Asymmetrie aldol reaction of acetaldehyde and isatin derivatives for the total syntheses of ent-convolutamydine e and cpc-1 and a half fragment of madindoline A and B

Article abstract of DOI:10.1021/ol901432a

The asymmetric aldol reaction of isatin derivatives and acetaldehyde has been developed using 4-hydroxydiarylprolinol as a catalyst, affording the aldol products with high enantioselectivity, these products being key intermediates in the synthesis of 3-hy

Full text of DOI:10.1021/ol901432a

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3854-3857
Asymmetric Aldol Reaction of
Acetaldehyde and Isatin Derivatives for
the Total Syntheses of
ent-Convolutamydine E and CPC-1 and
a Half Fragment of Madindoline A and B
Takahiko Itoh,† Hayato Ishikawa,† and Yujiro Hayashi*,†,‡
Department of Industrial Chemistry, Faculty of Engineering, and Research Institute for
Science and Technology, Tokyo UniVersity of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received June 24, 2009
ABSTRACT
The asymmetric aldol reaction of isatin derivatives and acetaldehyde has been developed using 4-hydroxydiarylprolinol as a catalyst, affording
the aldol products with high enantioselectivity, these products being key intermediates in the synthesis of 3-hydroxyindole alkaloids. Short
syntheses of ent-convolutamydine E and CPC-1 and a half fragment of madindoline A and B have been accomplished.
There are several 3-hydroxyindole alkaloids, such as con-
volutamydines,1 madindolines,2 and CPC-13 (Figure 1).
Convolutamydine E was isolated from the Floridian marine
bryozoan Amathia conVoluta by Kamano and co-workers.1c
Madindoline A and B, isolated from the fermentation broth
j
of Streptomyces nitrosporeus K93-0711 by Omura and co-
workers, are selective inhibitors of interleukin-62c consisting
of two portions such as a 3a-hydroxyfuroindoline fragment
and a substituted cyclopentenedione moiety. CPC-1 is a new
pyrrolidinoindoline-type alkaloid, isolated by Takayama and
co-workers.3 There are several total syntheses of these
biologically interesting natural products. While chiral con-
volutamydine A has been synthesized by five groups using
asymmetric direct aldol reaction of acetone catalyzed by
organocatalysts as a key step,4 there is only one report for
the asymmetric synthesis of convolutamydine E, in which a
† Department of Industrial Chemistry, Faculty of Engineering.
‡ Research Institute for Science and Technology.
(1) (a) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyama,
K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. (b) Zhang, H.-P.; Kamano,
Y.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Itokawa, H.; Pettit, G. R.
Tetrahedron 1995, 51, 5523. (c) Kamano, Y.; Kotake, A.; Hashima, H.;
Hayakawa, I.; Hiraide, H.; Zhang, H.-P.; Kizu, H.; Komiyama, K.; Hayashi,
M.; Pettit, G. R. Collect. Czech. Chem. Commun. 1999, 64, 1147.
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M.; Takahashi, Y.; Tanaka, H.; Komiyama, K.; Omura, S. J. Antibiot. 1996,
49, 1091. (b) Takamatsu, S.; Kim, Y.-P.; Enomoto, A.; Hayashi, M.; Tanaka,
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10.1021/ol901432a CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

