycloaddition of electron-deficient
carbonꢀcarbon triple bonds with azomethine ylides. The
Org. Lett., Vol. 13, No. 17, 2011
4683