Catalytic enantioselective formal Hetero-Diels-Alder reactions of enones with isatins to give spirooxindole tetrahydropyranones

Article abstract of DOI:10.1002/chem.201300595

Organocatalytic formal hetero-Diels-Alder reactions of enones with isatins, which gave highly enantiomerically enriched functionalized spirooxindole tetrahydropyranones via an enamine-based mechanism, were developed. The catalyst systems were identified by a screen of combinations of amines, acids, and additives. With the identified catalyst systems, various spirooxindole tetrahydropyranones were synthesized in high yields with high diastereo- and enantioselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201300595

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DOI: 10.1002/chem.201300595
Catalytic Enantioselective Formal Hetero-Diels–Alder Reactions of Enones
with Isatins to Give Spirooxindole Tetrahydropyranones
Hai-Lei Cui[a, b] and Fujie Tanaka*[a, b]
Spirooxindole frameworks are common in bioactive natu-
ral products and pharmaceutical leads.[1] The development
of efficient synthetic strategies to access spirooxindole
motifs has been a challenge.[1,2] The demand for concise
asymmetric methods that provide a set of highly enantio-
merically enriched spirooxindoles is high.[1,2] Although syn-
theses of many types of spirooxindoles, including spirooxin-
dole-derived cyclohexanones[2a,b] and lactols,[2c] have been re-
ported,[1,2] there are groups of spirooxindole motifs of inter-
est that have not been efficiently and/or enantioselectively
synthesized. The spirooxindole tetrahydropyranones are one
such group.[3] Tetrahydropyranones are important core struc-
tures, and they can be transformed to substituted tetrahy-
dropyrans and related derivatives;[4] spirooxindole tetrahy-
dropyranones should also be useful for further diversifica-
tion. Herein, we report the development of concise, catalytic
enantioselective formal hetero-Diels–Alder (hDA) reactions
Scheme 1. a) Formal hDA reactions to give spirooxindole tetrahydropyra-
nones. b) Diels–Alder reactions of preformed dienes (route A) and hDA
of enones with isatins that gave spirooxindole tetrahydropy-
ranones (Scheme 1).
Formal hDA reactions, including highly enantioselective
reactions that directly use enones as reactants (route B) to give tetrahy-
dropyranones.
ACHTUNGTRENNUNG
versions, are common routes to tetrahydropyranones.[4]
However, most of the reported hDA reactions that give tet-
rahydropyranones use silyl enol ether derived dienes or si-
loxybutadiene derivatives as dienes (Scheme 1b, route A)
whether the catalysts are metal catalysts[4a–c] or hydrogen-
bond-providing catalysts.[4d–f] We reasoned that enamine ac-
tivation of enones in situ should provide concise, atom-eco-
nomical routes to tetrahydropyranones (Scheme 1b,
route B).[5] Although enamine-based Diels–Alder reactions
of unsaturated ketones that give cyclohexanones and cyclo-
hexenes have been extensively reported,[2a,b,6,7] correspond-
ing enamine-based hDA reactions of enones that give tetra-
hydropyranones are known to be difficult.[5] To efficiently
identify useful catalysts for the hDA reactions, we sought
amine-acid and amine-acid-additive combination catalysts;
we hypothesized that appropriate combinations would allow
in situ associations and interactions among the catalyst com-
ponents and reactants for the desired diastereo- and enan-
tioselective catalysis via the enamine formation.
First, combinations of amines and acids were screened in
the reaction of enone 1a and isatin 2a for the formation of
hDA product 3aa (Table 1, entries 1–14). In this screening,
reactions in the presence of amine A with acid I, amine F
with acid I, and amine A with acid J in toluene gave good
results (Table 1, entries 1, 6, and 9, respectively; diastereo-
meric ratio (d.r.) 5.2:1–11:1, the major diastereomer 84–
87% enantiomeric excess (ee)).
Next, to further optimize the reaction, the use of additives
was tested (Table 1, entries 15–20). We reasoned that inter-
actions between thiourea O and the two oxygens of 2a
should reduce undesired imine formation of 2a with the cat-
alyst amine and should accelerate the desired hDA reaction.
