Enantioselective synthesis of spiro[cyclohexane-1,3′-indolin]- 2′-ones containing multiple stereocenters via organocatalytic Michael/aldol cascade reactions

Article abstract of DOI:10.1016/j.tetlet.2013.02.030

Organocatalytic reactions of 3-olefinic oxindoles and pentane-1,5-dial were investigated to provide access to substituted spirocyclohexane oxindoles via Michael/aldol cascade reactions. Of particular interest, we have examined the stereochemical outcome o

Full text of DOI:10.1016/j.tetlet.2013.02.030

Tetrahedron Letters 54 (2013) 2311–2314
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of spiro[cyclohexane-1,30-indolin]-20-ones
containing multiple stereocenters via organocatalytic Michael/aldol cascade
reactions
⇑
Arun K. Ghosh , Bing Zhou
Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Organocatalytic reactions of 3-olefinic oxindoles and pentane-1,5-dial were investigated to provide
access to substituted spirocyclohexane oxindoles via Michael/aldol cascade reactions. Of particular inter-
est, we have examined the stereochemical outcome of electron withdrawing and electron-donating
groups on the oxindole ring nitrogen. Interestingly, we have observed that the N-protecting group on
the oxindole has critical effect on aldol ring closure leading to ultimate stereochemical outcome of the
hydroxyl center. The overall process is quite efficient and afforded products with multiple stereocenters
in high yields and excellent enantioselectivities (>99% ee).
Received 9 January 2013
Revised 4 February 2013
Accepted 8 February 2013
Available online 27 February 2013
Keywords:
Organocatalyst
Spiroindole
Ó 2013 Elsevier Ltd. All rights reserved.
Michael reaction
Aldol reaction
Asymmetric catalysis
Spiro[cyclohexane-1,30-indolin]-20-one is an important struc-
tural motif for many bioactive natural products as well as for
medicinal agents.1,2 Over the years, various stereoselective syn-
thetic protocols have been developed.3–5 However, enantioselec-
tive and efficient methods for construction of these structural
features did not emerge until recently.6–9 Organocatalytic cascade
reactions leading to functionalized cyclohexane rings were earlier
developed by Enders et. al.10 In the context of our design and syn-
thesis of molecular probes, we have incorporated a spiro-indoline
structural template as a P20-ligand in the HIV-1 protease active
site.11 For further access to spiroindoline scaffolds, we have inves-
tigated the feasibility of organocatalytic Michael/aldol cascade
reactions involving 3-olefinic oxindole and pentane-1,5-dialde-
hyde.12–15 Recently, Wang and co-workers have reported a related
work and their report prompted us to disclose our investigation in
this area.16 Herein, we report (R)-diphenylprolinol silyl ether-cata-
lyzed tandem Michael/aldol reaction leading to the synthesis of a
variety of spiro[cyclohexane-1,30-indolin]-20-one derivatives with
four/five contiguous chiral centers in excellent yield and optical
purity. Interestingly, protecting groups on the indolin-2-one nitro-
gen played important roles in the stereochemical outcome of the
final aldol ring closure. The electron-withdrawing N-protecting
group in the presence of (R)-catalyst provided spiro[cyclohexane-
1,30-indoline] derivatives with 6-(R)-hydroxy configuration. On
the other hand, the electron-donating N-protecting group fur-
nished spiro[cyclohexane-1,30-indoline] derivatives with 6-(S)-hy-
droxy configuration as the major product.
We initially investigated a catalytic domino reaction of 3-ole-
finic oxindole 1a and pentane-1,5-dial 212,13 using organocalatyst
A (10 mol %) in THF at ambient temperature, under an aerobic
atmosphere as shown in Scheme 1. The desired tandem Michael/al-
dol product 5a was isolated in 41% yield. As shown in Table 1, the
ratio of diastereomers was moderate (3.5:1:0.5:0.3). However, the
major product 5a showed excellent enantioselectivity (96% ee, Ta-
ble 1, entry 1) in HPLC analysis.17 The overall process presumably
proceeded through a Michael reaction resulting in intermediate 3
followed by an intramolecular aldol reaction providing intermedi-
ate 4. Addition of an acidic co-catalyst, such as ortho-fluorobenzoic
acid, trifluoroacetic acid, or acetic acid, failed to improve the yield
(Table 1, entries 2–4). We investigated other organic solvents such
as CH2Cl2, toluene, N,N-dimethylformamide (DMF), hexane, and
CH3CN (entries 5–9). As it turned out that the choice of solvent
was crucial to this Michael-aldol tandem reaction and the best re-
sults were obtained using DMF as the solvent, affording 5a as the
major diastereomer (6:1:0.5:0.4) in 80% yield and showed excel-
lent enantioselectivity for the major diastereomer (>99% ee, entry
8). An attempt to perform the reaction at lower temperature re-
sulted in low conversion (entry 10).
We subsequently explored substrate scope and limitations un-
der the optimized reaction conditions (Fig. 1). As evidenced by
the results in Table 2, the reaction proceeded smoothly with aro-
⇑
Corresponding author. Tel.: +1 765 494 5323.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.030

