Organocatalytic asymmetric conjugate additions of oxindoles and benzofuranones to cyclic enones

Article abstract of DOI:10.1055/s-0029-1219955

The asymmetric catalytic synthesis of densely functionalized molecules that contain vicinal quaternary and tertiary stereocenters is a challenge for modern chemical methodology. Here we show that a chiral primary amine, derived from natural molecules, efficiently catalyzes the stereoselective conjugate addition of oxindoles to cyclic enones, leading directly to valuable chiral scaffolds. Proof-of-concept for extending the method to benzofuranone derivatives is also provided. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219955

1704
CLUSTER
Organocatalytic Asymmetric Conjugate Additions of Oxindoles and
Benzofuranones to Cyclic Enones
Asymmetric
C
a
atalytic Sy
b
A
d
i
jacent
o
Tertiary
a
ndQuate
P
rnaryStereoce
e
nter
s
sciaioli,a Xu Tian,b Giorgio Bencivenni,a Giuseppe Bartoli,a Paolo Melchiorre*b,c
a
b
c
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
ICIQ, Institute of Chemical Research of Catalonia, Av. Països Catalans 16, 43007 Tarragona, Spain
ICREA, Institució Catalana de Recerca i Estudis Avançats, Pg. Lluís Companys 23, 08010 Barcelona, Spain
E-mail: pmelchiorre@iciq.es
Received 31 March 2010
centers can be created at once. However, inferring high
control over stereochemistry is difficult, as the catalyst
must provide high levels of stereoselectivity in a sterically
demanding C–C-bond-forming process.9 To date, the ac-
Abstract: The asymmetric catalytic synthesis of densely function-
alized molecules that contain vicinal quaternary and tertiary stereo-
centers is a challenge for modern chemical methodology. Here we
show that a chiral primary amine, derived from natural molecules,
efficiently catalyzes the stereoselective conjugate addition of oxin- ceptors employed in this powerful strategy have been re-
stricted to enals10a and nitroalkenes.10b–d The conjugate
doles to cyclic enones, leading directly to valuable chiral scaffolds.
Proof-of-concept for extending the method to benzofuranone deriv-
atives is also provided.
addition of prochiral oxindoles to a,b-unsaturated ketones
remains an elusive transformation.11
Key words: asymmetric catalysis, ketones, Michael addition, qua-
ternary carbon, organocatalysis
O
H
O
N
N
Me
Me
N
O
Reproducing the structural and stereochemical complexi-
ty inherent to natural molecules has always been a formi-
dable vehicle for reaction invention.1 This has inspired the
discovery of catalytic asymmetric methods2 which have
now become a fundamental part of the chemist’s reper-
toire for a variety of synthetic applications, especially in
relation to the study of biologically active compounds. In-
deed, many drugs used today are natural products or nat-
ural product derivatives.3 Despite the substantial advances
made to date, the catalytic and enantioselective generation
of carbon stereocenters with four other carbon substitu-
ents remains a daunting target for synthesis.4
O
N
O
HN
Me
gelsemine
spyrotryprostatin B
Cl
O
O
∗
∗
O
Cl
Et
O
N
H
Cl
N
Cl
H
promising anti-cancer agents
(Hoffmann-LaRoche)
Recently, significant effort has been directed toward the
enantioselective synthesis of 3,3-disubstituted oxindoles
and derivatives. This is because of the prevalence of this
privileged heterocyclic motif in biologically active natu-
ral molecules5 and pharmaceutically relevant compounds
(Figure 1).6 In recent years, many research groups have
taken up the challenge of stereoselectively assembling
structurally complex oxindoles endowed with a quaterna-
ry stereogenic center at C3. It has thus become a bench-
mark for testing the power and potential of a given
catalytic strategy. Both metal-7 and organic-based8 cata-
lytic reactions have provided efficient solutions to this is-
sue.
