Pigments of Fungi. LIX - Synthesis of (1S,3S)- and (1R,3R)-austrocortilutein and (1S,3S)-austrocortirubin from citramalic acid

Article abstract of DOI:10.1071/CH99091

The naturally occurring tetrahydroanthraquinone (1S,3S)-austrocortilutein (1) is synthesized for the first time in enantiomerically pure form by Diels-Alder cycloaddition between the functionalized butadiene derivative (8) and the chiral 1,3-dihydroxy-1,2,3,4-tetrahydro-5,8-naphthoquinone (9), the latter being derived from (R)-citramalic acid (3). The natural products (1S,3S)-austrocortirubin (2) and (1R,3R)-austrocortilutein (5) were also prepared for the first time by using the same strategy. CSIRO 2000.

Full text of DOI:10.1071/CH99091

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Volume 53, 2000
© CSIRO 2000
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Aust. J. Chem., 2000, 53, 245–256
Pigments of Fungi. LIX*†
Synthesis of (1S,3S)- and (1R,3R)-Austrocortilutein
and (1S,3S)-Austrocortirubin from Citramalic Acid
Melvyn Gill,A,B Michael F. HarteA and Abilio TenA
A School of Chemistry, The University of Melbourne, Parkville, Vic. 3010.
B Author to whom correspondence should be addressed.
The naturally occurring tetrahydroanthraquinone (1S,3S)-austrocortilutein (1) is synthesized for the first time in
enantiomerically pure form by Diels–Alder cycloaddition between the functionalized butadiene derivative (8) and
the chiral 1,3-dihydroxy-1,2,3,4-tetrahydro-5,8-naphthoquinone (9), the latter being derived from (R)-citramalic
acid (3). The natural products (1S,3S)-austrocortirubin (2) and (1R,3R)-austrocortilutein (5) were also prepared for
the first time by using the same strategy.
Keywords. Diels–Alder cycloaddition; functionalized butadiene; quinone.
Introduction
involves the chiral tetrahydronaphthoquinone dienophile (9)
as the AB ring precursor (Scheme 2). Our reasons for not
developing the earlier strategy in a monochiral sense [for
example, by asymmetric dihydroxylation5 of the olefinic
double bond in the intermediate quinone (7)] include, inter
alia, the chemical inefficiency of the later steps in that
sequence.4 Consequently, we devised the approach to
(1S,3S)-austrocortilutein (1) that is represented in
retrosynthetic terms in Scheme 2. Thus, we envisaged that
The fruiting bodies of theAustralasian fungus Dermocybe
splendida owe their spectacular colour to the presence of
mixtures of yellow and red tetrahydroanthraquinone pig-
ments that consist predominantly of (1S,3S)-austrocorti-
lutein (1) and (1S,3S)-austrocortirubin (2).1‡ These were the
first tetrahydroanthraquinones to be isolated from the higher
fungi and they are of special significance because of their
activity at low concentration against not only a range of
Gram-positive and Gram-negative bacteria and fungi1 but
also against melanoma cancer cells. The structure and stere-
ochemistry of these two compounds and their synthesis in
isochiral3 form have been described in earlier papers in this
series.1,4 We report here the first total synthesis of (1S,3S)-
austrocortilutein (1) and (1S,3S)-austrocortirubin (2) in
monochiral3 form beginning from (R)-citramalic acid (3).
(1R,3R)-Austrocortilutein (5), which we have isolated from
a toadstool that is closely related to D. splendida (see below),
is synthesized likewise beginning from (S)-citramalic acid
(4).
Results and Discussion
Our previous synthesis of the isochiral pigments (1) and
(2) involved a Diels–Alder reaction between the naphthop-
urpurin acetal (6) (as the precursor to the BC ring system) and
isoprene as the first step of the sequence (Scheme 1).4 Our
approach to the pigments (1) and (2) in monochiral form also
involves a Diels–Alder cycloaddition reaction, but in this
case one that takes place late in the synthetic sequence and
* This paper is dedicated to Professor D. W. Cameron with thanks for his support, guidance and friendship and in recognition of his contribution,
over many year, to quinone chemistry.
† Part LVIII, Aust J. Chem., 1999, 52, 1035; Part LX, Nat. Prod. Lett., 2000, in press; Part LXI, Aust. J. Chem., 1999, 52, 989.
‡ The quinones (1) and (2), and some minor quinones, are present in the intact toadstools mostly as the corresponding 8-O-␤-D-gentiobiosides.2
Manuscript received 27 July 1999
© CSIRO 2000
10.1071/CH99091
0004-9425/00/040245

246
M. Gill, M. F. Harte and A. Ten
1,3-dihydroxytetrahydroanthraquinones such as (1S,3S)-
austrocortilutein (1) should be accessible by way of a
Diels–Alder reaction between 1,3-dimethoxy-1-trimethyl-
silyloxybuta-1,3-diene (8)6 and the hitherto unknown chiral
tetrahydronaphthoquinone (9). Furthermore, the quinone
(9) should itself be available by an intramolecular
Friedel–Crafts reaction of the chiral aldehyde (10). In turn,
the aldehyde (10) would result from opening of the chiral
oxiran (11) with the Grignard or cuprate reagent derived
from 2-bromo-1,4-dimethoxybenzene. The chiral oxiran
(11) is available, in principle, in both enantiomeric forms
from citramalic acid by methods developed earlier in our
laboratory for other purposes.7
There were several stereochemical questions that needed
to be addressed before this plan could be put into practice.
Firstly, the Diels–Alder reaction between (8) and (9) must be
regioselective in the desired sense. In this regard it was
expected that the C 1 hydroxy group* in (9) would promote
the regioselectivity shown by hydrogen bonding to some
degree to the peri-quinone carbonyl group. It is well known
that hydrogen bonding of naphthoquinone carbonyl groups
by peri-phenolic hydroxy groups is a powerful control
element during cycloaddition processes.8 Secondly, the
intramolecular Friedel–Crafts reaction of the chiral aldehyde
(10) en route to the 1,3-diol (9) must proceed with a high
degree of stereoselectivity. Fortunately, it is known that the
use of certain Lewis acids in such reactions is chelation-con-
trolled and should promote the desired outcome in the
present case.9 Both of these aspects of the process will be dis-
cussed in more detail as they appear later in this paper.
The source of chirality in the retrosynthesis shown in
Scheme 2 is citramalic acid, which is commercially available
in both enantiomeric forms. Unfortunately, the commercial
material is expensive [e.g., $37/g for the (R)-enantiomer (3)
from Aldrich©] and, because of its position at the beginning
of the sequence, we considered it preferable to pursue a more
economical source of this raw material.
A great deal of effort has been invested in the synthesis of
citramalic acid in monochiral form due to its considerable
potential as a chiral building block in organic synthesis.10
Both enantiomers have been obtained by (i) classical resolu-
tion of the isochiral acid,11 (ii) microbiological methods10,12
and (iii) enantioselective synthesis.13 The most efficient syn-
thesis is due to Staring, Moorlag and Wynberg14 who
obtained (R)- and (S)-citramalic acids (3) and (4), respec-
tively, each in 100% e.e., by hydrolysis of the corresponding
(S)- and (R)-enantiomers (12) and (13) of 4-methyl-4-
(trichloromethyl)oxetan-2-one. The oxetanones (12) and
(13) are themselves obtained (83% yield, 100% e.e.) by
cycloaddition between ketene and 1,1,1-trichloroacetone in
the presence of quinine on the one hand and quinidine on the
other. Both oxetanones (12) and (13) are commercially avail-
able ($7/g from Aldrich©) and they provide, in our opinion,
the cheapest source of workable quantities of enantiomeri-
cally pure citramalic acid.
* Austrocortilutein numbering. However, under IUPAC recommendations, compound (9) is named as 5,7-dihydroxy-7-methyl-5,6,7,8-tetrahydro-
1,4-naphthoquinone.

Pigments of Fungi. LIX
247
signals due to the C 1 methylene protons [from ␦ 3.39 and
3.46 in (18) to ␦ 4.06 in (19)] proves that the ester is a
primary mesylate.15
Exposure of the mesylate (19) to DBU gave (R)-2-methyl-
2-[2Ј-(phenylmethoxy)ethyl]oxiran (11)† as a colourless oil,
[␣]D –9.4 (c, 3.0 in CHCl3), the structure of which is fully
consistent with the spectroscopic data. In particular, the 1H
n.m.r. spectrum shows a two-proton singlet at ␦ 4.50 and a
five-proton multiplet centred at ␦ 7.32 due to the benzylic
and aromatic protons, respectively, while the protons of the
C 2 methyl group resonate at ␦ 1.34 as a doublet (J 0.5 Hz)
due to long-range coupling with one of the methylene
protons at C 3. The diastereotopic methylene protons at C 3
form an AB quartet with components centred at ␦ 2.60 and ␦
2.70 while the protons of the C 1Ј and C 2Ј methylene groups
each give rise to multiplets due to geminal and vicinal cou-
plings.
The chemistry depicted in Scheme 3 and discussed above
brings us to what was our first target, the enantiomerically
pure oxiran (11);‡ pleasingly, each step proceeds in greater
than 80% chemical yield.