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A. K. Ghosh, B. Zhou / Tetrahedron Letters 54 (2013) 2311–2314
Ph
+
Ph
Ph
OTMS
A (10 mol %)
Ph
N
Ph
TMSO
N
H
H
O
H
O
H
O
H
O
+
Ph
N
_
Boc
Michael
O
1a
2
N
Ph
Ph
Boc
3
+
N
OHC
Ph
TMSO
H
Ph
Aldol
_
OH
O
O
O
N
N
Boc
5a
Boc
4
Scheme 1. Michael/aldol cascade with oxindole 1a and dialdehyde 2.
Table 1
CHO
Me
OHC
Michael/aldol reaction optimizationa
OHC
Ph
Ph
Ph
OH
OH
O
H
O
O
O
H
OH
O
N
N
A
O
+
Boc
Boc
N
10 mol %
N
5a
OMe
5b
5d
(99% ee)
(99% ee)
Boc
Boc
1a
2
5a
O
CHO
CHO
Entry
Solvent
T (h)
Yieldb (%)
drc
eed (%)
1
THF
THF
THF
THF
CH2Cl2
Toluene
Hexane
DMF
CH3CN
DMF
48
48
48
48
48
48
48
20
48
48
41
<10
<5
<5
<5
<5
<5
80
<5
16
3.5:1:0.5:0.3
n.d.
96
OH
OH
2e
3f
4g
5
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>99
n.d.
99
O
O
n.d.
n.d.
n.d.
n.d.
N
N
Boc
Boc
5c
(98% ee)
(99% ee)
6
7
8
CHO
CHO
O2N
n.d.
6:1:0.5:0.4
n.d.
7:1:0.5:0.4
9
Cl
10h
OH
OH
O
O
a
Unless otherwise noted, the reaction was performed by employing 1a
(0.1 mmol), dialdehyde (50% in water, 0.3 mmol), and organocatalyst
N
N
2
A
Boc
Boc
5e
NO2
5f
(99% ee)
(99% ee)
(0.01 mmol) in the indicated solvent (0.5 mL) at room temperature. n.d. = not
determined.
b
Isolated yield.
CHO
CHO
c
Determined by 1H NMR spectroscopy.
O
d
Determined by HPLC of the major diastereomer.
Ortho-fluorobenzoic acid (0.01 mmol) was added.
Trifluoroacetic acid (0.01 mmol) was added.
Acetic acid (0.01 mmol) was added.
e
OH
OH
f
O
O
g
N
N
h
This reaction was performed at 0 °C.
Boc
Boc
5g
5h
(99% ee)
CHO
(98% ee)
CHO
matic substituents to give desired products in high yields. The sub-
stituents on the aryl ring have little effect on the enantioselectivity
of the major isomer. Monosubstituted phenyl methyleneindolinon-
es proceeded with excellent enantioselectivity ranging from 98% to
99% ee (entries 1–7). However, electronic properties of aryl substit-
uents showed definite effect on diastereoselectivity. Electron-
donating groups resulted in better diastereoselectivity. As shown,
a high diastereomeric ratio of 7:1:0.5:0.4 was observed for 3-
methoxyphenyl substituted methyleneindolinone, whereas a dr
of 3:1:0.7:0.5 was observed for 3-nitro-phenyl substituted methyl-
eneindolinone (entry 3 vs 7). Reactions with both heterocyclic and
alkyl methyleneindolinones also proceeded with excellent enanti-
oselectivity (entries 8 and 9). We further examined the cyclization
reaction using an N-acetyl group in indole in place of an N-Boc pro-
tecting group. This resulted in product 5j in excellent yield with
excellent enantioselectivity; however, the diastereomeric ratio
(3:1:0.8:0.2; entry 10) was lower compared to the Boc-protected
derivative (entry 1).
OH
OH
O
O
N
N
Boc
Ac
5i
5j
(95% ee)
(95% ee)
Figure 1. Structure and enantioselectivity of major isomer.
sure with opposite hydroxyl stereochemistry as the major diaste-
reomer. The results in Table 3 show various N-alkyl protecting
groups, such as methyl, allyl, and benzyl groups, provided products
5k–5m as the major diastereomers in excellent yields (70–84%)
and excellent enantioselectivity for the major diastereomer
(>99%, entries 1–3). Furthermore, both electron-donating (Me)
and electron-withdrawing (Cl) substituents at the C4-position of
the phenyl group afforded the corresponding products in high
yields with excellent enantioselectivity for the major diastereomer
We then examined the effect of electron-donating N-protecting
groups on the oxindole. Interestingly, this resulted in aldol ring clo-

