Stereocontrolled total synthesis of (-)-eudistomin C

Article abstract of DOI:10.1021/ja055832h

A stereocontrolled total synthesis of (-)-eudistomin C was accomplished in 18-step sequence with an overall yield of 7.7%. The synthesis features the diastereoselective Pictet-Spengler reaction of a tryptamine derivative and the Garner aldehyde catalyzed

Full text of DOI:10.1021/ja055832h

Published on Web 10/07/2005
Stereocontrolled Total Synthesis of (-)-Eudistomin C
Tohru Yamashita, Nobutaka Kawai,† Hidetoshi Tokuyama, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received August 25, 2005; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Eudistomins, isolated from a Caribbean tunicate (Eudistoma
oliVaceum) by Rinehart and co-workers in 1984,1,2 are members
of the tetrahydro-â-carboline family of marine alkaloids. Among
eudistomins, eudistomin C (1), E (2), K (3), L (4), and F (5),
possessing the hitherto unknown oxathiazepine ring, have displayed
extremely potent antiviral activity against both DNA and RNA
viruses as well as antitumor and antimicrobial activity1c,2c (Figure
1). Therefore, this class of compounds has attracted a great deal of
attention as a synthetic target, and two examples of total syntheses3,4
and several synthetic approaches5 have been described to date. We
disclose herein the stereocontrolled total synthesis of (-)-eudistomin
C (1), featuring the highly efficient formation of the oxathiazepine
ring.
Figure 1. Structures of the eudistomins.
Scheme 1 Retrosynthetic Analysis
In previous synthetic studies,3-5 considerable difficulties were
encountered in the construction of an oxathiazepine ring containing
three heteroatoms and two chiral centers. Thus, ring closure by the
intramolecular alkylation of hydroxylamine oxygen with halomethyl
sulfide (i.e., disconnection at bond-a) has proved difficult3b presum-
ably due to alkylation at the nitrogen of the N,N-dialkylhydroxyl-
amine to form N-oxide.6 The other successful strategy utilizing the
intramoleculer Pictet-Spengler reaction based on disconnection at
bond-b provided an undesired diastereomer as the major product.4
Instead of using these problematic ring-closing reactions, we
planned to construct an oxathiazepine ring via the intramoleculer
alkylation of thiol 6 even though, to the best of our knowledge,
such transformation was unprecedented. The generation of the thiol
would be possible from MTM ether through the formation of
chloromethyl ether,7 followed by the introduction of the sulfur atom.
The diastereoselective construction of tetrahydro-â-carboline could
be made possible by the Pictet-Spengler reaction3 between
tryptamine derivative 7 and Garner aldehyde 8.8
The synthesis of indole segment 9 started from nitroaniline 10,
which was readily prepared from m-anisidine in four steps (Scheme
2).9 The conversion of 10 to iodoaniline derivative 11 was
conducted by a three-step sequence that included the Sandmyer
reaction, the selective reduction of the nitro group with Fe/FeCl2,
and trifluoroacetylation. Then, Mitsunobu reaction with TBS-
protected cis-butene diol (12) provided indole precursor 13,10 which
was subjected to the intramolecular Heck reaction conditions
reported by Macor and co-workers11 to give the desired tryptophol
derivative 14. After protection of indole NH with the Boc group
and desilylation of the TBS ether, hydroxylamine functionality was
then incorporated by the Mitsunobu reaction of 15 with N-Ns-O-
MTM hydroxylamine12 (16), which was derived from N-hydroxy-
phthalimide in two steps. Finally, deprotection of the Boc and Ns
groups13 under conventional conditions furnished the desired
tryptamine derivative 9.
model substrate of 9 lacking the bromo and methoxy groups gave
the undesired diastereomer as the major product (3:1) under standard
conditions (TFA in CH2Cl2, -78 °C), we conducted extensive
screening of the solvents and acid catalysts. Surprisingly, we found
that the reaction in the presence of a catalytic amount of chloroacetic
acid or dichloroacetic acid in toluene proceeds smoothly at 0 °C to
afford the desired diastereomer 18 with high selectivity (11:1)
(Scheme 3).
The next task was to transform the O-MTM ether to the
corresponding O-methylthiol. After the protection of indole NH of
18 with the R-chloroethoxycarbonyl (ACE) group,14 MTM ether
19 was treated with SO2Cl2 to give chloromethyl ether 207 (Scheme
3). Due to its instability, the crude 20 was immediately treated with
AcSH in the presence of Hunig’s base to furnish thiol acetate 21
in excellent yield. Then, removal of the acetonide and mesylation
of the resultant alcohol afforded cyclization precursor 22. To our
great satisfaction, upon heating with K2CO3 in MeOH, thiol acetate
22 underwent facile methanolysis and the subsequent ring-closing
alkylation took place smoothly to furnish the desired oxathiazepine
ring with the concomitant deprotection of the ACE group. It should
be emphasized that appreciable formation of the isoxazolidine ring
by the release thioformaldehyde followed by intramolecular cy-
We then focused our attention on the crucial Pictet-Spengler
reaction with Garner aldehyde 8. Since an initial attempt using a
† Visiting researcher. Astellas Pharma Inc., Hasune 3-chome, Itabashi-ku, Tokyo
174-8612, Japan.
9
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J. AM. CHEM. SOC. 2005, 127, 15038-15039
10.1021/ja055832h CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Preparation of the Indole Segmenta
by treatment with BBr3 to obtain (-)-eudistomin C (1). All of the
spectral data of the synthetic compound were identical to those of
natural (-)-eudistomin C.1,3
In conclusion, we have accomplished the stereocontrolled total
synthesis of (-)-eudistomin C (1) based on the development of
the Brønsted acid-catalyzed diastereoselective Pictet-Spengler
reaction and the unprecedented construction of an unusual oxa-
thiazepine ring. The 18-step sequence with an overall yield of 7.7%
has allowed us to conduct the gram-scale preparation of eudistomin
C as well as variety of its derivatives. Biological studies on the
natural and unnatural compounds will be reported in due course.
Acknowledgment. We thank Professor M. Nakagawa for
providing spectra of eudistomins and synthetic intermediates. This
work was financially supported by CREST and PRESTO, JST,
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan, and JSPS (predoctoral fellowship
for T.Y.).
Supporting Information Available: Experimental details and
spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) NaNO2, H2SO4, CH3CN, H2O; KI; (b)
Fe, FeCl2, 1 N HCl, EtOH, reflux; (c) TFAA, Py, CH2Cl2, 62% (three steps);
(d) (Z)-HOCH2CHdCHCH2OTBS (12), DEAD, PPh3, PhH, 90%; (e) cat.
Pd(OAc)2, Et3N, BnEt3NCl, DMF, 80 °C, 66%; (f) Boc2O, DMAP, CH2Cl2;
(g) CSA, MeOH, 97% (two steps); (h) Ns-NH-OMTM (16), DEAD, PPh3,
PhH; (i) Me2S, TFA, CH2Cl2, 97% (two steps); (j) PhSH, K2CO3, DMF,
94%.
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clization at hydroxylamine oxygen was not observed. Finally, the
Boc group and methyl group on phenolic oxygen were removed
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