Asymmetric organocatalytic three-component 1,3-dipolar cycloaddition: Control of stereochemistry via a chiral Bronsted acid activated dipole

Article abstract of DOI:10.1021/ja801034e

A Bronsted acid catalyzed three-component asymmetric 1,3-dipolar addition reaction between aldehydes, amino esters, and dipolarophiles by a new bisphosphoric acid, derived from the linked BINOL, furnished multiply substituted pyrrolidines in high yield with excellent enantioselectivities under mild conditions. Copyright

Full text of DOI:10.1021/ja801034e

Published on Web 04/03/2008
Asymmetric Organocatalytic Three-Component 1,3-Dipolar
Cycloaddition: Control of Stereochemistry via a Chiral
Brønsted Acid Activated Dipole
Xiao-Hua Chen,†,‡ Wen-Quan Zhang,† 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, Chengdu
Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, and
Graduate School of Chinese Academy of Sciences, Beijing, China
Received February 11, 2008; E-mail: gonglz@ustc.edu.cn
1,3-Dipolar cycloaddition of azomethine ylide to electron-
deficient olefins yields chiral pyrrolidines, an important class of
heterocyclic compounds with widespread applications to the
synthesis of biologically active compounds and natural products.1
These cycloaddition reactions represent an important class of
synthetic methods and have inspired much research interest in the
development of asymmetric catalytic variants.1,2 Elegant studies
in this field have often centered on chiral Lewis acid (LA) catalyzed
asymmetric 1,3-dipolar additions with azomethine ylides, in which
the stereochemistry is controlled via a chiral metal complex bonded
intermediate Ia or Ib (eq 1).2,3 Very recently, high stereoselectivities
were observed with the first organocatalytic asymmetric 1,3-dipolar
addition of an azomethine ylide to R,ꢀ-unsaturated aldehydes.4 This
reaction was catalyzed by chiral secondary amines through the
reversible formation of iminium ions with R,ꢀ-unsaturated alde-
hydes, which served to reduce the energy of the lowest unoccupied
molecular orbital of the dipolarophiles.5 However, this procedure
did not include dipolarophiles other than unsaturated aldehydes.4
lonate (4a) with dimethyl maleate (5a) under the influence of
10 mol % of BINOL-derived phosphoric acid 1a in the presence
of 3 Å molecular sieves in dichloromethane. To our delight, a
cycloaddition reaction smoothly furnished an endodiastereomer
6a in 78% yield, albeit with a low ee (Table 1, entry 1).
Encouraged by this preliminary result, a number of chiral
phosphoric acids derived from BINOL were evaluated. It
appeared that none of these catalysts provided a satisfactory
enantioselectivity, although they showed good catalytic ef-
ficiency (entries 1–6). Strikingly, a bisphosphoric acid, derived
from (R,R)-linked BINOL that was initially designed as a chiral
ligand,9 was the most promising catalyst and provided an almost
quantitative yield and excellent enantioselectivity of 98% ee
(entry 7). Halogen-containing solvents were most suitable for
the reaction, providing better results than those obtained with
other solvents (entries 7–12). No variation in the stereoselectivity
was observed by carrying out the reaction at 0 °C (entry 13).
Having established the optimal procedure, we next investigated
the effect of aldehydes in reactions with 4a and 5a (Table 2). A
wide range of aldehydes including aromatic, R,ꢀ-unsaturated, and
aliphatic variants could be tolerated, leading to the formation of
Table 1. Screening Catalysts and Optimization of Reaction
Conditionsa
Chiral Brønsted acids (BH), in particular, chiral phosphoric acids,
provide sufficient acidity required for the activation of imines lead-
ing to many new asymmetric procedures,6 including multicompo-
nent reactions.7 We envisioned that they are theoretically able to
form a chiral azomethine ylide dipole IIa or IIb with an azomethine
compound that would undergo an enantioselective 1,3-dipolar cyclo-
addition with dipolarophiles (eq 2). Herein, we report that an asym-
