Direct remote asymmetric bisvinylogous 1,4-additions of cyclic 2,5-dienones to nitroalkenes

Article abstract of DOI:10.1021/ol500700d

Here we report that cyclic 2,5-dienones can act as bisvinylogous precursors through in situ generation of linear trienamine species with a cinchona-derived primary amine, and exclusively remote ε-regioselective 1,4-additions to nitroalkenes were accomplished in moderate to high enantioselectivity. Moreover, a diversity of complex spirocyclic frameworks could be efficiently constructed in an enantioenriched manner from these multifunctional 1,4-adducts via subsequent vinylogous iminium and even cascade iminium catalysis of the same amine.

Full text of DOI:10.1021/ol500700d

Letter
pubs.acs.org/OrgLett
Direct Remote Asymmetric Bisvinylogous 1,4-Additions of Cyclic
2,5‑Dienones to Nitroalkenes
Zhi Zhou,† Xin Feng,† Xiang Yin,† and Ying-Chun 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
‡College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
S
* Supporting Information
ABSTRACT: Here we report that cyclic 2,5-dienones can act
as bisvinylogous precursors through in situ generation of linear
trienamine species with a cinchona-derived primary amine, and
exclusively remote ε-regioselective 1,4-additions to nitro-
alkenes were accomplished in moderate to high enantiose-
lectivity. Moreover, a diversity of complex spirocyclic frame-
works could be efficiently constructed in an enantioenriched manner from these multifunctional 1,4-adducts via subsequent
vinylogous iminium and even cascade iminium catalysis of the same amine.
transmitted along conjugated CC bonds.1 While previous
n 1935, Fuson established the principle of vinylogy; he
asymmetric examples focused mainly on the vinylogous
Ipointed out that electron density and reactivity could be
reactions with masked dienolates,2 recently, significant progress
has been made in the direct vinylogous versions with diverse
Scheme 1. Diverse Catalytic Modes of Linear Trienamine
unsaturated substances catalyzed by chiral metal complexes or
Intermediates
organic molecules, usually in high γ-regioselectivity.3 Never-
theless, the application of α,β,γ,δ-unsaturated systems in the ε-
regioselective bisvinylogous additions seems to be much more
challenging, and very limited attempts were reported in
bisvinylogous Mukaiyama aldol or Mannich reactions with
previously formed trienol silyl ethers.4 To the best of our
knowledge, direct asymmetric bisvinylogous addition reactions
have not been developed yet.
Dienamine catalysis has been demonstrated to be a powerful
protocol for the activation of unmodified α,β-unsaturated
carbonyl compounds in various asymmetric vinylogous
reactions.5 Recently, we and the Jørgensen group succeeded
in the transmission of HOMO-raising effect to the remoter ε-
position of α,β,γ,δ-unsaturated aldehydes or ketones via in situ
generation of trienamine intermediates. However, this catalytic
mode was dominantly explored in β,ε-regioselective normal-
electron-demand Diels−Alder reactions [Scheme 1, (a)].6 We
further developed an inducing strategy with interrupted cyclic
α,β,δ,ε-unsaturated ketones and realized a δ,ε-regioselective
inverse-electron-demand cycloaddition mode [Scheme 1, (b)].7
On the basis of the above results, it was envisaged that the latter
type of linear trienamine species from cyclic 2,5-dienones
would not likely act as electron-rich diene partners in normal-
electron-demand Diels−Alder reactions with activated alkenes,
probably because of the requisite formation of a sterically
hindered spirocyclic chiral center [Scheme 1, (c)]. Therefore,
the potential ε-regioselective Michael reaction might be
Received: March 6, 2014
Published: April 24, 2014
© 2014 American Chemical Society
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Letter
Table 1. Screening Conditions of Asymmetric Bisvinylogous
1,4-Addition of 2,5-Dienone 1a to Nitroalkene 2a
Table 2. Substrate Scope in Direct Asymmetric
Bisvinylogous 1,4-Additions of 2,5-Dienones 1 to
Nitroalkenes 2
a
a
b
c
entry
1
R2
time (h)
yield (%)
ee (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Ph
62 (68)
60
3a, 80 (71)
3b, 77
85 (−83)
86
2
3-FC6H4
2-BrC6H4
4-BrC6H4
4-Br-2-FC6H3
3,4-Cl2C6H3
4-CF3C6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
1-naphthyl
2-furyl
3
52 (48)
50
3c, 76 (70)
3d, 79
86 (−84)
85
4
5
60
3e, 82
85
b
c
6
50
3f, 81
85
entry
cat.
acid
solvent
time (h)
yield (%)
ee (%)
7
56 (50)
62
3g, 81 (72)
3h, 80
85 (−86)
81
1
C1
C2
C3
C1
C1
C1
C1
C1
C1
C1
C1
C1
C4
C1
C1
A1
A1
A1
A1
A1
A1
A1
A2
A3
A4
A5
A6
A1
A1
A1
toluene
toluene
toluene
o-xylene
m-xylene
DCM
67
65
64
62
60
58
62
64
58
65
56
64
67
72
72
56
54
53
65
67
84
−83
70
8
2
9
48
3i, 76
80
3
10
11
12
13
14
15
16
17
58 (56)
54
3j, 84 (68)
3k, 78
81 (−81)
4
79
79
81
82
60
67
84
83
5
81
65
3l, 80
6
2-thienyl
n-propyl
58
3m, 85
3n, 56
7
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
80
62
71
45
65
68
63
75
78
85
86
83
73
86
84
84
84
82
85
8
isopropyl
Ph
80
3o, 60
9
100
110
3p, 62
