First enantioselective synthesis of (R)-Convolutamydine B and e with N-(Heteroarenesulfonyl)prolinamides

Article abstract of DOI:10.1002/chem.200900944

Enantioselective synthesis of (R)-convolutamydine B and E by the reaction of actaldehyde with ketones using organocatalysts was reported. The reaction of 4,6-dibromoisatin with acetaldehyde was examined in presence of various chiral organo-catalysts. The

Full text of DOI:10.1002/chem.200900944

DOI: 10.1002/chem.200900944
First Enantioselective Synthesis of (R)-Convolutamydine B and E with
N-(Heteroarenesulfonyl)prolinamides
Noriyuki Hara, Shuichi Nakamura,* Norio Shibata, and Takeshi Toru[a]
One of the rapidly developing research areas in the field
of asymmetric synthesis is the catalytic reaction by using
small organic molecules called organocatalysts. The enantio-
selective aldol reaction using organocatalysts is recognized
volutamydine E have not been evaluated due to the scarcity
of the compounds. Recently, the syntheses of enantiopure
convolutamydines B and E through a diastereoselective ap-
proach[5] and the syntheses of enantiopure convolutamydi-
ne A through the enantioselective approaches using organo-
catalysts[6] or through a diastereoselective approach[7] have
been reported. However, there is no report for the synthesis
of optically active convolutamydines B and E through a cat-
alytic enantioselective reaction. Recently, we have reported
the synthesis of various (R)-convolutamydine A derivatives
with high enantioselectivity by the reaction of acetone with
isatins using novel bifunctional organocatalysts having heter-
oarylsulfonyl groups.[8,9] Here we report the first highly
enantioselective synthesis of (R)-convolutamydines B and E
using organocatalysts.
We first examined the reaction of 4,6-dibromoisatin (1a)
with acetaldehyde in the presence of various chiral organo-
catalysts 3–5. The reaction was carried out using 10 mol%
of organocatalysts, five equivalents of acetaldehyde, and five
equivalents of H2O at room temperature. After the aldol re-
action, the obtained intermediate aldehyde was reduced by
NaBH3CN in acetic acid to give (R)-convolutamydine E
(2a). The results are shown in Table 1.
Moderate or low enantioselectivity was obtained in the
reaction using proline 3 or diarylprolinol 4, which afforded
good results in the reaction of acetaldehyde with aldehydes,
imines, and b-nitrostyrene (entries 1 and 2).[2a–f,h–j] On the
other hand, the reaction using the TFA salt of N-(p-toluene-
sulfonyl)prolinamide (5a) rapidly proceeded to give (R)-2a
in high yield with 90% ee, whereas N-(methanesulfonyl)pro-
linamide (5b) showed lower enantioselectivity (entries 3 and
4). After optimization experiments of the arylsulfonyl group
in sulfonimides 5, we found N-(2-thiophenesulfonyl)prolina-
mide (5 f) to be an efficient organocatalyst in the reaction of
1a with acetaldehyde (entries 5–10). Solvent screening re-
vealed that a number of solvents were suitable, and THF
was found to afford the best result (entries 11–15, see also
Supporting Information). When the reaction was carried out
at À158C, the enantioselectivity improved slightly, but in
low yield (entry 17). The reaction using 5 f without water af-
À
to be one of the most powerful carbon carbon bond-form-
ing reactions.[1] Despite the significant progress of the enan-
tioselective reaction of various aldehydes using organocata-
lysts, there have been only a few reports on the reaction
using acetaldehyde. Very recently, Hayashi, List and Maruo-
ka have reported the highly enantioselective reactions of
acetaldehyde to aldehydes, imines, and b-nitrostyrenes using
organocatalysts.[2] On the other hand, there are no reports
for the organocatalytic enantioselective crossed-aldol reac-
tion between acetaldehyde as a nucleophile and a ketone as
an electrophile because of the higher reactivity of acetalde-
hyde as an electrophile.[3] Furthermore, the reaction of acet-
aldehyde with ketones constructs a stereogenic quaternary
carbon center, therefore, this type of reaction is a significant
challenge. In this report, we focused on the enantioselective
synthesis of convolutamydine B and E by the reaction of
acetaldehyde with ketones using organocatalysts. Convoluta-
mydines A–E were isolated from the Floridian marine bryo-
zoan Amathia convoluta by Kamano and co-workers.[4] Con-
volutamydines have a 4,6-dibromo-3-hydroxyoxindole as a
common skeleton and different side chain moieties at a qua-
ternary stereocenter on C-3. (R)-Convolutamydines A and
B are known to exhibit potent inhibitory activity on the dif-
ferentiation of HL-60 human promyelocytic leukaemia cells
at 0.1 (convolutamydine A) and 12.5 mgmLÀ1 (convolutamy-
dine B).[4b,c] However, the possible biological effects of con-
[a] N. Hara, Prof. Dr. S. Nakamura, Prof. Dr. N. Shibata,
Prof. Dr. T. Toru
Department of Frontier Materials
Graduate School of Engineering
Nagoya Institute of Technology, Gokiso
Showa-ku, Nagoya 466-8555 (Japan)
Fax : (+81)52-735-5442
E-mail: snakamur@nitech.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900944.
6790
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Chem. Eur. J. 2009, 15, 6790 – 6793

