A catalytic asymmetric hetero-Diels-Alder reaction of olefinic azlactones and isatins: Facile access to chiral spirooxindole dihydropyranones

Article abstract of DOI:10.1039/c4cc03896g

A catalytic asymmetric hetero-Diels-Alder (HDA) reaction has been achieved through hydrogen-bond directed γ-addition of olefinic azlactones to isatins. This methodology provides an efficient access to spirooxindole dihydropyranones in moderate to good yie

Full text of DOI:10.1039/c4cc03896g

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A catalytic asymmetric hetero-Diels–Alder
reaction of olefinic azlactones and isatins: facile
access to chiral spirooxindole dihydropyranones†
Cite this: Chem. Commun., 2014,
50, 8934
Received 21st May 2014,
Accepted 20th June 2014
Tai-Ping Gao, Jun-Bing Lin, Xiu-Qin Hu and Peng-Fei Xu*
DOI: 10.1039/c4cc03896g
www.rsc.org/chemcomm
A catalytic asymmetric hetero-Diels–Alder (HDA) reaction has been
achieved through hydrogen-bond directed c-addition of olefinic
azlactones to isatins. This methodology provides an efficient access
to spirooxindole dihydropyranones in moderate to good yields and
with excellent enantioselectivities.
A vinylogous reaction represents a robust strategy toward direct
functionalization at the g-position of a,b-unsaturated systems.1 Over
the past decade, with the rapid development of organocatalysis,2
the vinylogous reactivity of various nucleophiles was extensively
investigated to produce complex chiral molecules.3 Azlactones (or
oxazolones)4 are among the most useful starting materials for
the synthesis of a-amino acids and heterocyclic scaffolds,5 many
Scheme 1 The reactivity of azlactones in an asymmetric DA reaction.
examples have been reported using olefinic azlactones as electron- the development of a concise, atom-economical HDA reaction of
poor acceptors.6 However, the use of olefinic azlactones as pro- ketones with other dienes or dienolates is in high demand. Recently,
nucleophilic synthons still remains elusive. Recently, Jørgensen and Feng and co-workers12 reported an elegant chiral bisguanidine-
co-workers reported the first organocatalytic vinylogous addition of catalysed inverse-electron-demand hetero-Diels–Alder (IEDDA) reac-
olefinic azlactones with enals and 2,4-dienals with unprecedented tion of azlactones and chalcones with the use of azlactones as
reactivity patterns via covalent aminocatalysis.7 Despite this progress, dienophiles (Scheme 1). Isatins are bidentate activated ketones
the development of new transformation utilizing the vinylogous and always serve as exceptional electrophiles in asymmetric synthesis
reactivity of azlactone is still a desirable, yet challenging task.
of biologically relevant 3-hydroxyoxindole derivatives.13 As part of our
The hetero-Diels–Alder (HDA) reaction of carbonyl compounds is continuing efforts to develop novel asymmetric transformations,14
of fundamental importance for the construction of six-membered herein we reported a new HDA reaction enabled by g-addition of
oxygen-containing heterocycles.8 Therefore, enantioselective HDA olefinic azlactones to isatins. The catalytic asymmetric version of this
reactions using aldehydes as dienophiles are extensively investigated transformation would lead to a chiral spirooxindole dihydro-
based on metal-based chiral Lewis acid or hydrogen-bond donor pyranone derivative,15 which is a key structural element in a
catalysts, delivering synthetically important dihydropyran deriva- number of natural products and synthetic bioactive molecules.16
tives.9 However, highly enantioselective HDA reactions using ketones
To validate our hypothesis, a HDA reaction of isatin 1 and olefinic
as dienophiles are relatively rare.10 Furthermore, for the synthesis of azlactone 2a was chosen for the preliminary test and initial optimiza-
chiral dihydropyranones, most of the asymmetric HDA reactions are tion of the reaction parameters. Indeed, it was found that the desired
largely restricted to the use of specific siloxybutadiene derivatives as reaction took place in the presence of cinchona alkaloids A–C, all
dienes, such as Danishefsky’s diene and Brassard’s diene.11 Hence, bearing a bifunctional trans-1,2 amino alcohol moiety, to give
spirooxindole dihydropyranones 3a in moderate yields and selectivity,
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
with dihydroquinine giving the best results with respect to yield and
enantioselectivity (40% yield, 80% ee, Table 1, entry 3). To improve
the reactivity, well-documented bifunctional catalysts D and E were
Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China.
E-mail: xupf@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
also investigated. Unfortunately, no reaction occurred despite the fact
that both catalysts were shown as strong hydrogen-bond donor
and spectra of compounds 3. CCDC 991736. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c4cc03896g
8934 | Chem. Commun., 2014, 50, 8934--8936
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of the HDA reactiona
Entry
R1
R2
R3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
82 (3a)
75 (3b)
83 (3c)
79 (3d)
69 (3e)
75 (3f)
77 (3g)
75 (3h)
73 (3i)
63 (3j)
82 (3k)
75 (3l)
73 (3m)
88 (3n)
78 (3o)
