Catalytic asymmetric total synthesis of chimonanthine, folicanthine, and calycanthine through double michael reaction of bisoxindole

Article abstract of DOI:10.1002/anie.201201132

Direct access: Sterically hindered vicinal quaternary carbon stereocenters were constructed by catalytic enantio- and diastereoselective double Michael reaction, providing straightforward access to dimeric hexahydropyrroloindole alkaloids. A Mn(4-fluorobenzoate)₂/Schiff base complex and a Mg(OAc)₂/benzoic acid system were used as catalysts. Copyright

Full text of DOI:10.1002/anie.201201132

Angewandte
Chemie
DOI: 10.1002/anie.201201132
Synthetic Methods
Catalytic Asymmetric Total Synthesis of Chimonanthine, Folicanthine,
and Calycanthine through Double Michael Reaction of Bisoxindole**
Harunobu Mitsunuma, Masakatsu Shibasaki, Motomu Kanai,* and Shigeki Matsunaga*
Hexahydropyrroloindole alkaloids comprise a large family of
natural products with attractive biological activities.[1] Among
them, dimeric and oligomeric hexahydropyrroloindole alka-
loids bearing vicinal quaternary stereogenic carbon centers at
C3a and C3a’ have attracted significant interest as synthetic
targets.[2] Syntheses of chimonanthine (1), folicanthine (2),
and calycanthine (3; Scheme 1), which are in the simplest
been achieved by only a few groups.[4–7] The synthetic
difficulty mainly arises from two structural features of the
À
dimeric hexahydropyrroloindole core:
a
labile C3a C3a’
s bond[8] and sterically hindered vicinal quaternary stereo-
genic carbon centers. The first enantioselective total synthesis
of chimonanthine and calycanthine was reported by Overman
and co-workers; in this synthesis the contiguous quaternary
carbon centers were elegantly constructed by either diaste-
reoselective dialkylation or double Heck cyclization based on
the selected chiral auxiliaries.[4] Movassaghi and co-workers
established an efficient CoI-promoted reductive homodime-
rization of 3-bromo-hexahydropyrrolo indoles derived from
l-tryptophan, and achieved concise enantioselective total
syntheses of various hexahydropyrroloindole alkaloids,
including chimonanthine, calycanthine, and folicanthine.[5]
Sodeoka and co-workers also achieved total synthesis of
a related natural product, (+)-chaetocin, by using a related
homodimerization strategy.[6] In striking contrast to these
elegant precedents using stoichiometric amounts of chiral
sources, catalytic asymmetric approaches for the construction
of the dimeric hexahydropyrroloindole core still remain
particularly challenging. Very recently, Gong and co-workers
reported the first highly enantioselective catalytic asymmetric
total synthesis of (+)-folicanthine through substitution of 3-
hydroxyoxindole with an enecarbamate catalyzed by chiral
phosphoric acids.[7] Because the product in the key enantio-
selective reaction, 3-indolyl-substituted oxindole, could not
be directly converted into a dimeric hexahydropyrroloindole
motif, several additional steps were required to achieve the
total synthesis (12 steps in 3.7% overall yield). The results
prompted us to communicate our studies on a straightforward
catalytic asymmetric total synthesis of chimonanthine, caly-
canthine, and folicanthine. A chiral Mn(4-F-BzO)2/Schiff
base 4a catalyst (4-F-BzO = 4-fluorobenzoate, Scheme 2) and
Mg(OAc)2 promoted a sequential Michael reaction of a bisox-
indole with nitroethylene, thereby directly affording a key
intermediate with vicinal quaternary stereogenic carbon
Scheme 1. Representative dimeric hexahydropyrroloindole-derived
family of alkaloids.
