Organocatalytic Michael addition of indoles to isatylidene-3-acetaldehydes: Application to the formal total synthesis of (-)-chimonanthine

Article abstract of DOI:10.1021/ol400845c

A novel strategy for the enantioselective synthesis of 3,3′- disubstituted oxindoles by the organocatalytic Michael addition of indoles to isatylidene-3-acetaldehydes was developed, which can be used for the formal total synthesis of (-)-chimonanthine and the core structure construction of (+)-gliocladin C.

Full text of DOI:10.1021/ol400845c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Organocatalytic Michael Addition of
Indoles to Isatylidene-3-acetaldehydes:
Application to the Formal Total Synthesis
of (ꢀ)-Chimonanthine
Renrong Liu and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, 3663 N. Zhongshan Road,
Shanghai 200062, P. R. China
jlzhang@chem.ecnu.edu.cn
Received March 28, 2013
ABSTRACT
A novel strategy for the enantioselective synthesis of 3,30-disubstituted oxindoles by the organocatalytic Michael addition of indoles to isatylidene-3-
acetaldehydes was developed, which can be used for the formal total synthesis of (ꢀ)-chimonanthine and the core structure construction of (þ)-gliocladin C.
3,30-Disubstituted oxindoles are frequently found in
many biologically active natural products and widely
utilized as building blocks for alkaloid synthesis.1 In recent
decades, much effort has been devoted to the cata-
lytic asymmetric construction of oxindole framework
with chiral C3-quaternary centers, including (a) direct
asymmetric functionalization of 3-substituted oxindoles;2
(b) enantioselective intramolecular Heck reaction3 and
arylation reaction4; (c) asymmetric rearrangement of
indolyl acetates and carbonates;5 (d) enantioselective
substitution of 3-halo-30-substituted oxindoles;6 and (e)
cycloaddition of methyleneindolinones.7 However, to
€
(4) Kundig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G. Angew.
(1) For recent reviews, see: (a) Lin, H.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 36. (b) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (c) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv.
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r
10.1021/ol400845c
XXXX American Chemical Society

our surprise, as one of the readily available oxindole deriv-
atives, isatylidene-3-acetaldehydes have not been used
to construct optically active oxindoles with quaternary
stereocenters untill very recently.7k
Scheme 1. Retrosynthetic Analysis of (ꢀ)-Chimonanthine and
(þ)-Gliocladin C
3a,3a0-Bispyrrolidino[2,3-b]indolines and C3-(30-indolyl)-
hexahydropyrroloindole are two important substructures
present in a significant subset of natural alkaloids.8 How
to enantioselectively construct both of them has been a
longstanding challenge in organic synthesis and attracted
much attention over recent years. To date, only a few groups
have achieved total synthesis of these alkaloids. For the
synthesis of 3a,3a0-bispyrrolidino[2,3-b]indoline alkaloids,
Overman et al. enantioselectively constructed these struc-
tures by either diastereoselective dialkylation or double Heck
cyclization using a chiral auxiliary strategy.9 Movassaghi
et al. took advantage of a Co-promoted reductive homo-
coupling of L-tryptophan derived 3-bromohexahydropyrro-
loindoles and succeeded in completing the enantioselective
total synthesis of a series of 3a,3a0-bispyrrolidino[2,3-b]-
indoline alkaloids.10 Sodeoka et al. finished the total synth-
esis of a related natural product, (þ)-chaetocin, using a
similar homodimerization strategy.11 Recently, Gong et al.