The next phase of the synthesis takes us from the (R)-
oxiran (11) to the pivotal (1S,3S)-1,3-dihydroxy-1,2,3,4-
tetrahydronaphthoquinone (9) (Scheme 4). Accordingly,
2-bromo-1,4-dimethoxybenzene was prepared by bromina-
tion of 1,4-dimethoxybenzene with potassium bromide and
hydrogen peroxide in the presence of sulfuric acid16 and sub-
sequently transformed to the corresponding Grignard
reagent (20) in standard fashion. Addition of a tetrahydrofu-
ran solution of (20) at –78°C to the oxiran (11) in the pres-
Scheme 3. (i) NaOH, 5°C, H2O; (ii) CH2N2, CH2Cl2/EtOH; (iii)
LiAlH4, tetrahydrofuran, 65°C; (iv) acetone, p-toluenesulfonic acid,
24 h; (v) PhCH2Br, NaH, Bu4NI, tetrahydrofuran, 18 h; (vi) 1 M H2SO4,
tetrahydrofuran, 4 h; (vii) methanesulfonyl chloride, Et3N, CH2Cl2,
–10°C, 10 min; (viii) DBU, CH2Cl2, 1 h.
The Synthesis of (1S,3S)-Austrocortilutein (1)
Our route from the (S)-oxetanone (12) to the (R)-oxiran
(11) is summarized in Scheme 3. Thus, (R)-citramalic acid
(3) was prepared from the (S)-oxetanone (12) by Wynberg’s
method and was esterified with an excess of diazomethane to
give dimethyl (R)-citramalate (14), [␣]D –28.0 (c, 3.3 in
CHCl3), in 83% yield from (12). Treatment of the ester (14)
with an excess of lithium aluminium hydride in tetrahydro-
furan at reflux gave (R)-2-methylbutane-1,2,4-triol (15) as a
viscous oil, [␣]D +1.5 (c, 3.1 in EtOH). The vicinal hydroxy
groups of the triol (15) were simultaneously masked as the
dioxolan (16), [␣]D +8.8 (c, 3.0 in CHCl3), by treatment at
room temperature with acetone in the presence of p-toluene-
sulfonic acid during 24 h. It is known that the dioxolan (16)
predominates over the corresponding dioxan when this reac-
tion is conducted under conditions of thermodynamic
control.7
Benzylation of the residual hydroxy group in (16) gave an
excellent yield of the (R) benzyl ether (17) as a colourless oil,
[␣]D +2.4 (c, 4.2 in CHCl3), from which the acetal was
removed with sulfuric acid. The resulting (R) diol (18),* [␣]D
–9.3 (c, 4.1 in CHCl3), was mesylated selective at the
primary hydroxy group by using 1 equiv. of methanesulfonyl
chloride at –10°C in dichloromethane containing triethy-
lamine. Under these conditions the (R) methanesulfonate
(19) was obtained in high yield as a colourless oil, [␣]D +3.9
(c, 3.2 in CHCl3). A three-proton singlet at ␦ 3.02 in the 1H
n.m.r. spectrum of the ester (19) confirmed the presence of
the methanesulfonate group, while the downfield shift in the
Scheme 4. (i) Dilithium tetrachlorocuprate 0.1 M, tetrahydrofuran,
–78°C; (ii) H2/Pd/C, MeOH; (iii) 1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3(1H)-one, H2O, CH2Cl2, 6 h; (iv) SnCl4, –78 to –30°C,
3.5 h; (v) ceric ammonium nitrate, MeCN/H2O, 5 min.
* The (S) diol ent-(18) was obtained in monochiral form by the same method beginning from the (R)-oxetanone (13) (see above); in contrast ent-
(18) was produced in only 47% e.e. from the benzyl ether of 3-methylbut-3-en-1-ol by treatment with AD-mix-␣.5
† (±)-(11) is readily available from 3-methylbut-3-en-1-ol by benzylation followed by epoxidation of the olefinic double bond with magnesium
monoperoxyphthalate. Most of the subsequent new chemistry was developed using (±)-(11) before being applied to the monochiral series.
‡ The enantiomeric purity of (11) was confirmed by subsequent transformations that ultimately delivered the natural product (1).

248
M. Gill, M. F. Harte and A. Ten
ence of dilithium tetrachlorocuprate gave (S)-4-benzyloxy-
1-(2Ј,5Ј-dimethoxyphenyl)-2-methyl-4-phenoxybutan-2-ol
(21) as a colourless oil, [␣]D –7.2 (c, 1.9 in CHCl3), in 92%
yield. The structure (21) for the product is entirely consistent
and ␦ 6.80, due to the aromatic protons, and two methoxy
resonances, at ␦ 3.72 and ␦ 3.73. It is possible that the car-
bonyl compounds (24) and (25) are formed by initial loss of
the C 3 hydroxy group (as H2O) from (10) to give one or
other of the alkenes (26) and (27). Subsequent oxidative
cleavage of the resulting double bond in (26) would give the
aldehyde (24), while analogous cleavage of (27) would give
the ketone (25).
1
with the spectroscopic data. Thus, the H n.m.r. spectrum
contains an AB quartet with components centred at ␦ 2.73
and 2.82 due to the diastereotopic protons of the C 1 meth-
ylene group. A two-proton singlet at ␦ 4.40 assigned to the
benzylic protons of the protecting group and a complex four-
proton couplet, with components centred at ␦ 1.83 and 3.72,
accounts for the remaining methylene protons of the side
chain. Also present in the sprectrum are methoxy resonances
at ␦ 3.75 and 3.77, a C-methyl singlet at ␦ 1.10 and an enve-
lope of resonances between ␦ 6.70 and 7.38, which account
for eight aromatic protons.
Stereospecific cyclisation of the aldehyde (10) to the
tetrahydronaphthalene (23) is an important step in our
approach to (1S,3S)-austrocortilutein (1) since it is during this
step that the stereochemistry at C 3 is translated to C1. It was
achieved by treatment of the aldehyde (10) with tin(IV) chlo-
ride in dichloromethane at –78°C, which gave the (1S,3S)-diol
(23) as a colourless crystalline solid, [␣]D –6.8 (c, 2.6 in
CHCl3), in 84% yield. The structure and relative stereochem-
istry of the tetrahydronaphthalene (23) are in full accord with
the analytical and spectroscopic data. Thus, combustion anal-
ysis and mass spectrometry lead to the molecular formula
C13H18O4. In the 1H n.m.r. spectrum there are three-proton sin-
glets at ␦ 3.79 and 3.85, due to the aromatic methoxy groups,
a broad signal between ␦ 6.71 and 6.81 from two aromatic
protons, and characteristic set of signals from the protons of a
3-hydroxy-3-methyltetrahydroaromatic ring. Thus, one of the
C 2 protons appears as a double doublet at ␦ 1.85 (J 14.5 and
5.0 Hz) and the other as a double doublet of doublets at ␦ 2.26
(J 14.5, 2.2 and 2.2 Hz). The protons at C 4 appear as a doublet
(J 17.7 Hz) at ␦ 2.46 and a double doublet (J 17.7 and 2.2 Hz)
at ␦ 3.07. The alcoholic methine proton (H 1) appears as a mul-
tiplet at ␦ 5.17 and the protons of the C 3 methyl group res-
onate at ␦ 1.42. The protons at ␦ 2.26 and 3.07 are W-coupled
and can be assigned to Heq2 and Heq4, respectively, and there-
fore the signals at ␦ 1.85 and 2.46 must be due to Hax2 and
Hax4, respectively. The magnitude of the vicinal coupling con-
stants between H 1 and the protons at C 2 (J ≤ 5.0 Hz) pre-
cludes any trans-diaxial relationships and places the hydroxy
groups at C 1 and C 3 on the same face of the tetrahydroaro-
matic ring. Since the absolute stereochemistry at C 3 is known
to be (S), the configuration at C 1 in (23) must also be (S). The
1H n.m.r. data discussed above are very similar to the corre-
sponding chemical shifts and coupling constants observed in
the spectrum of the natural product (1).1
Hydrogenolysis of the benzyl ether group in (21) gave the
(S) diol (22) as a colourless oil, [␣]D –1.6 (c, 2.1 in CHCl3),
in quantitative yield. The composition of the important chiral
diol (22) was confirmed by combustion analysis and the
structure was in full accord with the spectroscopic data
(Experimental section). Oxidation of the primary alcohol
group in (22) to the corresponding aldehyde (10) in an
acceptable yield proved to be a major challenge and several
oxidizing agents were investigated before optimum condi-
tions were defined. The best yield of (10) (90%) was
obtained by using the Dess–Martin periodinane.17 The
reagent was prepared in the prescribed way and, when this
was stirred with the alcohol (22) in wet dichloromethane at
room temperature, gave the aldehyde (10), [␣]D +13.5 (c, 2.8
in CHCl3). The structure of the aldehyde (10) was confirmed
1
from the H n.m.r. spectrum in which the aldehydic proton
resonates at ␦ 9.83 as a triplet (J 2.2 Hz) due to vicinal cou-
pling with the protons of the C 2 methylene group. The
signals from the methylene protons themselves appear as an
AB quartet with components centred at ␦ 2.45 and 2.55. The
carbonyl carbon in (10) resonates at ␦ 203.2 in the 13C n.m.r.
spectrum.
The stereospecificity of the intramolecular Friedel–Crafts
reaction of (10) suggests that the Lewis acid chelates to the C 3
hydroxy group and to the carbonyl oxygen in (10), as shown
in Fig. 1. Consequently, if carbon–carbon bond formation
involves a chair-like transition state then the nucleophile can
only attack the re face of the aldehyde carbonyl group.
Less successful were attempts to oxidize the alcohol (22)
under Swern18 conditions [50% yield of (10)], by using pyri-
dinium dichromate19 (37% yield) and with tetrapropylam-
monium perruthenate20 (28%). With pyridinium dichromate,
the alcohol (22) gave not only the aldehyde (10) but also
1
16% of 2,5-dimethoxybenzaldehyde (24), the H n.m.r.
spectrum of which was identical with that of an authentic
sample. Similarly, the reaction of (22) with the perruthenate
reagent gave, inter alia, 1-(2Ј,5Ј-dimethoxyphenyl)propan-
2-one (25) (12%). The 1H n.m.r. spectrum of (25) contains
singlets at ␦ 2.13 and ␦ 3.63, due to the C 3 methyl and C 1
methylene protons, respectively, a multiplet between ␦ 6.70
Fig. 1. Lewis acid chelation in the intramolecular Friedel–Crafts
reaction of (10).

