Targeting structural and stereochemical complexity by organocascade catalysis: construction of spirocyclic oxindoles having multiple stereocenters

Full text of DOI:10.1002/anie.200903192

Communications
DOI: 10.1002/anie.200903192
Synthetic Methods
Targeting Structural and Stereochemical Complexity by
Organocascade Catalysis: Construction of Spirocyclic Oxindoles
Having Multiple Stereocenters**
Giorgio Bencivenni, Li-Yuan Wu, Andrea Mazzanti, Berardino Giannichi, Fabio Pesciaioli,
Mao-Ping Song, Giuseppe Bartoli, and Paolo Melchiorre*
Dedicated to Professor Alfredo Ricci on the occasion of his 70th birthday
The structural complexity and well-defined three-dimen-
sional architecture of natural molecules are generally corre-
lated with specificity of action and potentially useful biolog-
ical properties.[1] This complexity has inspired generations of
synthetic chemists to design novel enantioselective strategies
for assembling challenging target structures and reproducing
the rich structural diversity inherent in natural molecules.
This symbiotic correlation between natural compounds syn-
thesis and the discovery of effective asymmetric—generally
catalytic[2]—technologies lies at the heart of the synthetic
chemistry innovation.[3] Despite the substantial advances
made thus far, the construction of highly strained polycyclic
structures (particularly those that contain spiro-stereocen-
ters) and the generation of all-carbon quaternary stereocen-
ters still remain daunting targets for synthesis.[4,5]
Figure 1. Naturally occurring and biologically active spirocyclic oxin-
doles.
The spirocyclic oxindole core is featured in a number of
natural products[6] as well as medicinally relevant com-
pounds[7] (Figure 1), but its stereocontrolled synthesis, partic-
ularly installing the challenging spiro-quaternary stereocen-
ter, poses a great synthetic problem. Only a few venerable
asymmetric transformations, such as cycloaddition process-
es[8] or the intramolecular Heck reaction,[9] have proven
suitable for achieving this challenging goal.
Herein we show that asymmetric organocascade cataly-
sis,[10] which exploits the ability of chiral amines to efficiently
combine two modes of catalyst activation of carbonyl com-
pounds (iminium and enamine catalysis) into one mecha-
nism,[11] allows the direct, one-step synthesis of complex spiro-
oxindolic cyclohexane derivatives; these products have three
or four stereogenic carbon atoms and are obtained with
extraordinary levels of stereocontrol starting from simple
precursors. Specifically, we developed complementary orga-
nocatalytic multicomponent domino reactions based on two
distinct organocatalysts, A and B, which efficiently activate
carbonyl compounds such as ketones and aldehydes, respec-
tively, toward multiple asymmetric transformations in a well-
defined cascade sequence. Both strategies provide straight-
forward access to natural product inspired compound collec-
tions,[12] which would be difficult to synthesize by other
enantioselective methods.
[*] Dr. G. Bencivenni,[+] Dr. A. Mazzanti, B. Giannichi, F. Pesciaioli,
Prof. G. Bartoli, Dr. P. Melchiorre
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum—Universitꢀ di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
E-mail: p.melchiorre@unibo.it
L.-Y. Wu,[+] Prof. M.-P. Song
Department of Chemistry, Henan Key Laboratory of Chemical
Biology and Organic Chemistry, Zhengzhou University
Zhengzhou 450052 (P.R. China)
[+] These authors contributed equally to this work.
[**] The China Scholarship Council is gratefully acknowledged (grant to
L.-Y. Wu). This work was supported by Bologna University and by
MIUR National Project “Stereoselezione in Sintesi Organica”. P.M.
thanks one of the referees of the original submission for invaluable
advice.
The recent advances achieved in the field of chiral
secondary amine catalysis[13] have set the conditions for the
development of many asymmetric cascade reactions based on
the efficient activation of aldehydes.[11] However, minor
progress has been achieved in the corresponding transforma-
tions of ketones.[14] This lack in progress is a result of the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903192.
