Highly enantioselective one-pot synthesis of spirocyclopentaneoxindoles containing the oxime group by organocatalyzed michael addition/ISOC/ fragmentation sequence

Article abstract of DOI:10.1021/ol2024955

A highly diastereo- and enantioselective organocatalytic protocol for the synthesis of biologically important spirocyclopentaneoxindoles containing the oxime functional group from easily accessible 3-allyl-substituted oxindoles and nitroolefins has been d

Full text of DOI:10.1021/ol2024955

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6160–6163
Highly Enantioselective One-Pot
Synthesis of Spirocyclopentaneoxindoles
Containing the Oxime Group by
Organocatalyzed Michael Addition/ISOC/
Fragmentation Sequence
Xiang Li, Ying-Mei Li, Fang-Zhi Peng, Shou-Tao Wu, Ze-Qian Li, Zhong-Wen Sun,
Hong-Bin Zhang, and Zhi-Hui Shao*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming 650091,
China
zhihui_shao@hotmail.com
Received September 14, 2011
ABSTRACT
A highly diastereo- and enantioselective organocatalytic protocol for the synthesis of biologically important spirocyclopentaneoxindoles
containing the oxime functional group from easily accessible 3-allyl-substituted oxindoles and nitroolefins has been developed by a one-pot
Michael addition/ISOC/fragmentation sequence.
The spirocyclic oxindole scaffold is featured in a
large number of natural products and medicinally
relevant compounds.1ꢀ5 Thus, considerable efforts have
been devoted toward the development of enantioselective
methods to construct these spiroheterocyclic systems. Re-
markableadvanceshavebeenmade on the enantioselective
synthesis of pyrrolidinyl-spirooxindole compounds and
analogues1 as well as six-membered spirocyclic oxindole
derivatives.2 Quite recently enantioselective syntheses of
spirocyclic 2-oxindoles bearing a cyclopentene motif have
also been developed via tertiary phosphine or amine
catalyzed [3 þ 2] cycloaddition reactions.3 In contrast,
efficient methodologies for the direct catalytic asymmetric
construction of the spirocyclopentaneoxindole scaffold
have been rarely disclosed.
(1) For reviews: (a) Trost, B. M.; Brennan, M. K. Synthesis 2009,
3003. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
For selected recent examples:(d) Chen, X.; Wei, Q.; Luo, S.; Xiao, H.;
Gong, L. J. Am. Chem. Soc. 2009, 131, 13819. (e) Cheng, M.; Wang, H.;
Gong, L. Org. Lett. 2011, 13, 2418. (f) Jiang, X.; Cao, Y.; Wang, Y.; Liu,
L.; Shen, F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328. (g) Chen, W.;
Wu, Z.; Hu, J.; Cun, L.; Zhang, X.; Yuan, W. Org. Lett. 2011, 13, 2472.
(2) For selected recent examples: (a) Jiang, K.; Jia, Z.; Yin, X.; Wu,
L.; Chen, Y. Org. Lett. 2010, 12, 2766. (b) Jiang, K.; Jia, Z.; Chen, S.;
Wu, L.; Chen, Y. Chem.;Eur. J. 2010, 16, 2852. (c) Wei, Q.; Gong, L.
Org. Lett. 2010, 12, 1008. (d) Chen, W.; Wu, Z.; Pei, Q.; Cun, L.; Zhang,
X.; Yuan, W. Org. Lett. 2010, 12, 3132. (e) Companyo, X.; Zea, A.; Alba,
A.-N. R.; Mazzanti, A.; Moyanoa, A.; Rios, R. Chem. Commun. 2010,
46, 6953. (f) Wang, L.; Peng, L.; Bai, J.; Jia, L.; Luo, X.; Huang, Q.; Xu,
X.; Wang, L. Chem. Commun. 2011, 47, 5593. (g) Bencivenni, G.; Wu, L.;
Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (h) Duce, S.;
Pesciaioli, F.; Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.;
Bartoli, G.; Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860. (i) Shen,
L.; Shao, P.; Ye, S. Adv. Synth. Catal. 2011, 353, 1943. (j) Jia, Z.; Jiang,
H.; Li, J.; Gschwend, B.; Li, Q.; Yin, X.; Grouleff, J.; Chen, Y.;
Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133, 5053.