class of these alkaloids, have been intensively studied over
decades.[2,3] Enantioselective construction of the dimeric core
structure in chimonanthine and folicanthine, however, has
[*] H. Mitsunuma, Prof. Dr. M. Kanai, Dr. S. Matsunaga
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kanai@mol.f.u-tokyo.ac.jp
smatsuna@mol.f.u-tokyo.ac.jp
Prof. Dr. M. Kanai, Dr. S. Matsunaga
Kanai Life Science Catalysis Project
ERATO (Japan) Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
[**] We thank Prof. Kobayashi, Prof. Ohwada, Dr. Otani, and Dr. Ueno at
the University of Tokyo for generous technical supports. This work
was supported by Scientific Research on Innovative Areas from
MEXT, ERATO from JST, Grant-in-Aid for Young Scientists (A) from
JSPS, Inoue Science Foundation, and Takeda Science Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201132.
Scheme 2. Structures of Schiff bases 4a–4d and dinuclear Schiff base
complexes. Cat.=catalyst.
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centers in high enantio- and diastereoselectivity. The double
Michael adduct was successfully converted into chimonan-
thine (1) by reductive cyclization, while suppressing undesir-
À
able cleavage of the C3a C3a’ s bond.
Over the past decade, tremendous efforts have been
devoted towards catalytic asymmetric syntheses of 3,3’-
disubstituted oxindoles bearing quaternary carbon cen-
ters[9–12] as well as their applications in the enantioselective
synthesis of monomeric hexahydropyrroloindole motifs in
alkaloids.[1] Trials to apply the methodologies to the synthesis
of dimeric hexahydropyrroloindole alkaloids bearing vicinal
quaternary stereogenic carbon centers, however, had not
been reported until Gong and co-workers recently reported
the approach using 3-indolyl-substituted oxindole.[7] For
a more straightforward approach to the target core structure,
the use of bisoxindole as a substrate in the catalytic
Scheme 3. Retrosynthetic Analysis.
stereoselective double functionalization reaction is
ideal. To our knowledge, however, there are no
reports of a catalytic asymmetric reaction using
Table 1: Optimization of catalytic asymmetric Michael reaction.
À
bisoxindoles, possibly owing to the labile C3a C3a’
s bond and steric hindrance in formation of the
vicinal quaternary carbon centers. Our synthetic
strategy is summarized in Scheme 3. (À)-Calycan-
thine (3) and (+)-folicanthine (2) can be obtained
from (+)-chimonanthine (1) in one step by following
the reported procedure.[4,5a] In previous studies, the
Entry Metal source Ligand
Benzoic acid
T
t
Yield[d] ee
(x mol%) Ar: (y mol%)
[8C] [h] [%]
[%]
À
undesired cleavage of the C3a C3a’ s bond during
1[a,b]
2[a,b]
3[a,b]
4[a]
Ni(OAc)2
Co(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
4a (10)
4a (10)
4a (10)
4a (5)
4a (5)
4a (5)
4a (5)
4a (5)
none
none
none
Ph- (20)
4-MeO-C6H4- (20)
4-F-C6H4- (20)
4-F-C6H4- (10)
RT 57 96
RT 57 74
RT 57 65
3
11
55
85
84
86
91
9
reductive cyclization processes was often problem-
atic and gave the desired dimeric hexahydropyrro-
loindole core in low yield.[13] Thus, we planned to use
50
50
50
50
5
5
5
5
5
5
5
9
87
81
83
94
80
90
90
87
tert-butoxycarbonyl (Boc)-protected intermediate 5 5[a]
to minimize undesired cleavage of the C3a C3a’
s bond during the reductive cyclization process.
The intermediate 5 can be readily obtained from
6[a]
À
7[a]
8[a]
2,4,6-Me3-C6H2- (20) 50
9[a]
Mn(4-F-BzO)2 4a (4.3)
Mn(4-F-BzO)2 4a (4.3)
Mn(4-F-BzO)2 4a (2.2)
none
none
none
50
50
50
50
50
50
50
95
96
96
91
2
the key double Michael adduct 6. To minimize the
protection–deprotection process, we used Boc-pro-
tected bisoxindole 7 as a substrate in the key double
Michael reaction with nitroethylene.
