Highly enantioselective catalytic 1,3-dipolar cycloaddition involving 2,3-al enoate dipolarophiles

Article abstract of DOI:10.1021/ol9020964

A bisphosphoric acid-catalyzed 1,3-dipolar cycloaddition of buta-2,3-dienoates with azomethine ylides yields 3-methylenepyrrolidine derivatives with excellent enantioselectivity (up to 97% ee).

Full text of DOI:10.1021/ol9020964

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4946-4949
Highly Enantioselective Catalytic
1,3-Dipolar Cycloaddition Involving
2,3-Allenoate Dipolarophiles
Jie Yu, Long He, Xiao-Hua Chen, Jin Song, Wei-Jie Chen, 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 September 10, 2009
ABSTRACT
A bisphosphoric acid-catalyzed 1,3-dipolar cycloaddition of buta-2,3-dienoates with azomethine ylides yields 3-methylenepyrrolidine derivatives
with excellent enantioselectivity (up to 97% ee).
Due to the widespread application of pyrrolidine-containing
compounds in the synthesis of important biologically active
natural and unnatural molecules, the development of efficient
synthetic methods to access this structural motif in an
optically active form has long been an important project in
organic chemistry.1 The enantioselective synthetic methods
commonly used include 1,3-dipolar addition reactions of
azomethine ylides to electronically deficient alkenes using
chiral auxiliaries, chiral metal complex catalysts, and re-
cently, chiral organocatalysts.2,3 These methods provide
elegant entries to pyrrolidine derivatives substituted with
saturated C-C chemical bonds. 3-Methylene-pyrrolidine
derivatives containing a C-C double bond that increases the
structural flexibility in view of a tremendous number of
reactions associated with olefins are undoubtedly important
in synthetic chemistry either as building blocks or as
intermediates.
(1) (a) Pearson, W. H. Studies in Natural Product Chemistry; Atta-Ur-
Rahman, Ed.; Elsevier: New York, 1998; Vol. 1, p 323; (b) Sardina, F. J.;
Rapoport, H. Chem. ReV. 1996, 96, 1825. (c) Coldham, I.; Hufton, R. Chem.
ReV. 2005, 105, 2765. (d) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
ReV. 2006, 106, 4484. (e) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(2) For selected examples, see: (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.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 4236. (c)
Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (d)
Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M.
Angew. Chem., Int. Ed. 2004, 43, 5971. (e) Cabrera, S.; Arraya´s, 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) Herna´ndez-Toribio, J.; Arraya´s, R. G.;
Mart´ın- Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393. (i) Lo´pez-
Pe´rez, A.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 340.
(3) (a) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew. Chem.,
Int. Ed. 2007, 46, 5168. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Cordova, A.
Tetrahedron Lett. 2007, 48, 6252. (c) Xue, M.-X.; Zhang, X.-M.; Gong,
L.-Z. Synlett 2008, 691. (d) Liu, Y.-K.; Liu, H.; Du, W.; Yue, L.; Chen,
Y.-C. Chem. Eur. J. 2008, 14, 9873. (e) Nakano, M.; Terada, M. Synlett
2009, 1670.
(4) For reviews: (a) Ma, S. Aldrichimica Acta 2007, 40, 91. (b) Ma, S.
Chem. ReV. 2005, 105, 2829. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535. For selected examples, see: (d) Zhang, C.; Lu, X. J.
Org. Chem. 1995, 60, 2906. (e) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.;
Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119, 3836. (f) Wilson, J. E.;
Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426. (g) Cower, B. J.; Miller,
S. J. J. Am. Chem. Soc. 2007, 129, 10988. (h) Zhu, X.-F.; Lan, J.; Known,
O. J. Am. Chem. Soc. 2003, 125, 4716. (i) Wurz, R. P.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 12234. (j) Fang, Y. Q.; Jacobsen, E. N. J. Am. Chem.
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10.1021/ol9020964 CCC: $40.75
Published on Web 10/08/2009
 2009 American Chemical Society

