Highly Enantioselective Construction of Polycyclic Spirooxindoles by
Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone
Catalyzed by Proline-Sulfonamide
Xiao, J. A., Liu, Q., Ren, J. W., Liu, J., Carter, R. G., Chen, X. Q., & Yang, H.
(2014). Highly Enantioselective Construction of Polycyclic Spirooxindoles by
Organocatalytic 1, 3‐Dipolar Cycloaddition of 2‐Cyclohexenone Catalyzed by
Proline‐Sulfonamide. European Journal of Organic Chemistry, 2014(26),
5700-5704. doi: 10.1002/ejoc.201402953
10.1002/ejoc.201402953
John Wiley & Sons, Inc.
Accepted Manuscript
http://cdss.library.oregonstate.edu/sa-termsofuse
SHORT COMMUNICATION
Highly Enantioselective Construction of Polycyclic Spirooxindole
via Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone
Catalyzed by Proline-Sulfonamide
Jun-An Xiao,[a] + Qi Liu,[a] + Ji-Wei Ren,[a] Jian Liu,[a] Rich G. Carter,[b] Xiao-Qing Chen,[a] and Hua
Yang*[a]
Abstract: An enantioselective 1,3-dipolar cycloaddition of 2-cyclohexene-1-one and azomethine ylide generated in situ from isatin and
amino ester was developed by employing proline sulfonamide as the
catalyst. Consequently, novel polycyclic spirooxindole scaffolds with
three contiguous stereocenters were prepared in high yield (up to
95%) with excellent diastereo- (> 20:1 dr) and enantio-selectivity (up
to 99% ee).
The natural alkaloids and relevant compounds featured with the
spiro[pyrrolidin-3,2′-oxindole] ring system have proven to
possess interesting biological activities, including antiinflammatory, anti-diabetic, anti-tumoric, anti-tubercular, or
acetylcholinesterase (AChE) inhibitory activities.[1] Driven by the
thorough investigation of biological activites of these compounds,
much attention has been directed to develop the structurally
diversified and stereocontrolled methodologies to access these
spirooxindoles in last decades.[2] In particular, the 1,3-dipolar
cycloaddition of azomethine ylides to electron-deficient alkenes
has been found to be a versatile and atom-economic pathway to
prepare the spiro[pyrrolidin-3,2′-oxindole] scaffold.[3] However,
the catalytic asymmetric synthesis of spiro-[pyrrolidin-3,2′oxindole] has still been posing a challenging task to date, since
most of the established approaches are either racemic synthesis
or employing enantiopure starting materials.[4]
In recent years, organocatalysis has emerged as a versatile
tool for asymmetric synthesis.[5] In 2012, Gong and co-workers
described the first organocatalytic asymmetric method to
construct
spiro[pyrrolidin-3,2′-oxindole]
via
1,3-dipolar
cycloadditions of N-Ac-2-oxoindolin-3-ylidenes and in situ
formed azomethine ylides.[6] Subsequently, Xu[3a] and Tu[3b]
also employed the organocatalytic 1,3-dipolar cycloaddition
strategy to
enantioselectively prepare spiro-[pyrrolidin-3,2′oxindole]s. It should be noticed that only the linear dipolarophiles
have been used in the asymmetric synthesis of spiro[pyrrolidin3,2′-oxindole]core and pyrrolidine derivatives.[3, 7] A review of the
literature reveals that the catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides with cyclic dipolarophiles,
especially cyclic α-enones showing comparatively lower
reactivity toward this type of reaction, were rarely explored.[8]
[a]
[b]
[+]
J. Xiao,[+] Q. Liu,[+] J. Ren, J. Liu, Prof. Dr. X. Chen, Prof. Dr. H. Yang
College of Chemistry and Chemical Engineering
Central South University
Changsha 410083 (P. R. China)
E-mail: [email protected]
Prof. Dr. R. G. Carter
Department of Chemistry
Oregon State University
Corvallis, Oregon 97331 (USA)
E-mail: [email protected]
These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.DOI: 10.1002/ejoc.201402953
Thus, it would be highly desirable to explore the 1,3-dipolar
cycloadditions using cyclic enone, providing a facile access to
novel polycyclic spirooxindole ring systems (as shown in
Scheme 1) .
