Total synthesis of 1-hydroxydehydroherbarin and ascomycones A, B, naphthoquinone antibiotics

Article abstract of DOI:10.1590/S0103-50532012000200013

The first total synthesis of 1-hydroxydehydroherbarin and ascomycones A and B is reported. The biologically interesting ascomycones A and B were obtained in 18percent overall yield starting from 3-chloro-2,5-dimethoxybenzaldehyde as building block.

Full text of DOI:10.1590/S0103-50532012000200013

J. Braz. Chem. Soc., Vol. 23, No. 2, 280-284, 2012.
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Article
A
Total Synthesis of 1-Hydroxydehydroherbarin and Ascomycones A, B,
Naphthoquinone Antibiotics
Wen-Kai Dong,a Xiong Huang,a Dong-Cheng Xu,*,a Xin-Sheng Lia and Jian-Wu Xie*,a
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials,
Department of Chemistry and Life Science, Zhejiang Normal University, 321004, Jinhua, P. R. of China
A primeira síntese total de 1-hidróxi-desidroherbarina e ascomyconas A e B é relatada. As
ascomyconas A e B biologicamente interessantes foram obtidas com rendimento total de 18% a
partir de 3-cloro-2,5-dimetoxibenzaldeído como bloco de construção.
The first total synthesis of 1-hydroxydehydroherbarin and ascomycones A and B is reported.
The biologically interesting ascomycones A and B were obtained in 18% overall yield starting
from 3-chloro-2,5-dimethoxybenzaldehyde as building block.
Keywords: pyranonaphthoquinone, 1-hydroxydehydroherbarin, ascomyconesA, B, antibiotics,
total synthesis
Introduction
Results and Discussion
The ascomycones A and B (1 and 2), two novel
heptaketide-derived secondary metabolites, were
isolated by Opatz et al.1 in 2008 from cultures of an
unknown ascomycete. They exhibited antimicrobial
and cytotoxic activities. In addition, ascomycone B
(2) is an antifungal compound. On the other hand,
1-hydroxydehydroherbarin (3) was isolated by Gunatilaka
and co-workers in 2007.2 To the best of our knowledge,
there is no report for the total synthesis of ascomycones
A and B, and it is worthwhile to perform their syntheses.3
Moreover, pyranonaphthoquinone antibiotics 4 and 54
have pronounced biological properties, such as inhibitor
of HRV-3C protease, that was discovered by chemists at
Merck upon screening the fermentation broths of the fungus
Thysanophora penicilloides. The interesting biological
activity of 4 and 5 has aroused considerable interest among
the synthetic community, and many research groups have
reported their total synthesis.5
The plan for our synthesis of the pyranonaphthoquinones
is shown in Scheme 1. We envisioned that the natural
products possessed an acetal or hemiacetal ring, as such a
few functional group modifications lead retrosynthetically
to the naphthoquinone 6. This activated intermediate is
readily transformed to the naphthoquinone skeleton 7. A
cycloaddition of Brassard’s diene with the 2-chloro-1,4-
benzoquinone 8 was designed to provide 7.
The synthesis was initiated with these ideas in mind
(Scheme 2). To test the feasibility of our strategy, we first
prepared naphthoquinone 7 through a Diels-Alder reaction
of 2-chloro-1,4-benzoquinone 8a with 9 (Scheme 2).6-10
Unfortunately, the use of ethylene glycol as protecting
group on the compound 8a resulted in a mixture of
naphthoquinone 7a and 7c6 in the Diels-Alder reaction
(Scheme 2). On the basis of the experimental observations,
a possible mechanism was proposed to explain the
formation of compound 7c from 8a and 9 (Scheme 3).
Firstly, compound 8a was hydrolyzed slowly to afford
aldehyde I. Then the intermediate II was formed by Diels-
Alder reaction of I with 9 and the intermediate IV was
formed through oxidation, hydrolysis and decarboxylation
of III. Finally, compound 7c was obtained by aromatization.
We then found that yield and chemoselectivity
could be greatly improved by employing 2-chloro-1,4-
Hereinwepresentthefirsttotalsynthesisofascomycones
A and B (1 and 2), as well as the first total synthesis
1-hydroxydehydroherbarin (3).
*e-mail: xiejw@zjnu.cn, xu1127@yahoo.com