Pigments of Fungi. LIX
249
Oxidative demethylation of the tetrahydronaphthalene (23)
with ceric ammonium nitrate in aqueous acetonitrile gave
(1S,3S)-1,3-dihydroxy-1,2,3,4-tetrahydronaphthoquinone (9)
as a yellow gum, [␣]D –63 (c, 0.81 in EtOH), in quantitative
yield. High-resolution mass measurement confirmed the
molecular formula C11H12O4 and the 13C n.m.r. spectrum con-
tains carbonyl carbons resonances at ␦ 187.2 and 187.6.
With the important chiral dienophile (9) in hand, the diene
(8) necessary for assembly of the C ring in (1S,3S)-austrocor-
tilutein (1) was prepared from methyl acetoacetate in 62%
yield over two steps.6 To effect the requisite Diels–Alder reac-
tion between (8) and (9) a solution of the two in benzene was
stirred at room temperature for 9 h (Scheme 5). We did not
attempt to isolate the presumed adducts (28) and (29) but
rather added water and stirred the mixture vigorously in the air
for 12 h to cause aromatization to a mixture of the corre-
sponding naphthoquinones.At this stage the mixture consisted
of the hydroxy quinone (1) and its phenolic methyl ether (30)
derived from the adduct (28), and the quinones (31) and (32)
arising from the adduct (29). While the ratio of the adducts
(28) and (29) is controlled by the regioselectivity of the
Diels–Alder reaction, the ratio of the quinones (1) and (30) on
the one hand, and (31) and (32) on the other, could vary
depending on the conditions employed for aromatization of
the original adducts. The products obtained under the condi-
tions described above were separated by preparative thin-layer
chromatography into two yellow zones. The more mobile zone
(RF 0.40) consisted of a mixtureof (1S,3S)-austrocortilutein (1)
and its regioisomer (31) in a ratio of 4 : 1 and in a combined
yield of 40%.* The quinones (1) and (31) could not be sepa-
rated by using chromatography but they can be differentiated
Scheme 5. (i) Benzene, room temp., 9 h; (ii) H2O, O2, 12 h.
nevertheless, fractional crystallization of the mixture from
chloroform gave (1S,3S)-austrocortilutein (1) in pure form
as orange-yellow needles, m.p. 183–185°C, [␣]D +55 (c,
0.10 in CHCl3), in 22% yield from the chiral tetrahydro-
naphthoquinone (9). Some of the important physical and
spectroscopic properties of the synthetic material are com-
pared with those reported1 for the quinone from Dermocybe
splendida in Table 1. From this comparison it is clear that
both structurally and stereochemically the synthetic and
natural samples of (1S,3S)-austrocortilutein (1) are identi-
cal. This is the first report of the total synthesis of the natural
product (1) in monochiral form.
1
and their relative proportions quantified from the H n.m.r.
spectrum of the mixture. Of particular value in this regard are
the hydrogen-bonded phenolic hydroxy resonances, which are
well resolved at ␦ 12.20 for (1) and 12.24 for (31).
Likewise, the lower RF yellow zone (RF 0.20) consisted of
a mixture of the quinone 8-O-methyl ethers (30) and (32) that
were identified by 1H n.m.r. spectroscopy. In the case of the
reaction described above the ratio of the higher to lower RF
zones (hydroxy quinones to their ethers) was greater than
95 : 5. The methyl ethers (30) and (32) could be demethylated
to their counterparts (1) and (31) by using boron trichloride
at –78°C but this process was inefficient and was not
employed on a routine basis.
Although aerial aromatization of the cycloadducts (28) and
(29) was the most efficient in terms of the yield of the natural
product (1), other conditions were examined. When exposed
to DBU/oxygen the adducts (28) and (29) gave a preponder-
ance of the methyl ethers (30) and (31) (31% isolated yield)
over the hydroxy quinones (1) and (31) (4%). With silica gel/
oxygen and with DDQ equal amounts of the hydroxy and
methoxy quinones resulted (40–50% combined yield). Poor
yields (<20%) of the quinones (1) and (31) were recovered
from reactions with oxygen under acidic conditions.
The Synthesis of (1S,3S)-Austrocortirubin (2)
(1S,3S)-Austrocortirubin (2) should be available by
Diels–Alder cycloaddition of the (1S,3S)-tetrahydronaphtho-
quinone (9) with the known22 oxygenated diene (33)
(Scheme 6). Accordingly, the enol ether of methyl 4-
methoxy-3-oxobutanoate was generated, deprotonated, and
the enolate so formed was trapped with chlorotrimethylsi-
lane. The resulting diene (33) was obtained in 77% yield as
a colourless oil, the 1H n.m.r. spectrum of which consists of
signals from one trimethylsilyl group (␦ 0.29), three enolic
methyl ether groups (␦ 3.56, 3.61 and 3.67), and two olefinic
protons (␦ 4.46 and 5.82). The diene (33) is stable if stored
under nitrogen at –78°C but is prone to decomposition on
standing at higher temperatures for longer periods.
As was mentioned above, the tetrahydroanthraquinones
(1) and (31) could not be separated by chromatography;
When the diene (33) and the chiral quinone (9) were
stirred together at room temperature for 18 h (Scheme 6) and
* This ratio was not improved by carrying out the Diels–Alder reaction in the presence of Lewis acids such as tetraacetyl diborate.21

250
M. Gill, M. F. Harte and A. Ten
Table 1. Some physical and spectroscopic properties of natural and synthetic (1S,3S)-austrocortilutein (1)
Property
Natural product (1)1
183–185
Synthetic (1)
182–185
M.p. (°C)
[␣]D
+52 (c, 0.095 in CHCl3)
+55 (c, 0.10 in CHCl3)
1H n.m.r.A ␦
1.45 (3H, s, 3-Me)
1.45 (3H, s, 3-Me)
1.82 (1H, dd, 14.7, 5.1, Hax 2)
2.30 (1H, ddd, 14.7, 1.8, 1.8, Heq 2)
2.41 (1H, dd, 19.8, 1.5, Hax 4)
3.02 (1H, dd, 19.8, 1.8, Heq 4)
3.06 (1H, s, 3-OH)
1.82 (1H, dd, 14.7, 5.1 Hz, Hax 2)
2.32 (1H, ddd, 14.7, 1.8, 1.8, Heq 2)
2.41 (1H, dd, 19.8, 1.5, Hax 4)
3.01 (1H, dd, 19.8, 1.8, Heq 4)
3.08 (1H, m, 3-OH)
3.51 (1H, d, 5.1, 1-OH)
3.91 (3H, s, 6-OMe)
3.51 (1H, m, 1-OH)
3.91 (3H, s, 6-OMe)
5.08 (1H, m, H1)
5.08 (1H, m, H1)
6.65 (1H, d, 2.6, H7)
6.64 (1H, d, 2.4, H 7)
7.19 (1H, d, 2.6, H5)
7.17 (1H, d, 2.4, H 5)
12.21 (1H, s, 8-OH)
12.20 (1H, s, 8-OH)
␯
max (cm–1)
m/z
(e.i. 15 eV)
1667, 1639
1665, 1641
304 (55%), 286 (78), 271 (28), 268
(43), 262 (31), 247 (25), 246 (62),
245 (25), 244 (100), 243 (57), 219
(30), 218 (58), 151 (28), 43 (75), 18
(27)
304 (42%), 286 (77), 271 (24), 269
(21), 268 (88), 262 (33), 247 (24),
246 (61), 245 (24), 244 (100), 243
(56), 219 (34), 218 (59), 151 (36),
115 (22)
A 1H n.m.r. spectra were recorded in (D)chloroform at 300 and 400 MHz for the natural and synthetic quinones, respec-
tively.
the mixture of adducts so formed was aromatized by adding
distilled water and stirring vigorously in air, an orange-red
mixture of products was obtained. Preparative thin-layer
chromatography gave a major orange-red zone that was
composed of a mixture of the tetrahydroanthraquinone (34)
and its regioisomer (35) in a ratio of 4 : 1 by 1H n.m.r. spec-
troscopy. In particular, the spectrum shows clearly resolved,
hydrogen-bonded phenolic hydroxy signals at ␦ 13.01 [(34)]
and 13.07 [(35)]. The quinones (34) and (35) are coincident
by t.l.c. but were separated by fractional crystallization from
benzene. In this way the novel tetrahydroanthraquinone 5-O-
methyl ether (34) was obtained pure as pale red needles, m.p.
175–178°C, [␣]D +15.9 (c, 0.27 in CHCl3). The high-resolu-
tion mass spectrum of the quinone (34) confirmed the molec-
ular formula C17H18O7 while long-wavelength absorption at
276 and 454 nm in the electronic spectrum accords with a
1
methylated naphthazarin chromophore. The rest of the H
n.m.r. spectrum of (34) consists of signals from two methoxy
groups (␦ 3.85 and 3.94), a typically benzenoid aromatic
proton (␦ 6.65),23 and the methyl and methylene protons of
the tetrahydroaromatic ring. These signals are very similar in
chemical shift and multiplicity to those observed in the spec-
trum of (1S,3S)-austrocortilutein (2) (Table 2).
