Enantioselective construction of multifunctionalized spirocyclohexaneoxindoles through organocatalytic Michael-Aldol cyclization of isatin derived alkenes with linear dialdehydes

Article abstract of DOI:10.1039/c2ob26205c

Optically active spirocyclohexaneoxindole motifs are very important building blocks for preparations of biologically active complexes, natural products, and pharmaceutical compounds. Herein, we report the syntheses of enantiopure spirocyclohexaneoxindoles through domino Michael-Aldol reactions between isatin derived alkenes and pentane-1,5-dial in the presence of diphenylprolinol silyl ether as an aminocatalyst. As a result, a series of multistereogenic and functionalized spirocyclohexaneoxindoles have been obtained in good yields with moderate diastereoselectivities and excellent enantioselectivities. In addition, electronic circular dichroism (ECD) spectroscopy and time-dependent density functional theory (TD-DFT) were used to investigate the rational structures of spirocyclohexaneoxindoles.

Full text of DOI:10.1039/c2ob26205c

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PAPER
Enantioselective construction of multifunctionalized
spirocyclohexaneoxindoles through organocatalytic Michael–Aldol cyclization
of isatin derived alkenes with linear dialdehydes†
Xiao-Fei Huang, Zhao-Min Liu, Zhi-Cong Geng, Shao-Yun Zhang, Yong Wang* and Xing-Wang Wang*
Received 25th June 2012, Accepted 13th September 2012
DOI: 10.1039/c2ob26205c
Optically active spirocyclohexaneoxindole motifs are very important building blocks for preparations of
biologically active complexes, natural products, and pharmaceutical compounds. Herein, we report the
syntheses of enantiopure spirocyclohexaneoxindoles through domino Michael–Aldol reactions between
isatin derived alkenes and pentane-1,5-dial in the presence of diphenylprolinol silyl ether as an
aminocatalyst. As a result, a series of multistereogenic and functionalized spirocyclohexaneoxindoles
have been obtained in good yields with moderate diastereoselectivities and excellent enantioselectivities.
In addition, electronic circular dichroism (ECD) spectroscopy and time-dependent density functional
theory (TD-DFT) were used to investigate the rational structures of spirocyclohexaneoxindoles.
Introduction
Multistereogenic cyclohexanes1 and oxindoles2 are two very
important types of structural motif, whose derivatives are not
only prevalent in natural products, pharmaceutical compounds
and biologically active molecules, but also serve as versatile
intermediates in organic synthesis. Therefore, chiral multistereo-
Fig. 1 Naturally occurring and biologically active spirocyclic products.
genic spirocyclohexaneoxindole derivatives, which combine the
important backbones of cyclohexanes and oxindoles, are particu-
larly intriguing and are featured in a large number of natural pro-
ducts and medicinally relevant compounds (Fig. 1).3 For
multistereogenic spiro[cyclohexane-1,3′-indoline]-2′,4-diones via
[4 + 2] double Michael additions.6 Gong et al.,7 Wang et al.,8
and our group9 each reported highly enantioselective syntheses
of spiro[cyclohexanone-oxindole] and spiro[cyclohexenone-
oxindole] derivatives through organocatalytic cascade transform-
ations. In 2010, Rios’ and Chen’s groups independently found
that six-membered spirocyclic oxindoles, such as spiro[cyclohex-
enecarbaldehyde-oxindoles] and spiro[cyclohexanol-oxindoles],
could be constructed via an organocatalytic domino Michael–
Michael–Aldol reaction,10 or Michael–Michael–Michael–Aldol
sequences.11 However, to the best of our knowledge, there is no
literature reported for the enantioselective synthesis of six-
membered spirocyclohexaneoxindole compounds bearing both
formyl and hydroxyl functional groups. Herein, we present our
preliminary results on a tandem Michael–Aldol process between
isatin derived alkenes and pentane-1,5-dial catalyzed by a diphe-
nylprolinol silyl ether catalyst, which produces a series of multi-
stereogenic and functional spirocyclohexaneoxindoles in good
yields with moderate diastereoselectivities and excellent
enantioselectivities.
instance, compound A, a nonsteroidal PR modulator,3b,e is used
in female healthcare as a progesterone receptor antagonist, as
well as in contraception and the treatment of uterine fibroids,
endometriosis and hormone-related cancers. Gelsemine3c can
excite the central nervous system. SR 121463 A3a,d is an effec-
tive orally active vasopressin V2 antagonist.
