A regio- and stereo-selective synthesis of 2-hydroxy-3-methylochromycinone in three steps from 2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene

Article abstract of DOI:10.1039/b101756j

2-Hydroxy-3-methylochromycinone 4 has been synthesised using a three stage strategy. The Diels-Alder reaction between 2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene gives a single racemic diastereoisomer of 1-acetoxy-12a-bromo-3,3-dimethyl-7,12-dioxo-3,4,6,6a,7,12,12a,12b- octahydrobenzo[a]anthracen-8-yl acetate 5 in 63% yield, which may be epoxidised to give the bis-epoxide 8-acetoxy-12a-bromo-3,3-dimethyl-7,8-dioxo-3,4,4a,5,6,6a,7,12,12a,12b- decahydro-1aH-benzo[6,7]oxireno[2′,3′:10,10a]phenanthro[3,4-b]- oxiren-12-yl acetate 6 in 82% yield. The bis-epoxide 6 may be converted directly into 2-hydroxy-3-methylochromycinone 4 in 45% yield, or via one of two intermediates [e.g. 2,5-dihydroxy-3,3-dimethyl-1,7,12-trioxo-1,2,3,4,5,6,7,12- octahydrobenzo[a]anthracen-8-yl acetate 8] in 80-85% yield. The intermediate 8 shows moderate anticancer activity at μM concentrations against lung, breast and central nervous system cancers, while the target compound 4 is only active at 10^-4 M.

Full text of DOI:10.1039/b101756j

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A regio- and stereo-selective synthesis of 2-hydroxy-3-
methylochromycinone in three steps from 2-bromo-5-acetoxy-1,4-
naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-
diene†
1
Tomas Rozek,a John H. Bowie,a Simon M. Pyke,a Brian W. Skeltonb and Allan H. Whiteb
a Department of Chemistry, The University of Adelaide, South Australia, 5005
b Department of Chemistry, The University of Western Australia, Nedlands,
Western Australia 6907
Received (in Cambridge, UK) 23rd February 2001, Accepted 12th June 2001
First published as an Advance Article on the web 5th July 2001
2-Hydroxy-3-methylochromycinone 4 has been synthesised using a three stage strategy. The Diels–Alder reaction
between 2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene gives
a single racemic diastereoisomer of 1-acetoxy-12a-bromo-3,3-dimethyl-7,12-dioxo-3,4,6,6a,7,12,12a,12b-octahydro-
benzo[a]anthracen-8-yl acetate 5 in 63% yield, which may be epoxidised to give the bis-epoxide 8-acetoxy-12a-bromo-
3,3-dimethyl-7,8-dioxo-3,4,4a,5,6,6a,7,12,12a,12b-decahydro-1aH-benzo[6,7]oxireno[2Ј,3Ј:10,10a]phenanthro[3,4-b]-
oxiren-12-yl acetate 6 in 82% yield. The bis-epoxide 6 may be converted directly into 2-hydroxy-3-methylochromycinone
4 in 45% yield, or via one of two intermediates [e.g. 2,5-dihydroxy-3,3-dimethyl-1,7,12-trioxo-1,2,3,4,5,6,7,12-
octahydrobenzo[a]anthracen-8-yl acetate 8] in 80–85% yield. The intermediate 8 shows moderate anticancer activity
at µM concentrations against lung, breast and central nervous system cancers, while the target compound 4 is only
active at 10Ϫ4 M.
Introduction
We have initiated a programme to synthesise model angucy-
clinones related to ochromycinone (1, R1 = OH, R2 = R3 = H)1
and the anticancer active saquayamycins (2, R1, R2 and R3 are
carbohydrate residues of varying complexity),2,3 with a view to
producing model compounds with significant anticancer activ-
ity. We have already made 1 for R1 = OH, R2 = H, R3 = Me;
R1 = H, R2 = OH, R3 = Me; and R1 = R2 = OH, R3 = Me4,5
using Diels–Alder methodology.6–8 These quinones and their
first-formed Diels–Alder intermediates have shown modest
broad-spectrum anticancer activity at µM concentrations in the
60 tumor line test programme of the National Cancer Institute
[NCI (Washington, DC)]. To introduce the saquayamycin cis-
dihydroxy substitution at the A/B ring junction is a more dif-
ficult undertaking: to date, we have not achieved this aim.5
There is a third type of angucyclinone which is reported to
exhibit bio-activity, viz., that with a 2-hydroxy group in the A
ring: an example is 3 (the stereochemistry of the groups on the
A ring is unknown), a metabolite isolated from Streptomyces
phaeochromogenes.9 The aim of the work reported in this paper
is to synthesise racemic 2-hydroxy-3-methylochromycinone (4)
and to assess the anticancer activity of this model system. As
before,4,5 we utilise a gem-dimethyl substituent at the 3 position
in order that a single racemic diastereoisomer may be formed as
the final product.
