Trienamine catalysis with 2,4-dienones: Development and application in asymmetric Diels-Alder reactions

Article abstract of DOI:10.1002/anie.201200248

A tri-ing reaction: An asymmetric Diels-Alder cycloaddition of δ,δ-disubstituted 2,4-dienones is possible through the trienamine catalysis of cinchona-based primary amines (see scheme). An array of electron-deficient dienophiles, such as N-substituted maleimides and 3-alkenyl oxindoles, were tolerated, and multifunctional cyclohexene derivatives were obtained in excellent stereoselectivity and with high diastereomer ratios. Copyright

Full text of DOI:10.1002/anie.201200248

Angewandte
Chemie
DOI: 10.1002/anie.201200248
Asymmetric Catalysis
Trienamine Catalysis with 2,4-Dienones: Development and Applica-
tion in Asymmetric Diels–Alder Reactions**
Xiao-Feng Xiong, Quan Zhou, Jing Gu, Lin Dong, Tian-Yu Liu, and Ying-Chun Chen*
Since the seminal papers at the beginning of this century,[1]
asymmetric organocatalysis based on chiral amines has been
extensively and actively explored. A variety of catalytic
modes, which includes enamine, iminium, dienamine, and
SOMO pathways, have been elegantly applied to a large
number of asymmetric reactions, especially for aliphatic and
a,b-unsaturated aldehyde substrates.[2] Very recently, our
group as well as Jørgensen and co-workers have reported
a new reactive model, trienamine catalysis, for 2,4-dienals.
This method relies on the generation of an electron-rich
triene system in situ, which can perform as a diene counter-
part in the Diels–Alder (DA) reaction with an electron-
deficient dienophile, and gives exclusive b,e-regioselectivity
along with excellent stereoselectivity.[3]
It would be reasonable that such a trienamine catalytic
protocol should also be applicable to 2,4-dienone analogues
Scheme 1. Logical development of trienamine catalysis for 2,4-dienone
as the common enamine or iminium catalysis for a-enolizable
substrates. Conditions: i) 1a (20 mol%), TFA (40 mol%), 608C, tolu-
ketones or a,b-unsaturated ketones, respectively.[2a,b]
ene. X=9-quinyl.
Unfortunately, as outlined in Scheme 1, the expected trien-
amine catalysis was unsuccessful and almost no reaction
occurred between hepta-3,5-dien-2-one (2a) and the dieno-
phile N-phenylmaleimide (3a) when catalyzed by a primary
amine, such as 9-amino-9-deoxyepiquinine (1a, Table 1).[4] As
the two different trienamine intermediates I and II could be
formed, we reasoned that trienamine I might be preferred,
which would not promote the desired cycloaddition. As
a result, dienone 2b, which does not contain an a-enolizable
alkyl group, was used under the same conditions. However,
the a,d-regioselective DA cycloadduct 5a was isolated as the
sole product, albeit in low yield. It was later confirmed that
this reaction proceeded in a noncatalyzed manner, and
substrate 2b, rather than the trienamine III, directly acted
as the diene.[5] We envisaged that the introduction of another
methyl group at the d position of the dienone, as in the
structure of the 2,4-dienone 2c, would significantly inhibit the
reaction that proceeds through the undesired DA pathway, as
a quaternary center shown in the proposed product 5b has to
be formed. Moreover, the electron-donating effect of the d-
methyl group would also increase the HOMO energy of the
resulting trienamine intermediate IV,[6] which would further
facilitate the amine-catalyzed DA process.
