Total Synthesis of the Angucylinone Antibiotic (+)-Rubiginone B 21

Article abstract of DOI:10.1055/s-2003-41473

A new chiral synthesis of (+)-rubiginone B₂ is reported. The intramolecular cobalt-mediated [2+2+2]-cycloaddition of a triyne precursor, synthesized from (+)-citronellal, afforded a chiral anthracene, which led after a two-step oxidation to the angucyclinone antibiotic.

Full text of DOI:10.1055/s-2003-41473

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1886
LETTER
1
Total Synthesis of the Angucylinone Antibiotic (+)-Rubiginone B2
Total
S
ynthesis of
r
(+)-Rubiiginone 2
s
B
Kalogerakis, Ulrich Groth*
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstraße 10, 78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: ulrich.groth@uni-konstanz.de
Received 30 June 2003
neat, 92% ee)8 we have synthesized the chiral diyne 6
(Scheme 1). By employing our previously reported
method1 we used 6 for the synthesis of the triyne 9, which
after cyclization and two-step oxidation led to (+)-rubigi-
none B2 12 (Scheme 2).
Abstract: A new chiral synthesis of (+)-rubiginone B2 is reported.
The intramolecular cobalt-mediated [2+2+2]-cycloaddition of a
triyne precursor, synthesized from (+)-citronellal, afforded a chiral
anthracene, which led after a two-step oxidation to the angucycli-
none antibiotic.
Our synthesis began with a Corey–Fuchs olefination9 of
(+)-citronellal 1. The resulting dibromoalkene 2 was used
without further purification and converted to the protected
alkyne 3 by treatment with n-BuLi and then TMS-Cl10
(76% yield, 2 steps). Ozonolysis of 3 (Me2S workup) af-
forded 4 in quantitative yield, which was transformed
without purification via another Corey–Fuchs olefination
into the dibromoalkene 5. Treatment of 5 with n-BuLi and
hydrolysis of the resulting lithiated acetylene gave the
diyne 6 (74% yield, 3 steps).
Key words: angucyclinone antibiotics, benz[a]anthraquinones,
natural products, catalysis, cobalt, cycloaddition
The rubiginones (Figure 1),2 isolated from the strain of
Streptomyces griseorubiginosus, exhibit potential vincris-
tine-induced cytotoxicity against multi-drug-resistant tu-
mor cells. They feature the typical benz[a]anthraquinone
structure of the angucyclinone antibiotics, a growing class
of secondary metabolites with remarkable biological
properties.3 While several racemic syntheses of these an-
gucyclinones have been achieved,4 only a few asymmetric
total syntheses have been reported.5 The only known total
synthesis of (+)-rubiginone B2 has been reported by Car-
reño and co-workers based on the Diels–Alder reaction
between an enantiopure substituted naphthoquinone and a
racemic vinylcyclohexene through the kinetic resolution
of the diene. The natural product was synthesized with
80% ee and 9% overall yield for the longest sequence.6
a
b
c
TMS
O
Br
Br
1
2
3
Br
O
d
e
Br
TMS
TMS
TMS
O
HO
O
O
O
4
5
6
R
R
Scheme 1 Reaction Conditions: (a) 2 equiv CBr4, 4 equiv PPh3,
CH2Cl2, 0 °C, 30 min, then 1, 25 °C, 2 h. (b) i. 2 equiv n-BuLi, THF,
–80 °C, 1 h, ii. 2 equiv TMS-Cl, –80 °C to r.t., 18 h (76%, 2 steps).
(c) i. O3, CH2Cl2, –80 °C, 15 min, ii. Me2S, AcOH, –80 °C to r.t., 18
h. (d) 2 equiv CBr4, 4 equiv PPh3, CH2Cl2, 0 °C, 30 min, then 4, 25
°C, 2 h. (e) i. 2 equiv n-BuLi, THF, –80 °C, 1 h, ii. H2O, –80 °C to r.t.,
2 h (74%, 3 steps).
OMe
OMe
O
rubiginone A2 R= OH
rubiginone B2 R= H
rubiginone A1 R= OH
rubiginone B1 R= H
rubiginone C2 R= OCOCH(CH3)2
rubiginone C1 R= OCOCH(CH3)2
After addition of the lithiated diyne 6 to the benzaldehyde
71 and deprotection of the triple bonds of the resulting
triyne 8 with NH4F,11 the hydroxy group of the obtained
triyne was protected with TBDMSOTf.12 Cyclization of 9
with 10% CpCo(CO)213 in refluxing toluene under irradia-
tion (tungsten-lamp) gave the anthracene 10 in 74% yield.
By using 5% CpCo(CO)2 10 was obtained in 61% yield.
The use of the expensive CpCo(ethene)214 for the cycliza-
tion (see ref.1) of the triyne 9 was not necessary. Oxidation
with [Ag(Py)2]MnO415 led to the anthraquinone 11 (62%
yield), which was converted via photooxidation4c to (+)-
rubiginone B2 12 (67% yield).16 The spectroscopic data of
synthetic (+)-rubiginone B2 12 coincided with those of the
Figure 1
We have recently reported a new method1 for the con-
struction of the angucyclinone core via an intramolecular
cobalt-mediated [2+2+2]-cycloaddition of a triyne.7 Here-
in, we describe a new asymmetric access to the angucycli-
none antibiotic (+)-rubiginone B2 12. Starting from
20
commercially available R-(+)-citronellal ([a]D +13.0,
SYNLETT 2003, No. 12, pp 1886–1888
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41473; Art ID: G15103ST
© Georg Thieme Verlag Stuttgart · New York

