Organocatalytic synthesis of spiro compounds via a cascade Michael-Michael-aldol reaction

Article abstract of DOI:10.1039/c0cc01522a

The synthesis of spiro compounds via a Michael-Michael-aldol reaction is reported. The reaction affords spirooxindole derivatives in good yields and in almost diastereo- and enantiopure form. Moreover, the reaction works with several heterocycles such as oxindoles, benzofuranones, pyrazolones or azlactones rendering the final spiro compounds in good yields and excellent stereoselectivities.

Full text of DOI:10.1039/c0cc01522a

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Organocatalytic synthesis of spiro compounds via a cascade
Michael–Michael-aldol reactionw
a
a
a
´
Xavier Companyo, Alex Zea, Andrea-Nekane R. Alba,
Andrea Mazzanti,b Albert Moyanoa and Ramon Rios*ac
Received 21st May 2010, Accepted 3rd August 2010
DOI: 10.1039/c0cc01522a
The synthesis of spiro compounds via a Michael–Michael-aldol
reaction is reported. The reaction affords spirooxindole deriva-
tives in good yields and in almost diastereo- and enantiopure
form. Moreover, the reaction works with several heterocycles
such as oxindoles, benzofuranones, pyrazolones or azlactones
rendering the final spiro compounds in good yields and excellent
stereoselectivities.
Scheme 1 Proposed reaction.
Natural compounds present sometimes very complex scaffolds
with a well defined three-dimensional structure. This complexity
is generally correlated with stereospecificity in their biological
properties. One of the most common goals for organic chemists
is the development of new methodologies to build very complex
structures in a stereocontrolled fashion and, if possible, a
catalytic way. One of the great challenges in natural product
synthesis is the construction of spiro compounds in an enantio-
selective fashion. Several natural products have this motif in
their structure: gelsemine, spirotryprostatin B, marcfortine B,
phalarine, coerulescine, horsfiline, pseurotin, agarospirol, etc.1
For this reason, the quest for new synthetic methodologies that
allow the construction of spiro compounds is a common goal
for many chemists.
In this context, Melchiorre and Gong reported in 2009 an
extremely elegant synthesis of spirooxindoles via an organo-
cascade reaction with excellent yields and enantioselectivities
and moderate to good diastereoselectivities.7
Based on these previous reports and on our previous experience
working with oxindoles,8 we disclosed that oxindoles could react
with unsaturated aldehydes via a Michael–Michael-aldol reaction
to furnish the desired spirocyclic compounds (Scheme 1).
In any case, important challenges had to be addressed. In our
previous report, we disclosed that the addition of 2-substituted
oxindoles to unsaturated aldehydes catalyzed by diphenyl-
prolinol derivatives afforded the desired adducts in excellent
enantioselectivities but with poor diastereoselectivities. These
adducts epimerized slowly in solution, probably due to a retro-
Michael reaction. These findings opened our eyes to an easy and
straightforward access to spiro compounds. We envisioned that
oxindole could react with unsaturated aldehydes to lead to
compounds A or B. These additions would work in good
enantioselectivities but probably in poor diastereoselectivities
in the first step. However, the quaternary carbon formed in
compound B would be non-stereogenic, and this compound
would be desymmetrized by the last irreversible dehydration
after the aldol reaction (Scheme 2).
Organocatalytic domino or cascade reactions2 are one of the
common approaches that satisfy the criteria of economic and
effective processes and follow the rules of green and sustain-
able chemistry.3
In 2006, Enders and co-workers showed the potential of
organocatalysis for the synthesis of complex structures with a
triple cascade organocatalytic reaction, which led to the synthesis
of cyclohexanes with four stereocenters with exceptional degrees
of enantioselectivity and moderate to good diastereoselectivities.4
In 2007, Jørgensen and co-workers reported a powerful
triple domino asymmetric reaction between malononitrile
and unsaturated aldehydes, consisting in a Michael–Michael-aldol
reaction that built a cyclohexene in excellent yields and enantio-
selectivities, but in moderate to good diastereoselectivities.5 In
2009, Enders and co-workers employed the same concept
starting from nitromethane and unsaturated aldehydes, with
similar results.6
To our delight, when oxindole was treated with cinnamaldehyde
in the presence of catalyst I (20%) and benzoic acid (20%) in
toluene, the reaction rendered only one product, in diastereo-
and enantiopure form. It should be noticed that the use of
benzoic acid is crucial for the formation of these spiro
a
´
Department de Quımica Organica, Universitat de Barcelona,
Martı i Franques 1-11, 08028 Barcelona, Spain.
`
´
´
E-mail: rı´os.ramon@icrea.cat
b Dipartimento di Chimica Organica ‘‘A. Mangini’’ Alma Mater
`
Studiorum—Universita di Bologna Viale Risorgimento 4,
40136 Bologna, Italy
c ICREA, Passeig Lluis Companys 23, 08010 Barcelona, Spain
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data. See DOI: 10.1039/c0cc01522a
Scheme 2 Possible reaction pathway.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6953–6955 6953