A. K. Ghosh, B. Zhou / Tetrahedron Letters 54 (2013) 2311–2314
2313
Ph
Table 2
Enantioselective syntheses of spirooxindolesa
OHC
OHC
CHO
R1
O
+
N
R1
O
O
Boc
OH
O
6
A
1a
O
H
H
+
N
(10% mol)
Boc
N
A
(15 mol %)
Boc
65% yield
1a-i
2
5a-i
DMF, 40°C ,
7 days
Entry
R1
Pdtb (Y %)
drc (ee %)d
OHC
Ph
1
2
3
4
5
6
7
Ph
4-Me-Ph
5a (80)
5b (82)
5c (82)
5d (84)
5e (74)
5f (80)
5g (74)
5h (80)
5i (54)
5j (90)
6:1:0.5:0.4 (99)
6:1:0.5:0.3 (99)
7:1:0.5:0.4 (98)
5.5:1:0.5 (99)
5.2:1:0.5:0.5 (99)
3:1:0.5 (99)
3:1:0.7:0.5 (99)
6:1:0.5:0.3 (98)
6:1:0.7 (95)
3
2
3-OMePh
2-OMe-Ph
3-Cl-Ph
4-NO2-Ph
3-NO2-Ph
2-furyl
Pr
OH
O
N
5q
Boc
dr = 3:1:0.3:0.2
8e
9e
10f
(major isomer 99% ee)
Ph
3:1:0.8:0.2 (95)
Scheme 2. Reaction of oxindole 1a and 3-methylpentane-1,5-dial 6.
a
General reaction conditions: oxindole (0.1 mmol), dialdehyde 2 (50% in water,
0.3 mmol), and organocatalyst A (0.01 mmol) in DMF (0.5 mL) at 23 °C.
b
Isolated combined yield.
OHC
c
Determined by 1H NMR of crude product.
d
The ee was determined by chiral-phase HPLC analysis of major diastereomer.
The reaction was performed for 3 days.
Oxindole is protected as NAc.
Ph
e
A
OH
f
(10 mol %)
1a
2
+
O
DMF, 20 h
N
Boc
75% yield, >99% ee
(1 gram scale)
5a
Table 3
1. NaBH4
2. 4-NO2-PhCOCl
Et3N
Syntheses of spirooxindoles with N-alkyl groupsa
56% yield
for 2 steps
OHC
R1
R1
O
O
H
O
H
OH
O
A
O
+
O
N
O2N
(10% mol)
R2
N
Ph
R2
1k-p
2
5k-p
OH
O
Entry
R1
R2
Pdtb (Y%)
drc (ee %)d
N
Boc
1
2
3
4
5
6
Ph
Ph
Ph
p-ClPh
p-MePh
pNO2Ph
Me
Bn
Allyl
Allyl
Allyl
Allyl
5k (70)
5l (82)
5m (84)
5n (74)
5o (74)
5p (70)
6.5:1:0.5 (99)
6:1:0.5:0.3 (99)
7:1:0.4 (99)
6.5:1:0.3:0.2 (99)
7:1:0.5:0.5 (99)
2:1:0.5 (99)
7
Scheme 3. Synthesis of benzoate 7.
a
General reaction conditions: the reaction was performed by employing 3-ole-
unambiguously through X-ray crystallographic analysis. As shown
in Scheme 3, benzoate derivative 7 was prepared by reduction of
5a with NaBH4 followed by reaction of the resulting alcohol with
4-nitrobenzoyl chloride in the presence of Et3N in 56% yield over
two-steps. This was later recrystallized from methanol (23 °C).
Subsequent single crystal X-ray crystallographic analysis sup-
ported the assignment of the relative and absolute stereochemistry
shown in Figure 2 (see Supplementary data for the details of X-ray
analysis).19
In conclusion, we have developed a diastereoselective organo-
catalytic Michael/aldol cascade reaction that provided convenient
access to functionalized spirooxindoles with up to five consecutive
stereogenic centers, including a spiro quaternary center. The prod-
ucts were obtained in excellent yield and the major diastereomer
showed excellent enantioselectivity. In addition, depending upon
our selection of N-protecting group on the oxindole, we were able
to effectively control the stereochemical outcome of the hydroxyl
center upon aldol ring closure. Further studies and applications
of this methodology are the subject of current investigation in
our laboratory.
finic oxindole (0.1 mmol), dialdehyde 2 (50% in water, 0.3 mmol), and organocat-
alyst A (0.01 mmol) in DMF (0.5 mL) at room temperature for 2 days.
b
Isolated yield.
c
Determined by 1H NMR of crude product.
d
The ee was determined by chiral-phase HPLC analysis of major diastereomer.
(>99% ee, entries 4 and 5). Interestingly, the electron-withdrawing
4-NO2 derivative furnished moderate diastereoselectivity (entry 6)
compared to 4-Cl substituent (entry 4). However, the major isomer
showed excellent enantioselectivity.
We have also explored this Michael/aldol reaction with 3-meth-
ylpentane-1,5-dial 618 as shown in Scheme 2. This reaction pro-
ceeded smoothly and afforded spirocyclic oxindole 5q with five
consecutive stereogenic centers in 65% yield and excellent enanti-
oselectivity (99% ee). Interestingly, the aldehyde functionality at
the C3-position was isomerized from the axial to equatorial posi-
tion leading to the formation of the more stable C2–C3 anti-
product.
We have carried out the reaction of oxindole 1a and dialdehyde
2 up to a gram scale providing 5a in 75% yield (Scheme 3). This
product showed excellent enantioselectivity as well. The relative
configurations of compounds were assigned by extensive NOE
analyses of compounds 5a, 5d, 5o, and 5q. The absolute configura-
tions of the tandem Michael/aldol products were determined
Acknowledgments
Financial support of this work was provided by the National
Institutes of Health and Purdue University.

