Asymmetric [5+3] formal cycloadditions with cyclic enones through cascade dienamine-dienamine catalysis

Article abstract of DOI:10.1002/anie.201403753

A few aminocatalytic modes, such as iminium ions and different dienamines, have provided versatile tools for the functionalization of cyclic enones at various sites. Described here is a previously unreported cascade dienamine/dienamine catalytic pathway for β-substituted 2-cyclopentenones, and even 2-cyclohexenone. It involves domino α′-regioselective Michael addition and a γ-regioselective Mannich reaction with 3-vinyl-1,2-benzoisothiazole-1,1-dioxides to give fused or bridged architectures, which incorporate a spirocyclic skeleton, in excellent stereocontrol, thus furnishing unusual [5+3] formal cycloaddition reactions. Moreover, preliminary biological assays showed that some of the chiral products exhibited promising activity against some cancer cell lines, thus indicating that such skeletons might serve as leads in drug discovery.

Full text of DOI:10.1002/anie.201403753

Angewandte
Chemie
DOI: 10.1002/anie.201403753
Organocatalysis
Asymmetric [5+3] Formal Cycloadditions with Cyclic Enones through
Cascade Dienamine–Dienamine Catalysis**
Xiang Yin, Yi Zheng, Xin Feng, Kun Jiang, Xue-Zhen Wei, Ning Gao,* and Ying-Chun Chen*
Abstract: A few aminocatalytic modes, such as iminium ions
and different dienamines, have provided versatile tools for the
functionalization of cyclic enones at various sites. Described
here is a previously unreported cascade dienamine/dienamine
catalytic pathway for b-substituted 2-cyclopentenones, and
even 2-cyclohexenone. It involves domino a’-regioselective
Michael addition and a g-regioselective Mannich reaction with
3-vinyl-1,2-benzoisothiazole-1,1-dioxides to give fused or
bridged architectures, which incorporate a spirocyclic skeleton,
in excellent stereocontrol, thus furnishing unusual [5+3]
formal cycloaddition reactions. Moreover, preliminary biolog-
ical assays showed that some of the chiral products exhibited
promising activity against some cancer cell lines, thus indicat-
ing that such skeletons might serve as leads in drug discovery.
Scheme 1. Different aminocatalytic modes of cyclic enones.
T
he a,b-unsaturated cyclic ketones are versatile reactants in
organic chemistry. They have been extensively applied in
asymmetric catalysis by the covalent activation of a chiral
amine. The most common aminocatalytic mode for cyclic
enones, pioneered by Yamaguchi et al. and MacMillan et al.,
involves the generation of the LUMO-lowered iminium ion
intermediates A, thus enabling b- or a,b-functionalizations by
either Michael addition or cycloaddition reactions
(Scheme 1).[1,2] In contrast, the HOMO-raised cross-conju-
gated dienamine species B from cyclic enones and an amine
catalyst, based on an alternative strategy developed by Barbas
and co-workers,[3] could react with electron-deficient dieno-
philes in an a’,b-regioselective [4+2] cycloaddition manner.[4]
In addition, the group of Melchiorre further developed g-
regioselective vinylogous Michael additions or aldol reactions
with b-substituted 2-cyclohexenones by the formation of the
linear exo-dienamines C.[5]
architectures through the dienamines B.[6] We were fascinated
by the unprecedented catalytic pathway of a cyclic enone
substrate, a pathway wherein formation of the cross-con-
jugated dienamine[3] B is followed by formation of the linear
endo-type dienamine D.[7] As a result, chiral fused or even
bridged frameworks would be delivered from domino a’- and
g-regioselective additions to suitable reactants, containing
two electrophilic groups, in a formal [5+m] cycloaddition
(Scheme 1).[8]
The initial screening using a variety of multifunctional
electrophiles[9] showed that 3-styryl-1,2-benzoisothiazole-1,1-