1,5-diene should yield the single racemic diastereoisomer 5. The
polarisation of the diene and dienophile shown in Scheme 1,
together with steric interactions, should effect the reaction
shown and the 1-acetate substituent on the triene should ensure
that the reacting diene is that shown, and not the 1,5-diene of
the ring. The second step of the synthesis involves bis-epoxid-
ation to yield 6, with the stereochemistry of the epoxide
rings predicted to be as shown. Ring opening of both epox-
ides, elimination of two molecules of water and hydrogen
bromide, together with hydrolysis of the hemiketal formed at
the 1-position should produce the required racemic derivative 4.
Results and discussion
The strategy of the proposed synthesis is shown in Scheme 1. An
endo Diels–Alder reaction between 2-bromo-5-acetoxy-1,4-
naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-
1-Acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene
was
made in quantitative yield by enolising 5,5-dimethyl-3-
vinylcyclohex-2-en-1-one4 with lithium diisopropylamide at
Ϫ78 ЊC, followed by reaction of the enolate with pyridine and
acetic anhydride. The reaction of this triene with 2-bromo-5-
acetoxy-1,4-naphthoquinone in toluene at reflux and under
† Electronic supplementary information (ESI) available: further details
of the NMR spectra of compounds 5, 6, 8 and 9. See http://
www.rsc.org/suppdata/p1/b1/b101756j/
1826
J. Chem. Soc., Perkin Trans. 1, 2001, 1826–1830
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101756j

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Table 1 Torsion angles/Њ for compounds 5 and 7a
5
7
Ring A
12b–1–2–3
1–2–3–4
2–3–4–4a
1.6(2)
Ϫ25.8(1)
51.8(1)
59(2)
Ϫ63(1)
55(2)
3–4–4a–5
123.0(1)
30.3(1)
Ϫ2.6(2)
Ϫ150.6(1)
160.4(1)
145(1)
35(2)
Ϫ43(2)
163(1)
4–4–12b–1
4a–12b–1–2
5–4a–12b–1
4–4a–12b–12a
Ϫ152(1)
Ring B
12b–4a–5–6
4a–5–6–6a
5–6–6a–12a
Ϫ1.0(2)
Ϫ8.9(2)
40.3(1)
2(2)
Ϫ11(2)
42(1)
6–6a–12a–12b
6a–12a–12b–4a
12a–12b–4a–5
7–6a–12a–12b
6–6a–12a–12
Ϫ63.5(1)
51.5(1)
Ϫ20.5(2)
175.2(1)
67.2(1)
Ϫ64(1)
52(1)
Ϫ23(2)
176(1)
62(1)
Ring C
7–6a–12a–12
6a–12a–12–11a
12a–12–11a–7a
12–11a–7a–7
11a–7a–7–6
7a–7–6a–12a
11a–7a–7–O(7)
7a–11a–12–O(12)
Ϫ54.1(1)
34.2(2)
Ϫ5.7(2)
Ϫ3.3(2)
Ϫ17.6(2)
46.5(2)
Ϫ57(1)
57(1)
Ϫ25(2)
Ϫ7(2)
6(2)
26(2)
Ϫ174(1)
160(1)
Fig.
1
Projection of the Diels–Alder adduct 5, showing 50%
amplitude displacement ellipsoids for the non-hydrogen atoms,
hydrogen atoms having arbitrary radii of 0.1 Å.
166.9(1)
175.6(1)
a Values are given for the three fused non-aromatic rings of 5: carbon
atoms being denoted by number only.
Fig. 2 ROESY NMR data for bis-epoxide 6.
Scheme 1
nitrogen for 24 hours gave a 92% yield of the Diels–Alder
adduct 5.
The regiochemistry of 5 was confirmed as follows. Adduct 5
upon treatment with aqueous sodium hydroxide (saturated) in
tetrahydrofuran (1 : 4) gave the known 3-methylochromycinone
1 (R1 = OH, R2 = H, R3 = Me)4 in 20% yield. The regio- and
stereo-chemistries of 5 were confirmed by the results of an
X-ray study (Fig. 1). One formula unit comprises the asym-
metric unit of the structure. In terms of the fused ring system,
conformational parameters are shown in Table 1 and are in
close agreement with a similar system 7,10 after due allowance
for the change in the C(1)–C(2) bond order. Perhaps, in con-
sequence of the latter, and further, in conjugation with the
introduction of the bromine atom at the bridgehead in 5, we
find the bromine to adjacent hydrogen distances Br ؒ ؒ ؒ H(6a),
(12b) 2.91(2), 2.93(2) Å, with concomitant diminution of
Br–C(12a)–C(6a), C(12) [104.42 (8), 101.68 (8)Њ]. Ring C
(6a,7,7a,11a,12,12a) in both structures is essentially an
‘envelope’, with C(12a) at the flap, but there are considerable
differences in the torsions, in particular those associated with
departures of the ‘quinonoid’ oxygen atoms from the plane of
the aromatic ring.