Figure 1 Representative naturally occurring and biologically active
3,3-disubstituted oxindoles bearing all-carbon quaternary stereocen-
ters
Herein, we report the first highly stereoselective addition
of N-Boc-protected oxindoles 1 to cyclic enones 2 under
the catalysis of simple chiral primary amines, derived
from natural cinchona alkaloids (Equation 1). The result-
ing polycyclic adducts 3, having two contiguous stereo-
centers, one of which is quaternary by all-carbon
substitution, are formed with high levels of diastereo- and
enantioselectivity. Extension to 2(3H)-benzofuranone de-
rivatives, an unprecedented nucleophilic component for
conjugate additions, opens up new opportunities for the
asymmetric synthesis of valuable heterocyclic com-
pounds.
Among the various strategies devised to date, the direct
conjugate addition of 3-substituted oxindoles to activated
alkenes is one of the most versatile. An additional merit of
this approach is that vicinal quaternary and tertiary stereo-
For exploratory studies, we selected the reaction between
3-benzyl oxindole (1a) and cyclohexen-2-one (2a), a
combination of easily available starting materials that
SYNLETT 2010, No. 11, pp 1704–1708
Advanced online publication: 01.06.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0029-1219955; Art ID: Y00310ST
© Georg Thieme Verlag Stuttgart · New York

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Asymmetric Catalytic Synthesis of Adjacent Tertiary and Quaternary Stereocenters
1705
may simultaneously activate both the electrophilic and
nucleophilic components, no improvements were ob-
served (entry 5). Finally, by varying the acidic additives,
we found that 10 mol% of the primary amine A in combi-
nation with benzoic acid (20 mol%) provided the best re-
sults, efficiently catalyzing the process in toluene (0.2 M)
at room temperature over 24 hours (5.2:1 dr, 96% ee, en-
try 9). These conditions were selected to examine the
scope of the conjugate addition by evaluating a variety of
oxindole and cyclic enone combinations (Table 2).
O
O
R
primary amine
catalyst
R
*
+
O
n
*
N
n
n = 0, 1,
N
O
Boc
1
2
3
Boc
Equation 1 The direct conjugate addition developed in this study
would readily give access to valuable oxindole-based de-
rivatives 3.
Table 1 Optimization Studiesa
Our laboratory and others, independently, have recently
introduced 9-amino(9-deoxy)epi-cinchona alkaloids
(Figure 2), chiral primary amines easily derived from nat-
ural sources, as general and effective catalysts for a wide
variety of asymmetric b-functionalizations of ketones un-
der iminium ion catalysis.12,13 We have further demon-
strated the ability of catalyst A, derived from
hydroquinine, to combine orthogonal aminocatalytic
modes (iminium and enamine activations) into one mech-
anism,12d thus promoting cascade reactions with a,b-un-
saturated ketones13e and the challenging a,b-disubstituted
enals.13f Thus, we hypothesized that catalyst A would ef-
ficiently promote the stereoselective addition of benzyl
oxindole 1a to enone 2a. We report selected results of the
optimization studies in Table 1.
O
Bn
O
catalyst (20 mol%)
acid (40 mol%)
Bn
+
O
(S)
(R)
N
R
toluene (0.2 M)
1a: R = H
N
O
1b: R = Boc
2a
3
R
Entry Amine Acidb
R
Temp Time Conv.drc
(°C) (h) (%)c
ee
(%)d
1
A
A
A
A
C
A
A
A
A
p-NBA
p-NBA
p-NBA
p-NBA
H
H
H
r.t.
0
72 >95 2.4:1 80 (79)
72 32 3.5:1 91 (81)
72 <5
24 >95 5.5:1 92 (89)
48 37 2.5:1 82 (91)
2
3e
4
0
–
–
Boc r.t.
OMe
OMe
5
benzoic Boc
NBDP Boc r.t.
benzoic Boc r.t.
benzoic Boc
benzoic Boc r.t.
0
NH2
NH2
6
24 >95 4.2:1 93 (79)
24 >95 5.6:1 97 (84)
N
N
7
N
N
B
A
8
0
48
92 6.6:1 96 (93)
OH
9f
24 >95 5.2:1 96 (84)
NH2
a The reactions were carried out on a 0.1 mmol scale with 1.2 equiv
of 1 and [2a]0 = 0.2 M in toluene.
9-amino(9-deoxy)-
N
epi-cinchona alkaloids
b Abbreviations: p-NBA, 4-nitrobenzoic acid; NBDP, N-Boc-D-phe-
nylglycine.
