Organocatalytic enantioselective decarboxylative addition of malonic acids half thioesters to isatins

Article abstract of DOI:10.1002/adsc.201100410

The organocatalytic enantioselective decarboxylative addition of malonic acids half thioesters to isatins using a squaramide catalyst afforded the products with high enantioselectivity. These products are key intermediates in the synthesis of 3-substituted 3-hydroxy-2-oxindole derivatives. The first enantioselective synthesis of (-)-flustraminol B has been accomplished. Copyright

Full text of DOI:10.1002/adsc.201100410

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DOI: 10.1002/adsc.201100410
Organocatalytic Enantioselective Decarboxylative Addition of
Malonic Acids Half Thioesters to Isatins
Noriyuki Hara,a Shuichi Nakamura,a,* Yasuhiro Funahashi,a and Norio Shibataa,*
a
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-5245; e-mail: snakamur@nitech.ac.jp or nozshiba@nitech.ac.jp
Received: May 19, 2011; Published online: November 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100410.
Abstract: The organocatalytic enantioselective de-
carboxylative addition of malonic acids half thioest-
ers to isatins using a squaramide catalyst afforded
the products with high enantioselectivity. These
products are key intermediates in the synthesis of
3-substituted 3-hydroxy-2-oxindole derivatives. The
first enantioselective synthesis of (À)-flustraminol
B has been accomplished.
Keywords: aldol reaction; decarboxylative addition;
Figure 1. Biologically active compounds containing 3-substi-
enantioselectivity; organic catalysis
tuted 3-hydroxy-2-oxindole derivatives.
ester enolate equivalents to various electrophiles has
been reported.[6,7] Although these MAHTs are very
The development of mild, catalytic and enantioselec- attractive candidates for the generation of ester eno-
À
tive versions of C C bond forming processes is a late equivalents under very mild reaction conditions,
topic of paramount importance in modern organic there are no reports on the enantioselective decarbox-
chemistry. In this context, the enantioselective aldol ylative addition of MAHTs to ketones as well as isa-
reaction of ketones as electrophiles using organocata- tins. Therefore, the development of new synthetic
lysts continues to attract a great deal of interest, as it methods to achieve high enantioselectivity in decar-
provides an efficient access to chiral tertiary alco- boxylative aldol condensations between MAHTs and
hols.[1] In particular, the utilization of isatin as an elec- isatins is highly desirable. Herein our ongoing interest
trophile has attracted much attention because the re- was extended to the enantioselective reaction of isa-
action affords chiral 3-substituted 3-hydroxy-2-oxin- tins with ester enolate equivalents by the decarboxy-
dole derivatives, which are an important structural lative aldol reaction of MAHTs using various bifunc-
motif in biologically active compounds such as con- tional organocatalysts.
A
B
We first examined the reaction of 4,6-dibromoisatin
with MAHTs in the presence of various chiral orga-
Recently, we[3] and other groups[4] have reported nocatalysts 3–8. The results are shown in Table 1.
the highly enantioselective reaction of isatins with
The control experiment without any catalyst did
various ketones and aldehydes using novel proline-de- not give product 2a (run 1). Previously, our studies on
rived organocatalysts through enamine activation. the reaction of isatin with acetone or aldehydes have
However, it is difficult to use proline-derived catalysts shown that proline-derived organocatalyst 3 is an ef-
in the reaction of isatin with ester enolates. In gener- fective promoter. Therefore, we first tried to use pro-
al, the catalytic generation of ester enolates is not a linamide 3 for the reaction of 4,6-dibromoisatin 1
trivial task due to the low acidity of a-protons of with MAHT to give the product 2a in 56% yield but
esters.[5] Recently, the asymmetric decarboxylative ad- with 9% ee (run 2). Chiral phosphoric acid 4 did not
dition of malonic acid half-thioesters (MAHTs) as give the product 2a (run 3). Quinine 5a, 9-amino-epi-
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Organocatalytic Enantioselective Decarboxylative Addition of Malonic Acids Half Thioesters
Table 1. Decarboxylative aldol reaction of isatins with MAHTs using various organocatalysts.