Treatment of 5 with 2.5 equivalents of dimethyldioxirane in
anhydrous acetone at 0 ЊC for 16 h, gave the racemic bis-
epoxide 6 in a purified yield of 82%. We could not obtain a
crystal of 6 suitable for X-ray analysis. The bond connectivity
of 6 is confirmed by the spectroscopic data summarised in the
Experimental and the stereochemistry at the seven chiral
centres is confirmed by 2D NMR experiments. Full details of
1
the H NMR experiments for 6 are recorded in the electronic
supplementary information (ESI), including COSY and
ROESY experiments. Relevant ROESY data are summarised in
Fig. 2. A 12.6 Hz coupling constant between H6a and H6ax
indicates a pseudo trans-diaxial relationship, meaning that
these two hydrogens are on opposite faces of the molecule.
Conversely, H6eq interacts with H6a with a coupling constant
J. Chem. Soc., Perkin Trans. 1, 2001, 1826–1830
1827

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the racemic diastereoisomers shown was confirmed using 2D
NMR experiments. Full results of ROESY and NOESY
experiments are given in the ESI, while particularly relevant
spatial ROESY data are shown for 8 in Fig. 3.
The ROESY cross peaks between H2ax, H4ax and H5ax (4.30,
2.47 and 4.44 ppm) (Fig. 3A) confirm that these H substituents
are on the same side of the molecule, while the cross peaks
between the 3-methyl (1.26 ppm), H4ax and H2ax assign this
methyl group as equatorial. Other interactions are shown in
Fig. 3B. The relative stereochemistry of the two hydroxy groups
is syn, since the 5-OH (5.58) interacts with H4eq (3.07), which
additionally interacts with the 2-OH (4.15). Axial H6 is identi-
fied by coupling to H5ax with a coupling constant of 15.6 Hz,
indicating a large dihedral angle (pseudo trans-diaxial). The
stereochemistry of the analogous molecule 9 is derived similarly
(see ESI).
Fig. 3 ROESY NMR data for hydroxyketone (8).
of 4.2 Hz meaning these two hydrogens are on the same side of
the molecule. The intense 1,3-diaxial interactions between H6a,
H12bax and H4ax indicate that these hydrogens are all on the
same face of the molecule. There are cross peaks between H4ax
and 3-Meeq and H4eq and 3-Meax, but no cross peaks between
H4ax and 3-Meax or H4eq and 3-Meeq, confirming the stereo-
chemical relationship between the 3 and 4 substituents shown in
Fig. 2. The cross peaks between H5, 3-Meax and H4eq and the
lack of a cross peak between H5 and H12b show that H5 is
equatorial. Finally, an NOE difference experiment allows the
assignment of the relative stereochemistry of the 1,2-epoxide
ring compared with the rest of the molecule. Irradiation of the
H2 signal at 3.35 ppm enhances both of the 3-Me signals by
1.2%. Thus, H2 is equatorial and equidistant from each of the
two methyl groups.
Mechanistic rationales for the formation of 8 and 9 are
summarised in Scheme 2. The protonations of both epoxide
Bis-epoxide 6 can be converted to the racemic α-hydroxy-
ketone 4 in two ways. Firstly, treatment of 6 under acid condi-
tions, followed by reaction of the unpurified products under
basic conditions gives 4 in a purified yield of 45%.‡ Alter-
natively, the products of mild acid hydrolysis may be separated
and characterised and then converted to 4: in this case, the
overall yield from 6 is about 65%. The structure of 4 is con-
firmed by spectroscopic data. The infrared spectrum shows
three carbonyl vibrations: viz., 1693 (α-hydroxycarbonyl), 1666
(quinone carbonyl) and 1633 (peri-OH hydrogen bonded quin-
Scheme 2 (a) Hϩ; (b) Ϫ(AcOH ϩ H2O ϩ HBr); (c) Ϫ(H2O ϩ HBr).
one carbonyl) cmϪ1; the mass spectrum shows the characteristic
1
retro Diels–Alder fragmentation [Mϩ Ϫ C4H8O], while the H
rings in the ring opened carbocation forms are shown together
in cartoon form in Scheme 2. Attack of water at both carbo-
cation centres followed by elimination of acetic acid and
water yield the α-hydroxyketone 8 as the major product. The
formation of the minor product 9 involves an acetyl rearrange-
ment, as shown in Scheme 2.10 Both 8 and 9 can be converted
directly into the required angucyclinone product 4.