dioxide[10] (3a) was a good bis(electrophilic) partner in the
reaction with b-phenyl 2-cyclopentenone (2a). The [5+3]
formal cycloaddition product 4a,[11] which possesses four
contiguous chiral centers, including a quaternary spiro one,
was obtained under the catalysis of 9-amino-9-deoxyepiqui-
nine (1a) and benzoic acid (A1) in toluene at 358C
(Table 1).[12] The reaction exhibited high chemoselectivity,
thus proceeding in the above-mentioned a’-regioselective
Michael addition with a subsequent g-regioselective intra-
molecular Mannich reaction. Moreover, the stereoselectivity
was quite promising (80% ee, > 19:1 d.r.), while the yield was
only fair because of incomplete conversion after 84 hours
(Table 1, entry 1). Subsequently, a number of reaction param-
eters were investigated. While almost no reaction or inferior
results were observed in PhCF3, THF, and CH2Cl2 (Table 1,
entries 2–4), the use of the catalyst system of 1a and A1 led to
higher enantioselectivity in CHCl3, albeit with a poorer yield
(Table 1, entry 5). A few acid additives were then screened in
CHCl3 (Table 1, entries 6–8), and the enantiopure 4a could be
obtained by using 5-nitrosalicylic acid (A4), albeit with an
unsatisfactory yield (Table 1, entry 8). Inferior results were
observed under the catalysis of 6’-OH-9-amino-9-deoxyepi-
Recently, we also developed diastereodivergent [4+2]
cycloadditions of a variety of b-substituted cyclic enones and
polyconjugated malononitriles to construct chiral bridged
[*] Dr. Y. Zheng,[+] Dr. K. Jiang, Prof. Dr. N. Gao, Prof. Dr. Y.-C. Chen
College of Pharmacy, Third Military Medical University
Chongqing, 400038 (China)
X. Yin,[+] X. Feng, X.-Z. Wei, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting and Drug Delivery System of the
Ministry of Education, West China School of Pharmacy, and State
Key Laboratory of Biotherapy, West China Hospital, Sichuan
University, Chengdu, 610041 (China)
E-mail: ycchen@scu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful for financial support from the NSFC (21125206 and
21372160) and Third Military Medical University (2012XZH06).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403753.
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Table 1: Screening studies of [5+3] formal cycloaddition of b-phenyl-2-
cyclopentenone (2a) and the 1-azadiene 3a.[a]
Table 2: Substrate scope and limitations of [5+3] formal cycloaddi-
tions.[a]
Nr. R1
R2, R3
Ph, H
t [h] Yield [%][b] ee [%][c]
1
2
3
Ph
60
44a, 85
>99
(>99)
>99
(>99)
>99
(>99)
>99
>99
99
(72) (80)
60
(72) (82)
60
(72) (85)
60
60
60
60
60
84
84
84
84
84
84
p-MeOC6H4
3,5-(CF3)2C6H3
Ph, H
Ph, H
4b, 85
4c, 88
4
5
6
7
8
9
p-FC6H4
1-naphthyl
2-thienyl
2-furyl
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
4d, 79
4e, 84
4 f, 65
4g, 58
4h, 75
4i 73
4i, 87
4j, 84
4k, 74
4l, 71
–
Nr.
1
Solvent
Acid
t [h]
Yield [%][b]
ee [%][c]
98
97
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
toluene
PhCF3
THF
A1
A1
A1
A1
A1
A2
A3
A4
A4
A4
A4
A4
84
84
84
84
84
84
84
72
72
72
72
60
42
À80
–
–
À77
À86
À90
À95
À99
À84
99
trace
trace
23
38
33
55
62
48
66
2-benzofuryl
Me
>99[d]
>99
98
10[f] Me
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
11
12
13
14
15
16
17
18
19
20
21
22
nBu
cHex
tBu
>99
97
H
–
1-Propenyl
MeO2CCH CH- Ph, H
84
84
72
4m, 46
4n, 53
4o, 87
4p, 82
4q, 67
4r, 78
–
>99
>99
>99
95
>99
>99
–
9
=
10
11[d]
12[d,e]
Ph
Ph
Ph
Ph
Ph
nBu
p-ClC6H4, H
2-F-4-BrC6H3, H 60
2-furyl, H
2-styryl, H
cHex, H
71
85
99
99
60
60
84
[a] Unless noted otherwise, reactions were performed with the enone 2a
(0.2 mmol), 3a (0.1 mmol), amine 1 (20 mol%), and acid (40 mol%) in
solvent (1 mL) at 358C. [b] Yield of isolated product. [c] Determined by
HPLC analysis on a chiral column; d.r.>19:1 as determined by 1H NMR
analysis. [d] Adding 20 mol% of H2O. [e] 3a was added in three portions.
