Total synthesis of madindoline A

Article abstract of DOI:10.1016/S0040-4039(00)00939-4

The total synthesis of madindoline A was achieved. The key step of the synthesis is a reductive coupling of an acid-sensitive hydroxyfuroindoline derivative and a sterically hindered aldehyde using Sn(OTf)₂-NaBH(OAc)₃. After the redu

Full text of DOI:10.1016/S0040-4039(00)00939-4

Tetrahedron Letters 41 (2000) 6435±6439
Total synthesis of madindoline A
Seijiro Hosokawa, Kazuhiko Sekiguchi, Kanako Hayase, Yasushi Hirukawa
and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 15 May 2000; revised 1 June 2000; accepted 2 June 2000
Abstract
The total synthesis of madindoline A was achieved. The key step of the synthesis is a reductive coupling
of an acid-sensitive hydroxyfuroindoline derivative and a sterically hindered aldehyde using Sn(OTf)2±
NaBH(OAc)3. After the reductive coupling, the derived trione was subjected to intramolecular condensa-
tion to construct a madindoline skeleton. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: madindoline A; total synthesis; reductive coupling; tin(II) tri¯ate; intramolecular condensation.
Interleukin 6 (IL-6) is a multifunctional cytokine which acts on immune response and also
participates in in¯ammation, cancer cachexia, and stimulation of the proliferation of tumor cells
in an autocrine/paracrine manner.1 Thus, an inhibitor of IL-6 activity is considered to be a
promising candidate for treatment of these diseases. We have been interested in a search for an
inhibitor of IL-6 activity and investigated the synthesis of several natural products such as
norzoanthamine.2 Madindoline A (1) and B (2) were isolated from the culture of Streptomyces
-
nitrosporeus K93-0711 by Omura in 1996 as a selective inhibitor of IL-6 activity.3 Further,
Omura's group recently achieved the ®rst total synthesis of madindolines and determined the
-
absolute stereochemistry as shown in Fig. 1.4 During their synthetic investigations they developed
Figure 1.
* Corresponding author. Fax: +81 3 3260 8848; e-mail: kobayash@ps.kagu.sut.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00939-4

6436
an excellent methodology for enantioselective preparation of the hydroxyfuroindoline moiety.4
This method, however, was less stereoselective in application to the total synthesis. Thus, we
became interested in an alternative approach utilizing the chiral hydroxyfuroindoline as a starting
material. In the preceding paper,5 we described an enantioselective synthesis of cyclopentenedione
by developing a new method for the construction of a quaternary chiral carbon and regioselective
intramolecular condensation of triketone leading to a cyclopentenedione skeleton. Here, we
report the total synthesis of madindoline A.
Our initial attempts towards the total synthesis of madindolines were focused on a reductive
coupling of the cyclopentenedione aldehyde 35 and hydroxyfuroindoline 4,6 which would directly
a€ord the madindoline skeleton (Eq. (1)).7,8 Although cyclopentenedione aldehyde 3 could be
isolated by the oxidation of the corresponding alcohol, we were not able to achieve the reductive
coupling of 4 and 3 under various conditions mainly due to the ready deformylation of 3.
Therefore, we were forced to change to an alternative approach which involved the cyclopente-
nedione formation being carried out after coupling with furoindolidine 4. Another diculty we
observed during the above attempts was the instability of the furoindolidine 4 under acidic
conditions. Therefore, it became necessary to develop a new methodology for the reductive
coupling of acid-sensitive 4 and a sterically hindered aldehyde.
ꢀ1†
ꢀ2†
After a number of experiments by varying aldehydes, acids, additives, and reaction conditions,
we were able to develop NaBH(OAc)3±Sn(OTf)2 and NaBH(OAc)3±AcOH methods (Eq. (2)).9
Particularly, the NaBH(OAc)3±Sn(OTf)2 method was found to be e€ective for the reductive
coupling of furoindoline derivative 4. For example, coupling of acetoxyfuroindoline 4c and
tertiary aldehyde 85 gave the corresponding alkylated furoindoline 9 in 41% yield (Scheme 1).
Unfortunately the present methods were not successful for the coupling with aldehydes such as 3,
10±12 which are more straightforward for the synthesis of madindolines.
Since deprotection of the benzyl group in 9 was dicult, acetyl derivative 13 was prepared
from 8, and subjected to the reductive coupling with 4. Scheme 2 shows the preparation and
reaction of 13.