N
H
C
c Determined by 1H NMR analysis of the crude mixture.
d Determined by HPLC analysis on chiral stationary phases. Numbers
in parenthesis refer to the ee of the minor diastereomer.
e Reaction carried out in the presence of 1.5 equiv of DABCO.
f 10 mol% of A and 20 mol% of benzoic acid was used.
Figure 2 The primary amine catalysts used within this study
Indeed, 20 mol% of catalyst A in combination with an
acidic co-catalyst (40 mol%) effectively promoted the re-
action, furnishing the product with high enantioselectivity
but moderate levels of relative stereocontrol (entry 1). All
the attempts to improve the diastereoselectivity, either by
lowering the reaction temperature or by using an external
base to co-catalyze the process, did not reach useful syn-
thetic standards (entries 2 and 3). Next, we focused on us-
ing N-Boc-protected oxindole 1b as the nucleophilic
component. As expected, the electronic influence of the
Boc group greatly improved reactivity, lowering the pKa
of the oxindole.14 More importantly, the reaction manifold
was channelled toward a more diastereo- and enantiose-
lective path (entry 4). This was probably due to steric ef-
fects.
In addition to cyclohexen-2-one 2a (entries 1 and 2,
Table 2), other cyclic enones proved to be suitable sub-
strates. Using the cyclohexenone bearing two methyl
groups at the 5-position led to the formation of product 3b
with decreased reactivity but a high degree of stereocon-
trol (entry 3). While 2-cycloheptenones afforded good re-
sults when reacted with oxindole 1b (entry 5), 2-
cyclopentenone followed a remarkably lower enantiose-
lective path (entry 4). Oxindole with a methyl substituent
at the 3-position gave similar results in the conjugate ad-
ditions (entries 6–8). Using the more reactive 3-phenyl
oxindole afforded almost perfect enantiocontrol, albeit at
the expense of the relative stereochemistry (entry 9). In-
terestingly, the presented organocatalytic method allowed
When further optimizations were conducted in the pres-
ence of multifunctional catalyst C,13c,d which in principle
Synlett 2010, No. 11, 1704–1708 © Thieme Stuttgart · New York

1706
F. Pesciaioli et al.
CLUSTER
the fast and highly stereoselective synthesis of 3h (entry To determine the stereochemical outcome of the reaction,
10, see also Figure 1), a compound which has shown diastereomeric 3e was deprotected and further converted
promising biological properties as an anticancer agent and to the N-Tos derivative 4. Crystals from 4 were suitable
which has recently been patented by Hoffmann- for X-ray analysis, which unambiguously established the
La Roche.6d
relative as well as the absolute configuration for the major
diastereomer (Scheme 1).15
Finally, the pseudoenantiomeric catalyst B, derived from
hydroquinidine, accounted for the possibility of accessing
both antipodes of the products 3 (entries 2 and 7). Further
investigation demonstrated the possibility of extending
the reaction protocol to acyclic enones: reaction of 3-me-
thyl-substituted oxindole with trans-4-phenyl-3-buten-2-
one afforded the conjugate adduct in 95% ee but poor dr
(1.4:1, see Supplementary Information for compound
characterization and reaction conditions). As a limitation
of the method, b-substituted cyclic enones, which would
potentially give rise to challenging vicinal quaternary ste-
reogenic centers, did not react under the described condi-
tions.
Table 2 Primary Amine Catalyzed Asymmetric Conjugate Addi-
tion of N-Boc Oxindoles to Cyclic Enonesa
R1
Scheme 1 X-ray structure of the N-Tos derivative 415
O
O
R2
N
1
A or B (10 mol%)
PhCO2H (20 mol%)
Last, we wondered if the organocatalytic method could be
extended to benzofuranone derivative 5, a compound type
that had not previously been explored in the context of
asymmetric catalytic conjugate additions.16 We tested the
reaction of 3-benzyl benzofuranone 5 with cyclohexen-2-
one 2a under the catalysis of amines A and B (Scheme 2).
Notably, both the antipodes of the corresponding product
6 bearing a quaternary stereocenter were prepared with
good chemical yield and high enantioselectivity.