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LETTER
Total Synthesis of (+)-Rubiginone B2
1887
natural compound.2 The structure of 12 was proven by
two-dimensional NMR experiments (ROESY-, H,H-
COSY-spectra, see the H,H-correlations in Figure 2). Ad-
Acknowledgment
The authors are grateful to the Fonds der Chemischen Industrie and
the EU-Comission, Directorate XII, for financial support. We thank
Dr. H. Frauendorf, analytical laboratory of the institute of organic
chemistry at the university of Göttingen, for measuring the HRMS-
analysis of compound 10.
25
ditionally, the observed optical rotation value [a]D
+71.64 (c 0.275, CHCl3, 92% ee) agreed satisfactory with
the reported value [a]D25 +78.00 (c 0.5, CHCl3) for the nat-
ural product.
References
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OH
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12
11
Scheme 2 Reaction Conditions: (a) n-BuLi, 6, THF, –80 °C, 1 h,
then 7, –80 °C to –30 °C, 4 h (93%), (b) i. NH4F, Bu4NHSO4, CH2Cl2,
r.t., 48 h (96%), ii. TBDMSOTf, 2,6-lutidine, CH2Cl2, 25 °C, 2 h
(95%) (c) 10% CpCo(CO)2, toluene, reflux, hn, 4 h (74%). (d) 8 equiv
[Ag(Py)2]MnO4, CH2Cl2, 25 °C, 8 h (62%). (e) hn, air, CHCl3, 25 °C,
18 h (67%).
HH
1
6
O
CH3
H
3
CH3
O
O
O
H
O
11
H
H
H
H
10
H
H
H
H
H
H3CO
OCH3 O
H
Figure 2 H,H-correlations in ROESY- and H,H-COSY-Spectra
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Lett. 1981, 36, 3455.
(13) Experimental Procedure: A solution of CpCo(CO)2 (25.00
mg, 0.142 mmol, 10 mol%) in 2 mL toluene was added via
canula to a solution of triyne 9 (0.58 g, 1.42 mmol) in 120
mL toluene and the mixture was heated to reflux and
irradiated with a tungsten-lamp (osram vitalux 300 W) for 4
h. The organic phase was then concentrated in vacuo.
Chromatography on silica gel (Et2O–petroleum ether, 1:200)
provided anthracene 10 (0.29 g, 1.051 mmol, 74% yield) as
a white solid.
In summary, a new effective chiral synthesis of (+)-rubig-
inone B2 has been achieved starting from commercially
available R-(+)-citronellal in 11 steps and 15% overall
yield. Applications to the asymmetric synthesis of other
angucyclinone antibiotics using the reported method-
ology1 are currently under investigation.
Synlett 2003, No. 12, 1886–1888 © Thieme Stuttgart · New York