2,3-Allenoates, activated by nucleophilic catalysts such as
organic phosphines and amines to form dipoles, commonly
participated in [3 + 2] cycloaddition reactions with electroni-
cally deficient olefins and imines.4 In contrast, relatively few
reports described the cycloaddition reactions involving 2,3-
allenoates as dipolarophiles.5,6 Very recently, we found that
the chiral Brønsted acid bonded azomethine ylides could
undergo smooth 1,3-dipolar addition reactions with electroni-
cally deficient olefins and imines, yielding five-membered
nitrogenous heterocycles with high enantiopurity and struc-
tural diversity.7 To address the long-standing issues concern-
ing no readily available methods to access optically active
3-methylenepyrrolidine derivatives, we had great interest in
the development of 1,3-dipolar cycloaddition reaction be-
tween 2,3-allenoates and azomethine ylides (Scheme 1).
Herein, we report our preliminary results.
Table 1. Optimization of Reaction Conditionsa
entry
3
catalyst
solvent
PhCH3
yield (%)b
ee (%)c
1
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3a
3a
3a
3a
3a
3a
3a
1a
1b
1c
1d
1e
1f
1g
2
86
86
80
62
92
79
81
98
85
68
96
95
95
93
96
90
86
11
33
17
13
4
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
CHCl3
26
11
90
50
88
91d
92e
93f
93g
2
2
2
2
2
2
2
2
Scheme 1
94g h
,
92g h
,
93g h
,
2
Cl(CH2)2Cl
a Unless indicated otherwise, the reaction was carried out in 0.1 mmol
scale in PhCH3 (1 mL) with 3 Å MS (100 mg) for 36 h, and the ratio of
3a/4a/5 is 5/1.2/1. b Isolated yield. c Determined by HPLC. d The ratio of
3a/4a/5 is 3/1.2/1. e The ratio of 3a/4a/5 is 2/1.2/1. f The ratio of 3a/4a/5
is 1.5/1.2/1. g The ratio of 3a/4a/5 is 1.2/1.2/1. h The reaction underwent
for 72 h.
(entries 8-10). Tuning the ratio of buta-2,3-dienoate 3a
had little effect on the stereochemistry and the reaction
conversion, and thus, only 1.2 equiv of 3a to 5 was
sufficient for a complete reaction (entries 12-14). A
survey of the solvents indicated that halogen-containing
solvents were also suitable in terms of the enantioselec-
tivity, but the reaction proceeded relatively slower than
those in nonpolar solvents (entries 15-17).
The initial experiments included a reaction of 9-anthra-
cenylmethyl buta-2,3-dienoate (3a, 9-AnCH2) with 4-ni-
trobenzaldehyde and diethyl 2-aminomalonate (5) in the
presence of structurally diverse binol-based phosphoric
acids (Table 1). Although either of the monophosphoric
acids8 examined afforded a smooth cyclization reaction
yielding a 3-methylenepyrrolidine derivative, they pro-
vided poor enantioselectivity ranging from 4% to 33% ee
(entries 1-7). Under similar conditions, the bisphosphoric
acid 2 delivered an almost quantitative yield of 98% and
excellent enantioselectivity of 90% ee (entry 8).7a Varia-
tion of the substituent at the ester moiety of buta-2,3-
dienoates led to a conclusion that the introduction of a
bulky substituent was beneficial to stereochemical control
Having the optimized conditions in hand, we investi-
gated the generality for the aldehyde component (Table
2). The protocol tolerated a wide range of aldehyde
substrates. Generally, the aromatic aldehydes gave higher
enantioselectivity than aliphatic aldehdyes. The electronic
feature of the substituent on the aryl ring did not have a
significant effect on the stereoselectivity. Thus, high
enantioselectivity was observed for either the electron-
rich, neutral, or electron-poor aromatic aldehydes (89%-
96% ee, entries 1-11). An electronically rich cinnamal-
dehyde afforded a high yield and excellent enantioselec-
tivity (93% yield, 95% ee, entry 12). 2-Furanylaldehyde
participated in a clean reaction but with a moderate
(5) (a) Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett. 1989, 30, 6559.
(b) Jung, M. E.; Nishimura, N. J. Am. Chem. Soc. 1999, 121, 3529. (c)
Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113
.
(6) Laia, F. M. R.; e Melo, T. M. V. D. P. Tetrahedron Lett. 2009, 50,
6180
.
(7) (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.
(8) For general reviews on monophosphoric acid catalysis: (a) Akiyama,
T. Chem. ReV. 2007, 107, 5744. (b) Doyle, A. G.; Jacobsen, E. N. Chem.
ReV. 2007, 107, 5713. (c) Terada, M. Chem. Commun. 2008, 4097.
(9) For kinetic resolution of racemic allenes, see: (a) Ogasawara, M.
Tetrahedron: Asymmetry 2009, 20, 259. (b) Deska, J.; Ba¨ckvall, J.-E. Org.
Biomol. Chem. 2009, 7, 3379.
(10) CCDC 733422. See the Supporting Information for details.
Org. Lett., Vol. 11, No. 21, 2009
4947

