Asymmetrie [3+2] cycloadditions of allenoates and dual activated olefins catalyzed by simple bifunctional N-acyl aminophosphines

Article abstract of DOI:10.1002/anie.201000446

(Figure Presented) Bifunctional catalyst: Simple bifunctional N-Acyl aminophosphines such as 1 were developed to catalyze the first asymmetric [3+2] cycloaddition between allenoates and dual activated olefins. The cycloaddi- tion reactions afford multifun

Full text of DOI:10.1002/anie.201000446

Angewandte
Chemie
DOI: 10.1002/anie.201000446
Organocatalysis
Asymmetric [3+2] Cycloadditions of Allenoates and Dual Activated
Olefins Catalyzed by Simple Bifunctional N-Acyl Aminophosphines**
Hua Xiao, Zhuo Chai, Chang-Wu Zheng, Ying-Quan Yang, Wen Liu, Jun-Kang Zhang, and
Gang Zhao*
Recently, phosphine-catalyzed [3+2] cycloadditions of alle-
noates with electron-deficient olefins and imines—a process
which provides efficient access to a variety of synthetically
useful carbo- and heterocycles from readily available starting
materials—have received considerable research interest[1,2]
since the pioneering works of Lu and co-workers.[1j] As a
result of continuing efforts from many research groups in this
field, an array of new annulation reactions were disclosed, in
which a- or g-substituted allenoates,[3] allylic compounds,[4]
and electron-deficient olefins[5] were recognized as novel
“three-carbon-atom units” and “two-carbon-atom units”.
However, the development of enantioselective variants of
these transformations has met with very limited success. Up to
now, only a handful of chiral organocatalysts[6,7] have been
found to be effective for this kind of reaction, most of which
are monodentate phosphines.[6] Recently, two excellent
research reports highlighted the great potential of phos-
phine-containing molecules bearing additional active sites as
efficient catalysts in this kind of reaction. Miller and co-
workers pioneered the use of multifunctional a-amino acid
derived phosphines as efficient catalysts for allenoate–enone
cycloadditions.[7a] In addition to the high ee values achieved,
this system also provided regioselectivity opposite to those
obtained with monodentate phosphine catalysts in similar
reactions. Later, Jacobsen and co-workers demonstrated
bifunctional phosphine-containing thioureas catalyzed alle-
noate–imine cycloadditions with excellent enantioselectivi-
ties.[7b]
The problem of regioselectivity is common in [3+2]
cycloadditions of allenoates with electron-deficient olefins.
Such a problem could be circumvented by using dual
activated olefins, which was recently disclosed by Lu and
co-workers.[8] Despite this advantage, to the best of our
knowledge, no asymmetric example of this kind of reaction
has been reported. Recently, our group has focused on the
development of chiral organocatalysts from natural a-amino
acids, a cheap and readily accessible chiral source, and their
applications in various organic transformations.[9] a-Amino
acid derived aminophosphines and their N-protected counter-
parts have been used as efficient chiral ligands for numerous
metal-based reactions.[10] We envisaged that their modular,
bifunctional structures would also make them excellent
candidates for organocatalysts (Scheme 1). Herein, we de-
scribe highly regio- and enantioselective [3+2] cycloadditions
Scheme 1. Catalyst design for [3+2] cycloadditions. Ms=methanesul-
fonyl; TFA=trifluoroacetic acid.
between allenoates and arylidenemalononitriles and ana-
logues catalyzed by bifunctional N-acyl aminophosphines
derived from a-amino acids.
The N-acyl aminophosphines employed in this research
were easily accessed in four steps from commercially avail-
able Boc-protected amino alcohols (Boc = tert-butyloxycar-
bonyl) through modified literature procedures.[11] The struc-
tures of these catalysts are shown in Figure 1.