On the other hand, the enones and enals activated by
lowering the LUMO through the formation of iminium
intermediates with chiral amine organocatalysts proved to be
highly reactive toward the azomethine ylides in high
stereoselectivity.[9] Usually, this protocol is limited to enal and
linear enone dipolarophiles, which can easily form iminium
species with amine. In 2007, Chen and coworkers reported their
elegant work on the organocatalytic enantioselective 1,3-dipolar
cycloaddition of cyclohexenone with azomethine imines
catalyzed
by
9-amino-9-deoxyepicinchona
alkaloids.[10]
Unfortunately, this research field on the organocatalytic 1,3dipolar cycloaddition using cyclic enone remained dormant since
then.
Scheme 1. Construction of spiro[pyrrolidin-3,2′-oxindole] via organocatalytic
1,3-dipolar cycloaddition
In our previous work, proline p-dodecylphenylsulfonamide
(Hua Cat®) was successfully employed to catalyze the [4+2]
cycloaddition of cyclohexenone via the HOMO activation.[11] Our
continued interest prompted us to investigate this catalytic
system in 1,3-dipolar cycloadditions of cyclohexenone with
azomethine ylide facilitated by the LUMO activation of
cyclohexenone. Herein, we report an organocatalyzed
asymmetric 1,3-dipolar cycloaddition using cyclic enone and
azomethine ylides to construct novel polycyclic spiro[pyrrolidin3,2′-oxindole] scaffolds.
SHORT COMMUNICATION
Table 1. Optimization of the 1,3-dipolar cycloaddition reaction[a]
entry
solvent
catalyst
additive (mol%)
time
(h)
yield
[b]
(%)
ee
(%)
[c]
1[d]
DCM
5a
Et3N (10%)
36
67
94
2[d]
DCM
5b
Et3N (10%)
48
54
85
[d]
3
DCM
5c
Et3N (10%)
60
44
70
4[d]
DCM
5d
Et3N (10%)
36
68
96
[d]
5
DCM
6
Et3N (10%)
60
30
4
6[d]
DCM
6
-
48
86
17
[d]
7
DCM
7
Et3N (10%)
48
trace
n.d.
8[d]
DCM
8
Et3N (10%)
48
-
n.d.
[d]
DCM
5d
HAc (10%)
48
49
rac
10[d]
DCM
5d
DABCO (10%)
60
38
82
[d]
11
DCM
5d
-
60
51
12
12[d]
DCM
5d
Et3N (20%)
72
21
83
[e]
13
DCM
5d
Et3N (10%)
48
35
87
14[f]
DCM
5d
Et3N (10%)
48
50
86
[g]
15
DCM
5d
Et3N (10%)
48
49
90
16[h]
DCM
5d
Et3N (10%)
48
58
89
[i]
17
DCM
5d
Et3N (10%)
36
90
96
18[i]
DCM
5d
Et3N (5%)
48
57
89
9
[a]
Unless otherwise noted, the reaction was carried out in 0.2 mmol scale in
DCM (4 mL) at RT with the molar ratio of 1a/2/3a = 1:1.2:1.5 and 20 mol%
catalyst. [b]Isolated yield. [c]Determined by chiral HPLC. [d]1a/2/3a = 1:1.5:1.5.
[e]
1a/2/3a = 1:1:1. [f]1a/2/3a = 1:1.5:1.2. [g]1a/2/3a = 1:1.2:2. [h]1a/2/3a = 1:1.5:1.
