Total synthesis of Angucyclines. Part 18: A short and efficient synthesis of (+)-ochromycinone

Article abstract of DOI:10.1016/j.tetasy.2003.12.028

A short and highly enantiospecific (seven steps, 99% ee) synthesis of (+)-ochromycinone 2 in 19% overall yield is reported. Key steps are the regioselective Diels-Alder reaction of the juglone derivative 4 with the mixture of dienes 5 and 9 derived from 3-methylcyclohexanone (99% ee) and the photooxidation of 1-deoxyochromycinone 3 to the natural ketone 2. A pronounced concentration dependence of the specific rotation was observed for (+)-ochromycinone 2 in CHCl₃.

Full text of DOI:10.1016/j.tetasy.2003.12.028

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Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 713–718
Total synthesis of Angucyclines. Part 18: A short and efficient
synthesis of (+)-ochromycinone
*
€
Karsten Krohn, Md. Hossain Sohrab and Ulrich Florke
Department of Chemistry, University of Paderborn, Warburger Straße 100, 33098 Paderborn, Germany
Received 8 November 2003; revised 3 December 2003; accepted 19 December 2003
Abstract—A short and highly enantiospecific (seven steps, 99% ee) synthesis of (+)-ochromycinone 2 in 19% overall yield is reported.
Key steps are the regioselective Diels–Alder reaction of the juglone derivative 4 with the mixture of dienes 5 and 9 derived from
3-methylcyclohexanone (99% ee) and the photooxidation of 1-deoxyochromycinone 3 to the natural ketone 2. A pronounced
concentration dependence of the specific rotation was observed for (+)-ochromycinone 2 in CHCl3.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
its selectivity against H. pylori, for example, the low
activity against other common bacteria. This finding
stimulated our interest to develop a short and efficient
total synthesis of enantiomerically pure (+)-ochromyci-
none 2.
Recently Taniguchi et al.1 reported on the structure of a
new angucycline antibiotic (reviews2;3) YM-181741 1,
bearing a hydroxyl group at the C-3 methyl group of the
known4 angucycline antibiotic ochromycinone 2 (Chart
1). The authors also reported that YM-181741 1 showed
selective activity against Helicobacter pylori, the major
cause of stomach ulcers,5;6 with a MIC value of 0.2 lg/
mL.1 In fact, antibiotics with selective activity against H.
pylori are urgently needed since the treatment of ulcer
diseases with the broad-spectrum antibiotics such as
amoxicillin and clarithromycin7 causes diarrhoea by the
disturbance of intestinal microbial flora8 and also
increasing antibiotic resistance in H. pylori infection is
observed.9 Taniguchi et al. also found that ochromyci-
none 2 is twice as active as YM-181741 1 without losing
Several syntheses of racemic ochromycinone are known.
With the exception of the work of Katsuura and
Snieckus,10;11 who used an aromatic directed metallation
strategy, the Diels–Alder reaction with juglone deriva-
tives and appropriate dienes was mostly employed to
construct the tetrahydrobenz[a]anthraquinone skele-
ton.12–14 Larsen et al.15 achieved a kinetic resolution with
respect to a racemic diene in the Diels–Alder reaction
using a chiral catalyst in their asymmetric synthesis of
16
(+)-ochromycinone. In the work of Carreno et al., an
~
enantiomerically pure sulfinylquinone dienophile was
the source of asymmetry to affect a kinetic resolution of
a racemic diene in their synthesis of enantiomerically
enriched (+)-ochromycinone. Very recently, the related
(+)-rubiginone B2 (O-methyl ether of 2) was prepared
via an intramolecular [2+2+2] cycloaddition of a chiral
triyne precursor, derived from (+)-citronellal.17
O
O
R
OH
O
We now disclose a very short, simple, and efficient
enantiospecific synthesis of (+)-ochromycinone, using
the Diels–Alder strategy. However, in contrast to the
two known procedures, we have incorporated the com-
mercially available and surprisingly cheap enantiomeri-
cally pure (R)-(+)-3-methylcyclohexanone 6 (99% ee) as
the starting material for the enantiomerically pure diene
5 as shown in the retrosynthetic Scheme 1. 5-Acetoxy-2-
bromo-1,4-naphthoquinone 418 was used as the dienophile
R = OH: antibiotic YM-181741 1
R = H: ochromycinone 2
Chart 1. Structures of antibiotic YM-181741 1 and ochromycinone 2.