10
11
12
Ph
3q, 60
a
Unless noted otherwise, reactions were performed with 2,5-dienone 1
(0.15 mmol), nitroalkene 2 (0.1 mmol), amine C1 (20 mol %), and
acid A1 (40 mol %) in PhCF3 (1.0 mL) at 35 °C. Data in parentheses
d
13
e
14
b
c
were obtained with amine C2. Isolated yield. Determined by HPLC
f
15
analysis on a chiral column.
a
Unless noted otherwise, reactions were performed with 2,5-dienone
1a (0.15 mmol), nitroalkene 2a (0.1 mmol), amine C (20 mol %), and
(entry 7). Then an array of acid additives were explored in
combination with amine C1 in PhCF3 (entires 8−12), while
inferior results were generally obtained in regard to reaction
time, yield, and enantiocontrol. After extensively studying more
catalytic parameters,11 it was found that bifunctional primary
amine−thiourea12 C4 in combination with acid A1 also could
promote the Michael addition in PhCF3, but with similar
enantioselectivity and lower yield (entry 13). The reaction still
proceeded smoothly with lower catalyst loadings (entry 14). In
addition, comparable data were also produced at a larger scale
(1 mmol) catalyzed by amine C1 and benzoic acid A1 (entry
15).
Subsequently, a number of nitroalkenes were used in the
reactions with 2,5-dienone 1a catalyzed by amine C1 and
benzoic acid A1. As summarized in Table 2, nitroalkenes
bearing diversely substituted aryl or heteroaryl groups could be
well tolerated, and the corresponding bisvinylogous Michael
addition adducts were generally obtained in good yield and
enantioselectivity (Table 2, entries 1−13). Alkyl-substituted
nitroalkenes showed lower reactivity, and moderate data were
attained after longer times (entries 14 and 15). In addition, 2,5-
dienones 1b and 1c also smoothly produced the bisvinylogous
adducts (entries 16 and 17), and the sole isomer was observed
in the case of 1b with a γ-methyl group. Unfortunately, more
sluggish reactions were observed for ε-substituted 2,5-dienones,
and both diastereo- and enantioselectivity were disappointing.
We also tested more examples with amine C2, and the products
with an opposite configuration were attained in similar
enantiocontrol (data in parentheses).
b
acid (40 mol %) in solvent (1.0 mL) at 35 °C. Isolated yield.
c
d
Determined by HPLC analysis on a chiral column. With 20 mol % of
e
f
acid. With 10 mol % of C1 and 20 mol % of A1. At 1.0 mmol scale.
favored, furnishing the unprecedented direct bisvinylogous
conjugate addition via trienamine catalysis [Scheme 1, (d)].
This asymmetric catalytic mode might be extremely challenging
because not only would the HOMO-raising power of amine
catalyst be diminished, leading to reduced reactivity, but also
the reactive ε-site is quite remote from the chiral center of the
catalyst, rendering the stereocontrol much more difficult than
that of concerted β,ε- or δ,ε-regioselective cycloaddition
reactions.8
The initial screenings with 2,5-dienone 1a and diverse
Michael acceptors revealed that β-nitrostyrene 2a is a suitable
electrophilic partner under the catalysis of 9-amino-9-
deoxyepiquinine C1 and benzoic acid A1.9 To our gratification,
the reaction proceeded smoothly in toluene at 35 °C,
successfully furnishing the bisvinylogous 1,4-addition product
3a with a moderate yield and a good ee value (Table 1, entry
1). It should be noted that this reaction exhibited remarkable
chemo- and remote ε-regioselectivity, and a β,ε-regioselective
cycloaddition product as that observed in early trienamine
catalysis10 has not been detected. 9-Amino-9-deoxyepiquinidine
C2 afforded the product with an opposite configuration in
similar enantioselectivity (entry 2), but amine C3 with a free 6′-
OH group gave poorer results (entry 3). A few solvents were
tested (entries 4−7), and better data were produced in PhCF3
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Letter
iminium catalysis could be further conducted with the obtained
bisvinylogous 1,4-adducts by using the same amine catalyst,
efficiently furnishing enantioenriched spirocyclic or even
bisspirocyclic architectures with highly structural and stereo-
chemical complexity. These procedures efficiently provide an
alternative synthetic protocol for β,ε-functionalizations of cyclic
2,5-dienone substrates in a [4 + 2] cycloaddition manner. We
believe that the current work would help develop more reaction
versions in the field of asymmetric trienamine catalysis. More
results will be reported in due course.
Scheme 2. Sequential Trienamine−Vinylogous Iminium or
Even Iminium Catalysis To Access Complex Spirocyclic
Products
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures and characterization of new
products, CIF files of enantiopure products 5 and 11, NMR
spectra, and HPLC chromatograms. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ycchen@scu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the NSFC
(21122056, 21372160, and 21321061) and the National Basic
Research Program of China (973 Program, 2010CB833300).
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