(3) (a) Pinto, N.; Neel, M.; Panossian, A.; Retailleau, P.; Frison, G.;
Voituriez, A.; Marinetti, A. Chem.;Eur. J. 2010, 16, 1033. (b) Tan, B.;
Candeias, R. N.; Barbas, C. F., III J. Am. Chem. Soc. 2011, 133, 4672.
(c) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed. 2011,
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2011, 13, 4584.
r
10.1021/ol2024955
Published on Web 11/03/2011
2011 American Chemical Society

The 3-spirocyclopentane-2-oxindoles represent an im-
portant class of substructures which are widely encoun-
tered in a number of biologically active natural alkaloids4
(Figure 1) and drug candidates.5 However, the direct
catalytic enantioselective construction of these molecules
remains a daunting task. Generally their asymmetric
syntheses rely on chiral substrate-controlled methods. To
the best of our knowledge, so far there are only two general
reports concerning the catalytic enantioselective synthesis
of spirocyclopentaneoxindole scaffolds. Trost and co-workers
reported an elegant Pd-catalyzed asymmetric [3 þ 2] cy-
cloaddition of methyleneindolinones for the synthesis of
spirocyclopentaneoxindoles.6 During the course of our
current investigations, Barbas and co-workers represented
the only organocatalytic highly enantioselective synthesis
of bispirocyclic oxindole derivatives through a cascade
Michael-aldol reaction.7 However, the use of activated
methyleneindolinones connected to a ketone or ester moi-
ety as highly reactive Michael acceptors was required in
this cascade process wherein the cascade reaction with
methyleneindolinones connected to an aromatic group
did not proceed at all.7 Additionally, the diastereoselec-
tivity of the cascade reaction displayed a dependence on
the structure of 3-substituted oxindole substrates. For
example, the diastereoselectivity was high for reactions
with aryl 3-substituted oxindoles, whereas it became mod-
erate with alkyl 3-substituted oxindoles.7 Therefore, it is
highly desirable to develop a new and efficient direct
catalytic asymmetric method to synthesize structurally
diverse spirocyclopentaneoxindoles.
Recently asymmetric organocatalytic multistep one-pot
reactions have emerged as a powerful tool to efficiently and
stereoselectively construct complex molecules from readily
available simple starting materials in a single operation.8 As
part of our research interest in developing novel catalytic
asymmetric reactions,9 we herein describe a one-pot, orga-
nocatalyzed enantioselective intermolecular Michael addi-
tion/intramolecular silyl nitronate-olefin cycloaddition
(ISOC)/fragmentation reaction which provided biologically
important spirocyclopentaneoxindoles containing the oxime
functional group with three stereocenters including one
spiroquaternary stereocenter in good yields (up to 85%)
with excellent diastereoselectivity (up to >30:1 dr) and
enantioselectivity (up to >99% ee) (Scheme 1).
Although there have been several reports of intramo-
lecular silyl nitronate-olefin cycloaddition (ISOC),10 to
our knowledge, no processes have been described that
employ ISOC to catalytic asymmetric syntheses of spir-
ocyclic oxindoles.
Scheme 1. Strategy for the One-Pot Organocatalytic Asym-
metric Synthesis of Spirocyclopentaneoxindoles
Logically, a highly diastereo- and enantiostereoselective
Michael addition of 3-allyl-substituted oxindoles to nitroo-
lefins would be one critical element for an organocatalyzed
enantioselective one-pot intermolecular Michael addition/
ISOC/fragmentation sequence to the optically active spir-
ocyclopentaneoxindoles. Despite the potential utility of this
reaction due to the versatile transformations of olefin and
nitro groups, to our knowledge, there is only one report
concerning the organocatalytic asymmetric Michael addi-
tion of 3-allyl-substituted oxindole to nitroolefins.11c The
reaction diastereoselectivity is still modest for various aro-
matic nitroolefin substrates (3:1ꢀ9:1 dr).11c Both good
enantioselectivity and high diastereoselectivity (>10:1) for
3-allyl-substituted oxindoles to aromatic nitroolefins have
not been achieved so far. Therefore, it is highly desirable to
develop a highly diastereo- and enantiostereoselective orga-
nocatalytic Michael addition of 3-allyl-substituted oxi-
ndoles to nitroolefins.