The target compound 4 together with intermediates 8 and 9
have been tested for anticancer activity [by NCI (Washington,
DC)] against lung and breast cancer and cancer of the central
nervous system. All are active, the least active being 4, which
shows some activity at the 10Ϫ4 M concentration. In contrast,
intermediates 8 and 9 show activity at 10Ϫ6 M concentrations.
Further tests are being carried out with all three compounds.
In conclusion, the target molecule 2-hydroxy-3-methylo-
chromycinone 4 has been synthesised using a three stage
synthesis commencing with the Diels–Alder reaction between
2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-
ؒ
NMR spectrum, in particular, shows the peri-OH (12.22 ppm),
the two coupled doublets of H5 and H6 [7.58 and 8.36 ppm
(7.8 Hz)], and the H10 triplet (7.29 ppm) coupled to the two
overlapping doublets of H9 and H11 [7.68 ppm (3.9 Hz)].
An insight into the mechanism of the formation of 4 from 6
is forthcoming when the two major products of the toluene-p-
sulfonic acid catalysed ring opening of bis-epoxide 6 are
isolated and characterised.
Chromatography of this product mixture over silicic acid
gave 8 and 9 in yields of 55 and 20% respectively. Mass spectro-
metric analysis of the residual material identified small
amounts of other products corresponding to the further losses
of HBr, H2O and (H2O ϩ HBr) from each of 8 and 9. None of
dimethyl-5-vinylcyclohexa-1,5-diene. The angucyclinone
4
shows only minor anticancer activity, with the reduced deriv-
atives 8 and 9 showing moderate anticancer activity at µM
concentrations. Since the activities of these systems do not
match those of the saquayamycins 2, the dihydroxy substitution
at the A/B ring junction must be a key feature in determining
the activity of naturally occurring quinones like the saquaya-
mycins.
these minor products were further characterised. Either 8 or 9
(or a mixture of both) was treated first under acidic, then basic
conditions to give racemic 4 in yields ranging from 80 to 85%.
Since we were unable to obtain crystals of either 8 or 9 that
were suitable for X-ray analysis, the stereochemistry of each of
Experimental
Melting points were determined with a Kofler hot-stage appar-
atus equipped with a Reichart microscope and are uncorrected.
Flash chromatography was performed using Merck 60PF254
‡ The reason why acid treatment precedes base treatment, and why base
treatment alone must not be used, is because base treatment of 6 opens
the A ring to give 2-substituted anthraquinones.5,9
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J. Chem. Soc., Perkin Trans. 1, 2001, 1826–1830

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silica gel (230–400 mesh). Microanalyses were performed by the
University of Otago, Dunedin, New Zealand. Infrared spectra
were recorded with an ATI Mattson Genesis FT IR spec-
trometer (in liquid cells using deuteriochloroform as solvent).
Mass measurements were measured for Mϩ species with a
ؒ
Kratos Concept ISQ mass spectrometer at the University of
Tasmania (Dr N. Davies). Ultraviolet spectra were measured in
ethanol with a Hewlett Packard 845A Diode Array spectro-
1
meter. H and 13C NMR spectra were recorded using either
4.2, 6.0, 12.8 Hz, H6); 3.62 (1H, dd, 6.0, 12.0 Hz, H6a), 3.97
Varian Gemini 2000 (300 MHz 1H INOVA) or Varian 600 MHz
1H spectrometers (using deuteriochloroform as solvent unless
stated to the contrary). Signals were assigned by interpretation
of COSY, HMQC, HMBC and ROESY spectra. Electron
impact mass spectra were measured by direct insertion using a
Finnigan GCQ ion trap mass spectrometer The molecular ion
value and diagnostic fragmentations are recorded.