Initial experiments were performed with the reaction
between phenylidenemalononitrile 1a and ethyl 2,3-butadie-
noate 2 for catalysts evaluation (Table 1). Firstly, the influ-
ence of the structures of the N-protecting groups on the
reaction was examined with catalysts 4a–g derived from
l-phenylalanine. Catalyst 4c with the most acidic NH
function led to a racemic product after a long reaction time
(Table 1, entry 3). The catalysts with the less acidic benzoyl
group (4 f) and trifluoroacetyl group (4g) gave the highest
ee values, although a low yield was observed with 4 f (Table 1,
entries 6 and 7). The above observations, together with those
of Millerꢀs, all support the important role that the hydrogen-
bonding effect may play in the transition state of this kind of
[*] H. Xiao, Y.-Q. Yang, W. Liu, Prof. Dr. G. Zhao
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: zhaog@mail.sioc.ac.cn
Dr. Z. Chai, C.-W. Zheng, J.-K. Zhang, Prof. Dr. G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai, 200032 (P.R. China)
[**] We acknowledge research support from the National Basic Research
Program of China (973 Program, 2010CB833200), the National
Natural Science Foundation of China (Nos. 20172064, 203900502,
and 20532040), the Shanghai Natural Science Council, and the
Excellent Young Scholars Foundation of National Natural Science
Foundation of China (20525208). We also thank Prof. Yue-Peng Cai
(South China Normal University) for his great help in performing
X-ray crystallographic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000446.
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Communications
entries 12–17). In general, the presence of electron-with-
drawing substituents on the benzene ring is beneficial for the
reaction, although catalyst 4m with a 2-nitro group provided
poor yield and ee value (Table 1, entry 13), probably because
of the likely presence of an intramolecular hydrogen-bonding
between the NH function and the nitro group in this catalyst.
The best catalyst 4p with a 3,5-ditrifluoromethylbenzoyl
group gave the desired product with 87% yield and 85% ee in
only 1 h (Table 1, entry 16). Lowering the reaction temper-
ature to 08C did not bring an apparent enhancement in the
enantioselectivity, but a longer reaction time was required
and a reduced yield was observed (Table 1, entry 17).[13]
Notably, in all the cases examined above, exclusive regiose-
lectivity was observed with 3a as the single cycloadduct.
Having established the optimal conditions, we then
explored the generality of this reaction with a variety of
dual activated olefins (Table 2). The reaction is tolerant of a
broad range of olefins derived from aromatic aldehydes,
providing a series of chiral cyclopentenes in high yields and
with good to excellent enantioselectivities. However, olefins
derived from aliphatic aldehydes are not suitable substrates
for this reaction system.[14] A significant ortho site effect of the
Ar group was observed: apparently higher enantioselectiv-
ities were obtained for ortho-substituted substrates, irrespec-
Figure 1. Organocatalysts tested in this study. Bn=benzyl; Tf=tri-
fluoromethanesulfonyl; Bz=benzoyl.
Table 1: Screening of catalysts for the asymmetric [3+2] cycloaddition of
phenylidenemalononitrile 1a and ethyl 2,3-butadienoate 2.[a]
Entry
Catalyst
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4p
48
24
72
48
48
48
72
24
12
72
72
24
24
6
72
76
54
72
40
29
54
99
80
87
80
47
18
72
94
87
65
39
25
5
51
61
73
72
32
70
78
82
77
54
76
83
85
86
Table 2: Enantioselective [3+2] cycloadditions of ethyl 2,3-butadienoate
2 with 1 catalyzed by 4p.[a]
9
10
11
12
13
14
15
16
17[d]
Entry
1, Ar
Products
Yield [%][b]
ee [%][c]
2
1
12
1
2
3
4
5
6
7
8
1a, Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
87
99
92
99
99
99
99
99
79
99
88
99
93
96
81
93
87
82
90
88
80
85
93
96
97
91
91
95
93
85
87
86
80
86
85
86
90
99
92
92
97
80
1b, 2-FC6H4
1c, 2-ClC6H4
1d, 2-BrC6H4
1e, 2-MeOC6H4
1 f, 2,5-MeOC6H3
1g, 2,4-Cl2C6H3
1h, 1-naphthyl
1i, 4-FC6H4
1j, 4-ClC6H4
1k, 4-BrC6H4
1l, 4-MeOC6H4
1m, 3-FC6H4
1n, 3-ClC6H4
1o, 2-naphthyl
1p, Ph
[a] All reactions were carried out with 1a (0.1 mmol) and ethyl 2,3-
butadienoate 2 (0.2 mmol) in the presence of 4 (0.01 mmol) in toluene
(1.0 mL) at room temperature. [b] Yields of isolated products. [c] Deter-
mined by chiral HPLC analysis. [d] 20 mol% of 4p was used and the
reaction was conducted at 08C.