* Corresponding author. Tel.: +49-5251-602172; fax: +49-5251-6032-
45; e-mail: kk@chemie.upb.de
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.028

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K. Krohn et al. / Tetrahedron: Asymmetry 15 (2004) 713–718
2
1
3
O
1. base
2. (Tf)2O
+
O
C
O
O
O
A
12
4
O
OTf
8
OTf
7
B
D
6
7
OH
OH
3
2
+
Bu3Sn
O
O
Pd(PPh3)4
Br
9
5
+
Scheme 2. Synthesis of dienes 5/9 via Stille reaction of enoltriflates 7/8
with tributylvinylstannane.
OAc
O
6
5
4
Scheme 1. Retrosynthetic scheme using (R)-(+)-3-methylcyclohexa-
none 6 as the source of chirality in the synthesis of (+)-ochromycinone.
proton (CH2CH@C) of 7 and a broad singlet at d
5.66 ppm for olefinic proton (CH(CH3)CH@C) of 8.
A Stille reaction23;24 was used to prepare the dienes 5
and 9 by coupling the triflates 7 and 8 and tributylvi-
nylstannane in the presence of Pd(PPh3)4 (2 mol %) in
88% combined yield, similar to its execution in the de-
oxybrasiliquinone B synthesis.25 The use of a-halo-
alkanesulfonyl bromides by Block et al.26 for the
racemic vinylcyclohexenes was less convenient for our
purpose. The ratio of the dienes 5 and 9 reflected that of
the respective triflate starting materials. The respective
structures were assigned by characteristic signals in the
1H NMR spectra for 5 (triplet at d 5.78 ppm for
because the bromine atom was known to direct the
regiochemistry in the Diels–Alder reaction very effi-
ciently.19 Thus, the presence of an electron donating
substituent such as a methoxy14 group on the terminal
end of the diene can be avoided, reducing the number of
synthetic steps. In addition, the presence of the bromine
atom in the immediate Diels–Alder adduct facilitates the
aromatization of ring B by elimination of hydrogen
bromide.19 Our scheme further envisaged the mild
photooxidation at C-120 in the final step to convert the
precursor 3 into the natural product 2.
CH2CH@C) or
CH(CH3)CH@C).
9
(doublet at
d
5.64 ppm for
The Diels–Alder reaction of the dienes 5 and 9 with
juglone 4 afforded mixtures (as evidenced from NMR)
of two regioisomeric primary Diels–Alder products 10
and 11 in 79% combined yield (Scheme 3). The ratio of
the regioisomers slightly improved with respect to the
starting dienes 5 and 9 in favor of the desired isomer 10,
probably due to steric hindrance of the methyl group in
9 and the bromine atom in 4. Dehydrobromination,
saponification and dehydrogenation of 10/11 to 3 and 12
was induced in one operation by mild base treatment
(K2CO3 in methanol) in the presence of air. The major
aromatic isomer 3 was isolated in pure form and good
yield (48%) after crystallization from the mixture of 3
and 12.
2. Results and discussion
The starting materials for this investigation were readily
accessible from known compounds. Thus, 5-acetoxy-2-
bromo-1,4-naphthoquinone 4 was prepared following
the method of Grunwell and Heinzman18 by NBS-bro-
mination of 1,5-diacetoxynaphthalene. The synthesis of
the required diene 5 started with the deprotonation of
enantiomerically pure (R)-(+)-3-methylcyclohexanone 6
with different bases followed by trapping of the enolates
with triflic anhydride to yield the vinyltriflate 7 and its
regioisomer 8 (Scheme 2). We expected that the forma-
tion of the desired triflate 7 was favored over the regio-
isomer 8 due to steric hindrance of the methyl group
during kinetically controlled enolate formation. Three
different bases were tried to investigate the regioselec-
tivity of the enolate formation. The best result was
obtained using lithium tetramethylpiperidide (LTMP,
7:8 ¼ 5.4:1), followed by lithium diisopropylamide
(LDA, 7:8 ¼ 2.4:1) and lithium hexamethyldisilazide
(LHMDS, 7:8 ¼ 2:1). Antony and Maloney21 also
reported a kinetically controlled reaction with similar
results using trityllithium in monoglyme and ( )-3-
methylcyclohexanone. Hsung et al.22 synthesized vinyl
triflate 8 (yield 13%) from 3-methylcyclohex-2-enone,
but the synthesis of triflate 7 is reported here for the first
time. The isomeric ratio of the enol triflates 7 and 8 was
determined by GC. The assignment was possible by
analysis of the 1H NMR spectra of the mixtures,
showing a broad singlet at d 5.78 ppm for the olefinic
The minor isomer 12 was present in the mother liquor
and could eventually be obtained in crystalline form
after repeated column chromatography and preparative
TLC (8%). Both the aromatic regioisomers 3 and 12
25
D
were optically active {½aꢀ ¼ +114, (c 0.09, CHCl3) for 3
25
D
and ½aꢀ ¼ )173, (c 0.07, CHCl3) for 12} but the enan-
tiomeric purity of (+)-ochromycinone 2 was determined
later by chiral HPLC (see below). The 1D and 2D NMR
spectra supported the structures of the respective aro-
matization products. The structure of the minor product
12 was further confirmed by single crystal X-ray analysis
(Fig. 1), thus indirectly also proving the structure of the
major product 3.