To our gratification, it was found that the expected DA
reaction of 2c and 3a catalyzed by amine 1a and trifluoro-
acetic acid (TFA) in toluene at 608C was efficient.[7] Cyclo-
adduct 6a was isolated as a single endo diastereomer and,
more pleasingly, with excellent enantioselectivity (Table 1,
entry 1). It should be noted that only a trace amount of the
noncatalyzed DA product 5b was detected, as proposed
before. Subsequently, a number of reaction parameters were
explored. A much lower yield was obtained when the weaker
o-fluorobenzoic acid (OFBA) was used (Table 1, entry 2), but
good results were achieved in the presence of salicylic acid
(SA, Table 1, entry 3).[8] Both the yield of the reaction and the
ee value were decreased by applying sulfonic acids as the
additives (Table 1, entries 4 and 5). A lower yield and ee value
were obtained in chloroform (Table 1, entry 6), and almost no
reaction occurred in THF (Table 1, entry 7). The yield also
decreased upon lowering the loading of TFA, but without
effect on the enantioselectivity (Table 1, entry 8). Other chiral
primary amines derived from cinchona alkaloids were also
tested. 9-Amino-9-deoxy-epicinchonidine (1b) provided the
same enantioselectivity as 1a but with a lower yield (Table 1,
entry 9), whereas the demethylated derivative 1c[4f] could not
catalyze this reaction (Table 1, entry 10). Furthermore, 9-
amino-9-deoxyepiquinidine (1d) and 9-amino-9-deoxyepicin-
chonine (1e) delivered unsatisfying results and the product
[*] X.-F. Xiong, Q. Zhou, J. Gu, Dr. L. Dong, Prof. Dr. Y.-C. Chen
Key laboratory of Drug Targeting and Drug Delivery System of the
Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
E-mail: ycchenhuaxi@yahoo.com.cn
Dr. T.-Y. Liu, Prof. Dr. Y.-C. Chen
College of Pharmacy, The Third Military Medical University
Chongqing, 40038 (China)
[**] We are grateful for financial support from the NSFC (21125206 and
21021001) and the National Basic Research Program of China
(973 Program, 2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200248.
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Table 1: Screening studies of the Diels–Alder reaction of dienone 2c and
N-phenylmaleimide (3a) with trienamine catalysis.[a]
Table 2: Substrate scope of the Diels–Alder reaction.[a]
Entry
R
R1
R2
3
t [h] Yield [%][b]
ee [%][c]
1
2
3
4
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
X[f]
3a
3b
3c
3d
3c
3b
3c
3b
3c
3b
3b
3b
3b
3b
3b
3b
3b
3c
3c
24
24
24
42
16
46
24
24
18
36
48
48
48
36
60
48
48
34
34
6a, 75
6b, 80
6c, 84
6d, 80
6e, 84
6 f, 70
6g, 84
6h, 80
6i, 84
6j, 80
6k, 80
-
6l, 67
6m, 70
6n, 70
6o, 46
6p, 70
6e, 70
6g, 75
92
92
93
89
94
92
90
89[e]
94
90
96
-
96
82
62
85
89
80[g]
82[g]
5
p-ClC6H4
m-BrC6H4
p-MeC6H4
1-naphthyl
1-naphthyl
2-furyl
2-styryl
Ph-C C-
Ph
Ph
Ph
Entry
1
Solvent
Acid
t [h]
Yield [%][b]
ee [%][c]
6[d]
7
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1d
1a
1a
toluene
toluene
toluene
toluene
toluene
CHCl3
TFA
OFBA
SA
24
36
36
24
24
24
24
39
24
24
24
24
36
24
18
75
30
70
61
70
69
–
50
50
<10
51
40
80
78
85
92
87
94
71
81
88
–
93
93
–
8
9
TfOH
TsOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
SA
10
11
12
13
14[d]
15
16
17
18[d]
19[d]
ꢀ
THF
8[d]
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-(CH2)3-
-(CH2)2-
H
H
H
H
10
11
12
13
14[f]
15[g]
Ph
Ph
Ph
Me
Me
74[e]
66[e]
88[e]
87
93
2-styryl
p-ClC6H4
p-MeC6H4
TFA
TFA
[a] Reactions were performed with 2 (0.12 mmol), 3 (0.1 mmol), 1a
(20 mol%), and TFA (40 mol%) in toluene (1 mL)at 608C. [b] Yield of
isolated product. [c] By HPLC analysis on a chiral stationary phase;
d.r.>95:5 by 1H NMR analysis. [d] SA was used. [e] The absolute
configuration of 6h was determined by X-ray analysis.[10] The other
products were assigned by analogy. [f] X=4-methyl-3-pentenyl. [g] For
the opposite enantiomer catalyzed by 1d.
