Synthesis of (±)-pyranonaphthoquinone derivatives, a Cdc25A phosphatase inhibitor

Article abstract of DOI:10.1016/j.tetlet.2003.11.120

The novel pyranonaphthoquinone 2, carrying Cdc25A phosphatase inhibitory activity, has been successfully synthesized through tricyclic compound 16, which was obtained from 15 by using the intramolecular Michael addition. The precursor 9 was derived from 5

Full text of DOI:10.1016/j.tetlet.2003.11.120

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 939–941
Synthesis of ( )-pyranonaphthoquinone derivatives, a Cdc25A
phosphatase inhibitor
Akiko Shimbashi, Yuichi Ishikawa and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 16 October 2003; revised 19 November 2003; accepted 21 November 2003
Abstract—The novel pyranonaphthoquinone 2, carrying Cdc25A phosphatase inhibitory activity, has been successfully synthesized
through tricyclic compound 16, which was obtained from 15 by using the intramolecular Michael addition. The precursor 9 was
derived from 5-bromoveratraldehyde.
Ó 2003 Elsevier Ltd. All rights reserved.
The four pyranonaphthoquinones 1–4, carrying Cdc25A
inhibitory activity, were isolated from Streptomyces sp.
O
O
OH
O
O
OH
6
by the Eli Lilly group in 1999.1 Their structural features
are that the benzoquinone moiety possessing amino
substituents is located at an edge of the tricyclic mole-
cule, instead of inside similar to those of nanaomycins,2
eleutherin,3 and frenolicins.4 Accordingly, synthetic
examples of such molecules have not been reported, to
our knowledge.5 In addition to activation of cell cycle
progression by dephosphorylation of threonine and
tyrosine, expression of Cdc25A is closely related to
oncogenic transformations in the presence of RAS or
RB deletion mutants. These biological activities would
contribute to development of new cancer–chemothera-
peutic agents. Against such background, we initiated a
synthetic investigation of the pyranonaphthoquinones
1–4. We describe herein synthesis of ( )-2, carrying
relatively simple substitutions, as an early stage of access
to a family of pyranonaphthoquinones (Fig. 1).
O
O
CO2H
CO2H
MeHN
MeHN
OH
1
10
1
2
O
CO2H
O
O
S
Me
N
26
O
H
CO2H
MeHN
3,4: isomers at the C-26 position
Figure 1. Structures of Cdc25A phosphatase inhibitors.
alkyl substituents from 9. The naphthalene 9 might be
obtained from 5-bromoveratraldehyde 5.
Our retrosynthetic analysis indicated that tricyclic
compound 16 might be a readily accessible precursor of
2 (Scheme 1). The pyran ring moiety of 16 might be
constructed by using the intramolecular Michael reac-
tion of a,b-unsaturated aldehyde derivatives of 15,
which was produced by stepwise homologation of
Along this line, the synthesis commenced with conver-
sion of 5 by a known procedure into benzaldehyde 6,6
which on Horner–Wadsworth–Emmons coupling with
7,7 followed by selective hydrolysis afforded 8 in 77%
yield from 6 (Scheme 2). Treatment of 8 with KOAc–
Ac2O effected the desired cyclization to give naphthalene
9 in 92% yield. Compound 9 was submitted to basic
conditions,8 and then reduction with LiAlH4 to give 10.
Regioselective bromination of 10 with PyrÆHBr3 (80%
yield from 9),9 followed by oxidation and methylation
provided aldehyde 11 in 87% yield. Reaction of 11 with
dimethylsulfonium methylide10 gave epoxide 12 in
excellent yield. After isomerization of 12 under ZnBr2/
Keywords: Cell cycle progression; Cdc25A phophatase inhibitor; Pyr-
anonaphthoquinone; Intramolecular Michael reaction.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.120