THF=tetrahydrofuran.
m-MeOC6H4, H 84
4s, 77
>99
23
nBu
84
4t, 80
97
24
25
26
27
nBu
nBu
nBu
nBu
p-BrC6H4, H
2-thienyl, H
Ph, 5,7-Me2
Ph, 6-Cl
72
84
72
84
4u, 93
4v, 63
4w, 90
4x, 95
97
98
98
99
quinine (1b) and A4 (Table 1, entry 9), whereas using 9-
amino-9-deoxyepiquinidine (1c) provided the product having
the opposite configuration but with the same enantiocontrol
and with a slightly higher yield (Table 1, entry 10). It was
pleasing that better yield could be obtained by adding some
H2O without affecting the enantioselectivity (Table 1,
entry 11). Given that 3a has low solubility in CHCl3, the
yield was further improved by adding 3a in three portions
(Table 1, entry 12).
[a] Unless noted otherwise, reactions were performed with the enone 2
(0.2 mmol), 3 (0.1 mmol), 1c (20 mol%), A4 (40 mol%), and H2O
(20 mol%) in CHCl3 (1 mL) at 358C. The substrate 3 was added in three
portions. Data within parentheses were obtained with 1a. [b] Yield of the
isolated product. [c] Determined by HPLC analysis on a chiral column;
d.r.>19:1 as determined by by 1H NMR analysis. [d] The absolute
configuration of 4i was determined by X-ray analysis. See the Supporting
Information.[13] The other products were assigned by analogy. [f] With
1 mmol of 3a.
With the optimal reaction conditions in hand, we then
investigated a variety of 2-cyclopentenones and 3-vinyl-1,2-
benzoisothiazole-1,1-dioxides under the catalysis of either 1c
or 1a in combination with A4. The results are summarized in
Table 2. In general, the 2-cyclopentenones 2, having a variety
of b-aryl groups (Table 2, entries 1–5), including a strongly
electron-withdrawing group (Table 2, entry 4), were well
tolerated in the reactions with 3a, thus producing the
corresponding [5+3] cycloadducts in high yields and with
almost enantiomerical purity. A few heteroaryl-substituted 2-
cyclopentenones also provided the products with remarkable
enantioselectivity, though slightly lower yields were obtained
(Table 2, entries 6–8). It was pleasing that 2-cyclopentenones
with various linear or branched b-alkyl groups exhibited the
same reaction pattern, and the desired products were attained
with excellent enantiocontrol (Table 2, entries 9, and 11–13).
Even a higher yield with the same ee value was obtained on
a larger scale (Table 2, entry 10). However, simple 2-cyclo-
pentenone showed no reactivity under the current catalytic
conditions (Table 2, entry 14). Importantly, the 2-cyclopente-
nones 2 bearing b-alkenyl groups, could be smoothly utilized,
thus providing densely functionalized products in outstanding
enantioselectivity, albeit with lower yields because of side
reactions (Table 2, entries 15 and 16). In contrast, an array of
3-vinyl-1,2-benzoisothiazole-1,1-dioxides (3) with different
2
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substitutions were investigated in combination with the 2-
cyclopentenones. The expected products were generally
obtained with outstanding enantioselectivity and with good
to high yields (Table 2, entries 17–27), while a cyclohexyl-
substituted substrate showed much lower reactivity (Table 2,
entry 21). In addition, products with the opposite configu-
ration were produced with excellent results under the
catalysis of 1a (data within parentheses in Table 2).
Although simple 2-cyclopentenone did not give the
cycloadduct when using 3a, it was pleasing that a more
challenging bridged [5+3] product (6) was detected in the
reaction of 2-cyclohexenone 5 and 3a under the catalysis of 1c
and A4 in toluene at 508C (Scheme 2). The yield was very low
by the significantly deteriorated ee value observed after
a longer reaction time (for product 8b; data within paren-
thesis).
These products, which feature highly structural and
stereogenic complexity, encouraged us to explore their
potential application in chemical biology and medicinal
chemistry.[16] A number of compounds were investigated by
using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) assay in vitro.[9] It was pleasing to find that
some of them exhibited promising anticancer activity. As
summarized in Table 3, the lung adenocarcinoma epithelial
Table 3: Cellular evaluation of the cycloadducts against diverse cancer
cell-lines (IC50 in mm).[a]
Entry
1
A549
DU145 MDA-MB-231 Eca109 U937
1
2
3
4
5
6
7
8
(+)-4a
(+)-4c
(+)-4d
(+)-4 f
(+)-4u
(+)-4w
(À)-4a
(Æ)-8a
9.6
6.2
8.2
10.6
2.3
10.0
>200
>200
15.3
13.5
7.6
11.1
2.5
9.4
21.6
8.0
10.6
13.0
24.9
>200
196.3
31.4
38.8
11.6
15.4
21.8
27.1
>200
>200
13.6
26.1
20.1
26.4
18.0
30.5
>200
>200
9.0
>200
n.a.[b]
[a] For the detailed experiments, please see the Supporting Information.