Run
Cat.
R1
2
Time [h]
Yield [%]
ee [%][a,b]
1
2
3
4
5
6
7
8
–
3
4
5a
5b
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
24
48
24
24
36
36
48
48
48
48
48
48
48
60
60
120
48
–
56
–
–
9 (R)
–
87
93
77
95
96
91
94
87
92
83
trace
41
89
94
37 (R)
10 (R)
18 (R)
84 (S)
87 (R)
83 (R)
63 (S)
74 (S)
70 (R)
72 (R)
–
7
8a
8b
8c
8d
8a
8a
8a
8a
8a
8a
9
Ph
Ph
Ph
10
11
12
13
14
15
16[c]
17[d]
p-MeO-C6H4
p-Cl-C6H4
t-Bu
Bn
Ph
Ph
76 (R)
83 (R)
87 (R)
[a]
The ee value was determined by HPLC analysis.
The absolute configuration of 2 is provided in parentheses.
Catalyst loading is 5 mol%.
[b]
[c]
[d]
In an open flask.
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Table 2. Substrate scope.
Entry
R
Product
Time [h]
Yield [%]
ee [%][a,b]
1
2
3
4
4,6-Br2
4-Br
6-Br
5,7-Br2
H
4-Cl
4,6-I2
4-I
2a
2f
2g
2h
2i
2j
2k
2l
48
48
48
20
36
48
48
48
96
90
96
88
96
99
93
91
87
87
63 (92)
86
46 (89)
83
5
6
7[c]
8
92
91
[a]
The ee value was determined by HPLC analysis.
The ee value in parentheses is that obtained after a single recrystallization.
Catalyst loading is 20 mol%.
[b]
[c]
quinine 5b and thiourea 6 activated the reaction to potential for an explosion. Therefore, we attempted
give 2a in good yield but with low enantioselectivity the reaction in an open flask. This reaction also gave
(runs 4–6). In contrast to these results, the reaction the product with high enantioselectivity (run 17).
using bifunctional squaramides 7 and 8a–d, which
With these optimized conditions, the reaction of a
were developed by Rawal,[8] improved the enantiose- series of isatins and MAHTs using 8a was examined
lectivity of product (runs 7–11). The chiral squar- (Table 2).
A
Although the reaction of non-substituted isatin af-
We next examined the reaction of 1 with various forded product 2i with moderate enantioselectivity,
MAHTs using catalyst 8a. Although tert-butylthio the use of a variety of isatins such as 4,6-dibromo-, 4-
ester and benzylthio ester gave products 2d and 2e in bromo-, 6-bromo-, 5,7-dibromo-, 4-chloro-, 4,6-diiodo-
low yield, good yields and enantioselectivities were and 4-iodoisatins afforded the corresponding products
obtained in the reaction with arylthio esters 2b and 2c (2f–l) in good to excellent yields with high enantiose-
(runs 12–15).[9] Best enantioselectivity was obtained in lectivity (entries 1–8). As most of the products were
the reaction using phenylthio ester (run 8). Further- crystalline compounds, the enantiopurity of the prod-
more, the catalyst loading of 8a can be reduced to ucts can be improved by recrystallization. For exam-
5 mol% without a significant loss of enantioselectivity ple, a single recrystallization of 2g and 2i from
(run 16). Furthermore, the decarboxylative addition hexane/AcOEt afforded 2g and 2i with a high enan-
reaction affords the product with a large amount of tiopurity (entries 3 and 5). The absolute configuration
CO2, which contains the risk of high pressure and the of product 2i was determined by X-ray crystallogra-
Scheme 1. Synthesis of optically active (À)-flustraminol B 12.
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Organocatalytic Enantioselective Decarboxylative Addition of Malonic Acids Half Thioesters
phy (see Supporting Information), and the stereo-
From the above considerations and the absolute
chemistry of other products was tentatively assumed configurations of products, the transition state for the
by analogy.
reaction of the thioester enolate to isatin using a
We next tried to convert product 2g to chiral flus- chiral squaramide catalyst 8a is proposed (Figure 3).
traminol B (Scheme 1). Flustraminol B is a marine al- Since the thioester enolate approaches the Si-face of
kaloid that was isolated from the marine bryozoan isatin, therefore the (R)-isomer is preferably formed.