Selective removal of the more sterically encumbered 5-O-
methyl ether from the quinone (34) was achieved by using
boron trichloride at –78°C.24 Workup and chromatography
then gave (1S,3S)-austrocortirubin (2), [␣]D +34 (c, 0.54 in
CHCl3) {lit.1 [␣]D +34 (c, 0.54 in CHCl3)}, as bright red
needles from benzene, identical in all respects (Table 2) with
the major red pigment isolated from Dermocybe splendida.1
As the data in Table 2 reveal, the chemical shift of H 7 in the
spectrum of quinone (2) is ␦ 6.21, in line with the tautomer
shown, in which the quinone occupies the peripheral ring.
The Synthesis of (1R,3R)-Austrocortilutein (5)
All four stereoisomers of 1,3,8-trihydroxy-6-methoxy-3-
methyl-1,2,3,4-tetrahydro-9,10-anthraquinone (austrocorti-
lutein) are known as natural products.1,25 A synthesis of
(1R,3R)-austrocortilutein (5) based on the chemistry devel-
oped above requires, firstly, the preparation of the (1R,3R)-
Scheme 6. (i) Benzene, room temp., 18 h; (ii) H2O, O2, 12 h; (iii)
BCl3, CH2Cl2, –78°C, 4 h.

Pigments of Fungi. LIX
251
Table 2. Selected physical and spectroscopic properties for natural and synthetic (1S,3S)-austrocortirubin (2)
Property
Natural product (2)1
193–195
Synthetic (2)
M.p. (°C)
[␣]D
193–195
+34 (c, 0.543 in CHCl3)
+34 (c, 0.54 in CHCl3)
1H n.m.r.A ␦
1.48 (3H, s, 3-Me)
1.48 (3H, s, 3-Me)
1.88 (1H, dd, 14.7, 4.8, Hax 2)
2.35 (1H, ddd, 14.7, 1.8, 1.8, Heq 2)
2.59 (1H, d, 19.1, Hax 4)
3.19 (1H, dd, 19.1, 1.8, Heq 4)
3.95 (3H, s, OMe)
1.89 (1H, dd, 14.7, 4.8, Hax 2)
2.35 (1H, ddd, 14.7, 1.8, 1.8, Heq 2)
2.59 (1H, d, 19.1, Hax 4)
3.19 (1H, dd, 19.1, 1.8, Heq 4)
3.95 (3H, s, OMe)
5.20 (1H, m, H1)
5.21 (1H, m, H1)
6.21 (1H, s, H 7)
6.21 (1H, s, H 7)
12.69 (1H, s, OH)
12.69 (1H, s, OH)
13.32 (1H, s, OH)
13.33 (1H, s, OH)
␯
max (cm–1)
m/z
(e.i. 15 eV)
1600
1608
320 (60%), 304 (12), 303 (17), 302
(100), 300 (18), 287 (24), 285 (18),
284 (89), 260 (37), 259 (36), 245 (30),
244 (54), 242 (14)
320 (92%), 303 (16), 302 (72), 287 (38),
284 (42), 278 (21), 260 (49), 259 (50),
245 (30), 244 (100), 242 (22)
A 1H n.m.r. spectra were recorded in (D)chloroform at 300 and 400 MHz for the natural and synthetic quinones, respec-
tively.
tetrahydronaphthoquinone ent-(9) (Scheme 7) beginning
from the (R)-oxetanone (13), and cycloaddition of ent-(9)
with the diene (8). This chemistry precisely mirrors that
described in Schemes 4 and 5 and need only be mentioned
briefly here. As expected, the spectroscopic properties of
each of the intermediates are identical, with the obvious
exception of chiroptical properties, with those obtained
earlier for their respective antipodes.
on hydrolysis gave the (S) diol ent-(18), [␣]D +9.3 (c, 4.1 in
CHCl3). Mesylation of ent-(18) and treatment of the result-
ing ester ent-(19), [␣]D –3.8 (c, 3.2 in CHCl3), with DBU gave
(S)-oxiran ent-(11), [␣]D +9.6 (c, 3.0 in CHCl3), as a colour-
less oil. Treatment of ent-(11) with the Grignard reagent
(20) gave (R)-4-benzyloxy-1-(2Ј,5Ј-dimethoxyphenyl)-2-
methylbutan-2-ol ent-(21), [␣]D +7.0 (c, 2.0 in CHCl3),
which after catalytic hydrogenolysis and treatment of the
resulting (S) diol ent-(22) {[␣]D +1.6 (c, 2.1 in CHCl3)} with
the Dess–Martin periodinane gave the aldehyde ent-(10),
[␣]D –13.3 (c, 2.8 in CHCl3), in 88% yield. Cyclization of
ent-(10) in the presence of stannic chloride gave the
(1R,3R)-tetrahydronaphthalenediol ent-(23), [␣]D +7.1 (c,
2.6 in CHCl3). Oxidative demethylation of ent-(23) afforded
the new (1R,3R)-naphthoquinone ent-(9), [␣]D +62 (c, 0.80
in EtOH), which underwent a regioselective Diels–Alder
cycloaddition reaction with the diene (8) in benzene. In situ
aerial oxidation of the cycloadducts gave a mixture of
(1R,3R)-austrocortilutein (5) and its regioisomer (36) in a
1
4 : 1 ratio (by H n.m.r. spectroscopy). Fractional crystal-
lization of the mixture from methanol gave (1R,3R)-austro-
cortilutein (5) as bright orange-red needles, m.p.
183–186°C, [␣]D –63 (c, 0.24 in EtOH) {lit.25 [␣]D –61 (c,
0.24 in EtOH)}, which was indistinguishable in all respects
(Table 3) from the natural product (5) isolated from
Dermocybe sp. WAT 21568.25
We described previously a synthesis of the (S)-oxiran
ent-(11) from sodium (S)-citramalate.7 Here, the (S)-oxiran
ent-(11) was obtained more efficiently (and more economi-
cally) from the (R)-oxetanone (13). Thus, alkaline hydroly-
sis of (13) and methylation of the intermediate dicarboxylic
acid (4) gave dimethyl (S)-citramalate, [␣]D +28 (c, 3.3 in
CHCl3). Reduction to the triol ent-(15), [␣]D –1.96 (c, 3.3 in
CHCl3), and subsequent acetal formation gave the acetonide
ent-(16), [␣]D –9.0 (c, 2.9 in CHCl3). Benzylation gave the
(S) benzyl ether ent-(17), [␣]D –2.8 (c, 3.8 in CHCl3), which

252
M. Gill, M. F. Harte and A. Ten
Table 3. Some physical and spectroscopic properties for natural and synthetic (1R,3R)-austrocortirubin (5)
Property
Natural product (5)25
183–187
Synthetic (5)
M.p. (°C)
[␣]D
183–186
–61 (c, 0.24 in EtOH)
–63 (c, 0.24 in EtOH)
1H n.m.r.A ␦
1.43 (3H, s, 3-Me)
1.45 (3H, s, 3-Me)
1.78 (1H, dd, 14.6, 5.1, Hax 2)
2.27 (1H, ddd, 14.6, 2.2, 1.9, Heq 2)
2.37 (1H, dd, 19.9, 1.9, Hax 4)
2.99 (1H, dd, 19.9, 2.2, Heq 4)
3.30 (1H, br s, 3-OH)
1.81 (1H, dd, 14.5, 5.1 Hz, Hax 2)
2.29 (1H, ddd, 14.7, 2.2, 2.2, Heq 2)
2.40 (1H, dd, 19.8, 1.5, Hax 4)
3.01 (1H, dd, 19.8, 2.2, Heq 4)
3.07 (1H, br s, 3-OH)
3.71 (1H, d, 5.1, 1-OH)
3.88 (3H, s, 6-OMe)
3.49 (1H, m, 1-OH)
3.91 (3H, s, 6-OMe)
5.04 (1H, m, H1)
5.07 (1H, m, H1)
6.58 (1H, d, 2.6, H 7)
6.64 (1H, d, 2.6, H 7)
7.09 (1H, d, 2.6, H 5)
7.18 (1H, d, 2.6, H5)
12.19 (1H, s, 8-OH)
12.21 (1H, s, 8-OH)
␯
max (cm–1)
m/z
(e.i. 15 eV)
1667, 1639
1659, 1642
304 (55%), 286 (78), 271 (28), 268
(43), 262 (31), 247 (25), 246 (62),
245 (25), 244 (100), 243 (57), 219
(30), 218 (58), 151 (28), 43 (75), 18
(27)
304 (42%), 286 (77), 271 (24), 269
(21), 268 (88), 262 (33), 247 (24),
246 (61), 245 (24), 244 (100), 243
(56), 219 (34), 218 (59), 151 (36),
115 (22)
A 1H n.m.r. spectra were recorded in (D)chloroform at 300 and 400 MHz for the natural and synthetic quinones, respec-
tively.
chromatography was performed on Merck Kieselgel 60 GF254 on 20 by
20 cm glass plates (20 g/plate). Gel permeation chromatography was
carried out by using columns of Sephadex LH-20 (Pharmacia) sus-
pended and eluted with dichloromethane/methanol (1: 1).
All solvents were redistilled prior to use; tetrahydrofuran and
benzene were distilled from potassium benzophenone ketyl immedi-
ately prior to use. Other solvents and reagents were purified by using
published procedures.29 Lightpetroleum refers to the hydrocarbon frac-
tion boiling in the range 40–60°C.
Conclusions
The synthesis of the naturally occurring, biologically
active tetrahydroanthraquinones (1), (2) and (5), each in
monochiral form, is described for the first time. The method
focuses on the chiral tetrahydronaphthoquinone dienophiles
(9) and ent-(9), which are prepared from the commercially
available oxetanones (12) and (13), respectively, via the cor-
responding enantiomers of citramalic acid. In principle, the
method is applicable to a wide range of (1S,3S)- and
(1R,3R)-1,3-dihydroxy-1,2,3,4-tetrahydroanthraquinones by
changing the diene used in the Diels–Alder cycloaddition
step. Extension of the methodology described herein to
trans-1,3-dihydroxytetrahydroanthraquinone systems is
described in earlier parts of this series.26
Equipment
Elemental analyses were performed by Chemical and Micro
Analytical Services Pty Ltd, North Essendon, Victoria 3041. Melting
points were determined on a Kofler hot stage and are uncorrected.