In fact, reaction in the presence of amine A and acid J with
thiourea O was cleaner and faster than the reaction without
the thiourea; the reaction with the thiourea gave 3aa in
better diastereo- and enantioselectivities (d.r. 18:1 and 93%
ee; Table 1, entry 17) than did the reaction without the thio-
urea (Table 1, entry 17 vs. entry 9). The amine was essential
to give 3aa; reaction in the presence of only acid J and thio-
urea O did not afford 3aa. Use of a lower concentration of
the catalyst system also gave 3aa with high enantioselectivi-
[a] Dr. H.-L. Cui, Prof. Dr. F. Tanaka
Chemistry and Chemical Bioengineering Unit (Kyoto Lab)
Okinawa Institute of Science and Technology Graduate University
Mikuruma, 448-5 Kajii, Kamigyo, Kyoto 602-0841 (Japan)
E-mail: ftanaka@oist.jp
[b] Dr. H.-L. Cui, Prof. Dr. F. Tanaka
Chemistry and Chemical Bioengineering Unit
Okinawa Institute of Science and Technology Graduate University
1919-1 Tancha, Onna, Okinawa 904-0495 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300595.
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Table 1. Screening of catalyst systems in the formal hDA reaction.[a]
of aldol product 4 was observed before the formation of
3aa, although small amount of the aldol product co-existed
during the reaction.
The scope of the formal hDA reactions in the presence of
the identified catalyst system was examined by using a series
of isatins and enones (Tables 2 and 3). Various formal hDA
Table 2. Scope of the formal hDA reactions: products obtained from var-
ious isatins.[a]
Entry Amine Acid+additive
t
Conversion
d.r.[c] ee
[%][d]
[h] [%][b]
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
A
A
A
A
A
F
A
A
A
A
A
F
I
I
I
I
I
I
I
I
J
K
L
M
N
J
I
I
48
48
48
22
28
20
48
36
48
48
48
48
48
17
48
48
18
48
48
90
42
88
5.2:1
5.5:1
84
79
[a] Reaction conditions: enone (1.0 mmol) and isatin (0.2 mmol) in the
presence of amine A (0.04 mmol), acid J (0.08 mmol), and thiourea O
(0.04 mmol) in toluene (0.4 mL) at 248C. [b] Isatin 1 g-scale reaction. See
text. [c] Reaction in the presence of A (0.02 mmol), J (0.04 mmol), and
O (0.02 mmol).
3.2:1 À71
93
1.1:1
2.4:1
45
83
100
100
34
100
77
78
71
75
76
100
53
100
100
100
59
8.0:1 À85
1.6:1 28
1.0:1 À65
9
11:1
87
83
15
79
77
Table 3. Scope of the formal hDA reactions: products obtained from var-
ious enones.[a]
10
11
12
13
14
15[e]
16[f]
17[g]
18[h]
19[i]
20[g]
2.0:1
1.7:1
4.6:1
3.8:1
17:1
1.8:1
5.4:1
18:1
1.0:1
8.0:1
8.7:1 À75
À79
31
79
93
62
94
J+O
O
J+O
I+O
5.5 100
[a] Reaction was performed by using enone 1a (0.5 mmol) and isatin 2a
(0.1 mmol) in the presence of amine (0.02 mmol) and acid (0.04 mmol) in
toluene (0.2 mL) at 248C except where indicated. [b] Determined by
1H NMR based on the ratio of 3aa to 2a. [c] Determined by 1H NMR.
[d] The major diastereomer of 3aa; determined by HPLC. [e] Molecular
sieves (4 ꢁ) were added. [f] Acid I (0.06 mmol) was used. [g] Thiourea O
(0.02 mmol) was used. [h] Thiourea O (0.06 mmol) was used. [i] Amine A
(0.01 mmol), acid J (0.02 mmol), and thiourea O (0.01 mmol) were used.
ty (94% ee; Table 1, entry 19). For the reaction catalyzed by
amine F with acid I, addition of thiourea O improved the re-
action rate, but not the enantioselectivity (Table 1, entry 20).
Thus, the catalyst system composed of amine A, acid J, and
thiourea O (Table 1, entry 17) was
identified as the best among those
tested in terms of conversion, d.r.,
and ee for the formation of 3aa.
Under the best and the second best
conditions (Table 1, entries 17, 19, 1,
[a] Reaction conditions: enone (1.0 mmol) and isatin (0.2 mmol) in the
presence of A (0.04 mmol), J (0.08 mmol), and O (0.04 mmol) in toluene
(0.4 mL) at 248C. [b] Reaction in toluene (0.8 mL)/CH2Cl2 (0.1 mL). See
Ref. [8]. [c] Reaction in the presence of F (0.04 mmol) and J (0.08 mmol)
in CH2Cl2. See Ref. [9].
