Synthesis of chloroquinocin, a pyranonaphthoquinone antibiotic against Gram-positive bacteria

Article abstract of DOI:10.1016/j.tetlet.2007.01.020

Chloroquinocin 1 is an antimicrobial agent against Gram-positive bacteria, including MRSA (methicillin-resistant Staphylococcus aureus). A successful synthesis of 1 was attained through a unique chlorination of the corresponding naphthoquinone derivative 12 as a key step.

Full text of DOI:10.1016/j.tetlet.2007.01.020

Tetrahedron Letters 48 (2007) 1545–1548
Synthesis of chloroquinocin, a pyranonaphthoquinone
antibiotic against Gram-positive bacteria
Akiko Shimbashi and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
Received 18 November 2006; revised 24 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—Chloroquinocin 1 is an antimicrobial agent against Gram-positive bacteria, including MRSA (methicillin-resistant Staph-
ylococcus aureus). A successful synthesis of 1 was attained through a unique chlorination of the corresponding naphthoquinone
derivative 12 as a key step.
Ó 2007 Elsevier Ltd. All rights reserved.
Chloroquinocin 1, isolated from the culture broth of
Streptomyces sp. LL-A9227,1 shows a moderate inhibi-
tory activity against Gram-positive bacteria, including
MRSA2 (MIC = 16 lg/ml), which is one of the most
critical drug-resistant pathogens causing global infec-
tious diseases over the past decades.3 Although studies
on antibiotics against Gram-positive bacterial patho-
gens4 have been continued to overcome serious medical
concerns, the development of ultimate chemotherapeutic
agents effective against resistant-mechanisms remains
unreported up to now. From among the extensive efforts
to acquire highly potent agents, the inhibitory potential
of 1 against Gram-positive bacteria would make it an
interesting and significant lead for this purpose. In addi-
tion to a chlorine substituent, 1 has a novel pyranonaph-
thoquinone framework: a p-quinone moiety is settled at
the edge of the molecule. Our recent synthesis of this
class of natural products5 promoted us to include a
synthesis of 1, which would necessitate chlorine-intro-
duction and a careful construction of the chloro-enol
residue. We disclose herein our synthetic investigation
of 1.
We planned to take advantage of naphthalene derivative
5, which is used as a synthetic intermediate of pyrano-
naphthoquinone derivative 2,5 to elaborate the critical
chlorination step in the synthetic pathway (Scheme 1).
The pyran ring of chloroquinocin 1 might be con-
structed by using the Pd-induced cyclization reaction
of chlorinated naphthoquinone 3. The chlorine atom
at the quinone part of 3 might be induced by a chlorina-
tion reaction of a quinone, which was produced by the
oxidation of naphthalene 4. The precursor for 4 might
be obtained from aldehyde 5.
The synthetic route of 4 is outlined in Scheme 2.
Aldehyde
5
was synthesized from the known
aldehyde 6.5 The addition of trimethylsilylacetylene to
aldehyde 5 gave benzyl alcohol 7. Deoxygenation,
followed by silyl-deprotection and isomerization
through 8 and 9, afforded alkyne 10. Naphthalene 4
was produced by using the bromine–lithium exchange
of alkyne 10, followed by rapid quenching with
propionaldehyde.
Naphthoquinone 12 was obtained through the oxidation
of 4 to a quinone and TIPS-protection (Scheme 3). After
treatment with NCS/MeOH,6 the resulting acetal 13 was
exposed to the basic conditions to afford the chlorinated
naphthoquinone 3.
Keywords: Chloroquinocin; Methicillin-resistant Staphylococcus aur-
eus; Antibiotic; Gram-positive bacteria; Pyranonaphthoquinone;
Chlorination.
This chlorination steps7 might commence with the
nucleophilic reaction, owing to the electron-donating
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail:
nisiyama@chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.020