7200
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7200 –7203

Angewandte
Chemie
inherent difficulties in generating congested covalent inter-
mediates from chiral secondary amines and ketones.
Recently, we introduced 9-amino(9-deoxy)epi-hydroquinine
A, a chiral primary amine derived in a single step from the
cinchona alkaloid hydroquinine, as a general and selective
catalyst for ketone activations.[15] Catalyst A proved efficient
even for the catalysis of an intramolecular tandem reaction of
a,b-unsaturated ketones through an iminium–enamine path-
way.[16] We speculated that the versatility of A may be
additionally exploited to design a novel organocascade to
access valuable, spirocyclic scaffolds.[14b]
From the outset, a central tenet of our approach was the
identification of a suitable compound, 1, bearing the oxindole
moiety. As shown in Scheme 1, we anticipated that compound
1 would first act as a Michael acceptor, intercepting the
nucleophilic dienamine intermediate I generated by the
condensation of catalyst A with the a,b-unsaturated ketone
2.[14] The resulting carbon nucleophile II would then selec-
tively engage itself in an intramolecular, iminium-catalyzed
conjugate addition to afford the spiro-oxindole derivative
3.[17] Our organocascade strategy with enones was evaluated
by conducting the tandem reactions in toluene at 608C for 48–
72 hours, under an aerobic atmosphere. Optimization experi-
ments revealed that the best results in terms of both yield and
stereoselectivity were achieved using 20 mol% of amine A in
combination with an acidic co-catalyst, such as ortho-fluo-
robenzoic acid (30 mol%). Importantly, using the pseudo-
enantiomeric amine catalyst, prepared from hydroquinidine,
affords the opposite antipode of the spyrooxindole product,
ent-3, with similar results (see Figure 1 in the Supporting
Information). As highlighted in Scheme 1, there appears to be
significant tolerance toward structural and electronic varia-
tions of both the precursors, 1 and 2, to enable access to a
variety of complex spiro-oxindoles (3a–e) having three and
even four (compound 3 f) stereocenters with high diastereo-
meric ratio and excellent optical purity. Notably, the main
diastereomer can be easily isolated by simple column
chromatography.
Scheme 1. Tandem double Michael additions (enamine–iminium acti-
Moreover, the presented organocascade is also effective
with cyclohexenone derivatives, giving access to the highly
congested bicyclo[2.2.2]octanes 3g and 3h adorned with a
spiro-oxindole moiety. The spiro-bicycle 3h is a completely
unknown complex scaffold possessing two contiguous all-
carbon quaternary stereocentres, a daunting synthetic chal-
lenge for which only a few direct strategies have been devised
to date.[18]
vation sequence) toward spirocyclic oxindolic cyclohexanones. [a] Yield
of isolated product calculated on the sum of the diastereomers,
whereas other yields are given on the single major diastereomer.
[b] Enantiomeric excess obtained after a single crystallization.
To illustrate the value of our organocascade in the
synthesis of biologically relevant compounds, we carried out
the one-step preparation of the chiral spiro-oxindole 7
[Eq. (1)]. The spiro-oxindole 7 (recently patented by Hoff-
mann-La Roche)[19] serves as a specific and potent inhibitor of
the MDM2–p53 interaction, an innovative target for the
discovery of anticancer agents.[20] The biological properties of
this compound have been evaluated on the racemic mixture,
hence the availability of a fast and easy method for obtaining
stereochemistry-based structure and activity relationships
might enable the identification of a more selective and
potent antitumor lead.
