The first total synthesis of (±)-zenkequinone B

Article abstract of DOI:10.1016/j.tetlet.2011.02.103

The first total synthesis of tetrahydrobenzo[a]anthraquinone natural product (±)-zenkequinone B (1) is reported. The key step involves the TiCl₄-promoted intramolecular cyclization of 4-aryl-2-hydroxybutanal diethyl acetal 4 to give compound 3.

Full text of DOI:10.1016/j.tetlet.2011.02.103

Tetrahedron Letters 52 (2011) 3183–3185
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Tetrahedron Letters
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The first total synthesis of ( )-zenkequinone B
⇑
Rammohan Devulapally, Yung-Son Hon
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 62102, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of tetrahydrobenzo[a]anthraquinone natural product ( )-zenkequinone B (1) is
reported. The key step involves the TiCl4-promoted intramolecular cyclization of 4-aryl-2-hydroxybut-
anal diethyl acetal 4 to give compound 3. The total synthesis of ( )-zenekequinone B (1) has been accom-
plished in five steps from readily available 2-(chloromethyl)-9,10-dimethoxyanthracene (5) in 40.3%
overall yield.
Received 4 January 2011
Revised 1 February 2011
Accepted 20 February 2011
Available online 12 April 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Zenkequinone B
Tetrahydrobenzo[a]anthraquinone
Total synthesis
Friedel–Crafts reaction
There are several natural products which contain a tetra-
hydrobenzo[a]anthraquinone skeleton. Most of these are named
as angucyclines, which are well-known for their broad range of
biological properties including antifungal, antiviral, antibiotic,
antitumor, platelet aggregation, and enzyme inhibitory behavior
(Fig. 1).1 Recently, Lenta et al. reported the isolation and structural
elucidation of the tetrahydrobenzo[a]anthraquinone natural prod-
uct zenkequinone B (1) (Fig. 1) from the stem bark of the medium
sized African medicinal plant Stereospermum zenkeri.2b Tradition-
ally, its roots and leaves are used as medicine to cure fever and
microbial infections and its bark is used in the treatment of bron-
chitis.2 The antimicrobial activity of the zenkequinone B was eval-
uated against six multiresistant strains of pathogens and it showed
the best antimicrobial activity (MIC 9.50 mg/mL) against Gram-
negative Pseudomonas aeruginosa.2b
4-aryl-2-hydroxybutanal diethyl acetal3b lead to the formation of
2-tetralones in excellent yields.3 The 4-aryl-2-hydroxybutanal
diethyl acetal can be prepared by regioselective epoxide ring open-
ing of glycidaldehyde diethyl acetal (6) with benzyl magnesium
chloride in good yield.3b In order to extend the synthetic applica-
tions of our 2-tetralone methodology, we focused our attention
on the total synthesis of natural products. The important biological
activities of zenkequinone B (1) and its structure inspired us to de-
sign its first total synthesis. To the best of our knowledge, the total
synthesis of zenkequinone B (1) has not been reported to date. In
this communication, we wish to report a short, simple and efficient
synthesis of ( )-zenkequinone B (1) by using the TiCl4-promoted
intramolecular Friedel–Crafts type reaction as a key step.
Retrosynthetic analysis of ( )-zenkequinone B (1) was based on
the previously developed TiCl4-promoted intramolecular cycliza-
tion to give the 2-tetralones. We envisioned that the anthraqui-
none moiety and 1-methylcyclohexanol moiety in zenkequinone
Recently, we reported that the TiCl4-promoted intramolecular
cyclization of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones3a and
Me
OH
3
HO
O
R1
R2
CH3
O
2
O
O
O
O
1
O
12
7
OH
11
8
13
4
11a
7a
12a
10
9
4a
5
6a
6
OMe O
OH
OH
OR
O
O
R = H, R1 = CH3, R2 = H, (+)-ochromycinone (2c)
2d
)
R = CH3, R1 = CH3, R2 = H, (+)-rubiginone B2
R = H, R1 = CH3, R2 = OH, (+)-tetragomycin (
R = CH3, R1 = CH3, R2 = OH, MM-47755 (2f)
(
zenkequinone B (1)
(+)-rubiginoneB1(2a)
rebelomycin (2b)
2e
)
Figure 1. Structures of zenkequinone B (1) and several tetrahydrobenzo[a]anthraquinone natural products.
⇑
Corresponding author. Tel.: +886 939296854; fax: +886 5 2721040.
E-mail address: cheysh@ccu.edu.tw (Y.-S. Hon).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.02.103