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compounds. Without the addition of acid the reaction did not
work, probably because of retro-Michael reactions previously
reported. We think that the role of benzoic acid is to promote
the irreversible dehydration step. The reaction worked in other
solvents such as CHCl3 and AcOEt, albeit with lower conver-
sions and diastereoselectivities (see ESIw).
Then, we decided to study the scope of the reaction with a
variety of a,b-unsaturated aldehydes, realizing that the reaction
worked with aliphatic and aromatic unsaturated aldehydes with
excellent yields (entries 1–3, Table 1). Aromatic enals rendered
the final spiro compounds with excellent diastereo- and enantio-
selectivities. On the other hand, aliphatic enals gave lower
diastereoselectivities. The reaction tolerated several functional
groups like CN, NO2 or halogens (entries 4–6; Table 1) without
any loss of diastereo- or enantioselectivity.
Next, we decided to study the reaction with different
oxindoles. To our delight, the reaction afforded in all the
examples the final spirooxindole in diastereo- and enantiopure
form. Only when N-methyl substituted oxindole was used, the
enantioselectivity and diastereoselectivity decreased, showing
the importance of this hydrogen in the reactivity (entry 6;
Table 2). It is noteworthy that the reaction also tolerated
several functional groups such as nitro (entries 2 and 3;
Table 2) and halogens in different positions of the oxindole
ring (entries 4, 5 and 7; Table 2).
The relative configuration was determined by means of
NOE and NOESY NMR experiments (see ESIw), and the
absolute configuration was assigned by means of TD-DFT
calculations of the electronic circular dichroism (ECD)
spectra.9 As shown in Fig. 1 (ESIw), the spectra calculated
for 3a, assuming 1S, 2S, 6R configuration, match with the
experimental spectra (using (R)-I as catalyst). Both relative
and absolute configurations are in agreement with related
aminocatalytic conjugate additions promoted by catalyst I.5
Table 1 Reaction scopea
Table 3 Heterocycle scopea
Entry
R
Product
Yieldb (%)
d.r.c
eed (%)
Product Yieldb (%) d.r.c
eed (%)
1
2
3
4
5
6
Ph
Me
CO2Et
p-NO2Ph
p-CNPh
o-BrPh
3a
3b
3c
3d
3e
3f
71
65
58
82
77
53
>25 : 1
7 : 1
>25 : 1
>25 : 1
>25 : 1
>25 : 1
>99
99
>99
>99
>99
99
Entry Heterocycle
1
3a
4a
71
55
>25 : 1 >99
a
In a small vial, oxindole 1a (0.25 mmol) and aldehyde 2a–g (0.75 mmol)
were stirred in the presence of catalyst I (20 mol%, 0.05 mmol) and
benzoic acid (20 mol%, 0.05 mmol) at room temperature overnight.
2e
>25 : 1 >99
b
c
Isolated yield after column chromatography. Determined by
d
1H-NMR of the crude mixture. Determined by chiral HPLC.
3f
5a
6a
85
50
>25 : 1
93
Table 2 Oxindole scopea
4f,g
6 : 1 >99
5
7a
8a
85h
59
1.2 : 1 n.d.
Entry R1
R2
Ph
Product Yieldb (%) d.r.c
eed (%)
6f
1.2 : 1 >99/>99
1
2
3
4
5
6
7
H
3a
3g
71
62
90
82
90
62
73
>25 : 1 >99
>25 : 1 >99
>25 : 1 97
5-NO2 Ph
5-NO2 p-NO2Ph 3h
6-Cl
7-Cl
1-Me
5-Cl
a
Ph
Ph
Ph
Ph
3i
3j
3k
3l
>25 : 1 >99
>25 : 1 >99
15 : 1 83
>25 : 1 >99
In a small vial, heterocycle 3–8 (0.25 mmol) and aldehyde 2a (0.75 mmol)
were stirred in the presence of catalyst I (20 mol%, 0.05 mmol) and
benzoic acid (20 mol%, 0.05 mmol) at room temperature overnight.
b
c
Isolated yield after column chromatography. Determined by
a
1H-NMR of the crude mixture. Determined by chiral HPLC. Absolute
configuration was determined with the same method as that for 3a. f The
relative configuration of phenyls of the compound was trans by means of
NOE analysis. g Reaction run in AcOEt. h Only mono addition product
was isolated (see ESIw).
d
e
In a small vial, oxindole 1a–f (0.25 mmol) and aldehyde 2 (0.75 mmol)
were stirred in the presence of catalyst I (20 mol%, 0.05 mmol) and
benzoic acid (20 mol%, 0.05 mmol) at room temperature overnight.
b
c
Isolated yield after column chromatography. Determined by