[i]
1a/2/3a = 1:1.2:1.5. [j]TFT = α,α,α-trifluorotoluene. Other solvents were also
evaluated in this reaction. (MeOH, 36 h, 70% yield, -28% ee; toluene, 36 h,
90% yield, 87% ee; DCE, 48 h, 86% yield, 94% ee; CHCl3, 60 h, 82% yield,
93% ee; α,α,α-trifluorotoluene, 12 h, 91% yield, 94% ee)
Initially, in the presence of triethylamine (10 mol%), proline pmethylphenylsulfonamide 5a was found to smoothly catalyze the
three-component 1,3-cycloaddition using isatin 1a, 2cyclohexenone 2, and diethyl aminomalonate 3a in a ratio of
1a/2/3a = 1:1.5:1.5. To our delight, excellent diastereo- (>20:1)
and enantioselectivity (94% ee), albeit with moderate chemical
yield (67%), were obtained (Table 1, entry 1). Encouraged by
this result, various proline sulphonamide catalysts were
screened and 5d gave the optimium yield and enantioselectivity
(Table 1, entries 2-4). Interestingly, a bifunctional catalyst 6
bearing both secondary amine and tertiary amine motifs was
therefore designed and synthesized via the direct coupling
between N-Boc proline and 1-benzylpiperazine followed by
deprotection of Boc protecting group. Presumably, it can activate
2-cyclohexenone and azomethine ylide simultaneously. Indeed,
this catalyst afforded relatively higher yield without adding any
additive. Unsatisfyingly, poor ee values were observed with or
without additive (Table 1, entries 5-6). Noticeably, when using
pyrrolidine as the catalyst, only the hemiaminal was formed. No
desired
product
was
observed
using
2,2,6,6tetramethylpiperidine as the catalyst (Table 1, entries 7-8). In
addition, different additives were also being screened for this
reaction. It was found that the additive had a significant effect on
this reaction. The addition of acetic acid afforded the racemic
product in decreased chemical yield. DABCO was less efficient
than triethylamine toward this reaction (Table 1, entries 9-10).
Furthermore, this reaction was carried out without any additive
and only moderate yield and poor ee (12%) were observed
(Table 1, entry 11). Intriguingly, an increase in the amount of
triethylamine (20 mol%) led to extremely sluggish reaction in
decreased chemical yield and enantioselectivity (entry 12).
Subsequently, the effect of molar ratio of reactants was studied
for this reaction. It was found that the reaction with molar ratio of
1a/2/3a at 1:1.2:1.5 gave the best chemical yield and
enantioselectivity (Table 1, entry 17). Next, the efficiency of
different solvents was also tested. Dichloromethane was found
to be the best for this transformation, although α,α,αtrifluorotoluene also can significantly facilitate the reaction and
provide both excellent chemical yield and enantioselectivity (see
table footnote).
Having established the optimal conditions, the scope of this
1,3-dipolar cycloaddition was investigated (as shown in Chart 1).
For 5- or 6-substituted isatins, the reaction proceeded well and
moderate to good yields and excellent enantioselectivity were
usually achieved to afford the corresponding cycloadduct 4a-4g.
However, the empolyment of 7-chloro isatin (4h) significantly
decreased
the
enantioselectivity
(83%
ee)
and
diastereoselectivity (7.7:1). Presumably, this could be explained
as that the presence of chlorine at C7 of isatin introduced the
steric hindrance for the N-H isatin moiety, interfering with the
hydrogen bond formation of N-H with catalyst. Moreover, using
different aminomalonic acid diester such as dimethyl
aminomalonate and di-iso-propyl aminomalonate also showed
good reactivity toward this 1,3-dipolar cycloaddition (4i-4o).
Surprisingly, the employment of cyclopentenone and
cycloheptenone in this reaction did not afford the corresponding
cycloadduct. Finally, the absolute configuration of 4j was
unequivocally established by X-ray crystallographic analysis of a
single crystal.[12]
We next turned our attention to examine the reactivities of Nprotected isatins in this reaction. However, to our surprise, the
enantioselectivity were severely eroded when using N-methyl or
benzyl isatin (Scheme 2), albeit with the maintained chemical
yield. These results suggested that the N-H isatin moiety has a
SHORT COMMUNICATION
sizable influence on the stereoselectivity and might be involved
with the stereocontrol in this reaction. However, the exact
catalytic mechanism still needs further investigation.