metric, catalytic, and three-component 1,3-dipolar cycloaddition
between aldehydes, amino esters, and electron-deficient olefins
could be realized by using the chiral BH activated dipole to control
the stereochemistry, yielding multiply substituted pyrrolidines with
high enantioselectivity (up to 99% ee). This procedure allows a
rapid diversity-oriented synthesis8 of chiral pyrrolidine derivatives.
To validate our hypothesis, we performed a three-component
reaction of para-nitrobenzaldehyde (3a) and diethyl aminoma-
entry
catalyst
solvent
CH2Cl2
yield (%)b
ee (%)c
1
1a
1b
1c
1d
1e
1f
2
78
74
88
87
83
78
96
92
88
98
84
72
97
8
6
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
3
25
46
43
23
98
97
88
97
58
4
5
6
7
8
2
9
2
PhCH3
10
11
12
13
2
ClCH2CH2Cl
CH3CN
THF
2
2
12
98
d
2
CH2Cl2
a The reaction was carried out in 0.2 mmol scale in a solvent (2 mL)
with 3 Å MS (300 mg), and the ratio of 3a/4a/5a is 1.2/1/5. b Isolated yield
based on 6a and 4a. c Determined by HPLC. d The reaction was performed
at 0 °C for 72 h.
† University of Science and Technology of China.
‡ Chengdu Institute of Organic Chemistry.
9
5652 J. AM. CHEM. SOC. 2008, 130, 5652–5653
10.1021/ja801034e CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
with dimethyl fumarate.10 An almost racemic [3 + 2] adduct was
obtained using N-methyl maleimide as the dipolarophile.11 How-
ever, no obvious change in the enantioselectivity was observed
employing dimethyl aminomalonate (4b) to replace 4a as a reaction
component (entries 3 and 4). Importantly, R-phenylglycine methyl
ester (4c) was also able to undergo the three-component 1,3-dipolar
additions, affording adducts with four contiguous stereogenic
centers including a quaternary carbon with high enantiomeric
excesses (entries 5 and 6). Notably, the few reported chiral Lewis
acid catalyzed dipolar addition reactions involving structural
analogues of 4c-derived azomethines with dipolarophiles have
mostly shown enantioselectivities of <81% ee.3c,e,12
In conclusion, we have described a Brønsted acid catalyzed
three-component asymmetric 1,3-dipolar addition reaction13 be-
tween aldehydes, amino esters, and dipolarophiles by a new bisphos-
phoric acid derived from the linked BINOL, furnishing multiply
substituted pyrrolidines in high yields with excellent enantioselec-
tivities under mild conditions. The procedure is easy to perform and
allows a rapid, diversity-oriented, and enantioselective synthesis
of pyrrolidine derivatives. The concept that the stereoselectivity may
be controlled by use of a chiral Brønsted acid bonded dipole may
lead to new findings in asymmetric catalytic 1,3-dipolar addition
reactions with dipolarophiles other than electron-deficient olefins.
Acknowledgment. We are grateful for financial support from
NSFC (20732006, 20325211) and CAS.
Table 2. Scope of Aldehydes of the Asymmetric Three-Component
1,3-Dipolar Addition Reactionsa
entry
6
R
time (h)
yield (%)b
ee (%)c
1
6b
6c
6d
6e
6f
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-MeO2CC6H4
4-BrC6H4
24
48
24
24
72
72
72
96
72
96
48
96
96
96
96
96
96
95
97
94
88
89
94
92
67
97
82
93
87
90
92
75
70
74
99
96
95
98
99
2
3
4
5
6
6g
6h
6i
4-FC6H4
98
d
7
3-ClC6H4
90
d
8
2-BrC6H4
94
9
6j
6k
6l
6m
6n
6o
6p
6q
6r
4-ClC6H4
93
d
10
11
12
13
14
15
16
17
2-Cl,4-FC6H3
Ph
97
d
91
d
4-MeOC6H4
1-nphthyl
2-nphthyl
90
d
84
d
87
d
4-MeOPhCHdCH
4-MePhCHdCH
c-C6H11
93
d
92
d,e
76
a The reaction was carried out in 0.2 mmol scale in dichloromethane (2
mL) with 3 Å MS (300 mg), and the ratio of 3/4a/5a was 1.2/1/5. b Isolated
yield based on 6 and 4. c Determined by HPLC. d The ratio of 3/4/5a is 1/
1.2/10. e Reacted with dimethyl aminomalonate (4b).
Table 3. Scope of Amino Esters and Dipolarophiles of the
Asymmetric Three-Component 1,3-Dipolar Addition Reactionsa
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.
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R1
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Ph
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