[b] n.a.=not available.
Scheme 2. Construction of bridged [5+3] product with 2-cyclohexe-
none.
as a result of side reactions, and the enantioselectivity was
also disappointing. Fortunately, it was found that the amine
catalyst could play a significant role in the reaction outcome.[9]
A commercially available chiral amine, (R,R)-1,2-diphenyl-
ethanediamine (1d), predominantly produced the desired
product 6 with much higher enantioselectivity.[14] An excellent
ee value (91%) with a moderate yield for 6 was finally
obtained by employing 1e as the catalyst.[15]
The bis(electrophilic) partners are not limited to 3-vinyl-
1,2-benzoisothiazole-1,1-dioxides. Benzylidenemalononitrile
(7) was successfully employed, though lower reactivity was
observed. As outlined in Scheme 3, the densely substituted
cell line A549, prostate cancer cell line DU145, esophageal
squamous carcinoma cell line Eca109, breast cancer cell line
MDA-MB-231, and leukemic monocyte lymphoma cell line
U937, were evaluated. Compounds (+)4a, (+)4c, (+)4d,
(+)4 f, (+)4u, and (+)4w significantly inhibited proliferation
of these five cancer cells in a dose-dependent manner
(Table 3, entries 1–6). The compound (+)4u showed high
potency in inhibiting the growth of A549 and DU145 cell
lines, with IC50 (half maximal inhibitory concentration)
values of 2.3 and 2.5 mm, respectively (Table 3, entry 5).
Importantly, it was noted that the biological effect was highly
stereospecific, as very poor activity was observed for the
enantiomer of 4a (Table 3, entry 7 versus entry 1). In
addition, the compound (Æ)-8a (79% ee) exhibited a very
limited effect on inhibiting the proliferation of diverse cancer
cell lines (Table 3, entry 8). Such preliminary results sug-
gested that the promising cytotoxic activity of the [5+3]
cycloadducts is not related to the electrophilicity of the enone
moiety. Using these observations to design better inhibitors is
under investigation.
In conclusion, we have developed a previously unreported
cross-conjugated dienamine/endo-dienamine catalysis with b-
substituted 2-cyclopentenones and 2-cyclohexenone in the
presence of chiral primary amines. By using 3-vinyl-1,2-
benzoisothiazole-1,1-dioxides as bis(electrophilic) partners,
the unprecedented formal [5+3] cycloadditions were accom-
plished to give fused or bridged frameworks, incorporating
a spirocyclic skeleton, in excellent enantiomeric purity and
with highly structural and stereogenic complexity. Moreover,
some of the chiral products showed promising biological
activity in some cancer cell lines, thus indicating that such
Scheme 3. Benzylidenemalononitrile as the bis(electrophilic) reagent.
bicyclic products 8 were produced with exclusive diastereo-
selectivity, but only moderate enantioselectivity could be
obtained after extensively optimizing the catalytic condi-
tions.[9] The newly generated primary amino group in the
product was noticed to have some catalytic activity and could
affect the enantiocontrol in the catalytic process, as evidenced
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Xia, D.-Q. Xu, C. Wu, L. Zhao, Z.-Y. Xu, Chem. Eur. J. 2012, 18,
1055.
skeletons might serve as leads in drug discovery. We also
believe that this new reaction will lead to the development of
a variety of formal [5+m] cycloadditions with cyclic enone
substrates. More results will be reported in the future.
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Received: March 26, 2014
Published online: && &&, &&&&
[6] X. Feng, Z. Zhou, R. Zhou, Q.-Q. Zhou, L. Dong, Y.-C. Chen, J.
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Keywords: cancer · cycloaddition · organocatalysis ·
regioselectivity · synthetic metehods
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4
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Organocatalysis
X. Yin, Y. Zheng, X. Feng, K. Jiang,
X.-Z. Wei, N. Gao,*
Y.-C. Chen*
&&&& — &&&&
Asymmetric [5+3] Formal Cycloadditions
with Cyclic Enones through Cascade
Dienamine–Dienamine Catalysis
A fusion work: The title reaction is
described for b-substituted 2-cyclopente-
nones or 2-cyclohexenone and bis(elec-
trophilic) 3-vinyl-1,2-benzoisothiazole-
1,1-dioxides. The a’-regioselective
regioselective Mannich reaction leads to
fused or bridged frameworks with excel-
lent stereoselectivity. Some of the chiral
products exhibited promising anticancer
activity.
Michael addition and subsequent g-
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!