Specific rotations were measured on a Perkin–Elmer 241 MC polarime-
ter; concentrations refer to solutions in chloroform unless otherwise
designated. Ultraviolet spectra were obtained with a Perkin–Elmer
Lamda 2 spectrophotometer by using 10 mm quartz cells for solutions
in ethanol. Infrared spectra were obtained as potassium bromide disks
(solids) or between sodium chloride plates (oils) by using Perkin Elmer
983G Grating or 1600 series Fourier-transform spectrophotometers.
N.m.r. spectra were recorded with JEOL JNM-GX-400 (399.65 MHz,
Experimental
General Methods And Materials
Where compounds have been prepared in both isochiral and
monochiral form by the same procedure, details are described only for
experiments in the optically active series. In those cases where the data
from the isochiral compounds differ from those of their enantiomeri-
cally pure counterparts, the pertinent data for the former are listed in
square brackets. In those cases where both enantiomers of a compound
are synthesized, the procedure is described for only one enantiomer and
the specific rotation of the enantiomer is listed in brackets.
All reactions were performed in oven-dried (140°C) glassware
under a positive pressure of dry nitrogen. After workup, organic sol-
vents were dried (MgSO4 or Na2SO4) and removed under reduced pres-
sure. Analytical thin-layer chromatography (t.l.c.) was performed on
Merck precoated plates (0.25 mm, Kieselgel 60 GF254) and visualized
both in daylight and under short (254 nm) and long (360 nm) wave-
length ultraviolet light. Colourless compounds on t.l.c. were exposed to
phosphomolybdic acid (5% w/v solution in propan-2-ol) followed by
heating at 130°C. Flash pad chromatography27 and flash chromatogra-
phy28 employed Merck Kieselgel 60 silica gel. Preparative thin-layer
1
1H; 100.4 MHz, 13C), VARIAN UNITY 300 (299.95 MHz, H; 75.43
MHz, 13C), JEOL JNM-FX-100 (99.55 MHz, 1H; 25.00 MHz, 13C) and
JEOL JNM-FX-90Q (89.55 MHz, 1H; 22.50 MHz, 13C) spectrometers,
for solutions in (D)chloroform unless indicated otherwise. Electron
impact mass spectra were obtained with a V.G. Micromass 7070F spec-
trometer operating at 70 eV unless indicated otherwise. The mass of
each ion is given followed by its relative abundance. In general, only
peaks of relative abundance greater than 20% of the base peak are
quoted.
Dimethyl (R)-Citramalate (14)
A solution of sodium hydroxide (10 M, 40 ml) was added dropwise
to a suspension of the (S)-oxetanone (12) (14.0 g, 69.0 mmol) in water
(70 ml) at 5°C. The mixture was stirred at room temperature for 18 h,
acidified to pH 1 with concentrated hydrochloric acid (10 M) and evap-
orated under reduced pressure. The crude acid (3) was extracted from

Pigments of Fungi. LIX
253
2982, 1495, 1368, 1245, 1212, 1114, 1057 cm–1. ␦H (100 MHz) 1.28
(3H, s, 4-Me), 1.36 and 1.40 (each 3H, s, 2,2-Me2), 1.92 (2H, t, J 6.7
Hz, H2 1Ј), 3.59 (2H, t, J 6.7 Hz, H2 2Ј), 3.71 (1H, d, J 8.5 Hz, H5), 3.91
(1H, d, J 8.5 Hz, H 5), 4.49 (2H, s, CH2Ph), 7.32 (5H, m, ArH). ␦C (75
MHz) 25.0, 26.9, 27.2, 39.5, 66.7, 73.1, 74.3, 80.1, 108.8, 127.5, 127.6,
128.3, 138.3. m/z (40 eV) 235 ([M–Me]+, 42%), 192 (36), 91 (100), 43
(51).
the residue with warm ethyl acetate (4 × 80 ml). Benzene (50 ml) was
added to the combined extract and evaporation of the solvents gave (R)-
citramalic acid (3) as a viscous oil (9.30 g, 91%), which was not puri-
fied further. The diacid (3) was dissolved in dichloromethane/ethanol
(2.5 : 1) (400 ml) and diazomethane [prepared in situ by the dropwise
addition of concentrated aqueous sodium hydroxide to Diazald© (52.0
g, 243 mmol)]30 was bubbled into the solution over 30 min. Excess
diazomethane was destroyed by the dropwise addition of glacial acetic
acid, toluene (40 ml) was added and the solvent was evaporated.
Distillation of the residue gave dimethyl (R)-citramalate (14) [10.02 g,
83% from (12)] as a colourless oil, b.p. 80–100°C/2 mmHg; [␣]D –28
(R)-2-Methyl-4-(phenylmethoxy)butane-1,2-diol (18)
A solution of the acetonide (17) (2.55 g, 10.2 mmol) in tetrahydro-
furan (25 ml), water (4 ml) and aqueous sulfuric acid (1 M, 20 ml) was
stirred at 40°C for 4 h. After neutralization with aqueous sodium
hydroxide (1 M), the products were extracted into ether (4×60 ml). The
combined extract was washed with brine (3×40 ml), dried and evapo-
rated. Flash pad chromatography of the residue using a gradient solvent
system (ether/ethyl acetate) gave the (R) diol (18) (1.98 g, 92%) as a
viscous oil, b.p. 165–175°C/0.6 mmHg; [␣]D –9.3 (c, 4.1) {(S) ent-(18)
[␣]D +9.3 (c, 4.1), lit.7 [␣]D +9.5 (c, 4.0)}. ␯max 3405, 2869, 1454, 1366,
1096, 1056 cm–1. ␦H (400 MHz) 1.18 (3H, s, 2-Me), 1.71 (1H, ddd, J
15.0, 6.3, 3.4 Hz, H 3), 1.97 (1H, ddd, J 15.0, 8.8, 3.8 Hz, H3), 3.39
(1H, d, J 11.2 Hz, H1), 3.46 (1H, d, J 11.2 Hz, H1), 3.65 (1H, ddd, J
9.8, 6.3, 3.8 Hz, H 4), 3.76 (1H, ddd, J 9.8, 8.8, 3.4 Hz, H 4), 4.43 (2H,
s, CH2Ph), 7.29–7.38 (5H, m, ArH). ␦C (75 MHz) 24.2, 37.8, 66.8, 70.0,
72.4, 73.4, 127.8, 128.4, 137.4. m/z (15 eV) 161 ([M–49]+, 35%), 108
(100), 107 (26), 91 (30), 85 (90), 58 (25).
(c, 3.3) {(S) ent-(14) [␣]D +28.0 (c, 3.3), lit.7 [␣]D +27.8 (c, 2.20)}. ␯
max
3504, 2953, 1733, 1435 cm–1. ␦H (300 MHz) 1.42 (3H, s, 2-Me), 2.66
(1H, d, J 16.4 Hz, H 3), 2.96 (1H, d, J 16.4 Hz, HЈ3), 3.67 and 3.78 (each
3H, s, OMe). ␦C (75 MHz) 26.2, 44.0, 51.8, 52.9, 72.5, 171.3, 175.9. m/z
(40 eV) 145 ([M–31]+, 1%), 117 (49), 85 (39), 43 (100).
(R)-2-Methylbutane-1,2,4-triol (15)
A solution of dimethyl (R)-citramalate (14) (5.28 g, 30.0 mmol) in
tetrahydrofuran (20 ml) was added dropwise with stirring to a solution
of lithium aluminium hydride (3.76 g, 100 mmol) in tetrahydrofuran
(150 ml). When evolution of hydrogen had ceased, the mixture was
heated at reflux for 18 h, cooled to 0°C and the excess reducing agent
was destroyed by the successive addition of water (4 ml), aqueous
sodium hydroxide (2.5 M, 6 ml), and a further aliquot of water (10 ml).
After stirring for 1 h at room temperature, the mixture was filtered and
the filter cake was washed with tetrahydrofuran (200 ml) and absolute
ethanol (200 ml). The filtrate and washings were combined and evapo-
rated. The residue was passed through a short column of silica gel with
methanol/dichloromethane (9: 1) as eluent to afford the (R) triol (15)
(3.03 g, 84%) as a viscous oil, b.p. 130–140°C/0.1 mmHg; [␣]D +1.5 (c,
3.1 in EtOH) {(S) ent-(15) [␣]D –1.96 (c, 3.3 in EtOH), lit.7 [␣]D –1.5 (c,
3.07 in EtOH)}. ␯max 3348, 2935, 1377, 1127, 1054 cm–1. ␦H [90 MHz,
(D4)methanol] 1.16 (3H, s, 2-Me), 1.74 (2H, t, J 6.8 Hz, H2 3), 3.37 (2H,
s, H2 1), 3.72 (2H, t, J 6.8 Hz, H2 4). ␦C [75 MHz, (D4)methanol] 24.4,
41.4, 59.2, 70.5, 73.4. m/z (40 eV) 89 ([M–CH2OH]+, 11%), 71 (23), 43
(100), 18 (86).
(R)-2-Hydroxy-2-methyl-4-(phenylmethoxy)butyl
Methanesulfonate (19)
Methanesulfonyl chloride (790 ␮l, 10.2 mmol) was added over 5
min to a stirred solution of the (R) diol (18) (2.15 g, 10.2 mmol) and tri-
ethylamine (2.14 ml, 15.3 mmol) in dichloromethane (15 ml) at –10°C.