Chart 1. Scope of the 1,3-dipolar cycloaddition. [a]
Scheme 2. 1,3-Dipolar cycloaddition of N-protected isatins.
To further expand the synthetic utility of this cycloaddition
reaction, the reduction and decarboxylation reaction of the
corresponding spirooxindoles were carried out (Scheme 3). A
simple protocol of sodium borohydride in methanol can
successfully afford the corresponding alcohol 11 as a single
isomer in 86% yield and 96% ee. On the other hand, the
decarboxylated product was obtained via a two-step process,
including the mono-hydrolysis of diester followed by
decarboxylation. As a result, a mixture of exo:endo isomers
(70:30) was obtained. No apparent erosion of enantioselectivity
occurred and 91% and 95% ee were observed respectively.
Presumably, the exo-isomer would be thermodynamically
favourable. More interestingly, ibophyllidine-like compounds
14a-14c were synthesized in moderate yields and high
enantiopurity via Fischer indole synthesis.[13] These resulting
polycyclic structures simultaneously bear both indole and isatin
motifs, which therefore might possess interesting biological
activities.
Scheme 3. Transformation of the spirooxindole compounds.
[a]
Unless otherwise noted, the reaction was carried out in 0.2 mmol scale in
DCM (4 mL) at RT with a molar ratio of 1/2/3 at 1:1.2:1.5. [bDetermined by 1H
NMR. [c]Isolated yield. [d]Determined by chiral HPLC.
In summary, an enantioselective 1,3-dipolar cycloaddition of
cyclohexenone with azomethine ylide generated in situ from
SHORT COMMUNICATION
isatin and aminomalonate diester, catalyzed by readily available
proline p-dodecylphenylsulfonamide, was developed with high
yield and excellent stereoselectivities (up to 99% ee, > 20:1 dr).
This catalytic system could effectively activate the
cyclohexenone and enable the formation of hydrogen-bonding
between catalyst and dipole. It would significantly broaden the
synthetic application of cyclic enone in the enantioselective 1,3cycloaddition reaction and afford a facile access to novel
polycyclic spirooxindole ring systems, which could provide new
opportunities for medicinal chemistry and drug discovery.
Experimental Section
Typical experimental procedure for the asymmetric synthesis of
polycyclic spirooxindole 4a: Isatin 1a (0.20 mmol), aminomalonate
diester 3a (0.30 mmol, 1.5 equiv.), 2-cyclohexane-1-one 2 (23.0 mg, 0.24
mmol, 1.2 equiv.) and catalyst (20 mol%) were added to the designed
solvent (2 mL) followed by adding triethylamine (2.00 mg, 10 mol%).
After completion of the reaction (monitored by TLC), organic solvent was
removed in vacuo. Then the residue was purified via flash
chromatography to yield spirooxindole 4a as a white solid (72.0 mg, yield
90%, > 20:1 dr, 96% ee); m.p. 230-231°C; [α]D20 = +17.6 (c=0.3 in CHCl3);
1
H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H),
7.17 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H),
4.08-4.28 (m, 4H), 3.92 (s, 1H), 3.30-3.34 (m, 2H), 1.19-2.11 (m, 2H),
1.64-1.81 (m, 4H), 1.18-1.23 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ
207.9, 181.5, 170.1, 169.1, 143.0, 129.9, 129.7, 126.3, 121.6, 110.1,
76.7, 70.4, 62.0, 61.5, 59.5, 45.1, 40.1, 22.9, 22.5, 14.5, 14.3; IR (KBr) ν
3302, 2936, 1725, 1619, 1245, 1187, 1028, 851, 759 cm-1; HRMS (TOFES+) m/z: [M+Na]+ calcd for C21H24N2O6Na 423.1532, found 423.1519;
HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8
mL/min, UV: 254 nm), tR = 14.3 min (minor), 19.9 min (major).