In the final step, the precursor 3 was converted to (+)-
ochromycinone 2 by photooxygenation with diffuse

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K. Krohn et al. / Tetrahedron: Asymmetry 15 (2004) 713–718
715
170
160
150
140
130
120
110
100
90
O
Br
80 -100 °C
14 h
+
+
OAc
O
O
4
5
9
O
O
Br
H
Br
H
+
80
0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
concentration (g/100 mL)
OAc
O
OAc
10
11
Figure 2. Dependency of the specific rotation on the concentration of
(+)-ochromycinone 2 in CHCl3.
K2CO3
MeOH
K2CO3
MeOH
O
O
effect,32;33 as shown in Figure 2, has not yet been
observed at such low concentrations and may be largely
attributed to p-stacking.34 Interestingly, the effect was
not observed in the more polar solvent acetonitrile and
is also not seen for the deoxy compound 3. Evidently,
the increase in polarity by the presence of the C-1 car-
bonyl group contributes to the interaction of the an-
thracyclinone molecules. In view of these observations,
the determination of ee in previous enantioselective
syntheses by specific rotation15;16 have to be revisited. To
check the enantioselectivity of our product, we used
HPLC chromatographic techniques on an enantio-
selective stationary phase (Chiralcel OD-H-type col-
umn) and a partially racemic product (80% ee) as the
reference material (details see Experimental). Not sur-
prisingly, our product showed 99% ee, since the starting
material had 99% ee and no racemization-prone step
occurred during our synthesis.
OH
O
OH
O
hν, O2
12
3
O
O
OH
O
2
Scheme 3. Synthesis of the benzo[a]anthraquinones 3 and 12 by Diels–
Alder reaction and photooxidation of 3 to (+)-ochromycinone 2.
In summary, we have reported a very short (seven steps
from commercially available material) and highly
enantiospecific (99% ee) synthesis of (+)-ochromycinone
in 19% (LTMP as the base) or 12% (LDA as the base)
overall yield. A large dependency of the specific rotation
on the concentration of 2 in CHCl3 was observed for the
first time for angucyclinones.
Figure 1. Molecular structure of 12.
3. Experimental
sunlight in 70% yield after chromatographic purification
followed by crystallization. This mild oxidation reaction
was discovered in our laboratory during the synthesis of
a daunomycinone/rabelomycinone hybrid20 (compare27)
and is now frequently used as the last reaction step in
angucycline synthesis.16;17;28–30 The relevant anisotropic
spectroscopic data of the synthetic material 2 were in
agreement with those reported for the natural
ochromycinone.13;31
For general methods and instrumentation see refer-
ence.35 Conditions for the GC analysis: Initial temper-
ature: 50 ꢁC; final temperature: 100 ꢁC; temperature
program: 5 ꢁC/min; initial time: 0; end time: 10 min;
solvent: CH2Cl2; column type: 25 m, 0.25 mm (inner
diameter), FS-OV-1-CB- 0.1, CS 32180-72; carrier gas:
helium; flow rate: 1 mL/min (carrier gas); detector type:
FID.
To determine the enantiomeric excess (ee), we first
determined the specific rotation of 2 in chloroform. To
our great surprise, we found a great dependency of the
specific optical rotation on the concentration of 2. To
the best of our knowledge, such a pronounced nonlinear
Conditions for the HPLC analysis: column type: Chi-
ralcel OD-H; detector type: UV (operated at 254 nm);
pump A type: L-700; solvent A: hexane 80%; solvent B:
isopropanol 20%; volume injected: 20 lL; flow rate:
0.7 mL/min.

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K. Krohn et al. / Tetrahedron: Asymmetry 15 (2004) 713–718
3.1. (R)-5-Methylcyclohex-1-enyl trifluoromethanesulfo-
nate 7 and (R)-3-methylcyclohex-1-enyl trifluoro-
methanesulfonate 8
resulting solution was washed sequentially with a 10%
aqueous ammonium hydroxide (3 · 50 mL) solution and
water (3 · 50 mL). This solution was dried (Na2SO4),
filtered, and concentrated at reduced pressure. Flash
chromatography of the residue on silica gel (pentane)
gave a mixture of dienes 5 and 9 as colorless oil 1.26 g
(88% combined yield, 5:9 ¼ 2.4:1 by NMR).
