Enantioselective total synthesis of convolutamydines B and E

Article abstract of DOI:10.1021/ol052871p

The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction. The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes t

Full text of DOI:10.1021/ol052871p

ORGANIC
LETTERS
2006
Vol. 8, No. 4
677-679
Enantioselective Total Synthesis of
Convolutamydines B and E
Tomoaki Nakamura, Shin-ichi Shirokawa, Seijiro Hosokawa, Atsuo Nakazaki, and
Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo UniVersity of Science (RIKADAI), 2641
Yamazaki, Noda-shi, Chiba, 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received November 27, 2005
ABSTRACT
The first enantioselective total synthesis of convolutamydines B and E has been achieved using our vinylogous Mukaiyama aldol reaction.
The synthesis features highly diastereoselective vinylogous Mukaiyama aldol reaction with isatin instead of aldehydes to construct a chiral
center of convolutamydines. Additionally, the absolute configuration of natural convolutamydine B has been determined as R by its CD
spectrum.
Convolutamydines A-E (1-5) isolated from the Floridian
marine bryozoan Amathia conVoluta by Kamano et al. are
members of a family of oxindole alkaloids having a 4,6-
dibromo-3-hydroxyoxindole as a common skeleton (Figure
1).1 Each convolutamydine differs in a side chain moiety at
ated cells, in the tumor cell line HL-60. The possible
biological effects of the other convolutamydines (C-E, 3-5)
have not been evaluated due to the scarcity of these
derivatives. Furthermore, the stereochemistry of the chiral
center at C-3 has not yet been established. The 3R config-
uration was assumed on the basis of the empirical rule for
the correlation of CD spectra and absolute configuration
proposed by Aimi et al.2 Although syntheses of convo-
lutamydines (A, C, and E) have already been reported by
several groups, these have all been of racemic compounds.3
These facts prompted us to attempt an enantioselective
synthesis of convolutamydines in order to determine the
absolute stereochemistry as well as to provide these com-
pounds for biological study. The most straightforward
approach to this class of compounds is apparently a nucleo-
Figure 1. Structures of convolutamydines A-E (1-5).
C-3. Convolutamydines A and B (1, 2) induce the appearance
of characteristic features, associated with normally differenti-
(2) Takayama, H.; Shimizu, T.; Sada, H.; Harada, Y.; Kitajima, M.; Aimi,
N. Tetrahedron 1999, 55, 6841-6846.
(3) (a) Garden, S. J.; Torres, J. C.; Ferreira, A. A.; Silva, R. B.; Pinto,
A. C. Tetrahedron Lett. 1997, 38, 1501-1504. (b) Miah, S.; Moody, C. J.;
Richards, I.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 1997, 2405-
2412. (c) Jnaneshwara, G. K.; Bedekar, A. V.; Deshpande, V. H. Synth.
Commun. 1999, 29, 3627-3633. (d) Jnaneshwara, G. K.; Deshpande, V.
H. J. Chem. Res., Synop. 1999, 632-633. (e) Kawasaki, T.; Nagaoka, M.;
Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron 2004, 60, 3493-
3503.
(1) (a) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyama,
K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783-2784. (b) Zhang, H.-P.;
Kamano, Y.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Itokawa, H.; Pettit, G.
R. Tetrahedron 1995, 51, 5523-5528. (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,
1147-1153.
10.1021/ol052871p CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/19/2006

philic addition of an appropriate nucleophile to 4,6-dibro-
moisatin; however, such a strategy was employed only for
the synthesis of convolutamydine A by base-mediated aldol
reaction racemic with acetone. To the best of our knowledge,
the first example of enantioselective addition (up to 77%
ee) to isatin was very recently reported by Tomasini et al.
using organocatalysis.4 We recently developed a highly
stereoselective vinylogous Mukaiyama aldol reaction using
vinylketene silyl N,O-acetal 6a (Scheme 1).5 Substrates for
3). A large excess of TiCl4 decreased both chemical yield
and selectivity (entry 4). However, method A did not afford
8 in a reproducible manner. During these experiments, we
observed that the reaction mixture becomes homogeneous
when TiCl4 was added. Therefore, we attempted to change
the order of addition. Thus, the mixture of isatin 7 and TiCl4
in dichloromethane was stirred at 0 °C for 30 min before
addition of 6a at -78 °C (Method B). This procedure
afforded 8 in good yield with excellent selectivity and
reproducibility (entry 5). The observed stereoselectivity is
noteworthy considering (1) the high degree of remote
asymmetric induction and (2) the electrophile is a ketone,
albeit it is a part of ketoamide.
Scheme 1. Vinylogous Mukaiyama Aldol Reaction
TiCl4-mediated reaction of Z-vinylketene N,O-acetal 6b
and isatin 7 was also attempted, producing the corresponding
adduct in relatively low yield with a 1.7:1 diastereomeric
ratio. These differences in chemical yield and selectivity are
in good agreement with the previous results using aldehydes.5
For the introduction of a C2 unit as the side chain of a
convolutamydine, it may be more suitable to introduce an
acetate unit rather than crotonate unit. Consequently, isatin
7 was also subjected to an aldol reaction with 6c and 6d
under typical Evans and Mukaiyama conditions, respectively.
In both cases, the corresponding aldol adduct was isolated
in relatively low yield with low selectivity as shown in Figure
2. Therefore, only the vinylogous Mukaiyama aldol reaction
vinylogous Mukaiyama aldol reaction were limited to alde-
hydes, and we were also interested in the reaction with isatin
derivatives.
Prior to the reaction with 4,6-dibromoisatin, we used isatin
7 as a model substrate in order to establish the optimal
conditions (Table 1). As per the previous protocol, titanium
Table 1. Optimization of Vinylogous Mukaiyama Aldol
Reaction with Isatin (7)
isatin TiCl4 concn
entry method (equiv) (equiv) (mM)
yield
(%) dra
T (°C)
Figure 2. Typical nucleophiles for aldol reaction.
1
2
3
4
5
A
A
A
A
B
2.0
4.0
6.0
6.0
6.0
2.0
2.0
2.0
3.0
2.0
10
5
5
5
5
-78 to -20 32
9:1
-78 to -20 60 30:1
-78 to -20 90 31:1
-78 to -20 50 23:1
using 6a proceeded in a stereoselective manner.
We reported that vinylketene N,O-acetal 6a had a con-
formation such that the dienolate was orthogonal to the
oxazolidin-2-one.5 Approach of isatin 7 from the upper face
of the dienolate plane should be hindered by steric interaction
with the isopropyl group of the chiral auxiliary (Figure 3,
-78
69 60:1
a Determined by H NMR analysis.
1
tetrachloride (2 equiv) was added to the dichloromethane
solution of isatin 7 at -78 °C, followed by the dropwise
addition of 6a (method A). Then the reaction mixture was
stirred at -20 °C to obtain 8 in 32% yield. It was quite
interesting to find that the reaction proceeded in a stereo-
selective manner (9:1 ratio).6
High yield with excellent selectivity was observed by using
an excess of isatin 7 (6 equiv) in 5 mM concentration (entry
(4) Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q.
B.; Tomasini, C. J. Org. Chem. 2005, 70, 7418-7421.
(5) Shirokawa, S.-i.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604-
13605.
(6) See the Supporting Information for determination of the stereochem-
istry.
Figure 3. Transition states of vinylogous Mukaiyama aldol reaction
(XN ) oxazolidinone.)
678
Org. Lett., Vol. 8, No. 4, 2006