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A. Shimbashi, S. Nishiyama / Tetrahedron Letters 48 (2007) 1545–1548
O
OH
O
O
OH
Cl
O
O
HO
CO2H
MeHN
O
chloroquinocin (1)
2
OBn OMe
OBn OMe OH
O
O
OMe OTIPS
Br
Cl
MeO
CHO
MeO
MeO
OMe
OMe
Me
Me
3
4
5
Scheme 1. Structure and retrosynthetic analysis of chloroquinocin 1.
OBn OMe
OBn OMe
OBn
Br
Br
ref. 5
TMS
b
a
MeO
MeO
CHO
MeO
CHO
OMe
OH
OMe
OMe
7
5
6
OBn OMe
OBn OMe
OBn OMe
Br
Br
Br
c
d
TMS
TMS
MeO
MeO
MeO
OMe
Cl
OMe
OMe
Me
8
10
9
OBn OMe OH
e
MeO
OMe
Me
4
Scheme 2. Reagents and conditions: (a) trimethylsilylacetylene, n-BuLi, THF, À78 °C to rt, 96%; (b) MsCl, Et3N, CH2Cl2, rt, 82%; (c) LiEt3BH,
THF, rt, 92%; (d) TBAF, THF, rt, 77%; (e) propionaldehyde, n-BuLi, THF, À78 °C, 78%.
O
O
OMe OTIPS
OBn OMe OH
O
O
OMe OH
a
b
MeO
MeO
MeO
Me
OMe
Me
Me
12
11
4
O
OMe OTIPS
O
OMe OTIPS
Cl
Cl
c
d
MeO
MeO
MeO
O
Me
O
Me
13
3
Scheme 3. Reagents and conditions: (a) DDQ, 1,4-dioxane, H2O, rt, 71%; (b) TIPSOTf, 2,6-lutidine, CH2Cl2, rt, 88%; (c) NCS, MeOH, rt; (d) DBU,
CH2Cl2, 0 °C, 67% in two steps.