As a part of our ongoing research on catalysis by
bimetallic Schiff base complexes, we recently
reported homodinuclear Ni2/4a, Co2(OAc)2/4a, and
Mn2(OAc)2/4a complexes (Scheme 2) for Michael
reactions of various nucleophiles with nitroal-
kenes.[14] Therefore, we first applied these complexes
and related dinuclear Schiff base complexes[15] for
the reaction of nitroethylene[16] and Boc-protected
10[c]
11[c]
12[c]
13[c]
14[c]
15[c]
Mn(4-F-BzO)2 4a (0.88) none
24 87
Mn(4-F-BzO)2 4b (5)
Mn(4-F-BzO)2 4c (5)
Mn(4-F-BzO)2 4d (5)
none
none
none
5
5
5
19
14
75
30[e]
0
[a] Catalyst was prepared prior to use in metal source/ligand ratio of 2:1.
[b] Reaction was run in the absence of molecular sieves (5 ꢀ). [c] Catalyst was
prepared prior to use in a metal source/ligand ratio of 1:1. [d] Determined by
1H NMR analysis of the crude mixture. [e] ent-8 was obtained as major enantiomer.
bisoxindole 7, which was readily synthesized from commer-
cially available oxindole and isatin in 87% yield (in two
steps). Among the catalysts screened (Table 1, entries 1–3),
Mn2(OAc)2/4a gave the best enantioselectivity, affording
product 8 in 55% ee (entry 3). After optimization of the
reaction conditions, such as additives and temperature,
product 8 was obtained in 87% yield and 85% ee after five
hours when using the Mn2(OAc)2/4a catalyst in the presence
of molecular sieves (5 ꢀ) and benzoic acid (20 mol%) at
508C (Table 1, entry 4). 4-Methoxybenzoic acid and 4-fluo-
robenzoic acid gave comparable results (Table 1, entries 5–6),
and product 8 was obtained in 91% ee with 10 mol% of 4-
fluorobenzoic acid (Table 1, entry 7). Because sterically
hindered 2,4,6-trimethylbenzoic acid resulted in poor enan-
tioselectivity (9% ee, Table 1, entry 8), we speculated that the
active catalyst species would be generated in situ by exchang-
ing the counterion on Mn from acetate to benzoate deriva-
tives in entries 4–7. We then utilized Mn(4-F-BzO)2 as a metal
source, and a catalyst prepared from Mn(4-F-BzO)2, and
ligand 4a in a ratio of 2:1 gave the product in 90% yield and
95% ee (Table 1, entry 9). In striking contrast to our previous
examples,[17] the catalyst from Mn(4-FBzO)2 and ligand 4a
mixed in 1:1 ratio also gave 8 in high enantioselectivity
(Table 1, entry 10, 96% ee).[18] The catalyst loading was
successfully reduced to 2.2 mol%, while the high enantiose-
lectivity was maintained (Table 1, entry 11, 96% ee). With
2
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0.88 mol% catalyst, product 8 was obtained in good yield
after 24 h, but the enantioselectivity slightly decreased
(Table 1, entry 12, 91% ee). Other Schiff bases, 4b, 4c, and
4d, resulted in poor enantioselectivity (Table 1, entries 13–
15), thus suggesting that the hydroxy groups in Schiff base 4a
played an important role in constructing a highly enantiose-
lective active catalyst.
We then tried to utilize the Mn(4-F-BzO)2/Schiff base 4a
(ratio 1:1) catalyst for one-pot double Michael reaction. The
Schiff base catalyst, however, had only moderate reactivity
toward the second Michael reaction, possibly owing to severe
steric hindrance. Even after intensive optimization of the
reaction conditions, desired product 6 from a double Michael
reaction was obtained in up to only 44% yield (from 7) and
5:1 d.r. when using 18 mol% catalyst (Scheme 4A, 99% ee).