We then focused on the development of a complementary
organocascade strategy based on the activation of aldehydic
compounds, in which the spiro-oxindole cyclohexane archi-
tecture was constructed with the simultaneous creation of
Angew. Chem. Int. Ed. 2009, 48, 7200 –7203
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7201

Communications
three bonds and four stereogenic centers in a single chemical
step (Table 1).
synthetic problems using disparate tactics. Here the asym-
metric one-step construction of multiple stereocenters in
complex spirocyclic oxindoles was achieved with very high
fidelity.[22] Such complexity- and diversity-generating process-
es, providing access to pre-validated nature-inspired com-
pound collections with appropriate efficiency, scale, purity,
and cost, and in a short period of time, may constitute a useful
synthetic approach in other scientific domains such as
medicinal chemistry and chemical biology research.[23]
Table 1: Triple organocascade mediated by chiral secondary amine B by
way of an enamine–iminium–enamine activation of aldehydes.[a]
Received: June 12, 2009
Published online: August 7, 2009
Keywords: cascade catalysis · heterocycles ·
.
molecular complexity · organocatalysis · spiro compounds
6
R1
R2
R3
R4
Yield d.r.[c]
[%][b]
de, ee
[%][d]
[1] a) Stereochemical aspects of drug action and disposition, (Eds.:
M. Eichelbaum, B. Testa, A. Somogyi), Springer, Heidelberg,
2003; b) A. M. Thayer, Chem. Eng. News 2007, 85, 11 – 19. Many
drugs used today are natural products or natural-product
derivatives, see: c) D. J. Newman, G. M. Cragg, J. Nat. Prod.
2007, 70, 461 – 477.
[2] J. T. Mohr, M. R. Krout, B. M. Stoltz, Nature 2008, 455, 323 – 332.
[3] K. C. Nicolaou, S. A. Snyder, Proc. Natl. Acad. Sci. USA 2004,
101, 11929 – 11936.
[4] a) Quaternary Stereocenters. Challenges and Solutions in Organic
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH, Wein-
heim, 2006; b) C. J. Douglas, L. E. Overman, Proc. Natl. Acad.
Sci. USA 2004, 101, 5363 – 5367; c) B. M. Trost, J. Chunhui,
Synthesis 2006, 369 – 396.
[5] For recent organocatalytic, asymmetric construction of oxin-
doles bearing an all-carbon quaternary stereocenter, see: a) P.
Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B.
Giannichi, L. Sambri, G. Bartoli, P. Melchiorre, Chem. Eur. J.
2009, DOI: 10.1002/chem.200802466; b) T. Bui, S. Syed, C. F.
Barbas III, J. Am. Chem. Soc. 2009, 131, 8758 – 8759; for an early
example, see: c) I. D. Hills, G. Fu, Angew. Chem. 2003, 115,
4051 – 4054; Angew. Chem. Int. Ed. 2003, 42, 3921 – 3924.
[6] a) H. Lin, S. J. Danishefsky, Angew. Chem. 2003, 115, 38 – 53;
Angew. Chem. Int. Ed. 2003, 42, 36 – 51; b) C. V. Galliford, K. A.
Scheidt, Angew. Chem. 2007, 119, 8902 – 8912; Angew. Chem.
Int. Ed. 2007, 46, 8748 – 8758.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Ph
Ph
Ph
Ph
Ph
Ph
Ph
propyl
CO2Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
Cl
74
70
35
50
50
47
12:1
>99
>99
>99
>99
98
>99
>99
98
>99
>99
98
>99
>99
>99
p-MeOPh
p-NO2Ph
p-FPh
o-MePh
Ph
Ph
Ph
Ph
Ph
16:1
>19:1
>19:1
>19:1
12:1
12:1
19:1
12:1
>19:1
>19:1
>19:1
19:1
Me 40
H
H
H
H
H
H
H
40
60
46
58
65
65
64
C(=O)Ph Me
CO2Et
CO2Et
CO2Et
CO2Et
Me
n-butyl Ph
benzyl
allyl
Me
Ph
Ph
19:1
[a] The triple organocascade proceeds by way of an enamine-catalyzed
Michael addition of 4 to 1 and subsequent iminium-mediated Michael
addition of the chiral nucleophilic intermediate III to 5, and an enamine-
catalyzed intramolecular aldol reaction to afford IV. The last dehydration
step leads to the spirocyclic compounds 6. [b] Yield of the isolated major
diastereomer. [c] The diastereomeric ratio (d.r.) was determined by
1H NMR analysis of the crude reaction mixture. [d] The diastereomeric
and enantiomeric excess (de, ee) were determined by HPLC analysis on
chiral stationary phases.