The asymmetric synthesis of spirocyclohexaneoxindoles
involves the stereo-controlled installation of a spiroquaternary
chiral carbon center, which has been a challenging task.4
Recently, spirocyclic oxindole skeletons have been constructed
by asymmetric organocatalytic domino reactions.5 In 2009,
Melchiorre and co-workers pioneered the synthesis of
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou 215123, P. R. China. E-mail: wangxw@suda.edu.cn;
Fax: +86 (0)512 65880378; Tel: +86 (0)512 65880378
†Electronic supplementary information (ESI) available: detailed experi-
mental procedures, characterization data and HPLC chromatograms for
all compounds. CCDC 875824. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2ob26205c
In 2007, Hayashi and co-workers reported the first example of
a one-step synthesis of substituted cyclohexane derivatives with
8794 | Org. Biomol. Chem., 2012, 10, 8794–8799
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control of four stereogenic centers via a Michael–Henry
sequence using hexane-1,5-dial and 2-substituted nitroalkenes.12
Shortly after, Hong et al.13 and Córdova et al.14 found that
diphenylprolinol methyl ether15 could also effectively catalyze
the direct domino Michael–Aldol reaction of glutaraldehyde and
a Michael acceptor to afford highly functionalized cyclohexane
and cyclohexene compounds in high diastereoselectivities and
enantioselectivities. Based on these findings, we envisioned that
glutaraldehyde would act as a four-carbon unit which would be
useful to trigger a [4 + 2] spiroannulation through an asymmetric
domino Michael–Aldol reaction with isatin derived alkenes
(Scheme 1). It was hypothesized that catalyst I would activate
glutaraldehyde 2 to generate the intermediate enamine B, which
would react with the isatin derived electron deficient alkene 1 via
a Michael addition to form C. Subsequently, cyclization would
yield D through the intramolecular Aldol reaction. The desired
six-membered spirocyclic product 3 would then form through
hydrolysis of D (Scheme 1).
L-diphenylprolinol silyl ether I in chloroform at room tempera-
ture for 14 hours (Table 1, entry 1). The desired product 3a was
obtained in 30% yield (total 54% yield with 1.2 : 1 dr), albeit
with 98% ee for the major diastereomer. Then, the reactions with
substrates 1b and 1c bearing electron-donating groups (–CH3
and –Bn) were tested, which afforded the desired products 3b
and 3c with lower yields of 17% and 11%, respectively (Table 1,
entries 2 and 3). Subsequently, diethyl 2-(1-(benzyloxycarbo-
nyl)-2-oxoindolin-3-ylidene)malonate 1d was used for this reac-
tion, which produced 3d in 72% yield (total 87% yield with
4.8 : 1 dr) and 95% ee (Table 1, entry 4). Encouraged by this
outcome, the reaction of diethyl 2-(1-(tert-butoxycarbonyl)-2-
oxoindolin-3-ylidene)malonate 1e was investigated, and ent-3e
was obtained in 79% yield (total 90% yield with 7.3 : 1 dr) with
96% ee (Table 1, entry 5). By comparison, D-diphenylprolinol
silyl ether II, as an enantiomer of catalyst I, was also examined
for this transformation, and the corresponding desired product 3e
was obtained in 81% yield (total 92% yield with 7.3 : 1 dr) with
98% ee (Table 1, entry 6). Then –Boc protected 1f and 1g were
investigated for this transformation with catalysts I and II. The
corresponding products were obtained in 48–54% yields, with
95–≥99% ee values (Table 1, entries 7–10). Therefore, 1e was
selected as a model substrate and D-diphenylprolinol silyl ether
II as the optimal catalyst to further investigate the Michael–
Aldol sequence. To our delight, the spirocyclohexaneoxindole
structure in the crystalline solid state of ent-3e was finally
Results and discussion
Initially, the above mentioned organocascade strategy was evalu-
ated by conducting a reaction between diethyl 2-(2-oxoindolin-
3-ylidene)malonate 1a and pentane-1,5-dial 2 (50% aqueous
solution of tetrahydro-2H-pyran-2,6-diol) with 10 mol% of
Scheme 1 Envisaged mechanism for the organocatalytic asymmetric Michael–Aldol spiroannulation of isatin derived alkenes with linear
dialdehydes.