Analysis of the reaction mixture indicated that undesirable
À
cleavage of the C3a
C3a’ s bond occurred, giving byproduct 9.
The adduct 10, likely produced because of the slow proto-
nation of a nitronate intermediate after 1,4-addition, was also
problematic.[19] We speculated that a sterically less hindered
catalyst without bulky Schiff base ligand 4a would be suitable
to avoid these side reactions. Therefore, we screened various
achiral metal acetates to achieve a diastereoselective second
Michael reaction. Among the metal acetates screened,[20]
5 mol% of Mg(OAc)2·4H2O in the presence of 10 mol% of
benzoic acid gave the best diastereoselectivity and yield and
gave double Michael product 6 in 89% yield (determined by
NMR spectroscopy with an internal standard) and 19:1 d.r.
after 9.5 h (Scheme 4B).[21]
Scheme 4. A) One-pot double Michael reaction with Mn/ Schiff base
4a catalyst. B) Diastereoselective second Michael reaction with achiral
metal catalyst. Reagents and conditions: a) nitroethylene (1.2 equiv),
Mn(4-F-BzO)2/Schiff base 4a (ratio 1:1) catalyst (18 mol%), toluene,
molecular sieves (5 ꢀ), 508C, 1.5 h; then additional nitroethylene
(2 equiv), 2,6-di-tert-butylphenol (1 equiv), 508C, 12 h, 44% yield (from
7), 5:1 d.r., 99% ee; c) Mg(OAc)2·4H2O (5 mol%), benzoic acid
(10 mol%), nitroethylene (1.2 equiv), molecular sieves (5 ꢀ), 508C,
9.5 h, 89% yield, 19:1 d.r.
After the reaction conditions for the two key Michael
reactions were optimized (Table 1 and Scheme 4), we inves-
tigated the sequential Michael reactions as shown in
Scheme 5. After the first Mn-catalyzed asymmetric Michael
reaction, the Mn catalyst was removed by passing the reaction
mixture through a short pad of silica gel. The crude mixture of
8 was then subjected to a second Mg-catalyzed diastereose-
lective second Michael reaction with additional 1.2 equiva-
lents of nitroethylene, resulting in isolation of double Michael
adduct 6 in 69% yield and 95% ee with greater than 20:1 d.r.
Conversion of the nitro groups into methyl carbamates
proceeded to give 5 in 87% yield.
Scheme 5. Synthesis of (+)-1, (+)-2, and (À)-3: a) AcOH, conc. HCl (cat.), 1108C; b) Boc2O, DMAP, CH2Cl2, RT, 6 h; PtO2, AcOEt, H2, RT, 12 h,
87% (2 steps); c) nitroethylene (1.2 equiv), Mn(4-F-BzO)2/4a (ratio 1:1) cat. (2.2 mol%), toluene, molecular sieves (5 ꢀ), 508C, 9 h;
d) nitroethylene (1.2 equiv), Mg(OAc)2·4H2O (5 mol%), benzoic acid (10 mol%), THF, molecular sieves (5 ꢀ), 508C, 9.5 h, 69% yield (from 7 in 2
steps), 95% ee, >20:1 d.r.; e) NiCl2, NaBH4, dimethyl dicarbonate, MeOH, 87% yield; f) LiEt3BH, toluene, À788C to À408C, 1 h; 4m HCl in
AcOEt, RT, 5 h; TFA, RT, 15 h, 61% yield; g) sodium bis(2-methoxyethoxy) aluminum hydride, toluene, reflux, 4.5 h, 79% yield; h) aq. HCHO,
NaBH(OAc)3, MeCN, RT, 0.5 h, 79% yield; i) AcOH, H2O, 958C, 48 h, 57% yield. DMAP=4-dimethylaminopyridine, TFA=trifluoroacetic acid.