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1888
A. Kalogerakis, U. Groth
LETTER
Mp 136–138 °C. [a]D22 +86.43 (c 0.14, CHCl3). Rf = 0.31
(Et2O–petroleum ether, 1:100). IR (CCl4): 2935–2810 [C–
H (OCH3)] cm–1. 1H NMR (600 MHz, CDCl3): d = 1.16 (d,
3J = 6.6 Hz, 3 H, 3-CH3), 1.58 (m, 1 H, H-2), 2.00 (m, 1 H,
H-3), 2.14 (m, 1 H, H-2), 2.60 (dd, 2J = 16.5 Hz, 3J =10.5 Hz,
1 H, H-4), 2.95 (dd, 2J = 16.5 Hz, 3J = 3.9 Hz, 1 H, H-4), 3.14
(m, 1 H, H-1), 3.40 (d, 2J = 16.5 Hz, 1 H, H-1), 4.09 (s, 3 H,
OCH3), 6.73 (d, Jo = 8.0 Hz, 1 H, H-9), 7.18 (d, Jo = 8.6 Hz,
1 H, H-5), 7.37 (t, Jo = 8.0 Hz, 1 H, H-10), 7.62 (d, Jo = 8.0
Hz, 1 H, H-11), 7.82 (d, Jo = 8.6 Hz, 1 H, H-6), 8.44 (s, 1 H,
H-12), 8.78 (s, 1 H, H-7). 13C NMR (100 MHz, CDCl3): d =
21.79 (3-CH3), 25.83 (C-1), 28.88 (C-3), 31.35 (C-2), 39.14
(C-4), 55.45 (OCH3), 101.34 (C-9), 120.75 (C-12), 120.83
(C-11), 121.35 (C-7), 125.06 (C-10), 126.58 (C-6), 128.05
(C-5), 124.09, 130.34, 131.42, 132.64, 133.57, 155.38
(Cquart-arom.). EI-MS (70 eV): m/z = 276 (100%, M+), 261
(15%, M+ – CH3), 246 (7%, 261 – CH3), 233 (77%, 261 –
C2H4). HRMS: calcd 276.1514 for C20H20O, found
(16) Experimental Procedure: Anthraquinone 11 (60.00 mg,
0.195 mmol) was dissolved in 5 mL CHCl3 and irradiated
with a tungsten-lamp (osram vitalux 300 W) over 18 h. The
organic layer was then removed in vacuo. Chromatography
on silica gel (petroleum ether–Et2O, 1:2) provided (+)-
rubiginone B2 12 (42.00 mg, 0.131 mmol, 67% yield) as a
yellow solid.
Mp > 262 °C (dec.). [a]D25 +71.64 (c 0.275, CHCl3,
recrystallized from petroleum ether–CHCl3, 2:1). Rf = 0.14
(Et2O–petroleum ether, 1:4). IR (CCl4): 1673, 1677, 1708
(C=O) cm–1. 1H NMR (400 MHz, CDCl3): d = 1.20 (d, 3J =
6.4 Hz, 3 H, 3-CH3), 2.45 (m, 1 H, H-3), 2.55 (dd, 2J = 15.6
Hz, 3J = 11.0 Hz, 1 H, H-2), 2.67 (dd, 2J = 16.4 Hz, 3J = 11.0
Hz, 1 H, H-2), 2.98 (m, 2 H, H-1 and H-4), 4.04 (s, 3 H,
OCH3), 7.24 (d, Jo = 8.2 Hz, 1 H, H-9), 7.45 (d, Jo = 8.0 Hz,
1 H, H-5), 7.65 (t, Jo = 8.2 Hz, Jo = 7.8 Hz, 1 H, H-10), 7.71
(d, Jo = 7.8 Hz, 1 H, H-11), 8.20 (d, Jo = 8.0 Hz, 1 H, H-6).
13C NMR (150 MHz, CDCl3): d = 21.43 (3-CH3), 30.82
(C-3), 38.33 (C-4), 47.55 (C-2), 56.50 (OCH3), 117.15
(C-9), 119.68 (C-11), 129.60 (C-6), 132.99 (C-5), 135.34
(C-10), 120.56, 134.98, 135.07, 137.67, 149.13, 159.81
(Cquart-arom.), 181.59, 184.51, 198.89 (C=O). EI-MS (70
eV): m/z = 320 (100%, M+), 305 (15%, M+ – CH3), 292
(35%, M+– CO), 291 (15%, M+ – HCO), 261 (27%, 292 –
OCH3), 233 (24%, 261 – CO).
276.1508.
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Synlett 2003, No. 12, 1886–1888 © Thieme Stuttgart · New York