(1H, br s, H12b); 5.40 (1H, dd, 1.5, 1.8 Hz, H2); 5.54 (1H, td,
2.0, 4.2 Hz, H5); 7.37 (1H, dd, 1.2, 7.8 Hz, H9); 7.75 (1H, t, 7.8
Hz, H10); 8.00 (1H, dd, 1.2, 7.8 Hz, H11). 13C NMR (150 MHz)
δ 20.98 (CH3 acetate); 21.90 (CH3 acetate); 26.94 (CH3); 28.13
(C6); 30.14 (CH3); 32.16 (C3); 45.79 (C12b); 46.74 (C4); 59.3
(C6a); 62.32 (C12a); 119.46 (C5); 122.87 (C7a); 126.02 (C11);
127.10 (C2); 129.10 (C9); 133.64 (C4a); 134.11 (C11a); 135.05
(C10); 143.80 (C1); 149.62 (C8); 169.15 (CO acetate); 170.36
(CO acetate); 187.99 (CO, C12); 193.45 (CO, C7). m/z 487
(MHϩ, 10%); 489 (MHϩ, 10); 407 [Ϫ(CH3CO2H), 22]; 407
[Ϫ(HBr), 43]; 387 and 389 [Ϫ(CH3CO2H ϩ CH2CO), 53]; 365
[Ϫ(HBr ϩ CH2CO), 86]; 347 [Ϫ(HBr ϩ CH3CO2H), 100]; 305
[Ϫ(CH3CO2H ϩ CH2CO ϩ HBr), 58].
2-Bromo-5-acetoxy-1,4-naphthoquinone was prepared from
juglone (5-hydroxy-1,4-naphthoquinone) by
a
reported
procedure.10 5,5-Dimethyl-3-vinylcyclohex-2-en-1-one was
synthesised by a reported techique.11
1-Acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene
A hexane solution of freshly titrated butyllithium (2.32 M, 3.32
cm3) was concentrated in vacuo, and under nitrogen, the residue
dissolved in anhydrous tetrahydrofuran (10 cm3) and cooled to
Ϫ78 ЊC. Diisopropylamine (1.06 cm3) in anhydrous tetrahydro-
furan (10 cm3) was added and the mixture stirred for 30 min
at Ϫ78 ЊC. 5,5-Dimethyl-3-vinylcyclohex-2-en-1-one (1 g) in
anhydrous tetrahydrofuran (5 cm3) was added, the mixture
stirred for 45 min at Ϫ78 ЊC, quenched with acetic anhydride
(1.22 cm3), pyridine (0.14 cm3) and anhydrous tetrahydrofuran
(10 cm3). The mixture was allowed to warm to 20 ЊC over a
period of 45 min, hexane (100 cm3) and iced water (50 cm3)
were added, the organic layer was washed with aqueous sodium
hydrogen carbonate (saturated, 2 × 50 cm3), water (50 cm3),
dried (MgSO4) and the the solvent removed in vacuo to give the
crude product (1.22 g, 95% yield), which is best used immedi-
ately for the next stage of the synthesis. Distillation gave the
pure triene (0.92 g, 75% yield), bp 175–176 ЊC at 760 mmHg.
8-Acetoxy-12a-bromo-3,3-dimethyl-7,8-dioxo-3,4,4a,5,6,6a,7,
12,12a,12b-decahydro-1aH-benzo[6,7]oxireno[2Ј,3Ј:10,10a]-
phenanthro[3,4-b]oxiren-12-yl acetate 6§
A solution of dimethyldioxirane in acetone (81 cm3, 3.0 mmol)
was added to a solution of 5 (586 mg, 1.2 mmol) in acetone
(20 cm3) and allowed to stir at 0 ЊC for 16 h under nitrogen. The
reaction mixture was warmed to 20 ЊC, dried (MgSO4), and the
solvent removed in vacuo to give crude 6 (567 mg, 91%), which
was crystallised from dichloromethane–diethyl ether (1 : 1) as
colourless crystals (512 mg, 82% yield), mp 111 ЊC with decom-
position. The product is unstable and needs to be stored at
Ϫ20 ЊC under nitrogen. Found: C, 55.35; H, 4.3%; C24H23O8Br
requires C, 55.5; H, 4.5%. λmax/nm (log ε/molϪ1 dm3 cmϪ1) 267
(shoulder, 3.72), 314 (3.45), 342 (shoulder, 2.87). νmax (CDCl3)/
1
cmϪ1 1770, 1708, 1594, 1432, 1369, 1263, 1193. H NMR (600
MHz) δ 0.71 (1H, d, 13.8 Hz, H4); 1.20 (3H, s, CH3); 1.25 (3H,
s, CH3); 1.95 (3H, s, 1-acetate); 1.96 (1H, ddd, 1.2, 12.6, 14.0
Hz, H6); 2.27 (1H, d, 13.8 Hz, H4); 2.40 (3H, s, 8-acetate); 2.43
(1H, ddd, 2.4, 4.2, 14.0 Hz, H6); 2.96 (1H, br s, H5); 3.35 (1H,
br s, H2); 3.73 (1H, dd, 4.2, 12.6 Hz, H6a); 3.76 (1H, br s,
H12b); 7.40 (1H, dd, 1.2, 7.5 Hz, H9); 7.78 (1H, t, 7.5 Hz, H10);
7.96 (1H, dd, 1.2, 7.5 Hz, H11). 13C NMR (150 MHz) δ 20.97
(CH3, 8-acetate); 22.43 (CH3); 22.51 (CH3, 1-acetate); 27.71
(CH3); 28.05 (C6); 31.40 (C3); 41.44 (C4); 45.83 (C12b); 54.58
(C6a); 56.99 (C4a); 60.68 (C5); 61.21 (C12a); 67.04 (C2); 83.78
(C1); 122.68 (C7a); 125.70 (C11); 130.30 (C9); 134.66 (C11a);
135.23 (C10); 149.57 (C8); 169.13 (CO, 8-acetate); 169.57 (CO,
1-acetate); 189.34 (C12); 192.41 (C7). m/z 519 (MHϩ, 4%);
517 (MHϩ, 4); 479 and 477 [Ϫ(CH2CO), 5]; 461 and 459
[Ϫ(CH3CO2H), 5]; 379 [Ϫ(CH3CO2H ϩ HBr), 50]; 337 [Ϫ(CH3-
CO2H ϩ HBr ϩ CH2CO), 100]; 319 [Ϫ(CH3CO2H ϩ HBr ϩ
CH2CO ϩ H2O), 30].
