Synthetic studies on jadomycins: synthesis of dimethyljadomycin A

Article abstract of DOI:10.1016/j.tetlet.2010.01.014

Dimethyljadomycin A was synthesized as the first example for the construction of 8H-benzo[b]oxazolo[3,2-f]phenanthridine skeleton.

Full text of DOI:10.1016/j.tetlet.2010.01.014

Tetrahedron Letters 51 (2010) 1338–1340
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies on jadomycins: synthesis of dimethyljadomycin A
Yuhsuke Akagi, Shin-ichiro Yamada, Natsuno Etomi, Takuya Kumamoto, Waka Nakanishi,
*
Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Dimethyljadomycin A was synthesized as the first example for the construction of 8H-benzo[b]oxazolo[3,2-
f]phenanthridine skeleton.
Received 8 December 2009
Revised 24 December 2009
Accepted 7 January 2010
Available online 11 January 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Jadomycins
Antibiotics
Arylation
Tetralone
Isoleucine
Jadomycins A (1) and B (2) are unique 8H-benzo[b]-oxazolo[3,2-
f]phenanthridine polyketide antibiotics containing isoleucine unit
in the oxazolidinone ring, isolated from Streptomyces venezuelae1
In this Letter we report the synthesis of dimethyljadomycin A (4)
as the first example for the construction of 8H-benzo[b]oxazol-
o[3,2-f]phenanthridine skeleton.
10
11
12
OR2
O
O
9
O
H
R1O
7
O
8
HO
OH
13
O
6
5
O
O
H Me 4'
1'
3a
N
O
Me
N
4
Me
1
MeO
O
Me
3'
2
2'
3
O
MeO
O
jadomycin A (1: R1 = R2 = H)
jadomycin B (2: R1 = H; R2 = digitoxose)
dimethyljadomycin A ( 4: R1 = R2 = Me)
phenanthroviridin aglycon ( 3)
arnottin II (5)
together with phenanthroviridin aglycon (3). Biogenetically, jad-
omycins and gilvocarcins come from the related precursors,
UWM6 for jadomycins and MM2002 for gilvocarcins.2 It was re-
ported that jadomycin B (2) and the biosynthetic analogs with dif-
ferent amino acid units from isoleucine show cytotoxic activity
against several cell lines;1e,g,h however, the jadomycin skeleton
with five ring systems has never been synthesized until now. We
have synthesized the related polyketide kinamycin antibiotics.3
Although fully aromatized phenanthroviridin aglycon (3) had
been prepared by three groups,4 these approaches look hard to
be simply expanded to the synthesis of jadomycin skeleton. We re-
cently achieved the enantioselective synthesis of (ꢀ)-arnottin II (5)
with the
a-spirodehydrotetralone system by palladium-catalyzed
a
-arylation of 1-tetralone.5 Thus, a synthetic route for the jadomy-
cin skeleton using an -spirolactonyltetralone (see, 9 in Scheme 1)
a
as a key synthetic intermediate was designed.
o-Bromobenzoate 6 as an aryl unit for palladium-catalyzed cou-
pling reaction with tetralone 7 was prepared from 3,5-dimethylan-
* Corresponding author. Tel./fax: +81 43 290 2910.
E-mail address: benti@p.chiba-u.ac.jp (T. Ishikawa).
isole through
a
known 2-bromo-3-methoxy-5-methylbenz
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.01.014