The mixture was stirred for a further 10 min and diluted with
dichloromethane (40 ml). The organic phase was washed successively
with cold water (2×30 ml), cold hydrochloric acid (1 M, 2×30 ml), sat-
urated aqueous sodium hydrogen carbonate (2×30 ml), brine (2×30 ml),
dried and concentrated under reduced pressure. Flash pad chromatog-
raphy with ether as eluent gave the (R) mesylate (19) (2.82 g, 91%) as
a viscous colourless oil; [␣]D +3.9 (c, 3.2) {(S) ent-(19) [␣]D –3.8 (c,
3.2), lit.7 [␣]D –3.8 (c, 3.23)}. ␯max 3325, 2982, 1453, 1368, 1212, 1114,
1057, 1028, 983, 864, 736 cm–1. ␦H [90 MHz, (D4)methanol] 1.24 (3H,
s, 2-Me), 1.85 (2H, t, J 6.5 Hz, H2 3), 3.02 (3H, s, SO2Me), 3.66 (2H, t,
J 6.5 Hz, H2 4), 4.06 (2H, s, H2 1), 4.49 (2H, s, CH2Ph), 7.32 (5H, br s,
ArH). ␦C [22.5 MHz, (D4)methanol] 24.3, 37.1, 38.9, 67.1, 71.5, 74.1,
77.2, 128.7, 128.9, 139.6. m/z (15 eV) 289 ([M+1]+, 1.8%), 164 (44),
108 (33), 107 (94), 105 (100), 92 (81), 85 (26), 77 (41).
(R)-2,2,4-Trimethyl-1,3-dioxolan-4-ethanol (16)
To a stirred solution of the (R) triol (15) (1.49 g, 12.4 mmol) in
acetone (50 ml) was added p-toluenesulfonic acid (30 mg). The solution
was stirred at room temperature for 24 h and neutralized with sodium
hydrogen carbonate (1.0 g). The suspension was stirred for 30 min, fil-
tered and the filtrate was concentrated under reduced pressure. Flash
chromatography of the residue with ether/light petroleum (85: 15) as
eluent gave (R)-2,2,4-trimethyl-1,3-dioxolan-4-ethanol (16) (1.62 g,
82%) as a colourless oil, b.p. 60–70°C/0.1 mmHg; [␣]D +8.8 (c, 3.0)
{(S) ent-(16) [␣]D –9.0 (c, 2.9) lit.7 [␣]D –8.9 (c, 2.82)}. ␯max 3432, 2981,
1370, 1245, 1214, 1113, 1056 cm–1. ␦H (400 MHz) 1.35 (3H, s, 4-Me),
1.41 and 1.42 (each 3H, br s, 2,2-Me2), 1.74 (1H, ddd, J 14.4, 6.0, 4.0
Hz, H ␤), 1.92 (1H, ddd, J 14.4, 8.3, 4.6 Hz, H ␤), 2.53 (1H, br s, OH),
3.77 (1H, ddd, J 11.2, 6.0, 4.6 Hz, H ␣), 3.79 (1H, d, J 8.5 Hz, H5), 3.86
(1H, d, J 8.5 Hz, H5), 3.90 (1H, ddd, J 11.2, 8.3, 4.0 Hz, H␣). ␦C (22.5
MHz) 24.8, 26.8, 27.0, 41.0, 59.2, 74.5, 81.2, 109.4. m/z (15 eV) 145
([M–Me]+, 100%), 115 (51), 85 (84), 72 (24), 43 (24).
(R)-2-Methyl-2-[2Ј-(phenylmethoxy)ethyl]oxiran (11)
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.98 ml, 13.2 mmol) in
dichloromethane (10 ml) was added to a solution of the mesylate (19)
(3.28 g, 11.4 mmol) in dichloromethane (15 ml) and the solution was
stirred at room temperature for 1 h. The solution was diluted with
dichloromethane (40 ml) and the organic phase was washed succes-
sively with cold hydrochloric acid (5%, 2×30 ml), cold saturated
aqueous sodium hydrogen carbonate (2×30 ml) and brine (2×30 ml) and
the solvent was dried and evaporated. Flash pad chromatography with
ether/light petroleum (1: 1) as eluent gave the (R)-oxiran (11) (2.05 g,
94%) as a colourless oil, b.p. 110–120°C/0.4 mmHg; [␣]D –9.4 (c, 3.0)
(R)-2,2,4-Trimethyl-4-[2Ј-(phenylmethoxy)ethyl]-1,3-dioxolan (17)
{(S) ent-(11) [␣]D +9.6 (c, 3.0), lit.7 [␣]D +9.6 (c, 2.95)}. ␯
2861,
A solution of the alcohol (16) (2.15 g, 13.4 mmol) in tetrahydrofu-
ran (20 ml) was added dropwise to a stirred suspension of sodium
hydride (0.65 g, 60% dispersion in mineral oil, 16 mmol) in tetrahydro-
furan (30 ml). To the resulting grey suspension was added tetrabuty-
lammonium iodide (50 mg, 0.14 mmol) followed by benzyl bromide
(2.52 g, 14.7 mmol). The mixture was stirred for 24 h, diluted with cold
water (60 ml) and extracted into ether (3×50 ml). The combined extract
was washed with brine (3×20 ml), dried and concentrated under
reduced pressure. Flash chromatography of the residue with
dichloromethane/ether (9: 1) as eluent gave the (R)-1,3-dioxolan (17)
(3.07 g, 91%) as a colourless oil, b.p. 65–75°C/0.05 mmHg; [␣]D +2.4
max
1453, 1105, 738, 698 cm–1. ␦H (400 MHz) 1.34 (3H, d, J 0.5 Hz, 2-Me),
1.85 (1H, ddd, J 14.4, 6.6, 6.6 Hz, H1Ј), 1.95 (1H, dddd, J 14.4, 6.2,
6.2, 0.7 Hz, H1Ј), 2.60 (1H, dd, J 4.9, 0.5 Hz, H3), 2.70 (1H, dd, J 4.9,
0.5 Hz, H 3), 3.55 (1H, ddd, J 9.5, 6.6, 6.2 Hz, H2Ј), 3.59 (1H, ddd, J
9.5, 6.6, 6.2 Hz, H2Ј), 4.50 (2H, s, CH2Ph), 7.27–7.37 (5H, m, ArH). ␦C
(75 MHz) 21.5, 36.6, 54.0, 55.4, 66.6, 73.0, 127.6, 128.4, 138.2. m/z (40
eV) 192 (M+, 1.2%), 91 (37), 43 (100).
(±)-2-Methyl-2-[2Ј-(phenylmethoxy)ethyl]oxiran (±)-(11)
Benzyl bromide (100 g, 0.585 mol) was added dropwise over 30 min
to an ice-cold suspension of 3-methylbut-3-en-1-ol (51.0 g, 0.592 mol),
(c, 4.2) {(S) ent-(17) [␣]D –2.8 (c, 3.8), lit.7 [␣]D –2.9 (c, 3.88)}. ␯
max

254
M. Gill, M. F. Harte and A. Ten
sodium hydride (35.6 g, 60% dispersion in mineral oil, 0.890 mol), and
tetrabutylammonium iodide (1.8 g, 4.9 mmol) in dry tetrahydrofuran
(500 ml). The mixture was allowed to stir at room temperature for 16 h
and carefully diluted with ice-cold water (300 ml), extracted with ether
(3×300 ml), and the combined extract was washed with brine (2×300
ml), dried and evaporated. Distillation of the residue afforded 2-methyl-
4-phenylmethoxybut-1-ene (89.5 g, 87%) as a colourless oil, b.p.
to room temperature and then stirred for 18 h. The reaction mixture was
quenched with saturated aqueous ammonium chloride (30 ml) and the
organic phase was extracted into ether (3×70 ml). The combined extract
was washed with saturated aqueous sodium hydrogen carbonate (3×60
ml), brine (3×60 ml), water (80 ml), dried and concentrated under
reduced pressure. Flash pad chromatography of the residue using a gra-
dient solvent system of ether/light petroleum gave the (S)-tertiary
alcohol (21) (3.43 g, 92%) as a colourless oil, b.p. 200–210°C/0.25
mmHg (Found: C, 72.8; H, 8.0. C20H26O4 requires C, 72.7; H, 7.9%).
100–103°C/12 mmHg (lit.31 120–123°C/16 mmHg). ␯ 2935, 1649,
max
1452, 1360, 1102, 736, 697 cm–1. ␦H (400 MHz) 1.76 (3H, s, 2-Me),
2.36 (2H, t, J 6.8 Hz, H2 3), 3.59 (2H, t, J 6.8 Hz, H2 4), 4.54 (2H, s,
CH2Ph), 4.78 (2H, m, H2 1), 7.27–7.36 (5H, m, ArH). ␦C (100 MHz)
22.7, 37.8, 68.7, 72.9, 111.5, 127.5, 127.6, 128.3, 138.4, 142.9. m/z (15
eV) 176 (M+, 8.1%), 107 (31), 70 (100). A mixture of 2-methyl-4-
phenylmethoxybut-1-ene (10.0 g, 56.7 mmol) and magnesium
monoperoxyphthalate32 (21.0 g, 80 %, 34.0 mmol) in propan-2-ol/water
(1: 1) (300 ml) was stirred at room temperature for 24 h. Sodium
hydroxide (2.5 M, 200 ml) was added and the products were extracted
into chloroform (5×150 ml), dried and evaporated. Flash pad chro-
matography of the residue using a gradient solvent system of light
petroleum/ether gave the oxiran (±)-(11) (7.0 g, 64%) as a colourless oil
that, specific rotation aside, was identical to the material described
above.