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Then, the reductive cyclization from 5 was investigated in
detail. We anticipated that the problematic cleavage of the
in acetic acid and water at 958C led to the equilibrium
between (+)-1 and the isomeric (À)-calycanthine (3), and
(À)-3 was isolated in 57% yield.
À
C3a C3a’ s bond could be minimized by taking advantage of
the Boc groups; 1) reduction of imide moieties would proceed
In summary, we achieved a catalytic asymmetric total
synthesis of (+)-chimonanthine, (+)-folicanthine, and (À)-
calycanthine. (+)-Chimonanthine was obatined in seven
steps, 25% overall yield from commercially available oxin-
dole and isatin. The vicinal quaternary stereogenic carbon
centers were constructed by sequential Michael reactions of
N-Boc-protected bisoxindole with nitroethylene catalyzed by
a Mn(4-F-BzO)2/Schiff base 4a catalyst and a Mg(OAc)2/
benzoic acid system. A dimeric hexahydropyrroloindole core
À
at low temperature to avoid C C bond cleavage, and
2) electron-withdrawing Boc groups would decrease the
electron density of the nitrogen atom, thus suppressing
À
undesired C C bond cleavage, while the desired pathway to
form hexahydropyrroloindole cores via an iminium cation
would proceed chemoselectively.[22,23] As expected, the Boc-
protected intermediate effectively suppressed the cleavage of
À
the C3a C3a’ s bond. Treatment of 5 with commercially
À
available LiEt3BH in THF, however, gave desired product
11 in only 30% yield after acidic work-up. Competitive
intramolecular cyclization from a partially reduced adduct
afforded 12 (35%) and 13 was also observed in 15% yield
(Scheme 6). The use of LiEt3BH in toluene was effective to
was constructed in good yield without C C bond cleavage.
Received: February 10, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · asymmetric synthesis · salen ·
.
synthetic methods · total synthesis
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Scheme 6. Problems in reductive cyclization process in THF.
suppress the undesired pathway, possibly because conforma-
tion of the substrate was changed through the coordination of
the substrate to Li. The desired dimeric hexahydropyrroloin-
dole core 11 was then successfully obtained after acidic
treatment with HCl.[23a] Boc groups in 11 were also removed
by further addition of TFA to the reaction mixture, giving 14
in 61% yield from 5 in one pot (Scheme 5, conditions f). The
result of this step was superior to previous representative
reductive cyclization procedures that started from a nonpro-
tected or N-alkyl intermediate and used a strong reducing
reagent, such as LiAlH4, at a relatively high temperature.[13]
Because 14 is a known intermediate, 14 was transformed into
(+)-1, (+)-2, and (À)-3 by following the reported procedur-
es.[4,5a] Reduction of the methyl carbamate moieties with
sodium bis(2-methoyethoxy)aluminum hydride gave (+)-chi-
monanthine (1) in 79% yield. (+)-Folicanthine (2) was
obtained by methylation in 79% yield. Treatment of (+)-1
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À
[8] For discussion on the labile C3a
C
3a’ s bond and synthetic studies
À
to avoid cleavage of the C3a C3a’ s bond, see: J. T. Link, L. E.
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theses of complex cyclotryptamine alkaloids by Overman and
4
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co-workers, see a review in Ref. [2a]. For the representative
applications in higher-order polypyrrolidinoindoline alkaloids
synthesis, see: A. D. Lebsack, J. T. Link, L. E. Overman, B. A.
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[17] In previous reports on dinuclear Schiff base catalysts, mono-
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[18] Inductively coupled plasma (ICP) analysis suggested that the
structure and Mn/4a ratio in catalysts from Mn(4-F-BzO)2 would
be different from Mn2(OAc)2/4a catalysts derived from Mn-
(OAc)2. Because the precise structures of Mn(4-F-BzO)2/4a
catalysts have not yet been clarified, catalyst loading herein was
presented based on the amount of chiral ligand 4a. See the
Supporting Information.
