Total synthesis of (+)-madindoline A and (-)-madindoline B, potent, selective inhibitors of interleukin 6. Determination of the relative and absolute configurations

Full text of DOI:10.1021/ja9938074

2122
J. Am. Chem. Soc. 2000, 122, 2122-2123
configurations of (+)-madindoline A (1) and (-)-madindoline B
(2), the latter the enantiomer of natural madindoline B (vide infra).
As prelude to total synthesis, we devised an efficient, asym-
metric synthesis of the 3a-hydroxyfuroindoline ring system.6 On
the basis of our observation that m-CPBA oxidation of tryptophol
(3) furnished 3a-hydroxyfuroindoline (4) in 75% yield, we
explored the Sharpless asymmetric epoxidation protocol.7 Sto-
ichiometric oxidation [2.5 equiv t-BuOOH, 1.2 equiv (+)-DIPT,
1.0 equiv Ti(Oi-Pr)4, CH2Cl2 (0.01 M)] for 6 h at -20 °C led to
(-)-48 in 72% yield and 99% ee (Scheme 1); catalytic protocols
proved less effective (e.g., 37% yield; 28% ee). The absolute
configuration of (-)-4 (3aR,8aS), determined by single-crystal
X-ray analysis of the N-methyl-O-MTPA ester, proved consistent
with the Sharpless epoxidation mnemonic.7
Total Synthesis of (+)-Madindoline A and
(-)-Madindoline B, Potent, Selective Inhibitors of
Interleukin 6. Determination of the Relative and
Absolute Configurations
Toshiaki Sunazuka, Tomoyasu Hirose, Tatsuya Shirahata,
Yoshihiro Harigaya, Masahiko Hayashi,
Kanki Komiyama, and Satoshi Ohmura*
Research Center for Biological Function
The Kitasato Institute
and School of Pharmaceutical Sciences
Kitasato UniVersity, Minato-ku, Tokyo 108, Japan
Amos B. Smith, III*
Department of Chemistry
Laboratory for Research on the Structure of Matter
Monell Chemical Senses Center
Scheme 1
UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
ReceiVed October 26, 1999
Interleukin 6 (IL-6), a multifunctional cytokine, plays a central
regulatory role in host defense mechanisms.1 However, in tumor
cells IL-6 stimulates cell proliferation in an autocrine/paracrine
manner and is responsible for much of the metabolic change
known as cancer cachexia.2 Control of IL-6 activity thus holds
great promise both for the suppression of IL-6-dependent tumor
cell growth and for the relief of cancer cachexia.3
In our program to discover new IL-6 modulators, we recently
reported the isolation and planar structures of (+)-madindolines
A and B (1 and 2),4 novel antibiotics comprised of a 3a-
hydroxyfuroindoline ring connected at nitrogen via a methylene
bridge to a cyclopentene-1,3-dione ring. Structural assignments
were based on extensive 1- and 2-D NMR studies, in conjunction
with IR, UV, and MS data; the relative and absolute configura-
tions, however, remained undefined. Bioassays revealed potent,
selective inhibition of IL-6 activity in the IL-6-dependent cell
line MH60; importantly the response was dose-dependent.4 In
addition, (+)-madindoline A (1), the more potent congener,
inhibited the differentiation of osteoblast cells.4 Preliminary studies
suggest that 1 interacts with the IL-6 receptor.5 Unfortunately,
the original source, Streptomyces nitrosporeus K93-0711, no
longer produces these antibiotics.5
Having secured a viable asymmetric protocol to access the 3a-
hydroxyfuroindoline ring, we envisioned the total synthesis of 1
and 2 to entail reductive coupling of aldehyde 6 (Scheme 2) with
tryptophol (3), followed by the stereocontrolled introduction of
the 3a-hydroxyfuroindoline ring, exploiting the Sharpless protocol.