9
10
11
12
13
14
15
16[d,f]
17[d,f]
18[d,f]
19[d,f]
20[d,f]
21[e,f]
reaction.[12] Subsequent examination of catalysts 4h–k with
various chiral backbones gave more encouraging results
(Table 1, entries 8–11). The enantioselectivity seemed to be
dependent on the steric hindrance of R1 group, and the
bulkiest catalyst 4k (R1 = naphthalen-2-ylmethyl) gave the
highest ee value, and also required a long reaction time
(Table 1, entry 11). In view of the cost, accessibility, and
exceptionally high catalytic activity of catalyst 4i derived
from l-isoleucine (Table 1, entry 9), further optimization
efforts were performed by modifying the structure of this
catalyst (Table 1, entries 12–17). We then turned back to the
tuning of the NH function. Considering the good enantiose-
lectivity obtained with the N-benzoyl 4 f and the ready
modifiability of both the electronic and steric environment of
the benzoyl group, we used several substituted benzoyl groups
to replace the trifluoroacetyl group in catalyst 4i (Table 1,
1q, 2-BrC6H4
1r, 3-BrC6H4
1s, 4-BrC6H4
1t, 2-FC6H4
3s
3t
3u
1u, 2-thienyl
[a] Unless otherwise noted, all reactions were carried out with 1
(0.1 mmol) and 2 (0.2 mmol) in the presence of 4p (0.01 mmol) in
toluene (1.0 mL) for 1 h at room temperature. [b] Yields of isolated
products. [c] Determined by chiral HPLC analysis. [d] The product was
1
obtained with 95:5 d.r. as determined by H NMR spectroscopy. [e] The
product was obtained with 85:15 d.r. as determined by 1H NMR
spectroscopy. [f] Reaction time: 6 h.
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tive of the electronic nature of the substituents (Table 2,
entries 2–8). In addition, substrates bearing electron-with-
drawing substituents in general gave higher ee values than
those with electron-donating substituents. More importantly,
substrates 1p–u (2-cyano-3-arylacrylates) with two different
electron-withdrawing functions, which would allow selective
transformation to other useful structures, are also well
tolerated in the reaction. The corresponding chiral cyclo-
pentenes containing adjacent quaternary and tertiary stereo-
centers were obtained in high yields with exclusive regiose-
lectivity and good to excellent diastereoselectivities and
enantioselectivities (Table 2, entries 16–21).[15] Notably,
when PPh3 was employed as the catalyst for accesses to
racemic cyclopentenes 3p–u, poor regioselectivities and
moderate diastereoselectivities were observed. To our
delight, g-substituted racemic allenoate 5 also underwent
the reaction smoothly to give the desired products 6 in high
yields and moderate diastereoselectivities,[16] albeit with
somewhat decreased ee values (Scheme 2).
Figure 2. Possible transition state.
In conclusion, we have realized the first asymmetric
organocatalytic [3+2] cycloaddition between allenoates and
dual activated olefins using novel bifunctional N-acyl amino-
phosphine catalysts. The ready availability of the catalysts,
high yields, good to excellent enantioselectivities, and mild
reaction conditions make our system a valuable complement
to currently existing methods for accessing synthetically
useful multifunctional chiral cyclopentenes. Efforts toward
the application of the N-acyl aminophosphine catalysts in
other related reactions are currently underway in our
laboratories.
Experimental Section
Representative procedure (see Table 2, entry 1): To a stirred solution
of 2-benzylidenemalononitrile 1a (0.1 mmol) and catalyst 4p
(0.01 mmol) in toluene (1.0 mL), fresh ethyl 2,3-butadienoate
(0.2 mmol) was added by a syringe in one portion. Then the reaction
mixture was vigorously stirred for 1 h at room temperature. The crude
reaction mixture was directly purified by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate) to furnish the
corresponding product.
Scheme 2. The reaction between rac-5 and 1 catalyzed by 4p.
Received: January 26, 2010
Published online: May 17, 2010
To illustrate the utility of the present [3+2] cycloaddition
reaction, the enantiomerically enriched adducts 3d and 3q
were subjected to the dihydroxylation conditions reported by
Fu and co-workers[3d] to afford diastereomerically pure
polyfunctional cyclopentanes 7a and 7b in good to excellent
yields (Scheme 3).[16]
Keywords: asymmetric catalysis · cycloaddition · olefins ·
.
organocatalysis · phosphanes
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[11] See the Supporting Information for details.
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[13] See the Supporting Information for the screen of other solvents
(Table S2).
[14] See the Supporting Information for details (Scheme S1).
[15] See the Supporting Information for details of the determination
of compound 3s configurations.
[16] The configurations of product 6a and 7 were determined by
NOSY spectra. See the Supporting Information for details.
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