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Table 1 Evaluation of model substrates and catalystsa
Entry
Catalyst
Product
Yieldb (%)
drc
eed (%)
1
2
3
4
I
I
I
I
I
II
I
II
I
II
R1, R2 = COOEt, R3 = H (1a)
R1, R2 = COOEt, R3 = CH3 (1b)
R1, R2 = COOEt, R3 = Bn (1c)
R1, R2 = COOEt, R3 = Cbz (1d)
R1, R2 = COOEt, R3 = Boc (1e)
R1, R2 = COOEt, R3 = Boc (1e)
R1 = Ph, R2 = H, R3 = Boc (1f)
R1 = Ph, R2 = H, R3 = Boc (1f)
R1 = COOEt, R2 = H, R3 = Boc (1g)
R1 = COOEt, R2 = H, R3 = Boc (1g)
30 (54)/3a
— (17)/3b
— (11)/3c
72 (87)/3d
79 (90)/ent-3e
81 (92)/3e
48 (88)/ent-3f
52 (92)/3f
51 (85)/ent-3g
54 (90)/3g
1.2 : 1
n. d.e
n. d.
4.8 : 1
7.3 : 1
7.3 : 1
1.2 : 1
1.3 : 1
1.5 : 1
1.5 : 1
98
n. d.
n. d.
95
−96
98
−99
95
−96
>99
5
6f
7g
8g
9h
10h
a Reactions were performed with 1 (0.2 mmol), 2 (50% in water, 91 μL, 0.5 mmol) and 10 mol% catalyst in 1.0 mL CH2Cl2 at room temperature for
14 h. b Isolated yield for the major diastereomer. Total yields for both diastereomers in parentheses. c Determined by chiral HPLC analysis or by
1H NMR. d Determined by chiral HPLC analysis for the major enantiomer. e n. d. = not detected. f For 10 h. g For 35 h. h For 0.5 h.
Table 2 Optimization of reaction conditionsa
Fig. 2 X-ray crystal structure of ent-3e.
Entry Solvent Additive Time (h) Yieldb (%) drc
eed (%)
determined by single crystal X-ray diffraction analysis (Fig. 2),
which showed that the formyl and hydroxy groups are in the
1
2
3
4
5
6
7
8
CHCl3
H2O
MeOH
CH2Cl2
THF
Toluene
CH3CN
MTBE
DMF
CH2Cl2 E1
CH2Cl2 E2
CH2Cl2 E3
CH2Cl2 E4
CH2Cl2 E5
CH2Cl2 E6
CH2Cl2 E7
—
—
—
—
—
—
—
—
—
10
12
12
8
23
33
9
23
23
27
27
27
27
27
15
15
8
81
<5
<5
86
64
58
55
77
48
77
38
12
56
60
<5
84
79
85
81
7.3 : 1 98
—
—
trans configuration.18
n. d.h
n. d.
Using the optimal model substrate and catalyst, other para-
meters were further optimized, including the reaction solvent,
additive, reactant ratio and temperature, and the results are sum-
marized in Table 2. In protic solvents such as methanol and
water, no conversion was detected (Table 2, entries 2 and 3).
When aprotic solvents such as dichloromethane, tetrahydrofuran,
toluene, acetonitrile, methyl tert-butyl ether, and dimethyl for-
mamide were employed, moderate to good yields (48–86%), low
to moderate diastereoselectivities, and excellent enantioselectivi-
ties were obtained (>94% ee, 1.8 : 1 to 8.5 : 1 dr, Table 2, entries
4–9). Based on the screening results, dichloromethane was found
to be the best reaction medium for this reaction, which gave 3e
in 86% yield with >99% ee, 8.5 : 1 dr within 8 hours (Table 2,
entry 4). The effects of acid counteranions16 on the reaction were
investigated, including acetic acid, benzoic acid and its deriva-
tive, D- and L-camphorsulfonic acids, as well as R- or S-binol-
phosphoric acids. However, the results revealed that acid addi-
tives had a detrimental effect on the reactivity, as evidenced by
lower yields (Table 2, entries 10–16). When the amount of
8.5 : 1 >99
6.9 : 1 96
7.6 : 1 96
1.8 : 1 99
7.5 : 1 97
3.2 : 1 94
7.6 : 1 99
9
10
11
12
13
14
15
16
17e
18f
19g
—
97
—
n. d.
6.2 : 1 >99
6.6 : 1 99
—
n. d.
8.3 : 1 99
CH2Cl2
CH2Cl2
CH2Cl2
—
—
—
8.1 : 1 >99
8.4 : 1 >99
7.7 : 1 >99
8
3.5
a Reactions were performed with 1e (0.2 mmol), 2 (50% in water, 91 μL,
0.5 mmol) and 10 mol% catalyst II in 1.0 mL solvent at room
temperature. b Isolated major diastereomer. c Determined by H NMR of
1
crude products. d Determined by chiral HPLC analysis. e 1.5 equiv. of 2
was used. f 5 equiv. of 2 were used. g At 40 °C. h n. d. = not detected.