Aldehyde 6 in turn would derive from 8, the product of a ring-
closing metathesis reaction9 on diene 7, followed by conjugate
introduction of an n-butyl group and oxidation state adjustments.
Diene 7 required for ring metathesis would be constructed
beginning with an initial Evans asymmetric aldol10 on acrolein
Scheme 2
Intrigued by the novel architecture, the significant IL-6
inhibitory activity, and the scarcity of these natural products, we
recently undertook their total synthesis. Herein we report the first
total synthesis and assignment of the relative and absolute
(1) Richards, C. D. In Cytokines; Mire-Sluis, A. R., Thorpe, R., Eds.;
Academic: San Diego, CA, 1998; pp 87-108. Hirano, T. Int. ReV. Immunol.
1998, 16, 249-284 and references therein.
(6) Racemic 3a-hydroxyfuroindoline (()-4 had been prepared previously
by photosensitized oxygenation of tryptophol (3), see: Saito, I.; Imuta, M.;
Nakada, A.; Matsugo, S.; Matsuura, T. Photochem. Photobiol. 1978, 28, 531
and references therein.
(2) Strassmann, G.; Masui, Y.; Chizzoniti, R.; Fong, M. J. Immunology
1993, 150, 2341-2345 and references therein.
(3) Stein, B.; Kung Sutherland, M. S. Drug DiscoVery Today 1998, 3, 202.
(4) (a) Hayashi, M.; Kim, Y.-P.; Takamatsu, S.; Enomoto, A.; Shinose,
M.; Takahashi, Y.; Tanaka, H.; Komiyama, K.; Ohmura, S. J. Antibiot. 1996,
49, 1091. (b) Takamatsu, S.; Kim, Y.-P.; Enomoto, A.; Hayashi, M.; Tanaka,
H.; Komiyama, K.; Ohmura, S. J. Antibiot. 1997, 50, 1069.
(5) Hayashi, M., unpublished results.
(7) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(8) The structural assignment to each new compound is in accord with its
1
IR, H, and 13C, and high-resolution mass spectra.
(9) For recent reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
10.1021/ja9938074 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/17/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 9, 2000 2123
to furnish 10; a second diastereoselective aldol11 with methacrolein
would complete the diene synthesis, establishing the key stereo-
genicity at C(2′). Importantly, this strategy held the promise of
controlled access to each of the possible stereoisomers of the
madindoline skeleton, thereby permitting establishment of the
relative and absolute configurations of 1 and 2.
Scheme 5
With this scenario in mind, aldol reaction of oxazolidinone (+)-
1110,12 with acrolein proceeded in 89% yield with >99% de
(Scheme 3); methanolysis afforded â-hydroxyester (+)-10.8 A
second aldol with methacrolein,11 furnished a difficultly separable
mixture of diols (7a-c) in 70% yield. To establish the relative
stereochemistry of 7a-c, the corresponding 1,3-acetonides 12a-
c8 were prepared and separated by flash chromatography; NOE
analysis permitted stereochemical assignment.
Scheme 3
reductive alkylation (TiCl4, benzene; NaBH3CN, MeOH)15 fur-
nished 198 in 77% yield as a diastereomeric mixture.
Having achieved the union of (+)-17 with indoline, all that
remained to arrive at the madindolines was generation of the
enedione and indole moieties and elaboration of the 3a-hydroxy-
furoindoline ring. To this end, removal of the silyl groups in 19
(TBAF; 100% yield), followed in turn by selective silylation of
the primary hydroxyl (TESCl; 78% yield), oxidation (MnO2) and
acid hydrolysis (89% yield, 2 steps) afforded indole (+)-20.8
Oxidative ring-closure of (+)-20 [(+)-DET, Ti(Oi-Pr)4, t-BuOOH]
then yielded (+)-madindoline A (1) and (-)-madindoline B (2)8
(2.2:1, 45% yield).16 Synthetic crystalline (+)-madindoline A (1)