R1
Boc
O
X
R2
n
X
toluene (0.2 M)
r.t., 24 h
N
O
3
X
Boc
n
X
2
Entry R1, R2
Catalyst n, X
3
Yield drc
(%)b
ee
(%)d
1
2
3
Bn, H
Bn, H
Bn, H
A
B
A
A
A
A
B
A
A
A
1, H
1, H
3a
3a
80 5.2:1 96
94 5.2:1 98e
30 5.7:1 92
55 5.5:1 46
62 2.8:1 97
O
Bn
Bn
amine (20 mol%)
1, Me 3b
PhCO2H (40 mol%)
O
+
2a
toluene (0.2 M)
r.t., 72 h
4f,g Bn, H
5g Bn, H
0, H
2, H
1, H
1, H
2, H
1, H
1, H
3c
3d
3e
3e
3f
O
O
O
5
6
6: 61% yield, 2:1 dr, 94% ee
ent-6: 58% yield, 1.6:1 dr, 95% ee
A
B
6
7
Me, H
Me, H
94 4:1
94 6:1
95
Scheme 2 Asymmetric synthesis of benzofuranone derivative bea-
ring contiguous quaternary and tertiary stereocenters
97e
8g Me, H
9f Ph, H
70 2.5:1 95
95 1.6:1 98
In summary, we have presented a novel and easy way to
access densely functionalized molecules that contain vic-
inal quaternary and tertiary stereocenters.17 In view of the
abundance of important indole- and benzofuranon-de-
rived natural products bearing a quaternary stereocenter in
the 3-position of the heterocycle, we believe this method
could be useful in asymmetric synthesis. The research is
based on the development of the first, highly stereoselec-
tive addition of oxindole to cyclic enones, using a readily
available chiral primary amine catalyst. Moreover, we
have extended asymmetric organocatalytic transforma-
tions to include an unprecedented compound class, benzo-
furanone derivatives. We expect these nucleophilic
compounds will find application in other asymmetric
3g
10
3-ClPhCH2, Cl
3h
85 4:1
94
a The reactions were carried out at r.t. on a 0.2 mmol scale with 1.2
equiv of 1 and [2]0 = 0.2 M in toluene.
b Isolated yield (sum of diastereomers).
c Determined by 1H NMR analysis of the crude mixture.
d Determined by HPLC analysis on chiral stationary phases.
e The opposite enantiomer of 3 has been obtained.
f Reaction at 0 °C.
g Reaction carried out in the presence of 20 mol% of the catalyst over
48 h.
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Asymmetric Catalytic Synthesis of Adjacent Tertiary and Quaternary Stereocenters
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Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2009, 48,
7200.
transformations aimed at preparing valuable nature-
inspired compounds.
(9) For selected examples on the catalytic construction of
adjacent quaternary and tertiary chiral centers, see:
(a) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5482. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.;
Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed.
2005, 44, 105. (c) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2006, 45, 6366. (d) Bartoli, G.;
Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti,
A.; Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem. Int.
Ed. 2006, 45, 4966. (e) Streuff, J.; White, D. E.; Virgil, S.
C.; Stoltz, B. M. Nature Chem. 2010, 2, 192.
(10) (a) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti,
A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem. Eur. J. 2009, 15, 7846. (b) Bui, T.; Syed, S.; Barbas,
C. F. III. J. Am. Chem. Soc. 2009, 131, 8758. (c) Kato, Y.;
Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (d) He,
R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009,
131, 16620.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Li-Yuan Wu for preliminary experiments. We also thank
Dr. J. Benet-Buchholz and E. Escudero-Adán (X-ray Diffraction
Unit, ICIQ) for the structure of 4. This work was supported by
Bologna University and the Institute of Chemical Research of Cata-
lonia (ICIQ) Foundation.
References and Notes
(1) (a) Nicolaou, K. C.; Snyder, S. A. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11929. (b) Shenvi, R. A.; O’Malley,
D. P.; Baran, P. S. Acc. Chem. Res. 2009, 42, 530.
(2) (a) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature (London)
2008, 455, 323. (b) Grondal, C.; Jeanty, M.; Enders, D.