[a] Unless noted otherwise, reactions were performed with 2c
(0.12 mmol), 3a (0.1 mmol), 1 (20 mol%), and acid (40 mol%) in
solvent (1 mL) at 608C. [b] Yield of isolated product. [c] By HPLC analysis
on a chiral stationary phase; d.r.>95:5 by 1H NMR analysis. [d] With
20 mol% of TFA. [e] For the opposite enantiomer. [f] At 708C. [g] With
30 mol% of 1a and 60 mol% of TFA. TfOH: trifluoromethanesulfonic
acid; TsOH: p-methylbenzenesulfonic acid.
with a 2-styryl group could be used, and a remarkable ee value
was obtained (Table 2, entry 11). Unfortunately, the analo-
gous dienone substrate with a 2-phenylethynyl group exhib-
ited no reactivity under the same conditions (Table 2,
entry 12). Moreover, a d,d-unsymmetrically disubstituted
dienone showed excellent regioselectivity, and the less
hindered product 6l was exclusively generated (Table 2,
entry 13). Nevertheless, diminished enantioselectivity was
obtained for a cyclohexylidene dienone (Table 1, entry 14),
and only a moderate ee value was obtained for a dienone with
a cyclopentylidene motif (Table 2, entry 15). The catalytic
reaction was also applicable to d-phenyl-substituted dienones
(Table 2, entries 16 and 17). In comparison, 9-amino-9-
deoxyepiquinidine 1d was further tested for other dienone
substrates and the cycloadducts with the opposite configu-
ration were delivered with good ee values (Table 2, entries 18
and 19).[9]
To further demonstrate the generality of the chiral
primary amine based trienamine catalysis, more dienophiles
were explored in the reaction with d,d-disubstituted dienones
2. As outlined in Scheme 2, 3-olefinic oxindole 7 with an N-
tosyl (Ts) group could react with 2c, but a higher temperature
(808C) was required. Spirocyclic oxindole 8 was obtained
from this reaction with outstanding diastereo- and enantio-
was the opposite configuration (Table 1, entries 11 and 12).
Nevertheless, a much improved yield and ee value could be
obtained in combination with SA (Table 1, entry 13). A
slightly lower enantioselectivity was achieved at 708C with 1a
as the catalyst (Table 1, entry 14). A better yield with similar
enantioselectivity could be obtained by using a higher catalyst
loading (Table 1, entry 15).
With the optimized reaction conditions in hand, we then
investigated a variety of 2,4-dienones and maleimides in the
reaction catalyzed by 1a (20 mol%) and TFA (40 mol%) in
toluene at 608C. The results are summarized in Table 2. At
first, it was found that a slightly higher yield could be obtained
by using maleimides 3b or 3c with an N-aryl group that
contains electron-withdrawing substituents, probably owing
to the enhancement of dienophilicity (Table 2, entries 2 and
3). Pleasingly, good results were also obtained for N-
alkylmaleimide 3d, although a longer reaction time was
required (Table 2, entry 4). A series of 2,4-dienones with
diverse substituents were also explored. 1-Aryl substrates
with electron-withdrawing or electron-donating groups were
tolerated, which gave the cycloadducts in good yields and
excellent enantioselectivity (Table 2, entries 5–9). Similar
results were achieved with a 2-furyl-substituted dienone
(Table 2, entry 10). Importantly, a functionalized dienone
selectivity. Furthermore, benzylidenecyanoacetate
9 and
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cinchona alkaloids. The success of this catalytic mode was
based on the logical design and analysis of the results of the
reactions. Currently, the application of 2,4-dienones with
a d,d-disubstituted pattern was necessary for the amine-
catalyzed Diels–Alder reaction, otherwise the 2,4-dienones
would directly act as dienes in a noncatalyzed cycloaddition.[9]
In addition, the presence of an aryl or 2-styryl group at the
a position to the carbonyl group was also required to suppress
the detrimental formation of the unreactive trienamine
intermediate.[7] A diverse range of electron-deficient dieno-
philes have been successfully applied, which gave an array of
multifunctional cyclohexene derivatives in moderate to
excellent enantioselectivity (up to 96% ee) and exclusive
endo selectivity (> 95:5). We believe that this work will
arouse more research interest in asymmetric aminocatalysis
of unsaturated carbonyl compounds. Such studies are actively
under way in this laboratory, and more results will be reported
in due course.
Scheme 2. Diels–Alder reaction of other types of dienophiles.