[13] LiAlH4 and sodium bis(2-methoxyethoxy)aluminum hydride
(Red-Al) under harsh conditions were often utilized for
reductive cyclization of either non-protected or N-alkyl pre-
cursors, resulting in low yield.[3] Overman et al. developed
[19] When the pure desired product 6 was subjected to the reaction
conditions in Scheme 4A, adduct 10 was not observed. There-
fore, we speculate that 10 was obtained from a nitronate
intermediate before protonation.
À
elegant alternative stepwise route to avoid undesirable C C
[20] Other metal acetates gave unsatisfactory diastereoselectivity
and reactivity. Results in the presence of benzoic acid: Mn-
(OAc)2 (40% yield, 5.2:1 d.r.), Fe(OAc)2 (32% yield, 4.4:1 d.r.),
Co(OAc)2 (55% yield, 8.9:1 d.r.), Cu(OAc)2 (44% yield, 5.8:1
d.r.), LiOAc (55% yield, 4.3:1 d.r.).
[21] For a plausible transition-state model of the diastereoselective
second Michael reaction, see the Supporting Information.
[22] For detail explanation on the positive effects of Boc groups in
reductive cyclization process, see the Supporting Information.
Moreover, Boc groups would also play key roles in the double
Michael reaction to increase the acidity of protons in bisoxindole
as well as to improve the stereoselectivity by bidentate
coordination to Mn and Mg metal centers, see: Y. Hamashima,
T. Suzuki, H. Takano, Y. Shimura, M. Sodeoka, J. Am. Chem.
Soc. 2005, 127, 10164.
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M. Furutachi, Y. Kato, S. Matsunaga, M. Shibasaki, Angew.
Chem. 2009, 121, 2252; Angew. Chem. Int. Ed. 2009, 48, 2218;
d) Y. Kato, M. Furutachi, Z. Chen, H. Mitsunuma, S. Matsunaga,
M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 9168.
[15] For selected recent representative examples, see: a) H. Mihara,
Y. Xu, N. E. Shepherd, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2009, 131, 8384; b) S. Handa, V. Gnanadesikan, S.
Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 4925;
c) Y. Xu, L. Lin, M. Kanai, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2011, 133, 5791.
[16] Because nitroethylene is too reactive and readily polymerizes,
catalytic asymmetric reaction using nitroethylene is rather
limited. See, a) Y. Chi, L. Guo, N. A. Kopf, S. H. Gellman, J.
Am. Chem. Soc. 2008, 130, 5608; b) M. Wiesner, J. D. Revell, S.
Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, 130, 5610; c) T.
Bui, S. Syed, C. F. Barbas III, J. Am. Chem. Soc. 2009, 131, 8758;
d) H. Mitsunuma, S. Matsunaga, Chem. Commun. 2011, 47, 469.
[23] Reductive cyclization procedure using Boc-protected substrates
for constructing a monomeric hexahydropyrroloindole core via
iminium intermediates, see a) S. P. Govek, L. E. Overman, J.
Am. Chem. Soc. 2001, 123, 9468; b) S. P. Govek, L. E. Overman,
Tetrahedron 2007, 63, 8499; c) M. Movassaghi, M. A. Schmidt,
J. A. Ashenhurst, Org. Lett. 2008, 10, 4009.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Synthetic Methods
H. Mitsunuma, M. Shibasaki, M. Kanai,*
S. Matsunaga*
&&&& — &&&&
Catalytic Asymmetric Total Synthesis of
Chimonanthine, Folicanthine, and
Calycanthine through Double Michael
Reaction of Bisoxindole
Direct access: Sterically hindered vicinal
quaternary carbon stereocenters were
constructed by catalytic enantio- and
diastereoselective double Michael reac-
tion, providing straightforward access to
dimeric hexahydropyrroloindole alka-
loids. A Mn(4-fluorobenzoate)2/Schiff
base complex and a Mg(OAc)2/benzoic
acid system were used as catalysts.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!