Nature Chem. 2010, 2, 167. (c) Woodward, R. B.; Bader,
F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. J. Am. Chem.
Soc. 1956, 78, 2023. (d) Corey, E. J. Angew. Chem. Int. Ed.
2002, 41, 1650. (e) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945.
(11) For recent examples on the catalytic, asymmetric addition of
oxindoles to vinyl sulfones and vinyl ketones, generating a
single, quaternary stereocenter: (a) He, R.; Ding, C.;
Maruoka, K. Angew. Chem. Int. Ed. 2009, 48, 4559. (b) Li,
X.; Xi, Z.-G.; Luo, S.; Cheng, J.-P. Org. Biomol. Chem.
2010, 8, 77.
(12) (a) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. (b) Chen,
Y.-C. Synlett 2008, 1919. For the first use of primary amines
in iminium catalysis with enones, see: (c) Martin, N. J. A.;
List, B. J. Am. Chem. Soc. 2006, 128, 13368. For the first
demonstration that catalysts A or B can be used in iminium–
enamine cascades of enones, see: (d) Wang, X.; Reisinger,
C. M.; List, B. J. Am. Chem. Soc. 2008, 130, 6070.
(13) Selected examples: (a) Xie, J.-W.; Chen, W.; Li, R.; Zeng,
M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng,
J.-G. Angew. Chem. Int. Ed. 2007, 46, 389. (b) Bartoli, G.;
Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403. (c) Chen, W.; Du,
W.; Duan, Y.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C. Angew.
Chem. Int. Ed. 2007, 46, 7667. (d) Zhang, E.; Fan, C.-A.;
Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L. J. Am. Chem. Soc.
2009, 131, 14626. (e) Wu, L.-Y.; Bencivenni, G.;
Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem. Int. Ed. 2009, 48, 7196. (f) Galzerano, P.;
Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Melchiorre, P.
Angew. Chem. Int. Ed. 2009, 48, 7892.
(14) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(15) Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre, accession number
CCDC 771490(4), and are available free of charge via
www.ccdc.cam.ac.uk/data_request/cif.
(16) For an example of catalytic and enantioselective O-to-C
rearrangements of O-acylated benzofuranone derivatives,
see ref. 8b. For an early example, see: Black, T. H.; Arrivo,
S. M.; Schumm, J. S.; Knobeloch, J. M. J. Chem. Soc.,
Chem. Commun. 1986, 1524.
(3) (a) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70,
461. (b) Stereochemical Aspects of Drug Action and
Disposition; Eichelbaum, M.; Testa, B.; Somogyi, A., Eds.;
Springer: Berlin, 2003. (c) Kumar, K.; Waldmann, H.
Angew. Chem. Int. Ed. 2009, 48, 3224.
(4) (a) Quaternary Stereocenters. Challenges and Solutions in
Organic Synthesis; Christoffers, J.; Baro, A., Eds.; Wiley-
VCH: Weinheim, 2006. (b) Douglas, C. J.; Overman, L. E.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (c) Trost, B.
M.; Chunhui, J. Synthesis 2006, 369. (d) Bella, M.; Gasperi,
T. Synthesis 2009, 1583.
(5) (a) Lin, H.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2003,
42, 36. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (c) Galliford, C. V.; Scheidt, K. A. Angew.
Chem. Int. Ed. 2007, 46, 8748.
(6) (a) Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, D.;
Liotta, C. J. Org. Chem. 2001, 66, 3653. (b) Lo, M. M.-C.;
Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber,
S. L. J. Am. Chem. Soc. 2004, 126, 16077. (c) Kotha, S.;
Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165;
and references cited therein. (d) Lik, K.-C.; So, S.-S.;
Zhang, J.; Zhang, Z. WO 2006/136606, 2006. (e) Liu, J.-J.;
Zhang, Z. WO 2008/055812, 2008.
(7) Selected examples: (a) Madin, A.; O’Donnell, C. J.; Oh, T.;
Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc.
2005, 127, 18054. (b) Trost, B. M.; Zhang, Y. J. Am. Chem.