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A. K. Ghosh, B. Zhou / Tetrahedron Letters 54 (2013) 2311–2314
References and notes
1. For selected examples, see: (a) Serradeil-Le Gal, C.; Lacour, C.; Valette, G.;
Garcia, G.; Foulon, L.; Galindo, G.; Bankir, L.; Pouzet, B.; Guillon, G.; Barberis, C.;
Chicot, D.; Jard, S.; Vilain, P.; Garcia, C.; Marty, E.; Raufaste, D.; Brossard, G.;
Nisato, D.; Maffrand, J. P.; Le Fur, G. J. Clin. Invest. 1996, 98, 2729; (b)
Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D. C. J. Org. Chem.
2001, 66, 3653.
2. (a) Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 2003, 59, 4615; (b)
‘Spiroindolinone derivatives’: Liu, J.-J.; Zhang, Z. (Hoffmann-LaRoche A.G.), PCT
Int. Appl. WO2008/055812, 2008.
3. For selected reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945; For selected publications, see: (b) Madin, A.; ODonnell, C. J.; Oh, T.; Old,
D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054.
4. Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396.
5. (a) Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem., Int. Ed. 2008, 47,
5820; (b) Shintani, R.; Hayashi, S.-Y.; Murakami, M.; Takeda, M.; Hayashi, T.
Org. Lett. 2009, 11, 3754.
6. Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200.
7. (a) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008; (b) Companyo, X.; Zea, A.; Alba,
A.-N. R.; Mazzanti, A.; Moyano, A.; Rios, R. Chem. Commun. 2010, 46, 6953; (c)
Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem. Eur. J. 2010, 16, 2852.
8. (a) Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang, Q. C.; Xu, X.-Y.; Wang, L.-X. Chem.
Commun. 2010, 46, 8064; (b) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.;
Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
5053; (c) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc.
2011, 133, 15212.
9. Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133,
12354.
10. (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; (b)
Enders, D.; Huttl, M. R. M.; Runsink, G.; Raabe, G. Angew. Chem., Int. Ed. 2007,
46, 467.
11. Ghosh, A. K.; Schiltz, G.; Perali, R. S.; Leschenko, S.; Kay, S.; Walters, D. E.; Koh,
Y.; Maeda, K.; Mitsuya, H. Bioorg. Med. Chem. Lett. 2006, 16, 1869.
12. Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46,
4922.
13. Chintala, P.; Ghosh, S. K.; Long, E.; Headley, A. D.; Ni, B. Adv. Synth. Catal. 2011,
353, 2905.
14. Zhao, G.-L.; Dziedzic, P.; Ulla, F.; Eriksson, L.; Cordova, A. Tetrahedron Lett. 2009,
50, 3458.
15. Pellissier, H. Adv. Synth. Catal. 2012, 354, 237.
16. Huang, X.-F.; Liu, Z.-M.; Geng, Z.-C.; Zhang, S.-Y.; Wang, Y.; Wang, X.-W. Org.
Biomol. Chem. 2012, 10, 8794.
17. For details, please see Supplementary data.
Figure 2. ORTEP drawing of 5l and 7.
18. Sobhani, S.; Maleki, M. F. Synlett 2010, 383.
19. CCDC 897144 (5l) and CCDC 897143 (7) contain the Supplementary
crystallographic data for this Letter. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data
Supplementary data (experimental procedures and 1H, 13C NMR
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.02.030.