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
Supporting information for this article is available on the WWW
6790
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Chem. Eur. J. 2009, 15, 6790 – 6793