Mϩ 192.1150; C12H16O2 requires 192.1150. λmax/nm (log ε/
ؒ
molϪ1 dm3 cmϪ1) 247 (3.63), 277 (3.40). νmax (neat)/cmϪ1 2958,
1
1763, 1653, 1605, 1368. H NMR (300 MHz) δ 1.08 (6H, s,
2 × Me); 2.15 (3H, s, Me); 2.24 (2H, d, 1.2 Hz, H4); 5.12 (1H, d,
10.8 Hz); 5.23 (1H, d, 1.2 Hz, H6); 5.28 (1H, d, 17.4 Hz); 5.69
(1H, s, H2); 6.41 (1H, dd, 17.4, 10.8 Hz). 13C NMR (75 MHz)
δ 20.68 (CH3); 28.05 (2 × CH3); 31.99 (C3); 36.3 (CH2); 113.30;
121.20; 122.73; 136.84 (C5); 137.59; 144.73 (C1); 168.91 (CO).
m/z 193 [(MHϩ), 100%], 177 [Ϫ(CH4), 10], 151 [Ϫ(C2H2O), 22],
135 [Ϫ(C2H2O ϩ CH4), 47].
1-Acetoxy-12a-bromo-3,3-dimethyl-7,12-dioxo-3,4,6,6a,7,12,
12a,12b-octahydrobenzo[a]anthracen-8-yl acetate 5
A mixture of 5-acetoxy-2-bromo-1,4-naphthoquinone (3.08 g)
and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene (2.0 g)
in anhydrous toluene (160 cm3) was heated at reflux for 24 h
under nitrogen. The reaction mixture was cooled to 20 ЊC and
the solvent removed in vacuo to afford an orange residue (2.33
g, 92%), which was purified by flash chromatography on silica
eluting with dichloromethane–acetone (98 : 2) under nitrogen,
followed by crystallisation from propan-2-ol–diethyl ether
(1 : 1) (under nitrogen) to give colourless crystals of 5 (1.63 g,
63%) (mp 112 ЊC with decomposition), which oxidise readily on
contact with air. Found: C, 59.0; H, 4.6%; C24H23O6Br requires
C, 59.15; H. 4.75%. λmax/nm (log ε/molϪ1 dm3 cmϪ1) 258
(shoulder, 3.60), 312 (3.37). νmax (Nujol)/cmϪ1 1773, 1751, 1704,
1589, 1233, 1217, 1180. 1H NMR (600 MHz COSY and
GHMBC) δ 1.04 (3H, s, CH3); 1.12 (3H, s, CH3); 2.10 (3H, s,
1-acetate); 2.06 (1H, dd, 1.8, 12.9 Hz, H4); 2.30 (1H, ddd, 4.2,
12.0, 12.8 Hz, H6); 2.34 (1H, br d, 12.9 Hz, H4); 2.45 (1H, ddd,
Mild acid hydrolysis of 6
A mixture of 6 (400 mg), water (5 cm3), tetrahydrofuran
(80 cm3) and toluene-p-sulfonic acid (5 mg) was heated under
reflux for 16 h under nitrogen. With the system under nitrogen,
the solvent was removed in vacuo, dichloromethane (100 cm3)
was added, and the mixture washed with water (50 cm3), aque-
ous sodium chloride (saturated, 50 cm3), dried (MgSO4), and
the solvent removed in vacuo. The mixture was separated by
§ The numbering used in the NMR data for compound 6 is as indicated
in the title. The IUPAC name for compound 6 is 7-acetoxy-11a-bromo-
2,2-dimethyl-6,11-dioxo-2,3,4a,5,5a,6,11,11a,11b,11c-decahydro-1aH-
benzo[6,7]oxireno[2Ј,3Ј:10,10a]phenanthro[3,4-b]oxiren-11c-yl acetate.