was identical in all respects with natural (+)-1 [400 MHz 1H and
100 MHz 13C NMR, IR, HRMS, optical rotation, mp, mmp].
Synthetic (-)-madindoline B (2) was also identical with natural
madindoline B in all respects, except for the chiroptical properties
{[R]29 -30.0° (c 0.03 MeOH); natural, [R]24 +25.6° (c 0.3
Hydrolysis of the major acetonide (+)-12a (Scheme 4),
followed by ring-closing metathesis9 of (+)-7a8 (0.2 equiv Grubbs
catalyst, CH2Cl2) furnished cyclopentene (-)-138 in 69% yield.
Selective silylation (TBSOTf) of the less hindered allylic hydroxyl
and oxidation (MnO2) then provided (-)-148 in 86% yield (2
steps). For material advancement, the mixture of diols (7a-c)
was subjected directly to metathesis, protection, and oxidation;
flash chromatography afforded (-)-14 in 53% overall yield.
D
D
MeOH)}. Thus, (-)-madindoline B (2) is the enantiomer of
natural (+)-2.17 Confirmation of the relative configurations in 1
and 2 was achieved by X-ray analysis of synthetic (+)-1.
In summary, the first total synthesis of (+)-madindoline A (1)
and (-)-madindoline B (2), has been achieved via an efficient
and convergent strategy (19 linear steps, 7.8% overall yield). The
synthetic route not only provides ready access to these rare natural
products, but also defines for the first time their relative and
absolute configurations. Further refinements of the synthetic
scheme and preparation of analogues for biological evaluation
will be reported in due course.
Scheme 4
Continuing with the synthesis, conjugate addition (n-Bu2CuLi)
(Scheme 5), followed by phenylselenylation (PhSeBr) of the
derived enolate, and oxidative elimination (H2O2) furnished a
mixture comprised of (-)-15 and the exomethylene isomer (1:
1). Treatment of the mixture with RhCl3 converted the exo
congener to (-)-15;8 the overall yield for the three steps was 73%.
Stereoselective reduction of (-)-15 (NaBH4),8,13 silylation (TBSCl,
KH), and reduction (DIBAL) to furnish (+)-178 (74%, 3 steps),
set the stage for elaboration of the aldehyde and reductive coupling
to tryptophol. Toward this end, the oxidation (Dess-Martin)14
of (+)-17 proceeded smoothly; however, all attempts to achieve
reductive coupling of the derived aldehyde with tryptophol proved
unsuccessful. Formation of the intermediate imine appeared to
be the problem, presumably due to the poor nucleophilicity of
the indole nitrogen. With the more nucleophilic indoline (18),
Acknowledgment. Financial support was provided by the Ministry
of Education, Science, Sports and Culture (Japan), the Japan Keirin
Association, and a Kitasato University Research Grant for Young
Researchers (T.S.). We also thank the JSPS for a predoctoral fellowship
to T.H. and Dr. Kai for the X-ray analyses.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for relevant compounds (PDF). This
material is avilable free of charge via the Internet at http://pubs.acs.org.
JA9938074
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(15) White, W. A,; Weingarten, H. J. Org. Chem. 1967, 32, 213.
(16) Use of (-)-DET furnished (+)-1 and (-)-2 in 15 and 34% yield,
respectively. The lower selectivity vis-a´-vis the model oxidation is presumably
due to increased steric hindrance and/or the presence of the additional
stereogenic centers in (+)-20. Oxidation with m-CPBA furnished a 1:1 mixture
of (+)-1 and (-)-2.
(10) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
(11) Frater, G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40, 1269.
(12) The absolute stereochemistry of 11 was randomly selected.
(13) Stereoselectivity presumably derives from the OTBS moiety.
(17) The absolute configuration therefore of natural (+)-madindoline A is
3aR,8aS,2′R and (+)-madindoline B is 3aR,8aS,2′S.