Synthesis of eudistomin C and E: Improved preparation of the indole unit

Article abstract of DOI:10.1021/ol800527p

(Chemical Equation Presented) An improved synthesis of the indole unit, a key intermediate for eudistomin C, was established utilizing Makosza's indole synthesis. A concise total synthesis of eudistomin E was achieved on the basis of the improved synthesi

Full text of DOI:10.1021/ol800527p

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2369-2372
Synthesis of Eudistomin C and E:
Improved Preparation of the Indole Unit
Hiroaki Yamagishi, Koji Matsumoto, Kotaro Iwasaki, Tohru Miyazaki,
Satoshi Yokoshima, Hidetoshi Tokuyama,† and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received March 7, 2008
ABSTRACT
An improved synthesis of the indole unit, a key intermediate for eudistomin C, was established utilizing Makosza’s indole synthesis. A concise
total synthesis of eudistomin E was achieved on the basis of the improved synthesis.
Eudistomins, isolated from a Caribbean tunicate (Eudistoma
oliVaceum) by Rinehart and co-workers in 1984,1,2 have
attracted the interest of researchers because of potent
antiviral, antitumor, and antimicrobial activities, as well as
their unique structures including the hitherto unknown
oxathiazepine ring (Figure 1). Several synthetic studies3,4
† Current address: Graduate School of Pharmaceutical Sciences, Tohoku
University, Aramaki, Aoba, Sendai 980-8578, Japan.
Figure 1. Structures of the eudistomins.
(1) (a) Rinehart, K. L., Jr.; Kobayashi, J.; Harbour, G. C.; Hughes, R. G.,
Jr.; Mizsak, S. A.; Scahill, T. A. J. Am. Chem. Soc. 1984, 106, 1524. (b)
Kobayashi, J.; Harbour, G. C.; Gilmore, J.; Rinehart, K. L., Jr. J. Am. Chem.
Soc. 1984, 106, 1526. (c) Rinehart, K. L., Jr.; Kobayashi, J.; Harbour, G. C.;
Gilmore, J.; Mascal, M.; Holt, T. G.; Shield, L. S.; Lafargue, F. J. Am.
Chem. Soc. 1987, 109, 3378. (d) Kobayashi, J.; Nakamura, H.; Ohizumi,
and total syntheses5,6 have been reported by other groups,
and we have recently reported our own effort on a total
synthesis of eudistomin C (1), featuring a stereoselective
Pictet-Spengler reaction and the formation of the oxathi-
azepine ring by an intramolecular SN2 reaction (Scheme 1).7
Y. Tetrahedron Lett. 1986, 27, 1191
.
(2) (a) Lake, R. J.; Brenman, M. M.; Blunt, J. W.; Munro, M. H. G.
Tetrahedron Lett. 1988, 29, 2255. (b) Lake, R. J.; McCombs, J. D.; Blunt,
J. W.; Munro, M. H. G.; Robinson, W. T. Tetrahedron Lett. 1988, 29, 4971.
(c) Lake, R. J.; Blunt, J. W.; Munro, M. H. Aust. J. Chem. 1989, 42, 1201
.
(4) (a) Hermkens, P. H. H.; van Maarseveen, J. H.; Kruse, C. G.;
Scheeren, H. W. Tetrahedron Lett. 1989, 30, 5009. (b) Hermkens, P. H. H.;
van Maarseveen, J. H.; Berens, H. W.; Smits, J. M. M.; Kruse, C. G.;
Scheeren, H. W. J. Org. Chem. 1990, 55, 2200. (c) van Maarseveen, J. H.;
Hermkens, P. H. H.; Clercq, E. D.; Balzarini, J.; Scheeren, H. W.; Kruse,
C. G. J. Med. Chem. 1992, 35, 3223. (d) van Maarseveen, J. H.; Scheeren,
H. W.; Kruse, C. G. Tetrahedron 1993, 49, 2325.
(3) (a) Han, S. Y.; Lakshmikantham, M. V.; Cava, M. P. Heterocycles
1985, 23, 1671. (b) Behm, H.; Beurskens, P. T.; Plate, R.; Ottenheijm, H. C.
J. Recl. TraV. Chim. Pays-Bas 1986, 105, 238. (c) Still, I. W. J.; Strautmanis,
J. R. Tetrahedron Lett. 1989, 30, 1041. (d) Still, I. W. J.; Strautmanis, J. R.
Can. J. Chem. 1990, 68, 1408. (e) Kirkup, M. P.; Shankar, B. B.; McCombie,
S.; Ganguly, A. K.; McPhail, A. T.. Tetrahedron Lett. 1989, 30, 6809
.
10.1021/ol800527p CCC: $40.75
Published on Web 05/23/2008
2008 American Chemical Society

regioselective halogenation of 5-methoxyindole derivative
was also difficult. Although it would be possible to exclude
the regiochemical problems by using the Leimgruber-Batcho
indole synthesis,10 preparation of the starting nitrotoluenes
should be laborious. After intensive investigations toward
an improved synthesis of the indole unit 10, we decided to
apply the Makosza’s indole synthesis.11 Their procedure
involves introduction of a cyanomethyl group to the position
ortho to the nitro group of nitrobenzenes, and the subsequent
reduction of both nitro and cyano groups gives indoles.
According to their reported procedure, a mixture of
commercially available 2-bromo-4-nitroanisole (14) and
4-chlorophenoxyacetonitrile (15a) was treated with t-BuOK
to give a rather disappointing 2:1 mixture of the adducts
(Table 1). Although the selectivity was increased when the
Scheme 1
Table 1. Regioselectivity of the Introduction of a Cyanomethyl
Group
reagent
X
Y
temp (°C)
ratio (16:17)a
yield (%)b
15a
15a
15b
15c
15d
15e
a
Cl
Cl
H
Cl
H
H
H
Cl
Cl
Br
Me
0
-78
2:1
10:1
6:1
5:1
5:1
95
89
86
81
84
51
0
0
0
0
However, it was not particularly suited for a large-scale
preparation of 1 and its analogs because of a multistep
procedure to prepare the key intermediate 10, including a
Heck reaction to form the indole core,8 a Mitsunobu reaction9
to introduce the hydroxylamine moiety, and tedious protec-
tion-deprotection steps. In addition, preparation of the
substituted 2-iodoanilines 6 from m-anisidine was not very
efficient. Herein we disclose a concise route to synthesize
the indole unit with the hydroxylamine moiety 10 and its
application to the synthesis of eudistomin E.
Although a variety of indole syntheses have been devel-
oped, a selective synthesis of a multisubstituted indole is
not necessarily an easy task. A preliminary attempt to prepare
6-bromo-5-methoxyindol-3-yl-ethanol by Fischer indole syn-
thesis using 3-bromo-4-methoxyphenylhydrazine and dihy-
drofuran gave a mixture of regioisomers. In addition,
H
3:1
Ratio was determined by H NMR. b Isolated yields.
1
reaction was conducted at -78 °C, it seemed less practical.
In order to introduce a cyanomethyl group to the less-
hindered side of the nitro group, we examined more bulky
2,6-disubstituted phenoxyacetonitriles.12 After screening of
the reagents, we found that 2,6-dichlorophenoxyacetonitrile
(15b) gave the best result and furnished the desired product
with a 6:1 regioselectivity. The resulting mixture was purified
by recrystallization to afford 16 in 65% yield. Hydrogenation
of the cyano and nitro groups of 16 over rhodium on carbon
afforded the desired indole 18 in 52% yield with the bromo
substituent intact (Scheme 2).
With the indole core in hand, we then introduced the side
chain with the hydroxylamine moiety (Scheme 2). Indole
18 was subjected to a Mannich reaction to give gramine 19,
which after neutralization with an aqueous sodium hydroxide
solution was treated with sodium cyanide to afford 3-in-
(5) (a) For (-)-eudistomin L and (-)-debromoeudistomin L, see:
Nakagawa, M.; Liu, J.-J.; Hino, T. J. Am. Chem. Soc. 1989, 111, 2721. For
(-)-eudistomins, C, E, F, K, and L, see: (b) Nakagawa, M.; Liu, J.-J.; Hino,
T.; Tsuruoka, A.; Harada, N.; Ariga, M.; Asada, Y. J. Chem. Soc., Perkin
Trans. 1 2000, 3477. (c) Liu, J.-J.; Hino, T.; Tsuruoka, A.; Harada, N.;
Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2000, 3487. For (-)-
eudistomin F, see: (d) Liu, J.-J.; Nakagawa, M.; Harada, N.; Tsuruoka, A.;
Hasegawa, A.; Ma, J.; Hino, T. Heterocycles 1990, 31, 229.
(6) For (-)-debromoeudistomin L, see: Hermkens, P. H. H.; van
Maarseveen, J. H.; Ottenheijm, H. C. J.; Kruse, C. G.; Scheeren, H. W. J.
Org. Chem. 1990, 55, 3998.
(10) Batcho, A. D.; Leimgruber, W. Organic Synthesis; Wiley: New
York, 1990; Collect. Vol. VII; p 34.
(7) (a) Yamashita, T.; Kawai, N.; Tokuyama, H.; Fukuyama, T. J. Am.
Chem. Soc. 2005, 127, 15038. (b) Yamashita, T.; Tokuyama, H.; Fukuyama,
T. Synlett 2003, 738.
(11) Makosza, M.; Danikiewicz, W.; Wojciechowski, K. Liebigs Ann.
Chem. 1988, 203.
(8) Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996,
37, 4289.
(12) For halogenation of the nitrobenzenes to bias the regiochemistry
of the Makosza’s indole synthesis, see: Lerman, L.; Weinstock-Rosin, M.;
Nudelman, A. Synthesis 2004, 3043.
(9) Mitsunobu, O. Synthesis 1981, 1.
2370
Org. Lett., Vol. 10, No. 12, 2008

Scheme 2
Scheme 3
doleacetonitrile 20.13 After reduction of the cyano group of
20 with DIBAL to give imine 21, O-MTM hydroxylamine
hydrochloride14 in methanol-water was added to the reaction
mixture to furnish oxime ether 22 in good yield without
isolating the labile indoleacetaldehyde. Reduction of oxime
ether 22 with sodium cyanoborohydride afforded the requisite
indole unit 10 with the hydroxylamine moiety. Thus, the
novel synthetic route produced 10 from a commercially
available substrate in five steps and 22% overall yield.15
Having established an efficient synthetic route to 10, we
next focused on application to the synthesis of eudistomin
E (2), which has a bromo group at the 5-position. Although
the minor isomer 17 in the reaction of Makosza’s indole
synthesis (Table 1) was a suitable substrate, isolation from
the mixture of regioisomers was a tedious task.16 Therefore,
we opted to prepare the requisite indole unit by cyanom-
ethylation of symmetrical 2,6-bromo-4-nitroanisole and
removal of one of two bromo groups using the hydrodebro-
mination developed by Buchwald and co-workers17 after
formation of indole ring.
After introduction of a cyanomethyl group via Mannich
reaction, a selective hydrodebromination was performed
according to Buchwald’s procedure. That is, 27 was treated
with sodium borohydride in the presence of a palladium
catalyst. The reaction occurred preferentially at the less
hindered bromo group to furnish 28 in 69% yield. The cyano
group was converted into the hydroxylamine moiety in the
same manner as shown above to give 29 in good yield.
Having synthesized the requisite indole unit 29, we next
needed to optimize the crucial Pictet-Spengler reaction of
29 with Garner aldehyde (11).18 The conditions using
Table 2. Optimization of the Pictet-Spengler Reaction
The synthesis commenced with the methylation of com-
mercially available 2,6-dibromo-4-nitrophenol (23). The
cyanomethyl group was introduced to 24 using 4-chlorophe-
noxyacetonitrile (15a) to furnish 25 in 71% yield. Because
the reductive cyclization by catalytic hydrogenation of 25
was accompanied by partial debromination, the cyano and
nitro groups were sequentially reduced to give indole 26.
acid
temp (°C)
ratio (30:31)
yield of 30 (%)
Cl2CHCO2H
BF3·OEt2
ZnCl2
SnCl4
AlCl3
0 to rt
0
0
0
0
0
1.0:2.7a
1.0:1.0b
1.0:1.0b
1.6:1.0b
1.7:1.0b
1.7:1.0b
2.3:1.0a
26
(13) (a) Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm.
Bull. 1985, 33, 3696. (b) Lisas, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.;
Martin, S. F. J. Am. Chem. Soc. 2001, 123, 5918.
TiCl4
BrCH2CO2H
(14) Vlattas, I.; Vecchia, L. D.; Fitt, J. J. J. Org. Chem. 1973, 38, 3749.
(15) Our previous syntheis gave 10 from m-anisidine in fourteen steps
and 7.4% overall yield.
0 to rt
63
a Ratio was determined on the basis of the isolated yields. b Ratio was
determined by H NMR.
(16) Althought the production of 17 was increased when the reaction
was performed at 50 °C, the selectivity was 3:2 at most.
(17) Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336.
1
Org. Lett., Vol. 10, No. 12, 2008
2371

of indole NH of 30 with an R-chloroethoxycarbonyl (ACE)
group,19 the MTM group of 32 was converted into a
chloromethyl group by treatment with sulfuryl chloride.20
The resulting chloromethyl ether was immediately reacted
with thioacetic acid in the presence of Hunig’s base to furnish
thiol acetate 33. Removal of the acetonide and subsequent
mesylation of the resulting alcohol afforded mesylate 34.Meth-
anolysis of the thiol acetate induced a subsequent in-
tramolecular SN2 reaction and concomitant removal of
ACE group to furnish oxathiazepine 35 in 89% yield.21
Finally, the methyl ether and Boc group were cleaved to
afford eudistomin E (2). The spectroscopic data of
eudistomin E obtained are consistent with those reported
in the literature.1a
Scheme 4
In conclusion, we have developed a concise synthetic route
to the key indole intermediate for the synthesis of eudis-
tomins C. Moreover, by modification of this improved route,
we have achieved the total synthesis of eudistomin E. This
novel route to the key indole unit should be applicable to
the synthesis of a variety of derivatives starting from readily
available nitrobenzenes. The syntheses of a broad range of
eudistomin derivatives are currently underway and will be
reported in due course.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid (15109001, 16073205, and
17689003) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
dichloroacetic acid in toluene, which was optimal for the
synthesis of eudistomin C (desired:undesired ) 11:1),7a
afforded the undesired isomer 31 as the major product (Table
2). Using trifluoroacetic acid resulted in lower diastereose-
lectivity. When acetic acid was employed, the selectivity was
improved, but the substrate was not consumed because of
its low acidity. After extensive screening of acids including
Lewis acids, we found that bromoacetic acid afforded the
desired isomer 30 in 63% isolated yield.
OL800527P
(19) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T.
J. Org. Chem. 1984, 49, 2081.
(20) (a) Benneche, T.; Strande, P.; Undheim, K. Synthesis 1983, 762.
(b) Kozikowski, A. P.; Wu, J.-P. Tetrahedron Lett. 1987, 28, 5125.
(21) Alternatively, compound 35 was synthesized as follows: According
to the synthetic scheme described above, dibromoindole 27 was converted
into a eudistomin derivative 36 via a TiCl4-mediated Pictet-Spengler reaction
with 11. The Buchwald hydrodebromination reaction of 36 gave 35 in only
21% yield. Detailed procedures are provided in Supporting Information.
The Pictet-Spengler reaction product was then trans-
formed into eudistomin E according to the procedure
developed in our laboratory (Scheme 4).7a After protection
(18) (a) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18. (b) Dondoni,
A.; Perrone, D. Org. Synth. 1999, 77, 64.
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Org. Lett., Vol. 10, No. 12, 2008