Figure 1. Representative natural products containing the spir-
ocyclopentaneoxindole scaffold.
(4) (a) Li, S. Nat. Prod. Rep. 2010, 27, 57. (b) Miller, K. A.; Tsukamoto,
S.; Williams, R. M. Nat. Chem. 2009, 1, 63. (c) Greshock, T. J.; Grubbs,
A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.; Williams, R. M. Angew.
Chem., Int. Ed. 2008, 47, 3573. (d) Millera, K. A.; Williams, R. M. Chem.
Soc. Rev. 2009, 38, 3160.
(8) For a recent elegant review: Albrecht, Ł.; Jiang, H.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2011, 50, 8492.
(9) (a) Fan, B.; Li, X.; Peng, F.; Zhang, H.; Chan, A. S. C.; Shao, Z.
Org. Lett. 2010, 12, 304. (b) Li, X.; Peng, F.; Li, X.; Wu, W.; Sun, Z.; Li,
Y.; Zhang, S.; Shao, Z. Chem. Asian J. 2011, 6, 220.
(5) Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.;
Cohen, J.; Huselton, C.; Illenberger, A.; Kern, J. C.; Hudak, V. A.;
Marella, M. A.; Melenski, E. G.; McComas, C. C.; Mugford, C. A.;
Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker,
R. C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861.
(6) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396.
(10) For selected examples of ISOC in organic synthesis: (a) Dehaen,
W.; Hassner, A. Tetrahedron Lett. 1990, 31, 743. (b) Gottlieb, L.;
Hassner, A. J. Org. Chem. 1995, 60, 3759. (c) Namboothiri, I. N. N.;
Hassner, A.; Gottlieb, H. E. J. Org. Chem. 1997, 62, 485. (d) Ishikawa,
T.; Shimizu, Y.; Kudoh, T.; Saito, S. Org. Lett. 2003, 5, 3879. (e) Kudoh,
T.; Ishikawa, T.; Shimizu, Y.; Saito, S. Org. Lett. 2003, 5, 3875.
ꢀ
(f) Roger, P.-Y.; Durand, A.-C.; Rodriguez, J.; Dulcere, J.-P. Org. Lett.
ꢀ
(7) Tan, B.; Candeias, N. R.; Barbas, C. F., III. Nat. Chem. 2011, 3,
473. Also see:Zhang, S.; Xie, H.; Zhu, J.; Li, H.; Zhang, X.; Li, J.; Wang,
W. Nat. Commun. 2011, 2, 211.
2004, 6, 2027. (g) Raimondi, W.; Lettieri, G.; Dulcere, J.-P.; Bonne, D.;
Rodriguez, J. Chem. Commun. 2010, 46, 7247. (h) Hassner, A. Bull. Isr.
Chem. Soc. 2009, 20.
Org. Lett., Vol. 13, No. 23, 2011
6161

Recently, we reported a new class of bifunctional thio-
urea catalysts bearing central and axial chiral elements,
which showed good performance in the catalytic asym-
metric addition of 1,3-dicarbonyl compounds to nitro-
olefins.12,13 To extend the interest of these bifunctional
organocatalysts in asymmetric catalysis, we set out to
determine if these catalysts could exhibit high diastereo-
and enantioselectivity in the catalytic asymmetric Michael
addition of 3-allyl-substituted oxindoles to nitroolefins.
Also, we hoped to expand the application of these orga-
nocatalysts for new substrates and new types of asym-
metric reactions.
various types of cyclic compounds.16 The stereochemically
well-defined 1,6-enyne obtained from this methodology
might potentially have applications in the construction of
complex polycyclic molecules.
Table 1. Organocatalytic Asymmetric Michael Addition of
3-Allyl- and 3-Propargyl Substituted Oxindoles to Nitroolefinsa
Gratifyingly, with our bifunctional thiourea catalyst 5, a
significant improvement in dr was observed. Moreover, an
improvement in ee was observed (entries 1ꢀ5, Table 1).