[7] a) H. Venkatesan, M. C. Davis, Y. Altas, Snyder, D. C. Liotta, J.
Org. Chem. 2001, 66, 3653 – 3661; b) M. M.-C. Lo, C. S. Neu-
mann, S. Nagayama, E. O. Perlstein, S. L. Schreiber, J. Am.
Chem. Soc. 2004, 126, 16077– 16086; c) S. Kotha, A. C. Deb, K.
Lahiri, E. Manivannan, Synthesis 2009, 165 – 193, and references
therein.
[8] a) E. J. Corey, Angew. Chem. 2002, 114, 1724 – 1741; Angew.
Chem. Int. Ed. 2002, 41, 1650 – 1667. For application to the
synthesis of (+) and (À) Spirotryprostatin B, see: b) P. R.
Sebahar, R. M. Williams, J. Am. Chem. Soc. 2000, 122, 5666 –
5667. For the use of the asymmetric palladium-catalyzed
trimethylenemethane [3+2]-cycloaddition in the synthesis of
marcfortine B, see: c) B. M. Trost, N. Cramer, S. M. Silverman, J.
Am. Chem. Soc. 2007, 129, 12396 – 12397; d) B. M. Trost, N.
Cramer, H. Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086 –
3087.
The rationale behind this approach arises from the studies
by Enders and co-workers who demonstrated the catalytic
ability of the chiral secondary amine B to realize an enamine–
iminium–enamine sequential activation of aldehydes 4 and
a,b-unsaturated aldehydes 5.[11e] We later exploited the same
catalytic machinery to stereoselectively install all-carbon
quaternary stereocenters in complex molecules.[21] Here, by
including compound 1 as the third component of the three-
component cascade strategy, the triple organocascade pro-
vides a fast and easy access to challenging spirocyclohexene
oxindoles. This three-component cascade reaction proceeds
at 408C in the presence of the catalytic salt B·o-FC6H4CO2H
(15 mol%) in toluene by way of a catalyzed Michael/Michael/
aldol condensation sequence affording the complex products
6 with almost perfect stereocontrol.
[9] a) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 –
2963. For the use of the intramolecular Heck reaction in the
stereocontrolled total synthesis of (Æ )-gelsemine, see: b) A.
Madin, C. J. OꢀDonnell, T. Oh, D. W. Old, L. E. Overman, M. J.
Sharp, J. Am. Chem. Soc. 2005, 127, 18054 – 18065.
The described complementary approaches demonstrate
the potential of organocascade catalysis to face challenging
7202 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 7200 –7203

Angewandte
Chemie
[10] a) D. Enders, C. Grondal, M. R. M. Hꢁttl, Angew. Chem. 2007,
119, 1590 – 1601; Angew. Chem. Int. Ed. 2007, 46, 1570 – 1581;
b) A. M. Walji, D. W. C. MacMillan, Synlett 2007, 1477 – 1489;
c) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
2006, 118, 7292 – 7344; Angew. Chem. Int. Ed. 2006, 45, 7134 –
7186.
[11] a) B. List, Chem. Commun. 2006, 819 – 824. For meaningful
examples, see: b) T. Bui, C. F. Barbas III, Tetrahedron Lett. 2000,
41, 6951 – 6954; c) Y. Huang, A. M. Walji, C. H. Larsen, D. W. C.
MacMillan, J. Am. Chem. Soc. 2005, 127, 15051 – 15053; d) M.
Marigo, T. Schulte, J. Franzen, K. A. Jørgensen, J. Am. Chem.
Soc. 2005, 127, 15710 – 15711; e) D. Enders, M. R. M. Hꢁttl, C.
Grondal, G. Raabe, Nature 2006, 441, 861 – 863. See also
reference [14].