A). In addition, transition state 1 (T.S.1) is sterically more
favorable than transition state 2 (T.S.2) because in T.S.2 the
methyl group at the R-position of vinylketene N,O-acetal 6a
can sterically interact with the aromatic ring of isatin 7
(Figure 3).
With optimal conditions established, we next applied the
present protocol to the total syntheses of both enantiomers
of convolutamydines E and B and to the determination of
their absolute configurations. According to Aimi’s estima-
tion,2 we first attempted the synthesis of (R)-convolutamy-
dines which would be synthesized from 4,6-dibromoisatin
97 and vinylketene N,O-acetal ent-6a derived from D-valine
(Scheme 2).
With both enantiomers in hand, we next attempted to
determine the absolute configurations of convolutamydines
B and E by the comparison of the optical rotations.1b,c
However, the [R]D value of 13 and ent-13 ([R]28 <1 for
D
both 13 and ent-13) were much lower than the reported data
([R]25 +18) for natural convolutamydine B.1b Despite the
D
disagreement of these optical rotations, the CD spectrum of
R-isomer 13 was perfectly matched with that of the natural
product; 13 exhibits a negative Cotton effect in the long-
wave region (285-245 nm) and a positive effect in the short-
wave region (245-210 nm), while ent-13 exhibits exactly
the opposite behavior (Figure 4). Accordingly, convolutamy-
Scheme 2. Total Synthesis of Convolutamydines B and E
Figure 4. CD spectra of 13 (R-isomer, solid curve) and ent-13
(S-isomer, dashed curve).
The vinylogous Mukaiyama aldol reaction of 4,6-dibro-
moisatin 9 and ent-6a proceeded smoothly to afford aldol
adduct 10 quantitatively almost as a single isomer. Aldol
adduct 10 was then converted into a common intermediate
11 in three steps. (R)-Convolutamydine E (12) was obtained
from 11 by removal (99%) of the TMS group in 11.6 The
synthesis of (R)-convolutamydine B (13) was also achieved
by the simple transformations from 11 [tosylation, chlorina-
tion, followed by desilylation (40% yield in three steps)]. In
the same manner, (S)-convolutamydines B (ent-13) and E
(ent-12) were also synthesized from vinylketene N,O-acetal
6a derived from L-valine. In all cases, the synthetic convo-
lutamydines were in high enantiomeric excess (>97% ee)
as determined by chiral HPLC analyses, and spectral data
(1H and 13C NMR) and HRMS data were identical with those
of natural products.
dine B was unambiguously established as 3R. Unfortunately,
neither the [R]D value nor the CD spectrum of convolutamy-
dine E have been reported, so we have been unable to
determine the absolute configuration of convolutamydine E.
In summary, we have developed a highly stereoselective
addition to a isatin derivative for the first time by vinylogous
Mukaiyama aldol reaction. We also achieved the enantiose-
lective synthesis of convolutamydines B and E and deter-
mined the absolute configuration of convolutamydine B.
Acknowledgment. We thank Prof. Kenso Soai and Dr.
Itaru Sato (Tokyo University of Science) for the measurement
of circular dichroism spectra.
Supporting Information Available: Detail experimental
procedure and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) (a) Shepherd, R. G. J. Org. Chem. 1947, 12, 275-283. (b) Carlin,
R. B.; Forshey, W. O., Jr. J. Am. Chem. Soc. 1950, 72, 793-801. (c)
Sandmeyer, T. HelV. Chim. Acta 1919, 2, 234-242.
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