Absolute configurations of 3aꢀd were determined by com-
paring the HPLC retention times of products with those of
literature data.11c Given the importance of functionalized
1,6-dienes for the synthesis of various carbocycles,14 we
tested the Michael addition of 3-allyl oxindole 1a to 1-nitro-
4-phenyl butadiene 2e. We found that the desired chiral 1,6-
dinene 3e was obtained in good dr and ee values (entry 6). It
is noteworthy that no 1,6-addition was observed.15 The
substituted 3-allyl oxindole was also tested, giving the
desired product 3f in 85% yield with 20:1 dr and >99%
ee values (entry 7). Due to the rich chemistry involved with
the alkynyl group, we also investigated the Michael addition
of a previously unexplored 3-propargyl-substituted oxi-
ndole 1c in the presence of catalyst 5. The 3-propargyl-
substituted oxindole 1c was also shown to be a highly
efficient substrate in this process (98f99% ee, 8:1ꢀ30:1 dr,
entries 8ꢀ12). Notably, the optically active 1,6-enyne 3k
could be obtained with a complete regioselectivity in 10:1 dr
and 99% ee (entry 12). Transition-metal-catalyzed cycloi-
somerization reactions of 1,6-enynes have appeared as
highly attractive and unique tools for the synthesis of
yield
(%)b
ee
entry
1
2 (R2)
drc
(%)d
1e
2
1a
1a
Ph
Ph
87
90
>30:1
>30:1
(6:1)f
>30:1
(6:1)f
>30:1
(5:1)f
20:1
97
>99
(94)f
94
(91)f
94
(90)f
3
4
5
1a
1a
1a
4-Br-C6H4
4-MeO-C6H4
n-C7H15
89
96
92
98
(>20:1)f
12:1
(94)f
93
6
1a
1b
1c
1c
1c
1c
1c
(E)-PhCH=CH
Ph
90
85
84
80
90
90
86
7
20:1
>99
98
8
Ph
17:1
9
4-MeO-C6H4
4-CF3O-C6H4
4-CF3-C6H4
(E)-PhCH=CH
8:1
>99
99
10
11
12
14:1
30:1
>99
>99
10:1
a The reactions were performed with oxindoles 1 (0.1 mmol) with
nitroolefins 2 (1.1 equiv) in the presence of 10 mol % catalyst 5 in 0.3 mL
of solvent at ꢀ20 °C. b Isolated yields. c Determined by 1H NMR
analysis. d The ee of major diastereoisomer determined by HPLC
analysis using a chiral stationary phase. e CH2Cl2 was used as solvent.
f The results in parentheses are those of Barbas’ report (see ref 11c).
(11) For a related review: (a) Zhou, F.; Liu, Y.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381. For selected examples of asymmetric reactions
with 3-prochiral oxindoles:(b) Duan, S.; An, J.; Chen, J.; Xiao, W. Org.
Lett. 2011, 13, 2290. (c) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem.
Soc. 2009, 131, 8758. (d) He, R.; Shirakawa, S.; Maruoka, K. J. Am.
Chem. Soc. 2009, 131, 16620. (e) Kato, Y.; Furutachi, M.; Chen, Z.;
Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 9168. (f) Li, X.; Zhang, B.; Xi, Z.; Luo, S.; Cheng, J. Adv. Synth.
Catal. 2010, 352, 416. (g) Liu, X.; Wu, Z.; Du, X.; Zhang, X.; Yuan, W.
J. Org. Chem. 2011, 76, 4008. (h) Ding, M.; Zhou, F.; Qian, Z.; Zhou, J.
Org. Biomol. Chem. 2010, 8, 2912. (i) Galzerano, P.; Bencivenni, G.;
Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
Melchiorre, P. Chem.;Eur. J. 2009, 15, 7846. (j) Zhu, Q.; Lu, Y. Angew.
Chem., Int. Ed. 2010, 49, 7753. (k) Liao, Y.; Liu, X.; Wu, Z.; Cun, L.;
Zhang, X.; Yuan, W. Org. Lett. 2010, 12, 2896. (l) Shen, K.; Liu, X.;
Wang, W.; Wang, G.; Cao, W.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem.