COMMUNICATION
Table 1. Enantioselective addition of acetaldehyde to 1a in the presence
of various organocatalysts 3–5.[a]
Table 2. Enantioselective synthesis of convolutamydine E derivatives
2a–g.[a]
Entry
Isatin
Product
Reaction
time [h]
Yield [%]
ee[b,c] [%]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
1g
2a
2b
2c
2d
2e
2 f
2g
36
48
36
60
48
60
60
94
60
77
97
99
80
73
92 (>99)
2
86
92 (98)
92
Run Catalyst (mol%) Solvent
Reaction Yield [%] ee[b] [%]
time [h]
1
2
3
4
5
6
7
8
3 (10)
4 (10)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
48
60
40
23
50
50
36
36
30
36
62
67
84
56
77
65
71
94
78
78
99
89
42
44
99
62
67
99
63
60
3
89
92
5a (10)
5b (10)
5c (10)
5d (10)
5e (10)
5 f (10)
5g (10)
5h (10)
5 f (10)
5 f (10)
5 f (10)
5 f (10)
5 f (10)
5 f (5)
90
41
80
49
79
92
90
87
90
89
91
90
89
90
93
92
88
[a] Reaction conditions: 5 f (10 mol%), acetaldehyde (5 equiv),
NaBH3CN (5 equiv). [b] ee was determined by HPLC analysis. [c] ee in
parentheses is that obtained after single recrystallization.
9
10
11
12
13
14
15
16
Table 3. Enantioselective synthesis of convolutamydine
E
derivatives
2h–j.[a]
1,4-dioxane 36
CH3CN
DMF
DMSO
neat
THF
THF
36
45
45
36
48
120
48
48
17[c] 5 f (10)
18[d] 5 f (10)
19[e] 5 f (10)
THF
THF
Entry
R
Product
t [h]
Yield [%]
d.r.
ee[b] [%]
1
2
3
4
Me
Et
PhCH2
iPr
2h
2i
2j
2l
60
60
94
80
98
–
70:30
>98:2
97:3
–
98, 97
93, –
90, 9
–
[a] Reaction conditions: Organocatalyst (10 mol%), acetaldehyde
(5 equiv), H2O (5 equiv), NaBH3CN (5 equiv). [b] ee was determined by
chiral HPLC analysis. [c] The reaction was carried out at À158C.
[d] Without water. [e] Without TFA and H2O.
120
144
[a] Reaction conditions: 5 f (10 mol%), aldehyde (5 equiv), H2O
(5 equiv), NaBH3CN (5 equiv). [b] ee was determined by HPLC analysis.
forded 2a without loss of enantioselectivity, although the re-
action without water and TFA afforded 2a in low yield (en-
tries 18 and 19). It should be noted that most of 5 f was re-
covered by a single separation by column chromatography
and was reusable without further purification.
We next examined the preparation of various convoluta-
mydine E derivatives 2a–g using 5 f. The results for the reac-
tion using 10 mol% of 5 f are shown in Table 2. Although
the reaction of unsubstituted isatin (1b) with acetaldehyde
gave product 2b in good yield but with low enantioselectivi-
ty, the reaction of substituted isatins 1c–g gave products 2c–
g with high enantioselectivity (entries 2–7). As most of the
products were crystalline, almost enantiomerically pure con-
volutamydine E derivatives were easily obtainable by recrys-
tallization. For example, single recrystallization of 2a with
92% ee from hexane/ethyl acetate afforded almost enantio-
merically pure 2a (Table 2, entry 4).
We also examined the preparation of convolutamydine B.
(R)-Convolutamydine E (92% ee) was treated with TsCl
(10 equiv) in pyridine at 758C to give (R)-convolutamydi-
ne B in high yield without loss of enantiopurity (Scheme 1).
Single recrystallization of convolutamydine B with 92% ee
afforded almost enantiomerically pure (R)-convolutamydi-
ne B. The absolute stereochemistry of convolutamydine B