Vol. 23, No. 2, 2012
Dong et al.
281
OH
O
OH
OH
O
O
O
O
O
O
OH
O
O
O
O
O
O
O
1 ascomycone A
2 ascomycone B
3 1-hydroxydehydroherbarin
OH
O
OH
O
O
OH
O
O
HO
O
O
O
4 astropaquinone C
Figure 1. Structures of ascomycones A, B and 1-hydroxydehydroherbarin.
5 (-)-thysanone
R1
O
R2
O
O
O
OH
O
O
O
n
n
O
O
O
O
O
O
O
O
O
7a n = 1
7b n = 2
6a n = 1
6b n = 2
1 ascomycone A:
R1 = OH, R2 = OCH3;
2 ascomycone B:
R1 = OH, R2 = OH;
3 1-hydroxydehydroherbarin:
R1 = OCH3, R2 = OH
O
O
O
O
O
n
OTMS
O
Cl
Cl
O
O
+
O
9
8a n = 1
8b n = 2
10
Scheme 1. Retrosynthetic analysis of ascomycones A, B and 1-hydroxydehydroherbarin.
O
O
OH
O
OTMS
O
OH
O
O
1) THF, −30 oC, 30 min
then rt 2 h
Cl
Cl
O
O
+
+
2) silca gel, CH2Cl2, 14 h
O
O
O
O
O
O
8a
9
7c (28%)
7a (26%)
Scheme 2. Diels-Alder reaction of 8a with 9.
benzoquinone 8b which was protected with propanediol,
as a dienophile. The procedure for our synthesis of
the naphthoquinone skeleton 7b is shown in Scheme
4. The compound 2-(3-chloro-2,5-dimethoxyphenyl)-
1,3-dioxane 11 was accessed in 92% yield from
known aldehyde 10,11 by acetalization under Dean
Stark conditions. Several reports on the oxidation of
2-(3-chloro-2,5-dimethoxyphenyl)-1,3-dioxane (11)
toward 2-chloro-6-(1,3-dioxan-2-yl)cyclohexa-2,5-diene-
1,4-dione (8b) with silver(II) dipicolinate, silver(I) oxide,
cobalt(III) fluoride, and cerium(IV) ammonium nitrate
(CAN) as oxidants are known in the literature.13-15 Using
CAN the reaction time was minimized to 3 min in order
to reduce acetal hydrolysis to obtain 2-chloro-6-(1,3-
dioxan-2-yl)cyclohexa-2,5-diene-1,4-dione 8b in 78%
yield (Scheme 4).12 Then 7b was obtained in 62% yield