2,3-dienoate underwent a good reaction but gave a low
enantiomeric excess (entry 1). No reaction was observed for
4,4-dimethyl variant (entry 2). Interestingly, the presence of
a substituent at C2 of the allene was tolerable, leading to
the desired cycloaddition products with high stereochemical
outcomes (entries 3-5).
Table 2. Scope of Aldehydes of 1,3-Dipolar Addition
Reactionsa
Preliminary studies on the kinetic resolution of racemic
4-ethyl buta-2,3-dienoates that bear a alkyl substituent at C2
by the cycloaddition reaction with the azomethine ylides were
preformed (Table 4).9 These buta-2,3-dienoates reacted
entry
6
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
6a
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-MeO2CC6H4
4-BrC6H4
93
89
79
94
96
99
85
92
84
74
97
93
98
67
90
87
29
93
96
91
94
89
95
94
93
92
95
92
95
75
91
Table 4. Studies on the Kinetic Resolution of the Racemic
Buta-2,3-dienoatesa
4-ClC6H4
2,3-Cl2C6H4
Ph
4-MeOC6H4
2-Naphthyl.
4-MeOC6H3CHdCH
2-Furan
2-Thiophen
c-Propane
c-Hexane
9
10
11
12
13
14
15
16
17
yield of
69d e
,
entry R′
7
yield of 7b ee of 7d recovered 3c ee of 3d
28d e
,
n-C3H7
17f
1
2
Me 7f
Bn 7g
59
75
89
97
66
61
24
55
a The reaction was carried out in 0.1 mmol scale in PhCH3 (1 mL) with
3 Å MS (100 mg), and the ratio of 3a/4/5 is 1.2/1.2/1. b Isolated yield.
c Determined by HPLC. d The ratio of 3a/4/5 is 5/1.2/1. e The reaction was
performed for 60 h. f The reaction was performed for 6 days.
a The reaction was carried out in 0.1 mmol scale in PhCH3 (1 mL) with
3 Å MS (100 mg), and the ratio of 3/4/5 is 2/1.2/1. b Isolated yield bsaed
on the amino ester 5. c Isolated yield based on the allenoate 3. d Determined
by HPLC.
enantioselectivity (entry 13). Although thiophene-2-car-
baldehyde gave a comparably lower yield (67%), the
enantioselectivity was high (entry 14, 91% ee). R-Branched
aliphatic aldehydes proceeded with cleaner reaction than
linear aliphatic aldehydes. However, the stereoselectivity
was always low in the cycloaddition reactions involving
aliphatic aldehydes (entries 15-17).
readily with the azomethine ylide derived from 4-bromoben-
zaldehyde to yield the desired cyclic compounds of type 7
as sole products with high enantiomeric excess (89-97%
ee). Indeed, the racemic 4-ethyl buta-2,3-dienoates could be
resolved, but only moderated enantiomeric purity was
observed for the recovered starting materials.
The generality for the scope of buta-2,3-dienoate deriva-
tives was finally explored (Table 3). The substituents at either
The absolute configuration of the product was accessed by
X-ray crystallography analysis. As all the cycloaddition products
Table 3. Scope of Allene of 1,3-Dipolar Addition Reactionsa
Scheme 2
.
Dermination of the Absolute Configuration of the
Stereogenic Centers in 6h
entry
7
R1
R2
R3
yield (%)b
ee (%)c
1
2
3
4
5
7a
7b
7c
7d
7e
Ph
Me
H
H
H
H
Me
H
H
H
H
H
68
--
86
79
45
6
n.d.
88
92
94
CH2CO2Bn
Me
Bn
a The reaction was carried out in 0.1 mmol scale in PhCH3 (1 mL) with
3 Å MS (100 mg), and the ratio of 3/4/5 is 1.2/1.2/1. b Isolated yield.
c Determined by HPLC.
carbon of the allene have considerable influence on the
reaction performance. 9-Anthracenylmethyl 4-phenyl buta-
4948
Org. Lett., Vol. 11, No. 21, 2009

failed to grow crystal, we transformed 6h to a solid derivative.
The compound 6h was reduced with LiAlH4 and followed by
an acylation with 4-chlorobenzoyl chloride, giving a product 8
in overall 12% yield. The compound 8 could be grown to a
crystal suitable for X-ray analysis (Scheme 2). The X-ray
structure of 8 revealed an assignment of the configuration of
the stereogenic centers to be (4R, 5S).10
buta-2,3-dienoates. The presence of a carbon-carbon double
bond at the pyrrolidine ring would be useful in the structur-
ally diverse five-membered nitrogenous molecules.
Acknowledgment. We are grateful for financial support
from NSFC (20732006), CAS, MOST (973 program
2009CB82530), and the Ministry of Education.
In summary, we have disclosed an unprecedented 1,3-
dipolar cycloaddition of buta-2,3-dienoates with azomethine
ylides, yielding 3-methylenepyrrolidine derivatives with
excellent enantioselectivity. Notably, the protocol is poten-
tially applicable to the kinetic resolution of racemic 4-alkyl
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.
OL9020964
Org. Lett., Vol. 11, No. 21, 2009
4949