Typical experimental procedure of indolospirooxindole 14a: To a
solution of polycyclic spirooxindole 4a (0.2 mmol) in acetic acid (2 mL)
was added phenylhydrazine 13 (43.3 mg, 0.4 mmol, 2 equiv.). The
mixture was then refluxed for 2 hours, and cooled at rt. The acetic acid
was removed under reduced pressure. The residue was dissolved in
EtOAc (10 mL) and washed with sat. aq. NaHCO3 (30 mL x 2). The
aqueous phase was back extracted with EtOAc (5 mL x 2). The
combined organic phase was dried, and concentrated under reduced
pressure. The crude mixture was purified by silica gel column
chromatography to give indolospirooxindole 14a as a white solid (59.6
mg, yield 63%, > 20:1 dr, 99% ee); m.p.＞300°C; [α]D20 = +155.7 (c=0.5
in CHCl3); 1H NMR (DMSO-d6, 400 MHz) δ 10.17 (s, 1H), 10.13 (s, 1H),
7.29-7.31 (m, 1H), 6.93-6.97 (m, 2H), 6.85-6.91 (m, 2H), 6.69-6.84 (m,
2H), 6.52 (t, J = 7.2 Hz, 1H), 4.15-4.31 (m, 4H), 3.99 (d, J = 6.4 Hz, 1H),
3.81 (s, 1H), 2.63-2.94 (m, 2H), 1.84-2.00 (m, 2H), 1.22-1.26 (m, 6H); 13C
NMR (DMSO-d6, 100 MHz) δ 181.53, 170.3, 169.3, 142.9, 136.9, 131.3,
130.6, 128.7, 126.4, 125.6, 125.6, 121.4, 120.8, 118.0, 111.2, 109.6,
109.5, 75.8, 69.9, 61.8, 61.4, 44.5, 43.8, 22.3, 19.6, 14.5, 14.3; IR (KBr) ν
3387 (br), 2979, 1732, 1620, 1469, 1248, 1108, 860, 746 cm-1; HRMS
(TOF-ES+) m/z: [M+Na]+ calcd for C27H27N3O5Na 496.1848, found
496.1839; HPLC analysis: (CHIRALCEL OD-H, 25% i-propanol/hexanes,
1.0 mL/min, UV: 254 nm), tR = 26.4 min (minor), 29.1 min (major).
Supporting Information (see footnote on the first page of this article):
Experimental procedures, NMR spectral and analytical data for the 4a4o, 6, 10a, 10b, 11, 12, 14a-14c; HPLC chromatograms for the 4a-4o,
10a, 10b, 11, 12, 14a-14c .
Acknowledgements
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21175155, 21276282 &
21376270), Hunan Provincial Science & Technology Department
(2012WK2007), and Central South University.
Keywords: organocatalysis • 1,3-dipolar cycloaddition •
spirooxindole • 2-cyclohexene-1-one • isatin
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SHORT COMMUNICATION
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SHORT COMMUNICATION
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SHORT COMMUNICATION
What proline sulphonamide
organocatalyst can do?
The highly enantioselective
construction of polycyclic
spirooxindole via 1,3-dipolar
cycloaddition of cyclohexenone with
azomethine ylide was achieved by
employing prolinosulphonamides as
the catalyst. This catalytic system
essentially benefited from the iminium
activation and hydrogen-bonding
formation induced by the
prolinosulphonamides.
Jun-An Xiao, [a] + Qi Liu, [a] + Ji-Wei
Ren, [a] Jian Liu, [a] Rich G. Carter, [b]
Xiao-Qing Chen [a] and Hua Yang, [a] *
Page No. – Page No.
Highly Enantioselective Construction
of Polycyclic Spirooxindole via
Organocatalytic 1,3-Dipolar
Cycloaddition of 2-Cyclohexenone
Catalyzed by Proline-Sulfonamide
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SHORT COMMUNICATION
Author(s), Corresponding Author(s)*
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Title
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