282
Total Synthesis of 1-Hydroxydehydroherbarin and Ascomycones A, B, Naphthoquinone Antibiotics
J. Braz. Chem. Soc.
O
O
O
O
O
O
OTMS
O
Cl
Cl
Cl
O
Hydrolysis
O
9
O
O
O
8a
I
II
]
air, [O
HO
O
O
O
O
O
O
OTMS
Cl
Cl
aromatization
Hydrolysis
-CO2
7c
O
O
O
III
IV
Scheme 3. Possible mechanism for the formation of compound 7c from 8a and 9.
O
O
O
O
O
HOCH2CH2CH2OH
Cl
CHO
CAN, rt, 3 min
Cl
p-TsOH.H2O
CH3CN/H2O 1:1
toluene, reflux, 4 h
O
10
11 (92%)
1) 9, THF, −30 oC,
30 min, then rt, 1 h
OH
O
O
O
O
O
Cl
O
2) silica gel, CH2Cl2, 14 h
O
O
O
8b (78%)
Scheme 4. Preparation of 2-(1,3-dioxan-2-yl)-8-hydroxy-6-methoxynaphthalene-1,4-dione 7b.
7b (62%)
by the regioselective cycloaddition of 8b with 9, without
isolating the intermediate 7c.
yield (Scheme 4). Then the most active antifungal compound
ascomycone B (2) was obtained in 83% yield when 3 was
treated with excess boron tribromide in dichloromethane
at -78 °C to give selective O-demethylation at the peri-
position.17 In addtion, ascomycone A (1) was cleanly
obtained when ascomycone B was stirred in methanol. Our
synthetic ascomycones B and 1-hydroxydehydroherbarin
display 1H and 13C NMR, IR, and MS spectra identical to
those reported for the natural samples.
To avoid the formation of the anthraquinone side
product,16 the 8-hydroxyl group of compound 7b was
protected by O-methylation using iodomethane and silver(I)
oxide (Scheme 5). Reaction of 12 with acetonylpyridinium
chloride (13) and 1.2 equiv. of triethylamine gave the
6b as the sole product in a yield of 85%.16,17 Thus, upon
treatment of this acylmethyl substituted naphthoquinone
(6b) with triethylamine, it cyclized selectively to the
pyranonaphthoquinone dehydroherbarin (14) in 81%
yield.12,17 For the synthesis of 1-3, 14 needed to be further
deprotected. Therefore, compound 14 was first treated
with excess hydrochloric acid in tetrahydrofuran at room
temperature to give 1-hydroxydehydroherbarin (3) in 95%
Conclusions
In summary, we have developed an efficient total
synthesis of the biologically interesting ascomycones
A and B in 9 steps and 18% overall yield starting from

Vol. 23, No. 2, 2012
Dong et al.
283
Cl
N
O
O
O
O
OH
O
O
O
13
O
Ag2O, CH3I
O
13, Et3N
CHCl3, reflux 5 h, in the dark
O
O
CH3CN, rt, 12 h, in the dark
O
7b
12 (93%)
O
O
O
OH
O
O
O
2 mol L-1 HCl/THF 2:5
rt, 2 h, in the dark
Et3N, toluene reflux 6 h
in the dark
O
O
O
O
O
O
O
14 (81%)
6b (85%)
OH
O
O
O
O
O
OH
OH
O
OH
cat.H2SO4
MeOH
rt, 2 h
BBr3, −78 oC, 30 min
O
O
O
then rt, 2 h, in the dark
O
O
O
O
O
3 1-hydroxydehydroherbarin (95%)
2 ascomycone B (83%)
1 ascomycone A (80%)
Scheme 5. Completion of the total syntheses of ascomycones A and B (1, 2) and 1-hydroxydehydroherbarin (3).
3-chloro-2,5-dimethoxybenzaldehyde (10)as building block.
Notably, 1-hydroxydehydroherbarin was obtained in more
than 21% yield. Key features of our synthetic approach
include an efficient method on the oxidation of 11 toward
8b with CAN. The efficient approach and rapid synthetic
route reported here should be easily applied to the synthesis
of analogues for further biological testing, which will be
reported in due time.
2. Paranagama, P. A.; Wijeratne, E. M. K.; Burns, A. M.; Marron,
M. T.; Gunatilaka, M. K.; Arnold, A. E.; Gunatilaka, A. A. L.;
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Q.; Planta Med. 2009, 75, 1339; Singh, S. B.; Cordingley, M.
G.; Ball, R. G.; Smith, J. L.; Dombrowski, A. W.; Goetz, M.
A.; Tetrahedron Lett. 1991, 32, 5279.
Supplementary Information
5. Sperry, J.; Yuen, T. Y.; Brimble, M. A.; Synthesis 2009, 2561;
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Supplementary data are available free of charge as a
pdf file at http://jbcs.sbq.org.br.
Acknowledgments
We are grateful for the financial support from the
National Natural Science Foundation of China (20902083)
and the Natural Science Foundation of Zhejiang Province,
China (Y4090082).
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Total Synthesis of 1-Hydroxydehydroherbarin and Ascomycones A, B, Naphthoquinone Antibiotics
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Submitted: August 10, 2011
Published online: December 1, 2011
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