Soc. 2007, 129, 14548. (c) Kündig, E. P.; Seidel, T. M.; Jia,
Y.; Bernardinelli, G. Angew. Chem. Int. Ed. 2007, 46, 8484.
(d) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M.
Angew. Chem. Int. Ed. 2009, 48, 8037.
(8) Selected examples: (a) Lee, T. B. K.; Wong, G. S. K. J. Org.
Chem. 1991, 56, 872. (b) Hills, I. D.; Fu, G. Angew. Chem.
Int. Ed. 2003, 42, 3921. (c) Ogawa, S.; Shibata, N.; Inagaki,
J.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed.
2007, 46, 8666. (d) Tian, X.; Jiang, K.; Peng, J.; Du, W.;
Chen, Y.-C. Org.Lett. 2008, 10, 3583. (e) Chen, X.-H.;
Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem.
Soc. 2009, 131, 13819. (f) Bencivenni, G.; Wu, L.-Y.;
Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.;
(17) General Procedure
All the reactions were carried out with no precautions to
exclude moisture in undistilled toluene. In an ordinary vial
equipped with a magnetic stir bar, amine A or B (0.02 mmol,
6.5 mg, 10 mol%) and benzoic acid (0.04 mmol, 4.9 mg, 20
mol%) were dissolved in toluene (1 mL). After stirring at r.t.
for 10 min, the cyclic enones 2 (0.2 mmol) was added,
followed by the addition of oxindole 1 or benzofuranone 5
(0.24 mmol, 1.2 equiv). The vial was sealed, and the mixture
Synlett 2010, No. 11, 1704–1708 © Thieme Stuttgart · New York

1708
F. Pesciaioli et al.
CLUSTER
stirred for 1 d at r.t. The crude mixture was diluted with
CH2Cl2 and flushed through a short plug of silica, using
CH2Cl2–EtOAc (1:1) as the eluent. Solvent was removed in
vacuo, and the Michael adduct 3 or 6 was purified by flash
column chromatography (silica gel, hexane–EtOAc). All
new compounds gave satisfactory spectroscopic and
analytical data. As a typical example, the data of the
compound 3a are given.
min (minor, based on the racemic mixture)]; [a]Drt –17.37 (c
0.98, CHCl3, dr = 5.2:1, 96% ee). 1H NMR (400 MHz,
CDCl3): d = 1.47–1.64 (m, 2 H), 1.55 (s, 9 H), 1.70–1.81 (m,
1 H), 1.97–2.12 (m, 1 H), 2.15–2.32 (m, 1 H), 2.32–2.50 (m,
2 H), 2.55–2.61 (m, 2 H), [CH2 A-B type spectrum (3.04, d,
1 H, Jgem = –12.8 Hz), (3.30, d, 1 H, Jgem = –12.8 Hz)], 6.72–
6.77 (m, 2 H), 6.93–7.06 (m, 3 H), 7.13–7.31 (m, 3 H), 7.52–
7.57 (m, 1 H). 13C NMR (100 MHz, CDCl3): d = 25.1 (CH2),
26.4 (CH2), 28.3 (3× CH3), 41.4 (CH2), 42.2 (CH2), 43.0
(CH2), 46.2 (CH), 57.4 (C), 84.3 (C), 115.0 (CH), 123.6
(CH), 124.4 (CH), 126.9 (CH), 127.9 (CH), 128.6 (CH),
129.3 (C), 130.0 (CH), 135.1 (C), 140.3 (C), 148.8 (C),
177.2 (C), 210.6 (C). HRMS (EI): m/z calcd for C26H29NO4:
419.2096; found: 419.2092.
(R)-tert-Butyl 3-Benzyl-2-oxo-3-[(S)-3-oxocyclohexyl]-
indoline-1-carboxylate (3a, Entry 1, Table 2)
Isolated as a mixture of diastereomers (5.2:1 dr) by column
chromatography (hexane–acetone = 90:10) in 80% yield.
The ee (96% ee) was determined by HPLC on a chiral
stationary phase [Chiralpak AD-H; hexane–i-PrOH (98:2);
0.50 mL/min; l = 214, 254 nm; tR = 34.1 min(major), 41.7
Synlett 2010, No. 11, 1704–1708 © Thieme Stuttgart · New York