was assigned to be R in comparison with the CD spectrum
reported in the literature.[5] To our knowledge, this is the
first report on the synthesis of convolutamydine B and E
with high enantiopurity using chiral catalysts.
We also examined the reaction of 1a with various alde-
hydes in the presence of 10 mol% of 5 f. Although the reac-
tion with 2-methylbutanal did not afford any products, the
reaction with linear aldehydes afforded the products in high
yield with good enantioselectivity (Table 3).
Scheme 1. Synthesis of convolutamydine B from convolutamydine E.
Chem. Eur. J. 2009, 15, 6790 – 6793
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S. Nakamura et al.
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Although it is premature to provide a detailed mechanis-
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through a transition state having hydrogen bonding between
the amide proton and the 2-thienyl sulfur atom in 5 f to give
the (R)-isomer of the product (Figure 1).
Figure 1. Assumed transition state for the crossed-aldol reaction of 1a
with acetaldehyde using 5 f.
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In conclusion, the first enantioselective synthesis of con-
volutamydine E through a catalytic enantioselective aldol
reaction of acetaldehyde with isatins using N-(2-thiophene-
sulfonyl)prolinamide (5 f) has been developed. To the best
of our knowledge, this is the first highly enantioselective
crossed-aldol reaction of acetaldehyde with ketones. We
also showed the synthesis of enantiopure convolutamydi-
nes B and E. Further studies are in progress to study the po-
tential of these catalytic systems to other processes and the
reaction mechanism.
Experimental Section
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Typical procedure for the aldol reaction using 5 f: (R)-Convolutamydine
E (2a): To a mixture of 5 f (3.7 mg, 0.01 mmol), acetaldehyde (28 mL,
0.5 mmol) and water (9.0 mL, 0.5 mmol), 1a (30.5 mg, 0.1 mmol) was
added at room temperature. After stirring for 48 h, the solvent was re-
moved under reduced pressure to give a residue that was reduced by
NaBN3CN (31 mg, 0.5 mmol) in acetic acid (1.0 mL). After stirring for
3 h, aqueous HCl (1.0 mL, 1 molLÀ1) was added, and the mixture was ex-
tracted with Et2O. The combined organic extracts were concentrated
under reduced pressure to give a residue that was purified by column
chromatography (hexane/ethyl acetate 70:30) giving 2a (34.7 mg, 99%,
92% ee). Single recrystallization of 2a (92% ee) from hexane/ethyl ace-
tate afforded >99% ee of 2a.
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Acknowledgements
This work was supported by Grant-in-Aid for Young Scientists
(20750074) from JSPS.
B
Keywords: aldehydes · aldol reaction · enantioselectivity ·
heteroarylsulfonyl group · organocatalysis
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(R)-Convolutamydine B and E
COMMUNICATION
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Received: April 9, 2009
Published online: June 5, 2009
Chem. Eur. J. 2009, 15, 6790 – 6793
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6793