76 (3p)
77 (3q)
82 (3r)
98
99
99
75
99
94
99
95
499
95
499
85
97
94
73
76
99
93
5-Br
6-Br
7-Br
5-Me
7-Me
5,7-DiMe
5-Cl
6-Cl
5-F
5-Me
5-Br
H
H
H
9
Ph
Ph
10
11
12
13
14
15
16
17
18
Entry
Cat.
R1
Solvent
Yieldb (%)
eec (%)
4-FC6H4
4-FC6H4
3-BrC6H4
4-FC6H4
4-MeOC6H4
2-Naphthyl
Ph
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
F
F
F
F
F
F
F
F
F
F
F
F
F
H
H
H
H
H
H
H
H
Bn
Me
Ph
Et
Ts
Et
Et
Et
Et
Et
Et
Et
Et
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
37
42
40
Trace
Trace
55
36
42
60
28
47
56
n.r.
75
76
85
65
49
61
80
n.d.
n.d.
84
62
40
40
97
28
99
n.d.
94
99
90
80
84
98
90
98
H
H
H
Allyl
Isopropyl
Ph
a
Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol),
2 (0.1 mmol), and organocatalyst F (20 mol%) in DCE (1 mL) at 30 1C.
9
b
c
10
11
12
13
14
15
16
17
18
19d
20e
21f
Isolated yield. Determined by chiral HPLC analysis.
THF
to good yields (up to 88%) and with good to excellent enantio-
selectivities (up to 499%). The results in Table 2 show that
azlactones 2 with electron-withdrawing substituents gave better
enantioselectivities than those with electron-donating and bulky
substituents (Table 2, entries 13 and 14 vs. entries 15 and 16). With
regard to isatins, a wide range of substrates were well tolerated and
the nature of substituents had only a slight effect on the results
(entries 2–12). However, compared with C5 and C6 substituents of
isatins, a lower ee value was observed with the C7 substituent
(entries 2–4). It was found that an isatin with a dialkyl substituent
also worked well (entry 7). To extend the scope of substrates, our
further examination focused on the N-substituent of isatin. It was
DCM
DCE
CH3CN
Toluene
Acetone
DCE
DCE
DCE
94
82
89
83
a
Unless otherwise noted, the reaction was carried out with 1 (0.1 mmol), 2a
(0.1 mmol), and catalyst (0.02 mmol) in the indicated solvent (1 mL) at room
temperature. b Isolated yield. c Determined by chiral HPLC analysis. d The
reaction was carried out at 30 1C. e The reaction was carried out at 50 1C.
f
1.2 equiv. of 1 was used.
catalysts for the isatin activation (Table 1, entries 4 and 5). To our found that isatins with N-allyl and N-isopropyl groups reacted
delight, further investigation revealed that more rigid chiral tertiary smoothly with azlactones to afford the spirooxindoles in good yields
amine F–H were promising catalysts with b-isocupreidine17 (b-ICD) and high enantioselectivities (entries 17 and 18). The absolute
giving the best selectivity (84% ee, entry 6), although the yields were configuration of the products was assigned to be (R) by X-ray
still unsatisfactory (Table 1, entries 6–8). Surprisingly, a significant chromatography analysis of compound 3c (Fig. 1).18
improvement of enantioselectivity was achieved by changing the
A possible reaction mechanism for the present HDA reaction
N-substituent of isatin (entries 9–13). The ethyl group turned out to is illustrated in Scheme 2, although at the current stage a
be the best N-substituent in terms of yield and ee (56% yield and 99%
ee, entry 12). Detailed optimization of the solvents revealed that DCE
was the best among THF, DCM, acetonitrile, toluene and acetone
(entries 14–18). Better results were obtained when the reaction was
performed at 30 1C (entry 19 vs. entries 20 and 14). Slight improve-
ment of yield was also observed when 1.2 equiv. of 1 was used
(Table 1, entry 21).
With the reaction conditions optimized, the generality of the
HDA reaction was investigated with respect to both isatin 1 and
olefinic azlactone 2, and the results are given in Table 2.
Generally, all of the reactions proceeded smoothly to give the
Fig. 1 X-ray crystal structure of compound 3c.
corresponding spirooxindole dihydropyranones 3 in moderate
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Scheme 2 A possible reaction pathway.
stepwise vinylogous aldol/cyclization cascade cannot be ruled
out. Initially, both of the reaction partners are synergistically
activated by the bifunctional catalyst F to form the hydrogen-
bonding complex 4, which then undergoes [4+2] annulations
through Si face attack of dienolates to isatins to give intermedi-
ate 5. Finally, tautomerization and protonation of intermediate 5
give rise to the desired product 3 and regenerate the catalyst.
In summary, we have developed an efficient approach for the
construction of chiral spirooxindole dihydropyranones through
a HDA reaction of isatins and olefinic azlactones. Vinylogous
reactivity of azlactones was readily realized through bifunc-
tional activation of both of the reaction partners, and the
desired products were produced generally in good yields and
with good to excellent enantioselectivity. Further applications
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We are grateful to the NSFC (21032005, 21172097 and
21372105), the National Basic Research Program of China (no.
2010CB833203), the International S&T Cooperation Program of
China (2013DFR70580), the National Natural Science Founda-
tion from Gansu Province of China (no. 1204WCGA015), and the
‘‘111’’ program from MOE of P. R. China.
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8936 | Chem. Commun., 2014, 50, 8934--8936
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