Sci. 2010, 1, 590. (m) Trost, B. M.; Zhang, Y. Chem.;Eur. J. 2010, 16,
296. (n) Qian, Z.; Zhou, F.; Du, T.; Wang, B.; Ding, M.; Zhao, X.; Zhou,
J. Chem. Commun. 2009, 6753.
(12) Peng, F.; Shao, Z.; Fan, B.; Song, H.; Li, G.; Zhang, H. J. Org.
Chem. 2008, 73, 5202.
(13) After our work, Kim et al. reported enantioselective R-amina-
tion and R-hydrazination promoted by this organocatalyst, respectively.
(a) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659. (b) Jung, S. H.;
Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527.
(14) (a) Bassindale, M. J.; Edwards, A. S.; Hamley, P.; Adams, H.;
Harrity, J. P. A. Chem. Commun. 2000, 1035. (b) Pei, T.; Widenhoefer,
R. A. Org. Lett. 2000, 2, 1469.
Having proved excellent stereocontrol performance of
the organocatalyst 5, we next turned our attention to
investigate sequential one-pot Michael addition/ISOC/
fragmentation. Despite the potential of ISOC, there is no
report on the employment of this method to the asym-
metric synthesis of spirocyclic oxindoles. To explore the
feasibility of such a strategy, we initially examined the
diastereoselective ISOC/fragmentation sequence with
compound 3a obtained through the Michael addition
above as the building block. Pleasingly, the desired
ISOC/fragmentation proceeded smoothly to afford the
optically active spirocyclopentaneoxindole 4a in 84% yield
and >99% ee (eq 1). The complete transfer of chirality in
this reaction could be explained through the preferred
ꢁ
ꢁ
^
(16) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed.
(15) Csaky, A. G.; de la Herran, G.; Murcia, M. C. Chem. Soc. Rev.
2010, 39, 4080.
2008, 47, 4268.
6162
Org. Lett., Vol. 13, No. 23, 2011

nitronate conformation B17 driven by a 1,3-allylic
strain which provided the transient isoxazolidine A in
a highly diastereoselective manner. Surprisingly, the
ISOC/fragmentation reaction with 3-propargyl-subsi-
tuted Michael adduct 3g gave a complex and insepar-
able mixture.
Scheme 2. One-Pot Organocatalytic Asymmetric Synthesis of
Spirocyclopentaneoxindoles by Michael Addition/ISOC/Frag-
mentation
Then we investigated a one-pot organocatalyzed intermo-
lecular Michael addition/ISOC/fragmentation sequence. As
shown in Scheme 2, with our organocatalyst 5, awide variety
of spirocyclopentaneoxindoles containing an oxime func-
tional group were obtained in good yields with high diastereo-
(12:1f30:1 dr) and enantioselectivities (94f99% ee). Oximes
represent an important class of compounds with potential
pharmaceutical properties18 and are also a versatile func-
tional group since they can be easily transformed into
various functional groups. Thus, this would make these
newly synthesized spirocyclopentaneoxindole derivatives at-
tractive candidates for drug discovery.
In summary, a highly diastereo- and enantioselective
organocatalytic protocol for the synthesis of biologically
important spirocyclopentaneoxindoles containing the
oxime functional group from easily accessible 3-allyl-sub-
stituted oxindoles and nitroolefins has been developed by a
one-pot Michael addition/ISOC/fragmentation sequence.
Moreover, we have developed a highly syn-selective (up to
>30:1 dr) and enantioselective (up to >99% ee) Michael
addition of 3-allyl- and 3-propargyl substituted oxindoles
to nitroolefins catalyzed by a novel bifunctional thiourea
organocatalyst with central and axial chiral elements
recently developed by our group.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (20962023, 21162034) and the Program for New
Century Excellent Talents in University (NCET-10-0907).
Supporting Information Available. Representative ex-
perimental procedure, compound characterization data,
and copies of spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(18) Ashani, Y.; Silman, I. The Chemistry of Hydroxylamines, Oximes
and Hydroxamic Acids; Rappoport, Z., Liebman, J. F., Eds.; WILEY:
New York, 2008; p 609.
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