Flustra foliacea by Christophersen and Carlꢁ.[10] There Further studies are required to fully elucidate the
is only one report on the synthesis of racemic flustra- mechanistic detail of the addition reaction.
minol B by Suꢂrez-Castillo and co-workers.[11] The ab-
In conclusion, we have developed a highly enantio-
solute configuration of the hydroxy group at the C-3 selective decarboxylative addition of MAHTs to isa-
position could further modulate the biological activity. tins. To the best of our knowledge, this is the first ex-
Although it is of high importance to introduce chirali- ample for the decarboxylative addition of MAHTs to
ty at the C-3 position for flustraminol B with high ketones. The obtained products can be converted to
enantiocontrol, there are no reports on the enantiose- chiral flustraminol. This example is the first report for
lective synthesis of flustraminol B. To illustrate the the enantioselective synthesis of (À)-flustraminol B.
synthetic potential of this methodology, we synthe- Further studies focusing on the scope of the asymmet-
sized optically active flustraminol B, as shown in ric transformations of isatins are currently under in-
Scheme 1. The reaction of 92% ee of 2g with Mg/ vestigation and will be reported in due course.
MeOH, followed by alkylation with prenylbromide af-
forded compound 10, which can be converted to (À)-
flustraminol B in high yield without loss of enantio-
Experimental Section
purity. To the best of our knowledge, this is the first
report on the enantioselective synthesis of flustrami-
nol B.
Typical Procedure
Preliminary experiments have been performed to
elucidate the mechanism of the reaction. 3,4-BisACTHUNTGRNEUNG[3,5-
To a solution of isatin 1a (0.1 mmol, 30.4 mg) and catalyst
8a (0.01 mmol, 3.2 mg) in toluene (0.5 mL), malonic acid
half thioester (0.11 mmol, 21.6 mg) was added and the mix-
ture was stirred for 48 h. After removal of solvent, the resi-
due was purified by column chromatography on silica gel
(eluent: hexane/acetone, 70:30) to afford (R)-2a as a white
solid; yield: 43.9 mg (96%).
bis(trifluoromethyl)phenylamino]cyclobut-3-ene-1,2-
dione did not mediate the decarboxylation reaction of
MAHTs. Furthermore, 9-amino-epi-quinine 5b can
activate the reaction, but low enantiopurity of the
product is obtained (Table 1, entry 5). These results
imply that catalyst 8a could act in a bifunctional
manner, as previously proposed in the literature for
chiral squaramide catalysts.[8] The proposed activating
mechanism for the reaction of isatin with MAHTs
using a chiral squaramide catalyst is shown in
Figure 2. The squaramide functionality could activate
MAHTs by double hydrogen bonding, and the depro-
tonation and decarboxylation of carboxylic acid in
MAHTs at a basic site in squaramide was carried out
to give the thioester enolate. Next, two carbonyl oxy-
gens from isatin coordinate to hydrogen from proton-
ated 8a. The addition of the thioester enolate to isatin
in the coordination sphere of the chiral squaramide
led to a product with high enantioselectivity.
Figure 3. Assumed transition state for the decarboxylative
addition of MAHTs to isatins.
Figure 2. Proposed reaction mechanism for decarboxylative addition of MAHTs to isatins using bifunctional organocatalysts.
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Acknowledgements
MAHTs with aldehydes using metal catalysts, see:
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tachi, S. Mouri, S. Matsunaga, M. Shibasaki, Chem.
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D. G. Shore, S. Rousseaux, K, Fagnou, J. Org. Chem.
2009, 74, 6190–6198. Achiral aldol reaction of malonate
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er, B.-Y. Kçgel, K. Linz, H. Schick, H. Sonnenschein,
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This work was partly supported by a Grant-in-Aid for Young
Scientists B (20750074) from JSPS and the Toyoaki Founda-
tion.
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