A
solution of 2,2,6,6-tetramethlypiperidine (TMP)
(0.84 mL, 0.7 g, 4.9 mmol) in THF (15 mL) was cooled to
)10 ꢁC, and n-butyllithium in toluene (2.2 mL of a 2.5 M
solution) was added slowly. The mixture was stirred for
30 min at )10 ꢁC and subsequently cooled to )78 ꢁC. A
solution of the ketone 6 (Aldridge 0.55 mL, 0.5 g,
4.5 mmol) in THF (10 mL) was added by means of a
syringe pump within 1 h with intensive stirring. The
mixture was stirred for 2 h at )78 ꢁC, and trifluorome-
thanesulfonic acid anhydride (0.83 mL, 1.4 g, 4.9 mmol)
was added. The mixture was allowed to warm to 20 ꢁC
and stirring was continued for an additional 15 h. The
reaction mixture was quenched by addition of HCl
(0.1 M, 30 mL), neutralized by addition of NaHCO3
(5%, 1.0 mL), dried (Na2SO4), filtered, and concentrated
at reduced pressure. Flash chromatography of the resi-
due on silica gel (pentane/5% Et2O) gave a mixture of
triflates 7 and 8 as a colorless oil. Similar reactions were
performed with LDA and LHMDS; the isomer ratios
and the yields were determined by GC. (LTMP:
7:8 ¼ 5.4:1, 71% combined isolated yield; LDA: 7:8 ¼
2.4:1, 44% combined isolated yield; LHMDS: 7:8 ¼ 2:1,
by GC).
3.2.1. (R)-5-Methyl-1-vinylcyclohex-1-ene 5. 1H NMR
0
0
(200 MHz, CDCl3)
d
6.41 (dd, J1 ;2 a ¼ 10:7 Hz,
J1 ;2 b ¼ 17:5 Hz, 1H, 10-H), 5.78 (t, 1H, 2-H), 5.12 (d,
0
0
J1 ;2 b ¼ 17:5 Hz, 1H, 20b-H); 4.94 (d, J1 ;2 a ¼ 10:7 Hz,
1H, 20a-H); 2.05–2.43 (m, 3H), 1.62–1.94 (m, 3H), 1.26–
1.35 (m, 1H), 1.07 (d, J ¼ 6:0 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3) d 140.4 (C-10), 136.2 (C-1), 129.8 (C-
2), 110.0 (C-20), 32.8 (sec), 31.2 (sec), 28.8 (C-5), 26.3
(sec), 22.4 (CH3).
0
0
0
0
3.2.2. (R)-3-Methyl-1-vinylcyclohex-1-ene 9. 1H NMR
0
0
0
0
(200 MHz, CDCl3) d 6.38 (dd, J1 ;2 a ¼ 10:7 Hz, J1 ;2 b
¼
17:5 Hz, 1H, 10-H), 5.64 (d, J ¼ 3:9 Hz, 1H, 2-H), 5.12
(d, J1 ;2 b ¼ 17:5 Hz, 1H, 20b-H); 4.96 (d, J1 ;2 a ¼ 10:7 Hz,
1H, 20a-H); 2.05–2.43 (m, 3H), 1.62–1.94 (m, 3H), 1.26–
1.35 (m, 1H), 1.05 (d, J ¼ 7:0 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3) d 140.5 (C-10), 136.4 (C-2), 135.5 (C-
1), 110.5 (C-20), 31.7 (sec), 31.3 (C-3), 24.2 (sec), 21.9
(CH3), 21.7 (sec).
0
0
0
0
3.1.1. Data for (R)-5-methylcyclohex-1-enyl trifluoro-
methanesulfonate 7. *IR (KBr) 2961, 2934, 2874, 2853,
1694, 1460, 1422, 1368, 1352, 1248, 1221, 1145,
3.3. (3R)-12a-Bromo-1,2,3,4,6,6a,7,12,12a,12b-decahy-
dro-3-methyl-7,12-dioxotetraphen-8-yl acetate 10 and
(1S)-12a-bromo-1,2,3,4,6,6a,7,12,12a,12b-decahydro-1-
methyl-7,12-dioxotetraphen-8-yl acetate 11
1
1031 cmꢁ1; H NMR (200 MHz, CDCl3) d 5.78 (br s,
1H, 2-H), 2.17–2.58 (m, 3H, 6-H, 3-H2), 1.83–2.16 (m,
1H, 6-H), 1.65–1.83 (m, 2H, 4-H, 5-H), 1.17–1.34 (m,
1H, 4-H), 1.07 (d, J ¼ 6:4 Hz, 3H, 5-CH3); 13C NMR
(50 MHz, CDCl3) d 149.2 (C-1), 122.1 (CF3), 118.4 (C-
2), 35.9 (sec), 29.7 (C-5), 29.5 (sec), 23.8 (sec), 21.3
(CH3); *MS (EI/200 ꢁC) 244 (35) [Mþ], 110 (33), 95 (26),
94 (27), 83 (22), 79 (84), 69 (74), 55 (100), 41 (71), 39
(20), 28 (25) (*data for mixed triflates 7 and 8).