Y. Akagi et al. / Tetrahedron Letters 51 (2010) 1338–1340
1339
OMe
OMe
OMe
Pd2(dba)3, xantphos
MeO
Br
K3PO4, Na2S2O5
o-xylene
130 °C, 5 h
Me
CO2Me
O
Me
O
(56%)
O
6
7
8
OsO4 / NMO
acetone / CH2Cl2 / H2O
rt, 7 d
(95%)
1) NBS, AIBN, benzene
2) THF/H2O
3) IBX, DMSO
O
O
MeO
MeO
OMe
OMe
O
(59% in 3 steps)
O
O
Me
Me
O
O
9
10
Scheme 1.
aldehyde6 by successive reactions of benzylic bromination, the
Sommelet reaction,7 regioselective aromatic bromination, the
Pinnick oxidation, and methylation. Coupling reaction between 6
with 5-methoxy-1-tetralone (7) under the reported conditions5
afforded an expected enol-lactone 8 in 56% yield, which was easily
oxidized with a catalytic amount of osmium tetroxide in the
presence of N-methylmorpholine N-oxide to give a key intermedi-
a chromatographically separable mixture of diastereomers 13a
(½a 1D7
ꢁ
+37) and 13b (½a 1D8
ꢀ156) in 41% and 23% yields, respectively,
ꢁ
the structures of which were determined by application of 2D NMR
experiments. These isomers show quite similar signal patterns in
NMR spectra, except the chemical shifts of 60-methoxy substituent
on the phenyl pendant and the isoleucine unit in the 1H NMR spectra
(see, Supplementary data). Slow partial isomerization of the major
isomer 13a to the minor 13b was observed in the 1H NMR measure-
ment, in which ca. 2:1 equilibrium mixture was obtained when 13a
was kept to stand in deuteriochloroform for 10 days. This phenom-
enon strongly suggests that these diastereomeric isomers were due
to the restriction of rotation of the naphthoquinone–aryl bond. Tri-
als for the structural assignment of these diastereomers were unsuc-
cessful because of decomposition during purification.
ate a-spirolactonyltetralone 9 in 95% yield. Although direct intro-
duction of an oxygen function to the benzylic position of the
tetralone unit using conventional reagents such as 2,3-dichloro-
5,6-dicyanobenzoquinone, chromium(VI) oxide, pyridinium dichro-
mate, potassium permanganate, and ceric ammonium nitrate
failed, conversion to a masked naphthoquinone system 10 was
accomplished by stepwise reactions of bromination with N-bromo-
succinimide, displacement with hydroxyl group, and oxidation
with o-iodoxybenzoic acid (IBX) (Scheme 1).
Treatment of 10 with methylamine followed by thermal dehy-
dration reaction of 2-(aminonaphthoquinonyl)benzoic acid 11 gave
the phenanthroviridin skeleton 12 in good yield. On the other hand,
in the use of methyl isoleucinate as a nitrogen source the second
cyclization step of 13–14 failed even in reactions using dehydration
reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyl-
uronium hexafluorophosphate (Scheme 2). The naphthoquinone
carrying isoleucine unit obtained in the first step was produced as
Sniekus et al.4c reported a smooth isoquinoline construction in
the synthesis of phenanthroviridin aglycon (3) by oxidative cycli-
zation of 2-amino-3-(2-hydroxymethyl-phenyl)-1,4-dihydroxy-
naphthalene derivative. Thus, the carboxyl function in 13 was
reduced to an alcoholic one. Treatment of each isomer 13a and
13b with borane-tetrahydrofuran complex solution followed by
hydrolysis with lithium hydroxide gave the corresponding naph-
thoquinone derivatives 16a (½a D23
ꢁ
+186) and 16b (½a D23
ꢀ279) carry-
ꢁ
ing both o-hydroxymethylphenyl and amino acid functionalities,
which could be expected to simultaneously construct an oxazolid-
40% MeNH2 aq
MeOH
60 °C, 1 h
O
O
Δ, PhH
MeO
OMe
OMe
MeO
O
Me
O
(64% in 2 steps)
N
NHMe
CO2H
Me
Me
O
12
11
10
O
O
OMe
HO
OH
Me
MeO
O
H
O
methyl isoleucinate
Et3N
MeOH / H2O
60 °C, 2 d
H
Me
Me
N
HN
COOH
Me
Me
O
Me
CO2H
CO2Me
diastereomer A 13a: 41%
diastereomer B 13b: 23%
14
Scheme 2.

1340
Y. Akagi et al. / Tetrahedron Letters 51 (2010) 1338–1340
13a or 13b
0 °C, 15 h
BH3-THF
O
O
LiOH
THF / H2O
O
H
OMe
OMe
MeO
MeO
MeO
OMe
MnO2
O
O
O
CH2Cl2
rt, 40 h
H
Me
Me
0 °C, 1 d
H
Me
HN
CO2Me
15a (24%) ; 15b (36%)
HN
H Me
3a
O
N
Me
Me
Me
1
OH
Me
CO2H
OH
Me
O
16a (67%) ; 16b (83%)
4
48% on 16a ; 61% on 16b
Scheme 3.
inylisoquinoline ring leading to an 8H-benzo[b]oxazolo[3,2-f]phe-
nanthridine skeleton, albeit in unsatisfactory yield at the first
reduction step.8 Independent treatment of 16a and 16b with man-
ganese oxide, as expected, afforded the same single product in the
NMR spectra, in spite of the possible construction of diastereoiso-
mers at the stereogenic benzylic acetal position (C3a) (Scheme 3).
The spectral data indicated that the product was an expected
dimethyljadomycin A (4) and that absolute configuration at the 3a
position was deduced to be S due to positive NOE enhancement be-
tween the 3a-H and the 1-H. Jadomycin A (1) was firstly isolated
with 1–5% impurity1a and then identified to be a 10:1 diastereo-
meric mixture of 3aS and 3aR isomers.1f On the other hand, it was re-
ported that jadomycin B (2) was determined to be a 67:33
diastereomeric mixture containing a major 3aS isomer.1d Preferen-
tial formation of the 3aS isomers in both natural jadomycin A (1)
and synthetic dimethyljadomycin A (4) indicated that they are ther-
modynamically stable isomers. Unfortunately demethylation with
boron tribromide4c afforded an inseparable mixture of a desired
jadomycin A (1) and 11-bromojadomycin A albeit using HPLC.9 Tri-
als with borontrichlorideand lithium iodide-2,6-lutidine resulted in
no reaction and the formation of complex mixture, respectively.
In conclusion, dimethyljadomycin A (4) was synthesized through
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.014.
References and notes
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adomycin A (4) has made us examine a more general synthetic
approach to jadomycin A (1) itself and the related compounds with
a variety of amino acid residue by the use of more readily cleavable
phenol protecting groups for structure–activity relationship exper-
iments of bioactive jadomycins.
Acknowledgments
8. Trials for other conditions such as hydride reduction after conversion to acid
halide resulted in the decomposition of starting material.
9. The ratio of 1 and its brominated product is estimated to be ca. 3:2 by 1H
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (20590002) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
NMR spectrum. Formation of
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a brominated product under the similar