J. Chem. Soc., Perkin Trans. 1, 2001, 1826–1830
1829

View Article Online
flash chromatography over silica and under nitrogen, eluting
with dichloromethane–acetone (9 : 1) to give a major product 7
(130 mg, 43%) and a minor product 8 (90 mg, 27% yield).
(10%, 50 cm3) was added, followed by water (50 cm3), the
extract dried (MgSO4), and the solvent removed in vacuo. The
residue was crystallised from hot ethanol–methanol (1 : 1) as
fine orange crystals (38 mg, 45%), mp 172 ЊC with decom-
position. Mϩ = 336.0991; C20H16O5 requires 336.0997. λmax/nm
ؒ
2,5-Dihydroxy-3,3-dimethyl-1,7,12-trioxo-1,2,3,4,5,6,7,12-
octahydrobenzo[a]anthracen-8-yl acetate (8). Crystallised from
ethanol as light orange crystals [112 mg, purified yield from 6
37%], mp 184 ЊC with decomposition. Product 7 oxidises in air,
and should be kept at Ϫ20 ЊC under nitrogen. Found: C, 66.8;
H, 5.1%; C22H20O7 requires C, 66.7; H, 5.1%. λmax/nm (log ε/
molϪ1 dm3 cmϪ1) 250 (4.31), 284 (shoulder, 4.00), 345 (3.68).
νmax (Nujol)/cmϪ1 3436, 1772, 1769, 1749, 1671, 1656, 1589,
1274, 1184. 1H NMR (600 MHz) δ 0.84 (3H, s, CH3); 1.26 (3H,
s, CH3); 2.34 (1H, dd, 15.6, 16.8 Hz, H6); 2.43 (3H, s, 8-acetate);
2.47 (1H, d, 20.0 Hz, H4); 3.07 (1H, d, 20.00 Hz, H4); 3.22 (1H,
dd, 6.6, 16.8 Hz, H6); 4.15 (1H, br d, 4.2 Hz, 2-OH); 4.30 (1H,
d, 4.2 Hz, H2); 4.44 (1H, ddd, 6.0, 6.6, 15.6 Hz, H5); 5.58 (1H,
d, 6.0 Hz, 5-OH); 7.37 (1H, dd, 1.2, 7.8 Hz, H9); 7.77 (1H, t, 7.8
Hz, H10); 7.93 (1H, dd, 1.2, 7.8 Hz, H11). 13C NMR (150 MHz)
δ 18.34 (CH3); 20.12 (COCH3); 26.85 (CH3); 27.76 (C6); 37.85
(C4); 39.00 (C3); 66.62 (C5); 78.91 (C2); 122.23 (C7a); 123.74
(C11); 124.52 (C12b); 128.28 (C9); 133.56 (C11a); 133.76 (C10);
137.44 (C6a); 141.20 (C12a); 148.26 (C8); 165.98 (C4a); 168.21
(CO acetate); 179.86 (C12); 180.67 (C7); 196.03 (C1). m/z 396
(log ε/molϪ1 dm3 cmϪ1) 265 (3.96), 400 (3.21). νmax (Nujol)/cmϪ1
3440, 1693, 1666, 1633, 1589, 1348, 1284. 1H NMR (300 MHz)
δ 0.78 (3H, s, CH3); 1.35 (3H, s, CH3); 2.95 (1H, d, 17.4 Hz, H4);
3.21 (1H, d, 17.4 Hz, H4); 3.88 (1H, br s, 2-OH); 4.65 (1H, s,
H2); 7.29 (1H, t, 3.9 Hz, H10); 7.57 (1H, d, 7.8 Hz, H5); 7.68
(2H, br d, 3.9 Hz, H9, H11); 8.36 (1H, d, 7.8 Hz, H6); 12.22 (1H,
s, 8-OH). 13C NMR (75 MHz) δ 18.49 (CH3); 27.52 (CH3); 42.38
(C3); 43.34 (C4); 80.89 (C2); 115.04; 119.28; 123.44; 129.88;
132.87; 133.32; 133.56; 134.94; 136.90; 149.36; 163.81 (8-OH);
182.50; 186.91; 198.78. m/z 336 [(Mϩ ), 45%]; 318 [Ϫ(H2O),
ؒ
20]; 290 [Ϫ(H2O ϩ CO), 30]; 264 [Ϫ(C4H8O), 100]; 236
[Ϫ(C4H8O ϩ CO), 15].