Received: January 11, 2012
Revised: January 27, 2012
Published online: February 16, 2012
nitroalkene 11 were also tested and SA was found to be
a better acid additive in these reactions. Gratifyingly, high
stereoselectivity was still obtained for the corresponding
products 10 and 12, respectively, even under such relatively
harsh conditions. It should be noted that, in contrast to
trienamine catalysis with 2,4-dienals, endo selectivity, rather
than the abnormal exo selectivity,[3b,d] was obtained for the
cycloaddition of nitroalkene 11 to 2,4-dienone 2d.[11]
Keywords: asymmetric synthesis · Diels–Alder reaction ·
.
2,4-dienones · homogeneous catalysis · trienamines
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Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am.
Chem. Soc. 2011, 133, 15212.
The multifunctional characteristics of the 2,4-dienone DA
products can be used in chemoselective transformations to
access frameworks with high molecular complexity. For
example, the ketone group of adduct 6d can be diastereose-
lectively converted to the chiral alcohol 13 by employing
Noyoriꢀs
(S,S)-TsDPEN-Ru
transfer-hydrogenation
system.[12] Moreover, by using the reaction procedures
reported by Stang and White, the fused tetracyclic product
15 could be efficiently constructed with remarkable diaste-
reoselectivity, based on a sequential reduction/Friedel–Crafts
reaction sequence (Scheme 3).[13]
In conclusion, we have developed an asymmetric Diels–
Alder cycloaddition of 2,4-dienones by the trienamine
catalysis of readily available chiral primary amines of
[4] For reviews on cinchona-based primary aminocatal-
ysis, see: a) Y.-C. Chen, Synlett 2008, 1919; b) L.
Jiang, Y.-C. Chen, Catal. Sci. Technol. 2011, 1, 354;
c) G. Bartoli, P. Melchiorre, Synlett 2008, 1759; for
selected examples, see: d) J.-W. Xie, W. Chen, R. Li,
M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu,
J.-G. Deng, Angew. Chem. 2007, 119, 393; Angew.
Chem. Int. Ed. 2007, 46, 389; e) W. Chen, W. Du, Y.-
Z. Duan, Y. Wu, S.-Y. Yang, Y.-C. Chen, Angew.
Chem. 2007, 119, 7811; Angew. Chem. Int. Ed. 2007,
Scheme 3. Construction of a chiral polycyclic framework. TBAC=tetrabutylammo-
nium chloride, CSA=camphorsulfonic acid.
46, 7667; f) R. P. Singh, K. Bartelson, Y. Wang, H.
Su, X. Lu, L. Deng, J. Am. Chem. Soc. 2008, 130,
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2422; g) J. Zhou, V. Wakchaure, P. Kraft, B. List, Angew. Chem.
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Mancinelli, A. Mazzanti, G. Bartoli, P. Melchiorre, Angew.
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[9] More 2,4-dienones without d,d-disubstituted patterns have been
tested, but only the noncatalyzed DA cycloadducts were
obtained, see the Supporting Information.
[10] CCDC 864374 (6h) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[11] The absolute configuration for compounds 8, 10, and 12 has been
assigned on the basis of a presumed common catalytic mecha-
nism similar to that of cycloadducts 6. In addition, the relative
configuration for products 10 and 12 has been further studied by
2D NMR and NOE analysis, see the Supporting Information.
[12] a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97;
b) (R,R)-TsDPEN-Ru complex is a mismatched catalyst for
chiral compound 6d, and poor conversion was obtained; c) The
absolute configuration of the newly generated alcohol in product
13 was assigned on the basis of the well-established reaction
model of Noyoriꢀs asymmetric transfer-hydrogenation system.
[13] E. M. Stang, M. C. White, J. Am. Chem. Soc. 2011, 133, 14892.
[5] For more details, see the Supporting Information.
[6] For a discussion on orbital-energy control of cycloaddition
reactivity, see: R. Sustmann, Pure Appl. Chem. 1974, 40, 569.
[7] In contrast, an a-methyl-2,4-dienone with a d,d-disubstituted
pattern still exhibited no reactivity under the same conditions,
see the Supporting Information.
[8] G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P.
Melchiorre, Proc. Natl. Acad. Sci. USA 2010, 107, 20642.
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