3184
R. Devulapally, Y.-S. Hon / Tetrahedron Letters 52 (2011) 3183–3185
B (1) could be installed via oxidation of the 9,10-dimethoxyanthra-
cene moiety and nucleophilic addition of methylmagnesium
bromide to the ketone moiety of compound 3, respectively. Com-
treated with cyclohexylamine in dry CH2Cl2 in the presence of 4
Å molecular sieves to give the iminoacetal 7 in quantitative yields,
which was used directly for the next step without further purifica-
tion (Scheme 3).8
pound
3 could be synthesized from 4-aryl-2-hydroxybutanal
diethyl acetal 4 by using the TiCl4-promoted intramolecular cycli-
zation. The 4-aryl-2-hydroxybutanal diethyl acetal 4 could be pre-
pared via epoxide ring opening of glycidaldehyde diethyl acetal (6)
with the benzylic carbanion of the 2-(chloromethyl)-9,10-dimeth-
oxyanthracene (5) (Scheme 1, Method I).
The iminoacetal 7 was treated with LDA in dry THF at À78 °C
to generate the corresponding lithium enamide, which was subse-
quently treated with 2-(chloromethyl)-9,10-dimethoxyanthracene
(5) in the presence of catalytic n-Bu4NI to afford the desired 4-
aryl-2-oxobutanal diethyl acetal 11 in 90% yield. The 4-aryl-2-
oxobutanal diethyl acetal 11 was reduced with NaBH4 to give
4-aryl-2-hydroxybutanal diethyl acetal 4 in 96% yield. The 4-
aryl-2-hydroxybutanal diethyl acetal 4 was treated with TiCl4 in
dry CH2Cl2 at 0 °C over 20 min to give the desired cyclization
product 3 in 61% yield along with compound 12 in 5% yield.
The structures of compounds 3 and 12 were determined by 1H
NMR and 2D-NOESY (Nuclear Overhauser Effect Spectroscopy)
spectroscopic data. Compound 3 was treated with a mixture of
MeMgBr and anhydrous CeCl3 in dry THF at À78 °C to give com-
pound 13 (Scheme 4). Finally, the 9,10-dimethoxyanthracene
moiety in compound 13 was oxidized with the mild and neutral
oxidizing agent NBS9 in the presence of water in THF at room
temperature to give the ( )-zenkequinone B (1) in 98% yield. In
this way, the total synthesis of ( )-zenkequinone B (1) was
accomplished in five steps from readily available 2-(chloro-
methyl)-9,10-dimethoxyanthracene (5) in 40.3% overall yield.
The structure of the ( )-zenkequinone B (1) was determined by
its 1H, 13C NMR, DEPT, NOE, HMBC, IR and mass spectroscopic data.
Finally, the structure of ( )-zenkequinone B (1) was established by
We thought that the in situ generated benzylic carbanion of the
compound 54 could open the epoxide 6 to afford the 4-aryl-2-
hydroxybutanal diethyl acetal 4. Unfortunately, when compound
55 was treated with Mg, Rieke Mg, sodium naphthalenide, or lith-
ium naphthalenide followed by addition of epoxide 6 under differ-
ent conditions, compound 5 did not give the desired product 4.
Instead, the crude product mixture contained the chlorohydrin
9,6 2-methylanthraquinone, and the dimer of 5 (Scheme 2).
The unsuccessful synthesis of 4-aryl-2-hydroxybutanal diethyl
acetal 4 by Method I prompted us to design a new synthesis of
compound 4. We envisioned that nucleophilic attack by deproto-
nated N-(1,1-diethoxypropan-2-ylidene)cyclohexanamine (7) on
electrophile 5 would give the 4-aryl-2-oxobutanal diethyl acetal
11. Reduction of compound 11 would produce the 4-aryl-2-
hydroxybutanal diethyl acetal 4 as shown in Scheme 1, Method II.
The iminoacetal 7 was prepared from methacrolein diethyl ace-
tal7 (10). The ozonide generated from methacrolein diethyl acetal
(10) was treated with Et3N to give the pyruvaldehyde diethyl
acetal (8) in 82% yield. The pyruvaldehyde diethyl acetal (8) was
O
OH
OMe
OMe
OH
TiCl4-promoted
cyclization
Methyl Grignard
addition/oxidation
OMe
O
Method I
OEt
O
Cl
EtO
OEt
OEt
OMe
5
OMe
4
OMe
3
O
6
( )-Zenkequinone B (1)
Method II
alkylation-reduction
OMe
O
Imine formation
Cl
OEt
OEt
N
H3C
OEt
OEt
H3C
OMe
5
7
8
Scheme 1. Retro synthetic analysis of ( )-zenkequinone B.
OMe
OMe
OH
HO
Cl
OEt
OEt
OEt
OEt
OEt
Cl
a or b or c
O
+
+
OEt
OMe
5
OMe
6
9
4
observed
not observed
Scheme 2. Reagents and conditions: (a) Mg or Rieke Mg, THF or Et2O, CuBr (0.02 equiv) or without CuBr, various temperatures and times; (b) sodium naphthalenide, THF or
Et2O, various temperatures and times; (c) lithium naphthalenide, THF or Et2O, various temperatures and times.
OEt
OEt
OEt
OEt
OEt
OEt
N
Me
a
b
Me
Me
O
10
8
7
Scheme 3. Synthesis of iminoacetal 7. Reagents and conditions: (a) O3, CH2Cl2, À40 °C; Et3N, À40 °C to rt, 4 h, 82%; (b) cyclohexylamine, CH2Cl2, 4 Å MS, rt, 5 h, quantitative
yield.