From 8 and/or 9. The required product 4 can be produced
from either 8 or 9 by the same procedure as that used from 6
above. The crude yield from both procedures is greater than
90%, the purified yield (after crystallisation), 80–85%.
X-Ray structure determination¶
(Mϩ , 2%); 378 [Ϫ(H2O), 9]; 336 [Ϫ(H2O ϩ CH2CO), 61];
ؒ
A full sphere of ‘low temperature’ CCD area-detector diffrac-
tometer data was measured (Bruker AxS instrument, T ca. 153
K; ω-scans, 2φmax = 75Њ; monochromatic Mo Kα radiation,
λ = 0.71073 Å) yielding 40562 total reflections, merging to
10667 (Rint = 0.036) after ‘empirical’/multiscan absorption
correction (proprietary software), 6875 with F > 4σ(F) con-
sidered ‘observed’ and used in the full matrix least squares
refinement, refining non-hydrogen atom anisotropic displace-
ment parameters and (x, y, z, Uiso)H. Conventional residuals R,
Rw on |F| at convergence were 0.030, 0.028; neutral atom com-
plex scattering factors were employed within the Xtal 3.7 pro-
gram system.12 Pertinent results are given in Fig. 1, Table 1, and
the .cif deposition.§ C24H23BrO6, M = 487.4, monoclinic, space
group P21/c (C52h, No. 14), a = 8.8741(4), b = 20.104(1), c =
12.2989(6) Å, β = 101.637(1)Њ, V = 2149.0 Å3, Dc (Z = 4) = 1.506
g cmϪ3, µMo = 19.5 cmϪ1; specimen: 0.30 × 0.25 × 0.20 mm.
T min, T max = 0.71, 0.80.
318 [Ϫ(H2O ϩ CH2CO ϩ H2O), 42]; 290 [Ϫ(H2O ϩ CH2CO ϩ
H2O ϩ CO), 43]; 264 [Ϫ(H2O ϩ CH2CO ϩ C4H8O), 100].
2-Acetoxy-5-hydroxy-3,3-dimethyl-1,7,12-trioxo-1,2,3,4,5, 6,
7,12-octahydrobenzo[a]anthracen-8-yl acetate (9). Crystallised
from chloroform–diethyl ether (1 : 1) as light orange crystals
(74 mg, purified yield from 6 22%), mp 164–166 ЊC. Product 8
oxidises in the air and should be stored at Ϫ20 ЊC under nitro-
gen. Found: C, 65.5; H, 5.1%; C24H22O8 requires C, 65.75; H,
5.1%. λmax/nm (log ε/molϪ1 dm3 cmϪ1) 249 (4.08), 280 (shoulder,
3.81), 345 (3.46). νmax (Nujol)/cmϪ1 3474, 1770, 1733, 1689,
1650, 1640, 1587, 1243, 1193. 1H NMR (600 MHz) δ 1.01 (3H,
s, CH3, 8-acetate); 2.24 (3H, s, CH3, 2-acetate); 2.40 (1H, dd,
11.4, 16.8 Hz, H6); 2.43 (3H, s, CH3, 8-acetate); 2.58 (1H, br d,
20.2 Hz, H4); 2.81 (1H, d, 5.4 Hz, 5-OH); 3.07 (1H, d, 20.2 Hz,
H4); 3.23 (1H, dd, 7.0, 16.8 Hz, H6); 4.59 (1H, ddd, 5.4, 7.0,
11.4 Hz, H5); 5.43 (1H, s, H2); 7.27 (1H, dd, 1.2, 7.8 Hz, H9);
7.65 (1H, 7.8 Hz, H10); 7.91 (1H, dd, 1.2, 7.8 Hz, H11). 13C
NMR (600 MHz GHMQC) δ 20.70 (CH3); 20.74 (COCH3);
21.09 (COCH3); 27.48 (CH3); 28.76 (C6); 38.30 (C4); 39.42
(C3); 68.17 (C5); 80.96 (C2); 122.92 (C7a); 125.28 (C11); 126.79
(C12b); 129.02 (C9); 134.34 (C11a); 134.80 (C10); 138.35 (C6a);
142.74 (C12a); 149.10 (C8); 163.22 (C4a); 169.54 (CO acetate);
170.52 (CO acetate); 180.43 (C12); 181.63 (C7); 190.41 (C1).
¶ CCDC reference number 159020. See http://www.rsc.org/suppdata/pl/
b1/b101756j/ for crystallographic files in .cif or other electronic format.
References
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ؒ
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1830
J. Chem. Soc., Perkin Trans. 1, 2001, 1826–1830