d
1H-NMR of the crude mixture. Determined by chiral HPLC.
c
6954 Chem. Commun., 2010, 46, 6953–6955
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Finally, in order to show the broad utility of this procedure
we performed the reaction with several heterocyclic com-
pounds. In all the examples, the reaction furnished the spiro-
compounds in good yields and enantioselectivities, with
diastereoselectivities ranging from moderate (only two of the
four possible diastereomers were detected in all cases) to
excellent. The reaction could be performed with pyrazolones
(4a), benzofuran-2(3H)-ones (5a), benzofuran-3(2H)-ones (6a)
or even azlactones (8a). In all the examples the products have a
trans relative stereochemistry between both Ph groups (NMR
studies) even in 8a where both isolated products are epimers at
C1. The absolute configuration of compound 4a was 5S, 6S,
10R when S-catalyst was used (see ESIw). This allows us to
build spiro derivatives from different heterocycles giving this
reaction a very broad scope in terms of applicability. It should
be noticed that, when a-angelica lactone was used, only the
mono addition product was isolated (entry 5; Table 3).
In conclusion, we have developed a new methodology for
the construction of spirocompounds based on organocatalysis.
The final products were obtained in good yields and in a total
stereocontrolled fashion in most of the examples. Further
studies of the scope of this new reaction with different hetero-
cycles are ongoing in our laboratories.
K. Lahiri and E. Manivannan, Synthesis, 2009, 165, and references
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C. Grondal and M. R. Huttl, Angew. Chem., Int. Ed., 2007, 46,
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7 (a) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli and P. Melchiorre,
Angew. Chem., Int. Ed., 2009, 48, 7200; (b) for a nice example of
spirooxindoles via a 1,3-dipolarcycloaddition see: X.-H. Chen,
Q. Wei, S.-W. Luo, H. Xiao and L.-Z. Gong, J. Am. Chem. Soc.,
2009, 131, 13819. For a recent example of spirooxindoles via a [4+2]
cycloaddition: (c) Q. Wei and L.-Z. Gong, Org. Lett., 2010, 12,
1008. For a nice example of [2+2+2] annulation with oxindoles:
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2010, 16, 2852. For a recent example: W.-B. Chen, Z.-J. Wu,
Q.-L. Pei, L.-F. Cun, X.-M. Zhang and W.-C. Yuan, Org. Lett.,
2010, 12, 3132.
8 (a) N. Bravo, I. Mon, X. Companyo, A.-N. Alba, A. Moyano and
R. Rios, Tetrahedron Lett., 2009, 50, 6624. See also:
(b) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti,
B. Giannichi, L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur.
J., 2009, 15, 7846.
9 For recent reviews: (a) G. Bringmann, T. Bruhn, K. Maksimenka
and Y. Hemberger, Eur. J. Org. Chem., 2009, 2717; (b) N. Berova,
L. Di Bari and G. Pescitelli, Chem. Soc. Rev., 2007, 36, 914. See also:
(c) C. Diedrich and S. Grimme, J. Phys. Chem. A, 2003, 107, 2524;
(d) D. Casarini, L. Lunazzi, M. Mancinelli, A. Mazzanti and
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V. Kumar, M. Reichert, T. A. M. Goulder and G. Bringmann,
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We thank the Spanish Ministry of Science and Innovation
(MICINN) for financial support (Project AYA2009-13920-
C02-02). A.-N. R. Alba and X. Companyo are also grateful
to MICINN and to the Generalitat de Catalunya, respectively,
for their pre-doctoral fellowships. A. Mazzanti thanks the
University of Bologna (RFO funds 2008).
Notes and references
1 (a) H. Lin and S. J. Danishefsky, Angew. Chem., 2003, 115, 38
(Angew. Chem., Int. Ed., 2003, 42, 36); (b) M. M.-C. Lo,
C. S. Neumann, S. Nagayama, E. O. Perlstein and S. L. Schreiber,
J. Am. Chem. Soc., 2004, 126, 16077; (c) S. Kotha, A. C. Deb,
c
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Chem. Commun., 2010, 46, 6953–6955 6955