[16] F. Pesciaioli, F. De Vincentiis, P. Galzerano, G. Bencivenni, G.
Bartoli, A. Mazzanti, P. Melchiorre, Angew. Chem. 2008, 120,
8831 – 8834; Angew. Chem. Int. Ed. 2008, 47, 8703 – 8706.
[17] The second intramolecular conjugate addition step is so quick
that intermediate II could not be detected by 1H NMR
spectroscopy. However, the stereochemical outcome of the
process, as discussed in the Supporting Information, prompted us
to propose a stepwise double-Michael addition sequence, lead-
ing to a formal Diels–Alder product such as 3, more than a
concerted cycloaddition mechanism.
[18] E. A. Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004,
101, 11943 – 11948.
[19] “Spiroindolinone derivatives”: J.-J. Liu, Z. Zhang (Hoffmann-La
Roche AG), PCT Int. Appl. WO 2008/055812, 2008. The other
enantiomer, ent-7, is also accessible with high level of stereose-
lectivity (see Figure 2 in the Supporting Information).
[12] K. Kumar, H. Waldmann, Angew. Chem. 2009, 121, 3272 – 3290;
Angew. Chem. Int. Ed. 2009, 48, 3224 – 3242.
[13] For recent reviews on aminocatalysis: a) P. Melchiorre, M.
Marigo, A. Carlone, G. Bartoli, Angew. Chem. 2008, 120, 6232 –
6265; Angew. Chem. Int. Ed. 2008, 47, 6138 – 6171; b) C. F.
Barbas III, Angew. Chem. 2008, 120, 44 – 50; Angew. Chem. Int.
Ed. 2008, 47, 42 – 47.
[14] For early examples on secondary amine mediated Diels–Alder
reactions of enones which exploit the transient formation of the
dienamine intermediate I, see: a) R. Thayumanavan, B. Dheva-
lapally, K. Sakthivel, F. Tanaka, C. F. Barbas III, Tetrahedron
Lett. 2002, 43, 3817 – 3820; for application in the synthesis of
spirocyclic compounds, see: b) D. B. Ramachary, N. S. Chowdari,
C. F. Barbas III, Angew. Chem. 2003, 115, 4365 – 4369; Angew.
Chem. Int. Ed. 2003, 42, 4233 – 4237. See also: c) N. Halland, P. S.
Aburel, K. A. Jørgensen, Angew. Chem. 2004, 116, 1292 – 1297;
Angew. Chem. Int. Ed. 2004, 43, 1272 – 1277.
[20] a) P. Chꢂne, Nat. Rev. Cancer 2003, 3, 102 – 109; b) K. Ding, Y.
Lu, Z. Nikolovska-Coleska, S. Qiu, Y. Ding, W. Gao, J. Stuckey,
K. Krajewski, P. P. Roller, Y. Tomita, D. A. Parrish, J. R.
Deschamps, S. Wang, J. Am. Chem. Soc. 2005, 127, 10130 – 10131.
[21] A. Penon, A. Carlone, A. Mazzanti, M. Locatelli, L. Sambri, G.
Bartoli, P. Melchiorre, Chem. Eur. J. 2008, 14, 4788 – 4791.
[22] The relative and absolute configurations of compounds 3 and 6
were assigned by NMR NOE analyses, X-ray crystallography
(for compounds 3c and 6n), and by means of TD-DFT
calculations of the electronic circular dichroism (ECD) spectra,
as described in the Supporting Information. CCDC 726678 (6n)
and 726679 (3c) contain the supplementary 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.
[15] For recent reviews, see: a) G. Bartoli, P. Melchiorre, Synlett 2008,
1759 – 1771; b) Y.-C. Chen, Synlett 2008, 1919 – 1930, and refer-
ences therein.
[23] T. E. Nielsen, S. L. Schreiber, Angew. Chem. 2008, 120, 52 – 61;
Angew. Chem. Int. Ed. 2008, 47, 48 – 56.
Angew. Chem. Int. Ed. 2009, 48, 7200 –7203
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7203