described a novel chiral phosphoric acid catalyzed substitu-
tion of 3-hydroxyoxindoles to complete the enantioselective
total synthesis of (þ)-folicanthine.12 Very recently, Kanai
and Matsunaga established an elegant Mn2þ/Schiff base
and Mg(OAc)2/benzoic acid catalyst system to construct
these alkaloids by sequential Michael additions of N-Boc-
protected bisoxindole to nitroethylene.13 For the synthesis
of C3-(30-indolyl)hexahydropyrroloindole alkaloids, the
groups of Overman,14a,b Stephenson,14c and Movassaghi14d
have developed several methodologies to enantioselectively
construct the C3-(30-indolyl)hexahydropyrroloindole struc-
tures and achieved the total synthesis of (þ)-gliocladin C and
several other hexahydropyrroloindole alkaloids. Besides,
Trost et al. also demonstrated an efficient Pd-catalyzed
asymmetric addition of oxindoles to allenes for the synthesis
of the core structure of the (þ)-gliocladin C.14e
envisioned that both (ꢀ)-chimonanthine with the 3a,3a0-
bispyrrolidino[2,3-b]indoline structure and (þ)-gliocladin
C with the C3-(30-indolyl)hexahydropyrroloindole struc-
ture might be prepared from two enantiomers (R)-4a and
(S)-4a, which are obtained from the same starting materials
indoles and isatylidene-3-acetaldehydes with the concept
of iminium catalysis (Scheme 1).15 Although the amine-
catalyzed asymmetric Michael additions to β-monosubsti-
tuted R,β-unsaturated aldehydes have been well developed,
the conjugate additions to β-disubstituted unsaturated
aldehydes leading to quaternary carbon stereocenters are
scarcely explored,16 due to the fact that the steric effect
would lead to the 1,2-addition as the major reaction rather
than the 1,4-conjugate addition. Herein, we report our
effort on the enantioselective organocatalytic Michael ad-
dition to isatylidene-3-acetaldehydes, the readily available
β-disubstituted R,β-unsaturated aldehydes from isatins,17
to construct 3,30-disubstituted oxindoles bearing all-carbon
quaternary stereocenters.18 Furthermore, the synthetic
Despite these notable advances, to the best of our
knowledge, there is no report about the synthesis of these
two substructures from the same starting materials. We
(8) For reviews, see: (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007,
40, 151. (b) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46,
5488. (c) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 313.
(9) (a) Overman, L. E.; Paone, D. V.; Stearns, B. A. J. Am. Chem.
Soc. 1999, 121, 7702. (b) Overman, L. E.; Larrow, J. F.; Stearns, B. A.;
Vance, J. M. Angew. Chem., Int. Ed. 2000, 39, 213.
(10) (a) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed.
2007, 46, 3725. (b) Movassaghi, M.; Schmidt, M. A.; Ashehurst, J. A.
Angew. Chem., Int. Ed. 2008, 47, 1485. (c) Kim, J.; Ashenhurst, J. A.;
Movassaghi, M. Science 2009, 324, 238. (d) Kim, J.; Movassaghi, M.
J. Am. Chem. Soc. 2010, 132, 14376.
(15) For recent reviews, see: (a) Lelais, G.; MacMillan, D. W. C.
€
Aldrichimica Acta 2006, 39, 79. (b) Erkkila, A.; Majander, I.; Pihko,
P. M. Chem. Rev. 2007, 107, 5416. (c) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (d)
Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K. A.
Acc. Chem. Res. 2012, 45, 248.
(11) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.;
Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4078.
(12) Guo, C.; Song, J.; Huang, J.-Z.; Chen, P.-H.; Luo, S.-W.; Gong,
L.-Z. Angew. Chem., Int. Ed. 2012, 51, 1046.
(13) Mitsunuma, H.; Shibasaki, M.; Kanai, M.; Matsunaga, S.
Angew. Chem., Int. Ed. 2012, 51, 5217.
(14) (a) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339. (b) DeLorbe,
J.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am.
Chem. Soc. 2011, 133, 6549. (c) Furst, L.; Narayanam, J. M. R.;
Stephenson, C. R. J. Angew. Chem., Int. Ed. 2011, 50, 9655. (d) Boyer,
N.; Movassaghi, M. Chem. Sci. 2012, 3, 1798. (e) Trost, B. M.; Xie, J.;
Sieber, J. D. J. Am. Chem. Soc. 2011, 133, 20611.
(16) Only a few examples of a β,β-dialkyl substituted R,β-unsatu-
rated aldehyde were reported and gave unsatisfactory results in most
cases: (a) Asato, A. E.; Watanabe, C.; Li, X.-Y.; Liu, R. S. H. Tetra-
hedron Lett. 1992, 33, 3105. (b) Ma, A.; Ma, D. Org. Lett. 2010, 12, 3634.
(c) Banwell, M. G.; Beck, D. A. S.; Willis, A. C. ARKIVOC 2006, 163.
(d) Akagawa, K.; Kudo, K. Angew. Chem., Int. Ed. 2012, 51, 12786.
(17) Autrey, R. L.; Tahk, F. C. Tetrahedron 1967, 23, 901.