as difficult for several reasons. (1) Acetaldehyde is reactive
as an electrophile, causing a self-aldol reaction. (2) The
generated aldol product, an R,R-unsubstituted aldehyde, is
also reactive both as a nucleophile and as an electrophile,
promoting overreaction. (3) Dehydration is another side
reaction. In spite of these difficulties, our group first
successfully realized the asymmetric direct aldol reaction of
acetaldehyde using an organocatalyst.9
The organocatalyst-mediated reaction is one of the current
topics in synthetic organic chemistry, and several efficient
organocatalysts have been reported (Figure 2).10 Our group11
Figure 1. Natural products possessing the 3-hydroxyindole moiety
and its key intermediate.
diastereoselective vinylogous Mukaiyama aldol reaction was
employed as a key step.5 Although there are several
asymmetric syntheses of madindoline A and B,6,7 there are
only two synthetic methods for the enantioselective synthesis
of the 3a-hydroxyfuroindoline fragment of madindoline A
Figure 2. Organocatalysts examined in this study.
and Jørgensen’s group12 independently developed diaryl-
prolinol silyl ether as an effective organocatalyst.13 During
our investigation of the applications of the catalyst, we found
that trifluoromethyl-substituted diarylprolinol promotes cross-
and self-aldol reactions of acetaldehyde, affording the desired
products with excellent enantioselectivity.9 In this paper, we
describe the asymmetric direct aldol reaction of acetaldehyde
and isatin, which is applied to the short synthesis of ent-
convolutamydine E, the indole fragment of madindoline A
and B, and CPC-1.
j
and B: One is developed by Sunazuka, Omura, and co-
workers, in which Sharpless epoxidation was used as a key
step,6 while Kobayashi used vinylogous Mukaiyama aldol
reaction as a key reaction.5 Although CPC-1 was synthesized
via asymmetric allylation as a key step, its enantioselectivity
is not sufficient (42% ee).3 During the preparation of this
manuscript, Nakamura and co-workers reported the asym-
metric direct aldol reaction of acetaldehyde and isatin,
catalyzed by N-(heteroarenesulfonyl)prolinamide as an or-
ganocatalyst, which was applied to the synthesis of convo-
lutamydine B and E.8
One of the straightforward methods for the synthesis of
these natural products is to use a 3-hydroxyindole derivative
(Figure 1) as a key synthetic intermediate, which would be
generated via the asymmetric direct aldol reaction of acetal-
dehyde with isatin or its derivatives. The aldol reaction of
acetaldehyde as a nucleophile, however, has been regarded
We chose 1-benzylisatin (7a) as an electrophile, and the
aldol reaction with acetaldehyde was investigated (eq 1). The
(9) (a) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 2082. (b) Hayashi, Y.; Samanta, S.; Itoh, T.; Ishikawa,
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X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-J. Tetrahedron
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Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14, 8079.
(11) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
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(13) Selected examples of other group’s application of diarylprolinol
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2006, 441, 861. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova,
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Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S.
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Org. Lett., Vol. 11, No. 17, 2009
3855

reaction was performed in DMF at 4 °C in the presence of
trifluoromethyl-substituted diarylprolinol 1, which is an
effective catalyst in the cross-aldol reaction of acetaldehyde.
As the obtained product is unstable, it was isolated as diol
8a after reduction with NaBH4, in which the diol 8a was
obtained in 62% yield with 49% ee (entry 1). To improve
the enantioselectivity, the reaction conditions were investi-
gated (Table 1). First, the additive was screened to discover
Table 2. Effect of Protecting Group in the Aldol Reaction of
Acetaldehyde and Isatin Derivative 7a
entry
R
yield [%]b
ee [%]c
85
Table 1. Effect of Catalyst, Solvent, and Additive in the Aldol
Reaction of Acetaldehyde and 1-Benzylisatin 7aa
1
2
3
Bn (7a)
55
<5
73
72
73
H (7b)
PMB (7c)
MOM (7d)
TIPSOCH2 (7e)
86
86
85
4
5d
a Unless otherwise shown, reactions were performed employing isatin
derivative 7 (0.3 mmol), acetaldehyde (1.5 mmol), catalyst 6 (0.09 mmol),
ClCH2CO2H (0.18 mmol), and DMF (0.3 mL) at 4 °C for 48 h. b Isolated
yield. c Optical purity was determined by chiral HPLC analysis. d The
reaction time is 72 h.
time yield
[h]
ee
[%]c
entry catalyst solvent
additive
[%]b
1
2
1
1
1
1
2
3
4
5
6
6
6
6
6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH2Cl2
toluene
CH3CN
DMF
72
72
48
48
48
48
48
48
48
48
48
48
48
62
64
67
73
68
67
58
80
78
65
35
69
55
49
60
pNBAd
3
HCO2H
60
fording the diols 11 and 12 with good enantioselectivity
(Table 3). It is interesting to note that the absolute configura-
4
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
ClCH2CO2H
61
50
5
6
-20
-5
-21
73
7
8
9
Table 3. Generality of the Aldol Reaction of Acetaldehyde with
10
11
12
13e
25
29
Isatin Derivativesa
50
86
a Unless otherwise shown, reactions were performed employing 1-ben-
zylisatin (7a) (0.3 mmol), acetaldehyde (1.5 mmol), catalyst (0.03 mmol),
additive (0.06 mmol), and solvent (0.3 mL) at 4 °C for the indicated time.
b Isolated yield. c Optical purity was determined by chiral HPLC analysis.
d p-Nitrobenzoic acid. e Catalyst (0.09 mmol) and additive (0.18 mmol) were
employed.
entry
R1
R2
time [h]
yield [%]b
ee [%]c
1
H
Br
H
H (7e)
H (9)
Br (10)
72
48
48
73
83
86
85 (8e)
81 (11)
82 (12)
(R)
(R)
(S)
2d
3d
that a good yield with improved enantioselectivity was
observed when the reaction was carried out in the presence
of ClCH2CO2H14 (entry 4). Then, the catalyst was investi-
gated. When triethylsilyl ether 2 was employed, the enan-
tioselectivity decreased (entry 5). Diphenylprolinol 3 and its
trimethylsilyl ether 4 are not suitable (entries 6 and 7). In
contrast to these unsuccessful results, 4-hydroxydiarylprolinol
6, which was easily prepared from commercially available
4-hydroxyproline, gave good selectivity (73% ee, entry 9).
It is interesting to note that the corresponding 4-hydroxy-
diphenylprolinol 5 is not effective (entry 8). After screening
the solvent, DMF was found to be the best choice (entries
9-12). Increasing the loading of the catalyst afforded higher
enantioselectivity (86% ee, entry 13).
Next, the protecting groups on the nitrogen were examined
(Table 2). Although isatin itself does not react with acetal-
dehyde, not only Bn, but also p-methoxybenzyl, methoxym-
ethyl, and triisopropylsiloxymethyl groups are suitable
protecting groups, affording the products with good enan-
tioselectivity.
a Unless otherwise shown, reactions were performed employing isatin
derivative (0.3 mmol), acetaldehyde (1.5 mmol), catalyst 6 (0.09 mmol),
ClCH2CO2H (0.18 mmol), and DMF (0.3 mL) at 4 °C for 48 h. b Isolated
yield. c Optical purity was determined by chiral HPLC analysis. d DMF
(0.6 mL) was employed.
tions of 8e and 11 are R, while that of 12 is opposite (vide
infra).
From these intermediates, the natural products or part of
the natural product were synthesized as follows: The reaction
of 12 with NH4F in MeOH at 70 °C gave ent-convolutamy-
dine E (13) in 76% yield (eq 4, Scheme 1).
The reaction of 8e with NH4F, followed by reduction with
NaBH4, afforded 3a-hydroxyindole fragment 15, which is
known to be converted into madindoline A and B (eq 5,
Scheme 1).
The reaction of 8e with MsCl and pyridine gave mesylate
16, which reacted with NaN3 to provide azide derivative 17.
Under the optimized conditions, the generality of the
reaction was examined with 5,7-dibromoisatin (9) and 4,6-
dibromoisatin (10). Both reactions proceed efficiently, af-
(14) We found chloroacetic acid is an effective additive in the Michael
reaction, see: Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed
2009, 48, 1304.
3856
Org. Lett., Vol. 11, No. 17, 2009