940
A. Shimbashi et al. / Tetrahedron Letters 45 (2004) 939–941
O
O
OMe
O
O
OH
O
O
CO2Me
CO2H
MeO
MeHN
16
2
CHO
OBn OAc
OBn OMe OH
MeO
Br
MeO
CO2Et
MeO
OH
OMe
OMe
OMe
5
9
15
Scheme 1. Retrosynthetic analysis of 2.
CHO
OBn
OBn
CO2H
CO2Et
ref. 6
t
a, b
CO2 Bu
CO2Et
(EtO)2P(O)
MeO
Br
MeO
CHO
MeO
7
OMe
OMe
OMe
5
6
8
OBn OAc
OBn OH
OBn OMe
Br
c
d, e
i
f - h
OH
MeO
CO2Et
MeO
MeO
CHO
OMe
OMe
OMe
11
9
10
OBn OMe
OBn OMe
OBn OMe
Br
Br
O
Br
j, k
l, m
CO2Et
MeO
OTBDMS
MeO
MeO
OMe
OMe
OMe
14
12
13
OBn OMe OH
O
OMe
t - v
n, o
p - s
O
2
CO2Me
MeO
OH
MeO
OMe
O
15
16
Scheme 2. Reagents and conditions: (a) 7, NaH, THF, rt; (b) TFA, H2O, rt, 77% in two steps; (c) Ac2O, KOAc, reflux, 92%; (d) K2CO3, EtOH, rt; (e)
LiAlH4, THF, rt; (f) PyrÆHBr3, THF, 0 °C, 80% in three steps; (g) SO3ÆPyr, TEA, DMSO, CH2Cl2, rt, 93%; (h) MeI, K2CO3, DMF, rt, 94%; (i)
Me3SI, NaH, DMSO, THF, 0 °C, 92%; (j) ZnBr2, PhH, reflux; (k) (EtO)2P(O)CH2CO2Et, NaH, THF, )78 °C, 85% in two steps; (l) DIBAL, THF,
)78 °C, 93%; (m) TBDMSCl, imid., DMF, rt, 96%; (n) n-valeraldehyde, n-BuLi, THF, )78 °C; (o) TBAF, THF, 0 °C, 80% in two steps; (p) DDQ,
t-BuOH, H2O, CH2Cl2, rt; (q) MnO2, CH2Cl2, 40 °C; (r) PDC, DMF, rt; (s) TMSCHN2, MeOH, rt, 31% from 15; (t) BBr3, CH2Cl2, )78 to 0 °C,
41%; (u) MeNH2, THF, rt, 87%; (v) KOH, H2O, MeOH, 0 °C to rt, quant.
PhH conditions,11 the resultant aldehyde was subjected
to the Horner–Wadsworth–Emmons olefination to fur-
nish the a,b-unsaturated ester 13 in 85% yield. Com-
pound 13 was reacted with DIBAL, followed by
protection of an allyl alcohol to afford silyl ether 14 in
89% yield. Bromine–lithium exchange reaction of 14,
followed by rapid quenching with n-valeraldehyde12 and
deprotection of the silyl group, provided benzyl alcohol
15 in 80% overall yield. Upon stepwise treatment of 15
with DDQ and then MnO2, the resultant a,b-unsatu-
rated aldehyde was unexpectedly converted into a cyclic
aldehyde, which was immediately treated with PDC in
DMF, followed TMSCHN2 without purification, due to
its instability, leading to 16 in 31% yield from 15.13 After
treatment of 16 under acidic conditions to remove the
methyl group at the C-6 position (41%),14 exposure to
15
MeNH2 in THF underwent successful introduction of
a N-methyl group (87%), followed by hydrolysis with
KOH in MeOH quantitatively to give the pyranonaph-
thoquinone 2, contaminated by the corresponding trans-

A. Shimbashi et al. / Tetrahedron Letters 45 (2004) 939–941
941
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Scheme 3. Reagents and conditions: (a) Ac2O, Pyr, CH2Cl2, rt, 85%;
(b) DDQ, t-BuOH, H2O–CH2Cl2, 0 °C, 78%; (c) BBr3, CH2Cl2,
)78 °C, 34%; (d) MeNH2, THF, 0 °C, 99%; (e) K2CO3, MeOH, rt,
86%; (f) MnO2, CH2Cl2, 40 °C, 86%; (g) PDC, DMF, rt, 22%.
8. The combined yield in two steps (K2CO3/EtOH, then
LiAlH4/THF) was better than a one-step procedure only
using LiAlH4.
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n-valeraldehyde was rapidly added at low temperature.
13. An inseparable mixture of cis- and trans-isomers of alkyl
substituents in the benzopyran moiety was formed in a
ratio of ca. 1.6:1.
14. A ratio of the cis- and trans-isomers was changed to 1:1.5.
Under BBr3 conditions, two alkyl substituents of the
dihydropyran moiety adopt thermodynamically more
favorable trans-form than the corresponding cis-form.
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isomer of substituents in the benzopyran moiety
(cis:trans ¼ 4/1).16 To circumvent such undesired iso-
merization, compound 15 was acetylated, followed by
oxidation to give p-quinone 17 in 66% yield (Scheme 3).
Compound 17 was successively treated with BBr3, and
then a methylamino group was introduced in 33% yield
from 17. The following basic treatment provided 18
(86%), which on oxidation in two steps gave 2 in 19%
yield,17 spectroscopic data of which was superimposable
to those of the reported data.1
In conclusion, we have accomplished a total synthesis of
using intramolecular
( )-pyranonaphthoquinone
2
Michael addition for construction of the pyran ring
system. This synthetic route would be used for synthesis
of optically active derivatives and other pyranonaph-
thoquinones such as chloroquinocin.18
Acknowledgements
This work was supported by Grant-in-Aid for the 21st
Century COE program ꢀKEIO Life Conjugate Chemis-
tryꢁ, as well as Scientific Research C from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan.
15. Tao, X. L.; Cheng, J.-F.; Nishiyama, S.; Yamamura, S.
Tetrahedron 1994, 50, 2017–2028.
16. A 1:3 ratio of the cis- and trans-isomers after treatment
with MeNH2, changed to ca. 4:1 by KOH, which might
induce an isomerization through successive b-elimination
and Michael addition reactions.
References and notes
17. No contamination with the trans-isomer was monitored by
ODS-W TLC (0.5% aq NH4OAc–MeCN ¼ 3/2).
18. He, H.; Yang, H. Y.; Luckman, S. W.; Roll, D. M.;
Carter, G. T. J. Antibiot. 2002, 55, 1072–1075.
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