(18) For reviews of the catalytic asymmetric construction of all-
carbon quaternary stereocenters, see: (a) Corey, E. J.; Guzman-Perez,
A. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Douglas, C. J.; Overman,
L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (c) Hawner, C.;
Alexakis, A. Chem. Commun. 2010, 46, 7295.
B
Org. Lett., Vol. XX, No. XX, XXXX

utility of this transformation is well demonstrated by the
formal total synthesis of (ꢀ)-chimonanthine and the core
structure construction of (þ)-gliocladin C.
Table 2. Substrate Scope of Isatylidene-3-acetaldehyde and
Indolea
Table 1. Optimization of the Reaction Conditionsa
t
4, yield
ee
entry
1; R1, R2
2; R3
2a H
(h)
(%)
(%)
entry
additive
solvent
t (h)
yield (%)
ee (%)
1
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1a H, Bn
1b 5-Me, Bn
1c 5-MeO, Bn
1b 5-Me, Bn
1d 5-F, Bn
1e H, Me
35
40
40
30
40
40
40
40
40
40
50
40
60
48
60
40
45
4a 60
4b 60
4c 55
4d 72
4e 63
4f 52
4g 52
4h 60
4i 58
4j 54
91
96
93
94
91
97
93
96
91
86
92
94
88
90
95
96
95
2
2b 5-F
1
PhCO2H
ꢀ
EtOH
EtOH
toluene
CH2Cl2
i-PrOH
EtOH
EtOH
EtOH
EtOH
EtOH
5
72
60
40
45
55
58
15
55
63
60
63
80
61
59
76
82
83
87
84
91
3
2c 5-Cl
2d 5-Br
2e 5-Me
2f 6-F
2
40
30
30
30
40
3
4
3
ꢀ
5
4
ꢀ
6
5
ꢀ
7
2g 6-Cl
2h 6-Br
2i 6-CO2Me
2j 6-Me
2k 7-Cl
2l 7-Br
2a H
6b
7
H2O
PhCO2Na
buffer
buffer
buffer
8
9
8c
9d
10e
40
40
35
10
11
12
13
14
15
16
17
4k 53
4l 52
a Reaction conditions: 1a (1.0 equiv), 2a (2.0 equiv), 20 mol %
catalyst, 20 mol % additive, with solvent indicated 0.1 M at room
temperature. b 5.0 equiv H2O were added. c pH = 7 buffer (5.0 equiv)
was added; see Supporting Information for details. d pH = 7 buffer
(2.5 equiv) was added. e 40 mol % catalyst and pH = 7 buffer (5.0 equiv)
were added.
4m 67
4n 53
4o 65
4p 34
4q 54
2a H
2d 5-Br
2d 5-Br
2d 5-Br
a Reaction conditions: 1 (0.12 mmol, 1.0 equiv), 2 (0.24 mmol,
2.0 equiv), catalyst 3a (40 mol %), pH = 7 buffer (5.0 equiv, 12 μL),
EtOH (1.2 mL), at room temperature.
In the initial study, to our delight, the Michael addition
of indole 2a to isatylidene-3-acetaldehyde (Z)-1a did give
the desired product 4a with moderate enantioselectivity
in the presence of JørgensenꢀHayashi catalyst 3a and
benzoic acid (Table 1, entry 1). A series of other Jørgensenꢀ
Hayashi type catalysts were also screened.19 Gratifyingly,
the reaction proceeded smoothly to afford the desired
product in 80% ee without the additive benzoic acid
(Table 1, entry 2). No improvement in enantioselectivity
was observed in the other tested solvents such as toluene,
CH2Cl2, andi-PrOH (Table 1, entries 3ꢀ5). The addition of
5.0 equiv of water brought little benefit to this reaction
(Table 1, entry 6). When sodium benzoate was used as an
additive, the enantioselectivity exhibited a small increase
but only a 15% yield was obtained (Table 1, entry 7).
Further screening reaction conditions revealed that the
addition of neutral buffer could give a better enantioselec-
tivity up to 87% ee (Table 1, entry 8). To the best of our
knowledge, this is the first example using buffer to enhance
the enantioselectivity in the amine-catalyzed Michael
addition. Reducing the equivalents of buffer from 5.0 to
2.5 equiv resulted in a small decrease in the enantioselec-
tivity (Table 1, entry 9). Improvement of the catalyst
loading to 40 mol % gave product 4a in 60% yield with
the highest enantiomeric excess (91% ee, Table 1, entry10).