6437
Scheme 1.
Scheme 2.
As shown in Scheme 2, reductive coupling of 13 with furoindoline 4b and 4c gave 14b10 and 14c
in 66 and 40% yields, respectively. TBS derivative 14b eventually served as the key intermediate
for madindoline A.
Total synthesis of madindoline A is summarized in Scheme 3. Deprotection of the acetyl group
of 14b followed by Dess±Martin oxidation gave aldehyde 15, which was converted into 16 by
alkylation with EtLi following protection of the resulting alcohol. The carbon carbon double
bond of 16 was oxidized with a catalytic amount of OsO4 in the presence of N-methylmorpholine
N-oxide, and the resulting diol was further hydrolyzed to give a diastereomeric mixture of triol 17
in 75% yield (2 steps). The key intermediate triketone 18 was obtained in 70% yield by Swern
oxidation.11 On treatment with DBU in benzene, triketone 18 underwent regioselective cyclization
to produce cyclopentenedione derivative 1912 in 87% yield. The presence of vinyl-Me protons,
which appeared at ꢀ 2.01 as a singlet, strongly supported its structure. Finally, deprotection of 19 with
TBAF completed the total synthesis of madindoline A. The structure of synthetic madindoline A
(m.p. 123±124ꢁC; ‰ꢁŠD23=+144ꢁ (c=0.273, MeOH), ‰ꢁŠD24=+125ꢁ (c=0.353, CHCl3)) was con®rmed
1
by comparing H- and 13C-NMR spectra with those of natural madindoline A, kindly provided
-
by Professor S. Omura.
We have thus succeeded in the total synthesis of madindoline A. The key features of the present
synthesis are: (1) development of a novel Sn(OTf)2±NaBH(OAc)3 method for reductive coupling
of a sterically hindered aldehyde and acid-sensitive furoindoline; and (2) regioselective cyclization
of the triketone a€ording the requisite cyclopentenedione. Further correlation of 8 to madindoline
A unambiguously established the absolute stereochemistry of 8 which was tentatively assigned
based on mechanistic consideration.5

6438
Scheme 3.
Acknowledgements
-
We thank Prof. Satoshi Omura (Kitasato Institute) for providing NMR spectra of madindoline
A and B. We also thank Dr Toshiaki Sunazuka (Kitasato University) for helpful discussions.
This work was supported in part by the Fujisawa Foundation (S.H.) and Grant-in-Aid for
Scienti®c Research from the Ministry of Education, Science, Sports, and Culture, Japan.
References
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K.; Omura, S. J. Antibiot. 1996, 49, 1091. (b). Takamatsu, S.; Kim, Y. P.; Enomoto, A.; Hayashi, M.; Tanaka, H.;
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6. Furoindolines 4b and 4c were prepared from non-protected hydroxyfuroindoline 4a (RˆH).3
7. For reductive amination with NaBH(OAc)3: (a) Gribble, G. W.; Ferguson, D. C. J. Chem. Soc. Chem. Comm.
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395 and references therein.

6439
8. For other methods of reductive amination: (a) Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259±3261. (b) Borch,
R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897±2904. (c) Stowell, J. C.; Padegimas, S. J.
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9. Details of this method will be published elsewhere in due course.
10. ‰ꢁŠ2D5=^74.9ꢁ (c=0.57, CHCl3); 1H-NMR (400 MHz, CDCl3): ꢀ ^0.21 (3H, s), ^0.14 (3H, s), 0.86 (9H, s), 0.88 (3H,
d, J=7.1 Hz), 1.11 (3H, s), 1.23±1.35 (4H, m), 2.00 (2H, q, J=7.1 Hz), 2.10 (3H, s), 2.28 (1H, td, J=7.6, 11.7 Hz),
2.44 (1H, ddd, J=1.5, 5.1, 11.7 Hz), 3.15 (1H, d, J=14.9 Hz), 3.37 (1H, d, J=14.9 Hz), 3.45 (1H, ddd, J=5.1, 9.3,
11.7 Hz), 3.97 (1H, ddd, J=1.5, 7.6, 9.3 Hz), 4.04 (2H, s), 5.11 (1H, s), 5.45±5.51 (2H, m), 6.49 (1H, d, J=7.6 Hz),
6.71 (1H, t, J=7.6 Hz), 7.13 (1H, td, J=1.0 Hz), 7.18 (1H, dd, J=1.0, 7.6 Hz). 13C-NMR (100 MHz, CDCl3): ꢀ
^3.6, ^3.1, 14.0, 18.0, 20.8, 21.0, 22.2, 25.7, 31.5, 32.7, 41.4, 43.5, 54.4, 66.8, 69.1, 89.4, 104.6, 107.1, 117.8, 124.5,
129.7, 130.0, 130.2, 133.6, 152.4, 171.0.
11. Mancuso, J.; Swern, D. Synthesis 1981, 165.
25
12. ‰ꢁŠD = +73.3ꢁ (c=0.40, CHCl3); H-NMR (300 MHz, CDCl3): ꢀ ^0.31 (3H, s), ^0.24 (3H, s), 0.76 (9H, s), 0.81
(9H, s), 1.13 (3H, s), 1.16±1.36 (4H, m), 2.01 (3H, s), 2.15 (1H, dd, J=3.7, 12.8 Hz), 2.32 (1H, td, J=7.4, 11.6 Hz),
2.36 (2H, t, J=7.4 Hz), 3.04 (1H, ddd, J=4.6, 8.8, 11.6 Hz), 3.45 (1H, d, J=14.3 Hz), 3.73 (1H, d, J=14.3 Hz),
4.84 (1H, s), 6.64 (1H, d, J=7.9 Hz), 6.71 (1H, t, J=7.4 Hz), 7.10 (1H, d, J=7.4 Hz), 7.17 (1H, t, J=7.9 Hz).;
13C-NMR (75 MHz, CDCl3): ꢀ ^3.8, ^3.2, 9.4, 13.6, 17.3, 17.9, 22.7, 23.5, 25.6, 29.9, 43.1, 50.6, 54.0, 66.2, 89.4,
105.7, 107.8, 118.6, 124.4, 129.5, 130.1, 150.8, 156.7, 157.6, 180.4, 206.4, 206.5.
1