R. Devulapally, Y.-S. Hon / Tetrahedron Letters 52 (2011) 3183–3185
3185
OMe
O
OMe
OMe
O
OMe
OH
OMe
12 (5%)
OEt
OEt
4
OEt
Cl
a
b
c
OEt
O
OMe
5
OMe
11
OMe
4
OMe
Me OH
OMe
HO
Me
O
O
OMe
d
e
3
(61%)
OMe
13
(
)-Zenkequinone B (1)
Scheme 4. Synthesis of ( )-zenkequinone B (1). Reagents and conditions: (a) 7, LDA, n-Bu4NI, THF, À78 °C to rt, 8 h; 3 N HCl, 0 °C to rt, 1 h, 90%; (b) NaBH4, THF/MeOH (4:1),
0 °C to rt, 5 h, 96%; (c) TiCl4, CH2Cl2, 0 °C, 20 min; (d) CeCl3, MeMgBr, THF, À78 to À20 °C, 4 h, 78%; (e) NBS, H2O, THF, rt, 10 min, 98%.
2. (a) Lenta, B. N.; Vonthron-Senecheau, C.; Soh, R. F.; Tantangmo, F.; Ngouela, S.;
comparing the spectral data with the reported natural (À)-zenk-
Kaiser, M.; Tsamo, E.; Anton, R.; Weniger, B. J. Ethnopharmacol. 2007, 111, 8–12;
(b) Lenta, B. N.; Weniger, B.; Antheaume, C.; Noungoue, D. T.; Ngouela, S.; Assob,
equinone B data.2b
In summary, we have successfully achieved the first total syn-
thesis of antimicrobial natural product ( )-zenkequinone B (1) by
using the TiCl4-promoted Friedel–Crafts type intramolecular cycli-
zation for the preparation of the key intermediate 3. The overall
yield of the synthesis of ( )-zenkequinone B was 40.3% from the
2-(chloromethyl)-9,10-dimethoxyanthracene (5).
J. C. N.; Vonthron-Senecheau, C.; Fokou, P. A.; Devkota, K. P.; Tsamo, E.; Sewald,
N. Phytochemistry 2007, 68, 1595–1599.
3. (a) Hon, Y. S.; Devulapally, R. Tetrahedron Lett. 2009, 50, 2831–2834; (b) Hon, Y.
S.; Devulapally, R. Tetrahedron Lett. 2009, 50, 5713–5715.
4. To the best of our knowledge benzylic carbanion of the compound 5 has not
been reported to date.
5. The 2-(chloromethyl)-9,10-dimethoxyanthracene (5) was prepared from
commercially available 2-hydroxymethylanthraquinone in two steps by using
the procedure reported by Jiang, which involves the reduction/methylation of 2-
hydroxymethylanthraquinone with n-Bu4NBr, Na2S2O4 followed by addition of
NaOH and MeI to give the 2-(hydroxymethyl)-9,10-dimethoxyanthracene.
Chlorination of 2-(hydroxymethyl)-9,10-dimethoxyanthracene using SOCl2
gave the 2-(chloromethyl)-9,10-dimethoxyanthracene (5) in good yield; see:
Jiang, H.; Xu, H.; Ye, J. J. Chem. Soc., Perkin Trans. 2, 2000, 925–930.
6. Page, P.; Blonski, C.; Perie, J. Tetrahedron 1996, 52, 1557–1572.
7. The methacrolein diethyl acetal (10) was prepared from the commercially
available methacrolein using the procedure reported by Bischofberger, see:
Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.; Watson Lees, W.;
Bednarski, M. D.; Whitesides, G. M. J. Org. Chem. 1988, 53, 3457–3465.
8. (a) The inability to obtain lithium enolate of the pyruvaldehyde diethyl acetal
(8) using LDA prompted us to prepare iminoacetal 7; (b) The iminoacetal 7 was
prepared using a similar procedure reported by Tian et al. See: Tian, S.-K.; Hong,
R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900–9901.
Acknowledgments
We are grateful to the National Science Council (NSC) and
National Chung Cheng University for the financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.02.103.
References and notes
9. (a) The reaction was carried out with outstanding yield without addition of a
catalytic amount of sulfuric acid; (b) Kim, D. W.; Choi, H. Y.; Lee, K.-J.; Chi, D. Y.
Org. Lett. 2001, 3, 445–447.
1. Reviews: (a) Carreno, M. C.; Urbano, A. Synlett 2005, 1–25; (b) Krohn, K.; Rohr, J.
Top. Curr. Chem. 1997, 188, 127–195; (c) Rohr, J.; Thiericke, R. Nat. Prod. Rep.
1992, 9, 103–137.