Withthe optimalreaction conditions inhand, weinvesti-
gated the reaction scope by variation of two substrate
components. Generally, both electron-withdrawing and
-donating groups on the indole moiety were tolerated,
affording the corresponding products with >90% ee in
most cases (Table 2, entries 1ꢀ12). The substrates with
electron-withdrawing groups gave relatively higher ee’s
than those bearing electron-donating groups. The sub-
stituent effect on the isatylidene-3-acetaldehyde moiety
was also investigated, and high ee values were obtained
(Table 2, entries 13ꢀ16). The absolute configuration of
product 4o was determined to be an S-configuration by
single crystal X-ray analysis.20 The N-Me protected sub-
strate 1e was also well suited for this transformation
(Table 2, entry 17).
The synthetic utility of this reaction was showcased by
applying it to the catalytic enantioselective formal total
synthesis of (ꢀ)-chimonanthine (Scheme 2) and the core
structure of (þ)-gliocladin C (Scheme 3). The enantiose-
lective Michael addition with a gram scale of 1a and 20 mol %
catalyst (R)-3a gave (R)-4a in 65% yield and 85% ee (92% ee
from the mother liquid of recrystallization process) in 60 h.
Protection of the aldehyde and further alkylation furnished
compound 5 in 95% yield. Subsequent oxidation by
(19) For detailed catalyst screening and optimization of the reaction
conditions, see Supporting Information.
(20) See Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Formal Total Synthesis of (ꢀ)-Chimonanthine
Scheme 3. Synthesis of Core Structure of (þ)-Gliocladin C
In summary, we have developed the first example of the
organocatalytic asymmetric conjugate addition of indole
to isatylidene-3-acetaldehyde, which provides a facile ac-
cess to oxindoles bearing all-carbon quaternary stereocen-
ters at the 3-position with high enantioselectivity. This
transformation is easily scaled up to gram scale. The
method can be used for the enantioselective formal total
synthesis of (ꢀ)-chimonanthine and the core structure
construction of (þ)-gliocladin C. In addition, it is also
interesting to find that the buffer can enhance the enantios-
electivity, which may bring new applications to other
amine-catalyzed reactions. Further studies including in-
vestigation of other asymmetric transformations of isaty-
lidene-3-acetaldehyde are being carried out in this
laboratory and will be reported in due course.
DMSO/HCl gave rise to the compound 6 in 75% overall
yield.21 After further protection of aldehyde and allylation
of the vicinal quaternary stereogenic centers, compound 8
was obtained in 80% yield as the only isomer. Ozonolysis of
8 in CH2Cl2 and subsequent deprotection afforded product
10 in 47% overall yield from oxindole 4a in 7 steps, from
which (ꢀ)-chimonanthine could be then synthesized using
the procedure described by Overman.9a
Interestingly, compound 11 could be easily prepared in
high yield (Scheme 3) by a three-component Ugi reaction
of (S)-4a, tert-butyl isocyanide, and 4-methoxyaniline
under the catalysis of phenyl phosphinic acid, which
was developed by List.22 After treatment with DIBAL-H,
a cyclization compound 12 could be isolated in 56%
yield. Alternatively, protection of compound 11 by BSTFA
(bis(trimethylsilyl)trifluoroacetamide) and subsequent re-
duction by DIBAL-H afforded a N-TMS protected com-
pound 14 in 82% overall yield in two steps. The total
synthesis of (þ)-gliocladin C is then realized from compound
12 or 14 following the route explored by Stephenson.14c
Acknowledgment. We are grateful to the 973 program
(2011CB808600), National Natural Science Foundation
of China, Ministry of Education of China, and Ying
Tung Education Foundation (121014) for financial
support.
Supporting Information Available. Typical experimen-
tal procedure and characterization for all products,
and X-ray data of 4o in CIF format. This material
is available free of charge via the Internet at http://pubs.
acs.org.
ꢀ
ꢀ
(21) Szabo-Pusztay, K.; Szabo, L. Synthesis 1979, 276.
(22) Pan, S. C.; List, B. Angew. Chem., Int. Ed. 2008, 47, 3622.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX