Total synthesis of sulfur-containing pyrroloiminoquinone marine product, (±)-makaluvamine F using hypervalent iodine(III)-induced reactions

Article abstract of DOI:10.1039/a808715f

The first total synthesis of potent cytotoxic makaluvamine F 1, a sulfur-containing pyrroloiminoquinone marine product, has been accomplished using hypervalent iodine(III)-induced reactions.

Full text of DOI:10.1039/a808715f

Total synthesis of sulfur-containing pyrroloiminoquinone marine product,
(±)-makaluvamine F using hypervalent iodine(III)-induced reactions
Yasuyuki Kita,* Masahiro Egi and Hirofumi Tohma
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: kita@phs.osaka-u.ac.jp
Received (in Cambridge, UK) 9th November 1998, Accepted 20th November 1998
The first total synthesis of potent cytotoxic makaluvamine F
N3
1, a sulfur-containing pyrroloiminoquinone marine product,
5 steps
(58%)
has been accomplished using hypervalent iodine(III)-in-
duced reactions.
MeO
N
MeO
N
H
The makaluvamines,1 a new family of marine alkaloids, were
isolated from the Fijian sponge Zyzzya cf. marsailis (A–F) and
the Indonesian sponge Histodermella sp. (G). Among them,
MeO
MeO
Ac
PIFA–Me3SiOTf
(51%)
N
O
O
Br
HO
Br
HN
HN
MeO
N
H
S
H
S
2
N
N
H
N
N
H
H
H
Scheme 2
O
O
discorhabdin A
(prianosin A)
makaluvamine F 1
devoted only towards the preparation of the pyrroloiminoqui-
none and spirodienone units.
To the best of our knowledge, the total syntheses of sulfur-
containing discorhabdins and 1 have not yet been reported, in
spite of their potent cytotoxicity and their unique structure. This
is probably due to the difficulty of construction of the labile and
highly strained N,S-acetal skeletons. We report herein the first
total synthesis of potent cytotoxic makaluvamine F 1 using
hypervalent iodine(III)-induced reactions. Our synthetic strategy
for the total synthesis of 1 involves a final coupling reaction
between 2 and 2-aminodihydrobenzothiophene derivative 3.
In order to construct 3 bearing the N,S-acetal skeleton, it was
first essential to develop an efficient route for the synthesis of
the starting dihydrobenzothiophene bearing a hydroxy group. In
our previous report, various dihydrobenzothiophenes were
prepared from phenol ethers bearing an alkyl sulfide sidechain
via intramolecular cyclization using PIFA–BF3·Et2O followed
by treatment with aq. MeNH2 without yielding any sulfoxides
(Scheme 3).7 Using this method, 6-benzyloxy-5-bromodihy-
drobenzothiophene 4 was synthesized effectively.
O
R
O
Br
N
HN
S
H
S
H
N
H
O
N
H
N
N
H
H
O
discorhabdin B
discorhabdin D (prianosin D) (R = H)
prianosin C (R = OH)
makaluvamine F 1 exhibits the most potent biological activity
[e.g. cytotoxicity towards the human colon tumor cell-line
HCT-116 (IC50 = 0.17 m ) and inhibition of topoisomerase
M
II]1,2 and has an a-aminodihydrobenzothiophene skeleton
which is a labile N,S-acetal structure present in all sulfur-
containing discorhabdins.3 Synthetic studies towards makalu-
vamines and discorhabdins have been carried out by several
groups.4 We have also reported the total synthesis of dis-
corhabdin C (Scheme 1)5 and a facile and efficient synthesis of
pyrroloiminoquinone derivatives 2 using the hypervalent iodi-
ne(III) reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA)
(Scheme 2).6 However, in most cases these efforts have been
Next, we attempted to introduce the azido group at the
2-position of 4. Subsequent to the first report by Böhme and
Morf,8 acyclic a-azido sulfides have generally been synthesized
stepwise, via halogenation followed by azidation of sulfides,9 or
via thioketals.10 On the other hand, a-azidation of dihy-
MeO
MeO
PIFA–BF3•Et2O
CH2Cl2
S
Bn
O
S
Bn
OH
(MeO)n
(MeO)n
Br
N
Br
Br
Br
aq. MeNH2
(i) silylation
N
O
MeO
(ii) PIFA, CF3CH2OH
N
N
S
N
N
H
H
(MeO)n
H
H
O
discorhabdin C
(96–98%)
Scheme 3
Scheme 1
Chem. Commun., 1999, 143–144
143