A solution of 4 (2.4 g, 8.1 mmol) and the mixture of the
dienes 5 and 9 (ratio ca. 2.4:1, 0.9 g, 7.4 mmol) in dry
toluene (70 mL) was heated under argon for 12 h at
80 ꢁC followed by 2 h at 100 ꢁC (TLC monitoring). The
solvent was removed at reduced pressure and the
resulting material was purified by flash chromatography
(CH2Cl2) to afford a mixture of cycloadducts 10 and 11
(2.42 g, 79% combined yield, ratio 10:11 ¼ 2.6:1 by
NMR).
3.1.2. Data for (R)-3-methylcyclohex-1-enyl trifluoro-
methanesulfonate 8. 1H NMR (200 MHz, CDCl3) d
5.66 (br s, 1H, 2-H), 2.17–2.58 (m, 3H, 5-H, 6-H2), 1.83–
2.02 (m, 1H, 5-H), 1.65–1.83 (m, 2H, 3-H, 4-H), 1.17–
1.34 (m, 1H, 4-H), 1.08 (d, J ¼ 7:0 Hz, 3H, 3-CH3); 13C
NMR (50 MHz, CDCl3) d 149.5 (C-1), 124.4 (C-2),
115.8 (CF3), 30.3 (C-3), 30.0 (sec), 27.9 (sec), 21.7 (sec),
21.3 (CH3).
3.3.1. Data for (3R)-12a-bromo-1,2,3,4,6,6a,7,12,12a,
12b-decahydro-3-methyl-7,12-dioxotetraphen-8-yl acetate
10. *IR (KBr) 2956, 2923, 2869, 2847, 1776, 1705, 1667,
1596, 1450, 1368, 1324, 1265, 1237, 1189, 1102, 1015,
911, 868 cmꢁ1; *UV (CH2Cl2) kmax (lg e) 272 nm (3.55),
311 (3.39); 1H NMR (200 MHz, CDCl3) d 8.09 (dd,
J9;11 ¼ 1:1 Hz, J10;11 ¼ 7:9 Hz, 1H, 11-H), 7.77 (t,
J9;10 ¼ J10;11 ¼ 7:9 Hz, 1H, 10-H), 7.40 (dd, J9;10 ¼7:9 Hz,
J9;11 ¼ 1:1 Hz, 1H, 9-H), 5.46 (t, J ¼ 1:9 Hz, 1H, 5-H),
3.60 (dd, J ¼ 2:3 Hz, 6.2 Hz, 1H, 6a-H), 2.77 (m, 1H,
12b-H), 2.45–2.71 (m, 2H), 2.41 (s, 3H, COCH3), 2.33–
2.38 (m, 2H), 2.05 (m, 1H), 1.65–1.81 (m, 2H), 1.42–1.61
(m, 2H), 0.93 (d, J ¼ 6:6 Hz, 3H, 3-CH3); 13C NMR
(50 MHz, CDCl3) d 193.2 (C-7 or C-12), 191.3 (C-7 or
C-12), 169.7 (COCH3), 149.3 (C-8), 135.8 (quat), 135.3
(C-10), 135.0 (quat), 130.2 (C-9), 126.6 (C-11), 117.7 (C-
3.2. (R)-5-Methyl-1-vinylcyclohex-1-ene 5 and (R)-3-
methyl-1-vinylcyclohex-1-ene 9
A solution of the mixture of the triflates 7 and 8 (ratio
ca. 2.4:1, 2.86 g, 11.7 mmol, from LDA experiment) and
vinyltributylstannane (3.8 mL, 4.1 g, 12.89 mmol) was
added to a slurry of LiCl (5.2 g, 123 mmol) and
Pd(PPh3)4 (0.3 g, 2.0 mol %) in dry THF (110 mL). The
mixture was heated under reflux for 15 h, cooled to
room temperature, and diluted with pentane. The