hydrogen atom, mode A would be suitable, and the reaction
would proceed via transition state TS-1 to afford the R-isomer
predominantly (Figure 4). On the other hand, when the
Scheme 1. Total Synthesis of ent-Convolutamydine E, a Half
Fragment of Madindoline A and B, and CPC-1
Figure 4. Transition state models.
substituent is large, such as a bromine atom, mode A is not
suitable because of steric hindrance. Mode B would be the
choice. While steric repulsion between the substituent on
nitrogen and the aryl moiety of the catalyst 6 makes the
transition state TS-2 unfavorable, TS-3 would be suitable, which
would afford the S-isomer predominantly.
In summary, we have developed the asymmetric aldol
reaction of isatin derivatives and acetaldehyde catalyzed by
4-hydroxydiarylprolinol as an organocatalyst, to afford the
aldol product with high enantioselectivity. We applied the
present method to the short syntheses of ent-convolutamydine
E and CPC-1 and a half portion of madindoline A and B.
There are several noteworthy features in the present reaction.
(1) Newly developed diarylprolinol possessing the 4-hydroxy
group is an effective catalyst. (2) Synthetically useful chiral
intermediates for the synthesis of biologically active indole
alkaloids can be synthesized with high enantioselectivity. (3)
Reversal of the enantioface selection by the C5-substituent
of isatin was observed.
After removal of the triisopropylsiloxymethyl group with
NH4F, the reaction with MeI and NaH afforded 19. Reductive
amino cyclization with Red-Al, followed by reductive
amination, gave CPC-1 (21) (Scheme 1).
The absolute configuration of 8e and 11 is R, whereas that
of 12 is S. The reversal of the enantioface selection by the
substituent at C5 of the isatin derivative can be explained as
follows, although it is very difficult to evaluate the effect of
the 4-hydroxy group of the catalyst 6. We proposed that the
acidic proton of the hydroxy group of the diarylmethanol moiety
of the catalyst 6 activates the electrophilic aldehyde in the cross-
aldol reaction.9a A similar activation is expected in the reaction
of isatin derivatives. That is, the proton of the hydroxy group
of the catalyst 6 coordinates the carbonyl group of isatin, in
which there are two protonation modes such as A and B (Figure
3). When the substituent at C5 of isatin is small, such as a
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from The Ministry
of Education, Culture, Sports, Science, and Technology
(MEXT).
Supporting Information Available: Detailed experimen-
tal procedures, full characterization, copies of 1H, 13C NMR,
and IR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 3. Coordination modes to isatin derivatives.
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