6, and 9), no significant accumulation
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Catalytic Hetero-Diels–Alder Reactions of Enones
COMMUNICATION
products were obtained in high yields with high diastereo-
and enantioselectivities.[8,9] In addition, simple crystallization
of the major diastereomer of 3aa obtained by the formal
hDA reaction gave 3aa in 99% ee. The absolute stereo-
chemistry of the major diastereomer of 3aa was determined
to be (2’S,6’R), as shown in Table 2, by X-ray crystal-struc-
tural analysis of a derivative of 3aa.[10]
Acknowledgements
This study was supported by the Okinawa Institute of Science and Tech-
nology Graduate University, the MEXT Grant-in-Aid for Scientific Re-
search on Innovative Areas Grant Number 24105535, and the research
grant of Astellas Foundation for Research on Metabolic Disorders. We
thank Prof. Eunsang Kwon, Tohoku University, for the X-ray structural
analysis.
The reaction conditions with the catalyst system were
readily scaled. The reaction of isatin (1 g) in the presence of
amine A (10 mol%), acid J (20 mol%), and thiourea O
(10 mol%) for five days gave 3aa (1.5 g) in 86% yield (d.r.
6.9:1, major diastereomer 94% ee).
Keywords: asymmetric
heterocycles · organocatalysis · spiro compounds
catalysis
·
cycloaddition
·
The utility of the formal hDA reaction was further dem-
onstrated by transformations of the product (Scheme 2). Re-
duction, reductive amination, and allylation of 3aa gave sub-
stituted tetrahydropyranspirooxindole derivatives 5, 6, and
7, respectively.
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Scheme 2. Transformations of the formal hDA product.
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In summary, we have developed concise, atom-economi-
cal, highly diastereo- and enantioselective organocatalytic
formal hDA reactions of enones with isatins that gave sub-
stituted spirooxindole tetrahydropyranones under mild con-
ditions. We have demonstrated that the amine-based catalyst
systems useful for the reactions can be identified by a
search of the combinations of amines, acids, and additives.
Synthesis of catalysts containing all required functional moi-
eties in one molecule was not necessary. Further studies on
the full scope of the reactions catalyzed by the combination
catalyst systems and on the mechanisms are under investiga-
tion and will be reported in due course.
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Experimental Section
To a solution of primary amine A (0.04 mmol) and acid J (0.08 mmol) in
toluene (superdehydrated, 0.4 mL) were added thiourea O (0.04 mmol),
enone 1 (1.0 mmol), and isatin 2 (0.2 mmol). The mixture (initially, sus-
pension) was stirred at RT (248C), until isatin was consumed (monitored
by TLC). The mixture was purified by silica-gel flash-column chromatog-
raphy (hexane/EtOAc (2:1) or hexane/acetone (3:1)) to give 3.
Chem. Eur. J. 2013, 19, 6213 – 6216
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F. Tanaka and H.-L. Cui
4703–4832; i) for enamine-based formal hDA reactions of enones
with nitroso compounds, see: Y. Yamamoto, N. Momiyama, H. Ya-
mamoto, J. Am. Chem. Soc. 2004, 126, 5962–5963.
[9] For the formation of 3ja, reaction with the F–J catalyst system gave
better results than the reaction with the A–J–O catalyst system.
[10] CCDC-922764 (8; see the Supporting Information) contains the sup-
plementary 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.
[7] For enamine activation of aldehydes in Diels–Alder and related re-
actions, see: a) J.-L. Li, T.-Y. Liu, Y.-C. Chen, Acc. Chem. Res. 2012,
45, 1491–1500; b) C. Grondal, M. Jeanty, D. Enders, Nat. Chem.
2010, 2, 167–178; c) K. Juhl, A. Jorgensen, Angew. Chem. 2003, 115,
1536–1539; Angew. Chem. Int. Ed. 2003, 42, 1498–1501.
[8] For the reaction of the phthalimide-containing enone, the enone was
only partially soluble in the reaction mixture, which likely caused
the slow reaction.
Received: February 15, 2013
Published online: April 4, 2013
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