A. Shimbashi, S. Nishiyama / Tetrahedron Letters 48 (2007) 1545–1548
1547
O
OMe OTIPS
O
OH OH
Cl
Cl
b
a
MeO
MeO
O
O
Me
O
Me
14
3
OH
O
O
OH
Cl
d
Cl
c
O
1
O
MeO
MeHN
O
15
16
Scheme 4. Reagents and conditions: (a) BBr3, CH2Cl2, À78 °C, 26%; (b) PdCl2(MeCN)2, CH2Cl2, 92%; (c) MeNH2, THF, rt, 64%; (d) HCl, MeOH,
55 °C, 75%.
effect of the methoxy substituent of the quinone
part, followed by the attack of the solvent MeOH
to the oxonium ion, leading to 13. Fortun-
ately, this peculiar compound was a potential pre-
cursor of the desired chlorinated naphthoquinone
3. Upon reacted with DBU, the elimination of
one methoxy group smoothly proceeded to give
the desired 3.
Memorial Fund for the Advancement of Education
and Research.
References and notes
1. He, H.; Yang, H. Y.; Luckman, S. W.; Roll, D. M.; Carter,
G. T. J. Antibiot. 2002, 55, 1072–1075.
2. (a) Inoue, M.; Hashimoto, H.; Matsui, H.; Sakurai, N.;
Ohkubo, T. Chemotherapy 1989, 37, 869–876; (b) Blum-
berg, H. M.; Rimland, P.; Carroll, D. J.; Terry, P.;
Wachsmuth, I. K. J. Infect. Dis. 1991, 163, 1279–1285; (c)
Neu, H. C. Science 1992, 257, 1064–1073; (d) Brumfitt, W.;
Hamilton-Miller, J. N. Eng. J. Med. 1989, 320, 1188–
1196.
3. (a) Service, R. F. Science 1995, 270, 724–727; (b) Bax, R. P.;
Anderson, R.; Crew, J.; Fletcher, P.; Johnson, T.; Kaplan,
E.; Knaus, B.; Kristinsson, K.; Malek, M.; Strandberg, L.
Nature Med. 1998, 4, 545–546.
4. (a) Swartz, M. N. Proc. Natl. Acad. Sci. USA 1994, 91,
2420–2427; (b) Tomasz, A. N. Engl. J. Med. 1994, 330,
1247–1251.
5. (a) Shimbashi, A.; Ishikawa, Y.; Nishiyama, S. Tetrahedron
Lett. 2004, 45, 939–941; (b) Shimbashi, A.; Tsuchiya, A.;
Imoto, M.; Nishiyama, S. Bull. Chem. Soc. Jpn. 2004, 77,
1925–1930.
The final conversion of the chlorinated naphthoqui-
none 3 into chloroquinocin 1 was shown in Scheme
4. After simultaneous deprotection of the methoxy
and siloxy functions of 3, quinone 14 was reacted
with PdCl2(MeCN)2/CH2Cl2 to construct the pyran
ring. To deprotect the methoxy group at the C-2
position, pyranonaphthoquinone 15 was exposed to
MeNH2 and the following acidic conditions to afford
chloroquinocin 1.8 The spectroscopic data of syn-
thetic 1 was superimposable to that of the reported
data.1
In summary, the first synthesis of chloroquinocin 1 was
accomplished from the same intermediate 5 as that of
pyranonaphthoquinone derivative 2. The synthetic
approach to this unique pyranonaphthoquinone and
the distinctive chlorination mechanism will open up
the possibility to synthesize new leads for new chemo-
therapeutic agents.
6. Milanowski, D. J.; Gustafson, K. R.; Kelly, J. A.; McMa-
hon, J. B. J. Nat. Prod. 2004, 67, 70–73.
7. In the synthesis of 1, this chlorination reaction was the
crucial step for the construction of a chlorinated naphtho-
quinone. We have attempted the following approaches, in
addition to the process (13–3). When naphthalene deriva-
tive I, synthesized from intermediate 5, was used as a
precursor of chlorination, the desired chlorinated naphtha-
lene II was not obtained, but a complicated mixture
including the oxidized product III (Scheme 5). Moreover,
in the case of pyranonaphthoquinone IV, a chlorine atom
was induced the benzylic position to give the undesired
compound VI. Therefore, it was concluded that the
naphthoquinone as a precursor and NCS/MeOH condi-
tions were essential factors to build the chlorinated naph-
thoquinone framework.
Acknowledgements
The authors thank Haiyin He (Wyeth Research) for
the spectral data of chloroquinocin. This work was
supported by Grant-in-Aid for the 21st Century COE
program ‘Keio Life Conjugated Chemistry’, as
well as Scientific Research C from the Ministry of
Education, Culture, Sports, Science and Technology,
Japan. A.S. was financially supported by the same
program, as well as the Keio Gijuku Koizumi
8. 1H NMR spectral data of chloroquinocin: dH (400 MHz,
DMSO-d6) 0.90 (t, 3H, J = 7.2 Hz), 1.42–1.47 (complex,
2H), 1.91 (complex, 2H), 5.53 (dd, 1H, J = 2.9, 9.2 Hz),
5.85 (s, 1H), 7.22 (s, 1H), and 12.67 (s, 1H).

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A. Shimbashi, S. Nishiyama / Tetrahedron Letters 48 (2007) 1545–1548
OBn OMe
OBn OMe
OBn OMe
Br
Cl
Br
Br
NCS or SO2Cl2
O
O
O
a - e
O
O
MeO
MeO
MeO
CHO
OMe
OMe
OMe
5
I
II
O
OMe
Br
Cl
f - h
MeO
O
O
OMe
O
O
OMe
III
Cl
NCS or SO2Cl2
O
O
MeO
MeO
O
O
IV
V
OMe
O
MeO
O
Cl
VI
Scheme 5. Reagents and conditions: (a) Me3SI, DMSO, NaH, THF, 0 °C, 93%; (b) ZnBr2, PhH, reflux; (c) MeMgBr, THF, À20 °C to 0 °C; (d) IBX,
DMSO, THF, rt, 63% in three steps; (e) ethylene glycol, p-TsOHÆH2O, PhH, reflux, 77%; (f) propionaldehyde, n-BuLi, THF, À78 °C; (g) p-
TsOHÆH2O, PhH, rt; (h) DDQ, 1,4-dioxane, H2O, rt, 31% in three steps.