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Table 3 Substrate scope in the reactiona
Entry
Products
Time (h)
Yieldb (%)
drc
8.5 : 1
8.9 : 1
11.2 : 1
11.7 : 1
8.7 : 1
7.9 : 1
7.6 : 1
5.2 : 1
4.9 : 1
eed (%)
1
2
3
4
5
6
7
8
R1 = H, R2 = CO2Et (3e)
8
10
7
15
1.5
1
1
2
4
4
86
84
88
71
82
79
83
74
67
87
83
88
>99
>99
99
98
98
97
98
98
98
R1 = 5-CH3, R2 = CO2Et (3h)
R1 = 5-OCH3, R2 = CO2Et (3i)
R1 = 5,7-(CH3)2, R2 = CO2Et (3j)
R1 = 5-F, R2 = CO2Et (3k)
R1 = 5-Cl, R2 = CO2Et (3l)
R1 = 5-Br, R2 = CO2Et (3m)
R1 = 6-Br, R2 = CO2Et (3n)
R1 = H, R2 = CO2Mi e (3o)
R1 = H, R2 = CO2 Pr (3p)
R1 = H, R2 = CO2Bn (3q)
R1 = H, R2 = CO2Cy (3r)
9
10
11
12
11.5 : 1
11.2 : 1
11.8 : 1
>99
>99
>99
5
10
a Reactions were performed with 1 (0.2 mmol), 2 (50% in water, 91 μL, 0.5 mmol) and 10 mol% catalyst II in 1.0 mL CH2Cl2. b Isolated major
diastereomer. c Determined by 1H NMR of crude products. d Determined by chiral HPLC analysis.
glutaraldehyde 2 was decreased from 2.5 to 1.5 equiv., the yield
dropped slightly to 79%, albeit with maintained enantioselectiv-
ity (Table 2, entry 17 vs. 4). When 5.0 equiv. of 2 was used,
neither the yield nor the enantioselectivity were found to be
obviously affected in comparison with those using 2.5 equiv.
(Table 2, entry 18 vs. 4). In addition, the reaction in dichloro-
methane proceeded faster at 40 °C, which resulted in the opti-
cally pure product 3e in a lower yield of 81% (Table 2, entry 19
vs. 4). Thus, the established optimal reaction conditions were a
molar ratio of 1 : 2.5 between 1 and 2, a 10 mol% catalyst
loading of II and dichloromethane as the reaction solvent at
room temperature.
Having established the optimal reaction conditions, we further
explored the scope of the II catalyzed cascade Michael–Aldol
sequence between isatylidene malonic esters 1e, 1h–r and glutar-
aldehyde 2, and the results are summarized in Table 3. For
diethyl 2-(1-(tert-butoxycarbonyl)-2-oxoindolin-3-ylidene)malo-
nates 1e and 1h–n, moderate to high yields (71–88%), moderate
diastereoselectivities (5.2 : 1 to 11.7 : 1), and excellent enantio-
selectivities (97% to >99%) were obtained through this cascade
approach, irrespective of the variation in the electronic and steric
properties of the substituents attached to the phenyl rings of the
oxindole backbones (Table 3, entries 1–8). However, the reactiv-
ities of these reactions were found to be obviously effected by
the electronic properties of the substituents on the phenyl rings
of the oxindole backbones. Notably, the Michael–Aldol reactions
with substrates 1h–j bearing electron-donating groups (–Me,
–OMe) generally required longer reaction times (7–15 hours),
providing the desired products 3h–j in 71–88% yields with mo-
derate diastereoselectivities and excellent enantioselectivities
(Table 3, entries 2–4). In contrast, the substrates 1k–n bearing
halogen substituents (–F, –Cl, –Br) on the oxindole backbones
performed very well in the corresponding cascade reactions in
less than two hours, resulting in the desired products 3k–n in
74–83% yields with 5.2 : 1 to 8.7 : 1 dr and over 97% ee
(Table 3, entries 5–8). In addition, the other dialkyl 2-(1-(tert-
butoxycarbonyl)-2-oxoindolin-3-ylidene)malonates 1o–r, con-
taining dimethyl, diisopropyl, dibenzyl and dicyclohexyl groups,
were also investigated for this transformation, and all reactions
proceeded smoothly to produce the expected products in
67–88% yields with 98% to over 99% ee, and 4.9 : 1 to 11.8 : 1
dr (Table 3, entries 9–12). The catalytic results showed that the
substrate 1o, with the less bulky dimethyl substituent, gave the
product in a lower yield of 67% with 98% ee, whereas substrate
1r bearing the more bulky dicyclohexyl group was less reactive,
although it generated the desired product 3r in 88% yield with
over 99% ee (Table 3, entry 12).