Br
PhI=O–Me3SiN3
N3
i
ii
MeCN, –40 to –25 °C
S
6
1
+
S
Rn
Rn
HO
S
NH3
R = OMe, OAc
(42–70%)
–
CF3CO2
3•CF3CO2H salt
Scheme 4
Scheme 6 Reagents and conditions: i, H2, 10% Pd-C, EtOH–TFA; ii, 2,
MeOH, room temp.
drobenzothiophenes has never been reported, probably due to
readily occurring side reactions such as aromatization, sulfoxide
formation, benzylic oxidation and a-oxidation of the sulfur
atom under oxidative conditions. We examined the known
stepwise methods to obtain a-azidodihydrobenzothiophene.
However, the aromatization occurred exclusively to give
benzothiophene derivatives in the initial halogenation step.
Very recently, we developed a novel and direct a-azidation of
dihydrobenzothiophenes using a combination of PhINO and
Me3SiN3 (Scheme 4).11 However, the azidation of 4 gave only
a trace amount of the expected a-azido compound. This is
because there appears to be a large number of reactive sites on
phenol ether 4 toward the hypervalent iodine-induced azidation.
Hence, we then performed the azidation after debenzylation
followed by acetylation of 4 to give the corresponding a-azido
compound 5 in 46% yield. After hydrolytic deprotection of the
6-acetoxy group, 2-azido-5-bromo-6-hydroxy-dihydrobenzo-
thiophene 6 was finally obtained. The route to 6 from
commercially available methyl (4-hydroxyphenyl)acetate is
outlined in Scheme 5.
to give the TFA salt of 1, whose spectral data were identical to
those previously reported1 (Scheme 6).
In conclusion, the first total synthesis of (±)–makaluvamine F
has been achieved via a facile construction of the labile N,S-
acetal skeleton by a combination of hypervalent iodine
oxidation reactions. Synthetic studies towards more compli-
cated sulfur-containing discorhabdins and their analogs are now
underway.
Notes and references
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Br
CO2Me
iv,v
i–iii
(64 %)
(71%)
BnO
HO
HO
Br
Br
viii,ix
vi–vii
(34%)
(66 %)
BnO
S
BnO
S
4
Bn
Br
Br
x
(46%)
AcO
S
RO
S
N3
5 R = Ac
6 R = H
xi
(90%)
Scheme 5 Reagents and conditions: i, Br2, AcOH; ii, BnBr, K2CO3, EtOH;
iii, LiAlH4, THF; iv, I2, PPh3, imidazole, PhMe; v, AcSBn, NaOH, MeOH;
vi, PIFA–BF3·OEt2; vii, aq. MeNH2; viii, BF3·OEt2, EtSH; ix, Ac2O,
NaOAc, aq. NaOH; x, PhINO–Me3SiN3, MeCN, 240 to 225 °C; xi, 5%
NaOH, MeOH.
Sequential attempts to transform the azido group to the amino
group by catalytic hydrogenation or other reductive methods
under non-acidic conditions proved unsatisfactory (i.e.
2-amino-5-bromo-6-hydroxydihydrobenzothiophene
3
was
found to be quite labile under basic conditions). Furthermore,
Wittig-type reactions between the phosphine imine prepared
from 6 and several quinones were also unsuccessful. Finally, we
found that the catalytic hydrogenation of 6 using 10% Pd-C in
the presence of 4 equiv. of TFA resulted in complete reduction
to give 3 as a TFA salt in quantitative yield without any side
reactions. The final coupling reaction in MeOH between both
synthetic precursors, 3 (TFA salt) and 2, proceeded in 86% yield
11 H. Tohma, M. Egi, M. Ohtsubo, H. Watanabe, S. Takizawa and Y. Kita,
Chem. Commun., 1998, 173.
Communication 8/08715F
144
Chem. Commun., 1999, 143–144