A gram-scale synthesis of 3e was performed in the presence
of 10 mol% of catalyst II. As a result, 1.20 g of the desired
product 3e was readily isolated through column chromatography
in 82% yield with over 99 : 1 dr and 98% ee (Scheme 2). Fur-
thermore, the –Boc protecting group was easily removed in
TFA–CH2Cl2 (1 : 10), and the desired product 4 was obtained in
93% yield with over 99% ee. Finally, the spiro[cyclohexandiol-
oxindole] compound 5 could be converted from 4 through
NaBH4 reduction in 97% yield with 98% ee (Scheme 3).
Finally, the absolute configuration (AC) of the spirocyclohexa-
neoxindoles were determined by means of chiroptical
methods.17 In this study, ECD spectra were calculated by the
TD-DFT method, which has been proven to be useful in predict-
ing ECD spectra and assigning the AC of organic molecules.19
Based on the relative configuration obtained by X-ray diffraction
of 3e, the TD-DFT method was performed to calculate the elec-
tronic circular dichroism (ECD) spectra at the B3LYP/6-31G*
level. All conformations were calculated at the same level to
confirm their stability (no imaginary frequencies).20 As shown in
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Scheme 2 Operation of the reaction at gram-scale.
Scheme 3 Synthesis of the spiro[cyclohexandiol-oxindole] com-
pound 5.
Fig. 4 Experimental ECD spectra (full trace) and simulated spectra
(dashed trace) proving (a) the 1S,3R,6R-ent-3e absolute configuration
catalyzed by I (L-diphenylprolinol silyl ether) and (b) the 1R,3S,6S-3e
absolute configuration catalyzed by II (D-diphenylprolinol silyl ether).
dialdehydes catalyzed by readily available chiral diphenylproli-
nol silyl ether. The final products could be achieved in moderate
to good yields with excellent enantioselectivities and moderate
diastereoselectivities. The rational configurations of ent-3e and
3e were assigned by means of TD-DFT calculations of the ECD.
The theoretical data are in good agreement with the experimental
ECD spectra. There are several salient features of the present
protocol, including the use of aqueous starting materials, oper-
ational simplicity, excellent stereoselective control in the multi-
stereogenic formation, and the highly efficient one-pot synthesis
of the spirocyclohexaneoxindole structures. Further expansion of
the substrate scope of this catalytic system, as well as biological
evaluations of the resulting spiro compounds, are ongoing in our
laboratory.
Fig. 3 Optimization conformations of compound 3e (energies in
kcal mol−1).
Fig. 3, two most stable conformations of ent-3e (a and b), which
differ in the disposition of the CHO group, were located by DFT
(B3LYP/6-31G*) calculations. The structure of a is more stable
than b, with an energy difference of 2.50 kcal mol−1
.
Calculation of the ECD spectra of a (ent-3e) and c (3e) was
carried out using the TD-DFT-B3LYP/6-31G(d) level, as shown
in Fig. 4. Electronic excitation energies (nm) and rotational
strengths (Δε) were calculated for a and c. In order to cover the
220–300 nm range, 30 transitions were calculated. As shown in
Fig. 4, the simulated spectra are in good agreement with the
spectral data, and the 1S,3R,6R configuration could be reliably
assigned to compound ent-3e, catalyzed by I. The 1R,3S,6S
configuration of 3e was in agreement with that catalyzed by II.
Acknowledgements
The authors thank two reviewers for their constructive and perti-
nent comments. We are grateful for the financial support from
the National Natural Science Foundation of China (21072145,
21272166), the Foundation for the Author of National Excellent
Doctoral Dissertation of PR China (200931), and the Natural
Science Foundation of Jiangsu Province of China (BK2009115).
This project was funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
Conclusions
In summary, we have developed an efficient asymmetric
methodology for the construction of formyl, hydroxy, and ester
Notes and references
functionalized spirocyclohexaneoxindoles via
Michael–Aldol cyclization of isatin derived alkenes with linear
a
cascade
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