[␣]D –7.2 (c, 1.9) {(R) ent-(21) [␣]D +7.0 (c, 2.0)}. ␯ 3499, 2936,
max
1497, 1222 cm–1. ␦H (300 MHz) 1.10 (3H, s, 2-Me), 1.77–1.89 (2H, m,
H2 3), 2.73 (1H, d, J 13.4 Hz, H1), 2.82 (1H, d, J 13.4 Hz, H1),
3.70–3.74 (2H, m, H2 4), 3.75 and 3.77 (each 3H, s, OMe), 4.40 (2H, s,
CH2Ph), 6.70–6.81 (3H, m, ArH), 7.26–7.38 (5H, m, CH2Ph). ␦C (100
MHz) 26.8, 40.6, 42.5, 55.6, 55.8, 67.3, 72.8, 73.2, 111.3, 111.8, 118.7,
127.5, 127.6, 127.7, 128.3, 138.1, 151.8, 153.3. m/z (15 eV) 330 (M+,
3.7%), 312 (52), 179 (100), 164 (24), 152 (54), 91 (25).
(S)-4-(2Ј,5Ј-Dimethoxyphenyl)-3-methylbutane-1,3-diol (22)
A solution of the benzyl ether (21) (1.24 g, 3.75 mmol) in methanol
(30 ml) was exposed to hydrogen in the presence of 10% palladium-on-
charcoal (120 mg) for 12 h. The mixture was diluted with ethyl acetate
(100 ml) and the catalyst was filtered off using a pad of Celite© and the
residue was washed thoroughly with ethyl acetate. The filtrate was con-
centrated under reduced pressure and the residue was distilled to give the
(S) diol (22) (874 mg, 97%) as a colourless oil, b.p. 165–175°C/0.3
mmHg (Found: C, 64.9; H, 8.4. C13H20O4 requires C, 65.0; H, 8.4%). [␣]D
–1.6 (c, 2.1) {(R) ent-(22) [␣]D +1.6 (c, 2.1)}. ␯max 3401, 2934, 1499,
1222, 1024 cm–1. ␦H (400 MHz) 1.20 (3H, s, 3-Me), 1.65 (1H, ddd, J 14.4,
5.7, 3.5 Hz, H2), 1.85 (1H, ddd, J 14.4, 9.1, 4.4 Hz, H 2), 2.78 (1H, d, J
13.7 Hz, H4), 2.95 (1H, d, J 13.7 Hz, H4), 3.76 and 3.80 (each 3H, s,
OMe), 3.82 (1H, ddd, J 11.2, 5.7, 4.4 Hz, H1), 3.95 (1H, ddd J 11.2, 9.1,
3.5 Hz, H 1), 6.69–6.84 (3H, m, ArH). ␦C (100 MHz) 26.4, 42.4, 43.8,
55.6, 56.0, 59.8, 74.8, 111.6, 111.9, 118.9, 126.9, 151.5, 153.6. m/z 240
(M+, 2.9%), 152 (100), 137 (65), 71 (28), 43 (57), 28 (20).
Sharpless Asymmetric Dihydroxylation7of 2-Methyl-4-phenylmethoxy-
but-1-ene
(±)-2-Methyl-4-phenylmethoxybut-1-ene (182 mg, 1.03 mmol) was
added to a stirred mixture of AD-mix-␣ (1.40 g), t-butyl alcohol (5 ml)
and water (5 ml) at 0°C. The suspension was stirred at 0°C for 24 h and
sodium sulfite (1.5 g) was added. The reaction mixture was allowed to
warm to room temperature and stirred for 1 h. The products were
extracted into ethyl acetate (3×10 ml), and the combined extracts were
dried and evaporated. Flash pad chromatography of the residue using a
gradient solvent system of light petroleum/ether followed by distilla-
tion gave optically active (S)-2-methyl-4-(phenylmethoxy)butane-1,2-
diol ent-(18) (155 mg, 72%) {[␣]D +4.4 (c, 4.0)}. The specific rotation,
when compared with that of a sample of enantiomerically pure ent-(18)
(see above), corresponds to an e.e. of 47% for the product described
here.
(S)-4-(2Ј,5Ј-Dimethoxyphenyl)-3-hydroxy-3-methylbutanal (10)
(i) Dess–Martin periodinane. A solution of the Dess–Martin peri-
odinane (1.12 g, 2.63 mmol) in dichloromethane (45 ml) was added
dropwise to a vigorously stirred solution of the alcohol (22) (420 mg,
1.75 mmol) and water (48 ␮l, 2.7 mmol) in dichloromethane (45 ml)
over 20 min. The cloudy mixture was stirred at room temperature for 6
h and poured into water (50 ml) saturated with sodium hydrogen car-
bonate and containing sodium thiosulfate (2.35 g). The organic phase
was separated and washed with saturated sodium hydrogen carbonate
(2×40 ml), water (2×40 ml), dried and evaporated. Distillation of the
residue gave the (S)-butanal (10) (376 mg, 90%) as a colourless oil, b.p.
145–155°C/0.25 mmHg (Found: C, 64.8; H, 7.6. C13H18O4 requires C,
65.5; H, 7.6%). [␣]D +13.5 (c, 2.8) {(R) ent-(10) [␣]D –13.3 (c, 2.8)}.
2,5-Dimethoxyphenylmagnesium Bromide (20)
To a stirred solution of potassium bromide (26.7 g, 224 mmol) and
1,4-dimethoxybenzene (30.0 g, 210 mmol) in a mixture of water (150
ml) and ethanol (300 ml) was added sulfuric acid (10 M, 38 ml). The
solution was heated (gently) to reflux before hydrogen peroxide (90 ml,
30%) was added dropwise over 30 min. After a further 45 min at reflux,
water (150 ml) was added to the hot mixture, which was then allowed
to stand at room temperature overnight. The solution was decanted and
the solvent was evaporated. The residue was extracted with ethyl
acetate (3×200 ml) and the combined extracts were washed with dilute
sodium thiosulfate (3×200 ml), water (200 ml), dried and evaporated.
Flash pad chromatography of the residue using a gradient solvent
system of ether/light petroleum followed by distillation gave 2-bromo-
1,4-dimethoxybenzene (30.1 g, 62%) as a colourless oil, b.p. 107°C/0.2
mmHg (lit.16 164–166°C/55 mmHg). ␯max 2942, 1270, 1213, 667 cm–1.
␦H (400 MHz) 3.76 and 3.84 (each 3H, s, OMe), 6.82 (1H, dd, J 8.8, 2.6
Hz, H 5), 6.85 (1H, d, J 8.8 Hz, H 6), 7.29 (1H, d, J 2.6 Hz,
H3). ␦C (100 MHz) 55.8, 56.8, 111.9, 112.8, 113.6, 118.9, 150.2, 154.0.
m/z 218 ([M+2]+, 96%), 216 (M+, 95), 203 (99), 201 (100), 107 (27), 79
(28), 63 (21), 28 (36).
␯
max 3473, 2929, 1714, 1498, 1222, 1046 cm–1. ␦H (400 MHz) 1.30 (3H,
s, 3-Me), 2.45 (1H, dd, J 15.8, 2.2 Hz, H2), 2.55 (1H, dd, J 15.8, 2.2
Hz, H 2), 2.88 (1H, d, J 13.6 Hz, H4), 2.92 (1H, d, J 13.6 Hz, H4), 3.74
and 3.78 (each 3H, s, OMe), 6.69–6.83 (3H, m, ArH), 9.83 (1H, t, J 2.2
Hz, H 1). ␦C (100 MHz) 27.8, 42.9, 53.9, 55.6, 55.8, 72.4, 111.6, 112.3,
118.7, 126.4, 151.5, 153.5, 203.2. m/z 238 (M+, 4.5%), 194 (49), 152
(32), 151 (100), 137 (29), 121 (77), 91 (45), 77 (27), 43 (52), 28 (38).
(ii) Pyridinium dichromate. To a solution of the alcohol (±)-(22)
(100 mg, 0.417 mmol) in dichloromethane (2 ml) was added succes-
sively pyridinium dichromate (233 mg, 0.619 mmol), freshly activated
powdered 3 Å molecular sieves and glacial acetic acid (55 ␮l, 1.0
mmol). The solution was stirred for 1.5 h at room temperature, diluted
with ether (5 ml) and filtered through a pad of Celite©. The filtrate was
concentrated under reduced pressure and and the residue was purified
by flash pad chromatography using a gradient of light petroleum/ether
as eluent. Distillation gave the aldehyde (±)-(10) (37.0 mg, 37%) that
was, with the exception of specific rotation, identical with the material
described above. A less polar fraction gave 2,5-dimethoxybenzalde-
hyde (24) (11.2 mg, 16%), m.p. 49–51°C, which was identical to
authentic material.
A solution of 2-bromo-1,4-dimethoxybenzene (3.19 g, 14.7 mmol)
in tetrahydrofuran (15 ml) was added gradually, with stirring, to acti-
vated (I2) magnesium turnings (360 mg, 14.8 mmol) and the mixture
was heated at reflux for 4 h then cooled to room temperature.
(S)-4-Benzyloxy-1-(2Ј,5Ј-dimethoxyphenyl)-2-methylbutan-2-ol (21)
The Grignard reagent (20) was added dropwise to a stirred solution
of the (R)-oxiran (11) (2.17 g, 11.3 mmol) in tetrahydrofuran (15 ml)
containing a catalytic amount of dilithium tetrachlorocuprate (0.1 M,
1.0 ml, 0.10 mmol) at –78°C. The mixture was allowed to warm slowly

Pigments of Fungi. LIX
255
(iii) Tetrapropylammonium perruthenate. Amixture of the alcohol
(±)-(22) (143 mg, 0.596 mmol), N-methylmorpholine N-oxide (104 mg,
0.888 mmol) and powdered 3 Å molecular sieves (30 mg) in
dichloromethane (2 ml) was stirred at room temperature for 10 min.
Tetrapropylammonium perruthenate (12 mg, 0.034 mmol) was added
and the reaction mixture was stirred for 18 h at room temperature. The
mixture was diluted with ethyl acetate (20 ml) and filtered through a
pad of silica gel. The solvent was evaporated to dryness and the residue
was purified by flash pad chromatography using a gradient solvent
system of light petroleum/ether to give the aldehyde (±)-(10) (40.0 mg,
28%) together with unchanged (±)-(22) (15.7 mg, 11%) and
1-(2Ј,5Ј-dimethoxyphenyl)propan-2-one (25) (12.7 mg, 12%), b.p.
110–120°C/0.1 mmHg (lit.33 b.p. 100°C/0.07 mmHg). ␦H (300 MHz)
2.13 (3H, s, 3-Me), 3.63 (2H, s, H2 1), 3.72 and 3.73 (each 3H, s, OMe),
6.70–6.80 (3H, m, ArH).
(iv) Swern oxidation. A solution of dimethyl sulfoxide (0.60 ml,
8.5 mmol) in dichloromethane (2 ml) was added dropwise to a solution
of oxalyl chloride (0.37 ml, 4.2 mmol) in dichloromethane (8 ml) at –50
to –60°C. The reaction mixture was stirred for 2 min and a solution of
(±)-(22) (880 mg, 3.67 mmol) in dichloromethane (2 ml) was added
over 5 min. The mixture was stirred for a further 20 min and triethy-
lamine (2.6 ml, 19 mmol) was added. After 5 min, the reaction mixture
was allowed to warm to room temperature. Water (15 ml) was added
and the products were extracted into dichloromethane (2×15 ml). The
combined extract was washed with brine (30 ml), hydrochloric acid
(1 M, 3×30 ml), water (2×30 ml), and dried. The solvent was evaporated
and the residue was purified by flash pad chromatography using a gra-
dient of light petroleum/ether. Distillation gave the aldehyde (±)-(10)
(438 mg, 50%) that was, with the exception of specific rotation, identi-
cal with the material described above.
(46), 150 (95), 149 (21), 148 (100), 147 (50), 137 (21), 123 (24), 122
(24), 91 (31) 77 (22), 65 (26), 53 (20).
(1S,3S)-Austrocortilutein (1)
A solution of 1,3-dimethoxy-1-trimethylsilyloxybuta-1,3-diene (8)6
(40 mg, 0.20 mmol) and the (1S,3S)-naphthoquinone (9) (34.1 mg,
0.164 mmol) in benzene (5 ml) was stirred at room temperature for 9 h.
Water (7 ml) was added and the mixture stirred vigourously in an open
flask for 12 h. The mixture was diluted with dichloromethane (30 ml)
and washed with water (2×15 ml), dried and evaporated to dryness.
Preparative
thin-layer
chromatography
with
toluene/ethyl
formate/formic acid (50 : 49: 1) gave a mixture (20 mg, 40%) of
(1S,3S)-austrocortilutein (1) and its regioisomer (31) in a 4: 1 ratio by
1H n.m.r. spectroscopy. Fractional crystallization from chloroform gave
(1S,3S)-austrocortilutein (1) (11.1 mg, 22%) as orange-yellow needles,
m.p. 182–185°C (lit.1 183–185°C), [␣]D +55 (c, 0.10), lit.1 [␣]D +52 (c,
0.095) {(1R,3R)-austrocortilutein (5) [␣]D –63 (c, 0.24 in EtOH), lit.25
[␣]D –61 (c, 0.24 in EtOH)} (Found: M+, 304.0955. Calc. for C16H16O6:
M+, 304.0946). ␭max 221 (log⑀ 4.62), 270 (4.17), 283sh (3.93), 427 nm
(3.64). ␯max 3392, 2975, 1666, 1639, 1605, 1384, 1298, 1267, 1205,
1147 cm–1. ␦H (1), see Table 1; ␦H (5), see Table 3. m/z 304 (M+, 42%),
286 (77), 271 (24), 269 (21), 268 (88), 262 (33), 247 (24), 246 (61), 245
(24), 244 (100), 243 (56), 219 (34), 218 (59), 151 (36), 115 (22).
The tetrahydronaphthalene (31) was not obtained in spectroscopi-
cally pure form; consequently, the 1H n.m.r data that follow were
deduced from the spectrum of a mixture of (1) and (31) by subtraction
of the signals from the former. (1S,3S)-1,3,5-Trihydroxy-7-methoxy-3-
methyl-1,2,3,4-tetrahydroanthracene-9,10-dione (31) ␦H (300 MHz)
1.45 (3H, s, 3-Me), 1.82 (1H, dd, J 14.7, 5.1 Hz, Hax 2), 2.32 (1H, ddd,
J 14.7, 1.8, 1.8 Hz, Heq 2), 2.41 (1H, dd, J 19.8, 1.5 Hz, Hax 4), 3.05 (1H,
dd, J 19.8, 1.8 Hz, Heq 4), 3.08 (1H, m, 3-OH), 3.51 (1H, m, OH), 3.91
(3H, s, 7-OMe), 5.08 (1H, m, H1), 6.64 (1H, d, J 2.4 Hz, H6), 7.17 (1H,
d, J 2.4 Hz, H 8), 12.24 (1H, s, 5-OH).
(1S,3S)-5,8-Dimethoxy-3-methyl-1,2,3,4-tetrahydro-
naphthalene-1,3-diol (23)
A
solution of tin(IV) chloride (350 ␮l, 2.99 mmol) in
(1S,3S)-Austrocortirubin 5-O-Methyl Ether (34)
dichloromethane was added slowly to a solution of the aldehyde (10)
(175 mg, 0.734 mmol) in dichloromethane (8 ml) at –78°C. The solu-
tion was allowed to warm to –25°C over 3.5 h before triethylamine
(350 ␮l, 2.51 mmol) was added and the solution was diluted with
dichloromethane (50 ml). The solution was washed with cold sodium
hydroxide (1 M, 3×30 ml), water (2×30 ml), dried and evaporated. The
residue was crystallized from ethyl acetate to give the (1S,3S)-tetrahy-
dronaphthalene (23) as colourless prisms (147 mg, 84%), m.p.
167–169°C {(±)-(23) m.p. 163–165°C} (Found: C, 65.6; H, 7.9.
C13H18O4 requires C, 65.5; H, 7.6%). [␣]D –6.8 (c, 2.6) {(1R,3R) ent-
A solution of 1,3,4-trimethoxy-1-trimethylsilyloxybuta-1,3-diene
(33)22 (68.0 mg, 0.278 mmol) and the (1S,3S)-naphthoquinone (9) (33.2
mg, 0.160 mmol) in benzene (5 ml) was stirred at room temperature for
18 h. Water (10 ml) was added and the mixture was stirred vigorously
for 12 h in an open flask. The mixture was diluted with dichloromethane
(50 ml) and washed with water (2×25 ml), dried and evaporated.
Purification of the residue by using flash pad chromatography with
toluene/ethyl formate/formic acid (50: 49: 1) as eluent gave a mixture
(13.4 mg, 25%) of (1S,3S)-austrocortirubin 5-O-methyl ether (34) and
its regioisomer (35) in a 4: 1 ratio by 1H n.m.r. spectroscopy. Fractional
crystallization of the mixture from benzene gave the title compound
(34) (7.8 mg, 15%) as pale red needles, m.p. 175–178°C, [␣]D +15.9 (c,
(23) [␣]D +7.1 (c, 2.6)}. ␯
3265, 2962, 1480, 1256 cm–1. ␦H (400
max
MHz) 1.42 (3H, s, 3-Me), 1.65 (1H, br s, OH), 1.85 (1H, dd, J 14.5, 5.0
Hz, H2), 2.26 (1H, ddd, J 14.5, 2.2, 2.2 Hz, H 2), 2.46 (1H, d, J 17.7
Hz, H 4), 3.07 (1H, dd, J 17.7, 2.2 Hz, H 4), 3.26 (1H, br s, OH), 3.79
and 3.85 (each 3H, s, OMe), 5.17 (1H, m, H1), 6.71–6.81 (2H, m, ArH).
␦C, (100 MHz) 30.1, 37.7, 40.4, 55.6, 55.7, 63.9, 68.1, 107.4, 109.4,
124.8, 126.3, 151.5, 151.7. m/z 238 (M+, 3.3%), 202 (37), 187 (100),
159 (26), 18 (34).
0.27) (Found: M+, 334.1053. C17H18O7 requires M+, 334.1052). ␭
max
225 (log⑀ 4.70), 275 (4.16), 454 nm (3.77). ␯max 3442, 1684, 1646, 1478
cm–1. ␦H (300 MHz) 1.44 (3H, s, 3-Me), 1.82 (1H, dd, J 14.6, 5.1 Hz,
Hax 2), 2.28 (1H, ddd, J 14.6, 1.8, 1.8 Hz, Heq 2), 2.40 (1H, dd, J 19.9,
1.5 Hz, Hax 4), 3.01 (1H, dd, J 19.9, 1.8 Hz, Heq 4), 3.86 and 3.95 (each
3H, s, OMe), 5.09 (1H, m, H1), 6.65 (1H, s, H 7), 13.01 (1H, s, 8-OH).
m/z 334 (M+, 100%), 316 (21), 301 (75), 283 (23), 273 (46), 259 (53),
83 (54).
(1S,3S)-1,3-Dihydroxy-3-methyl-1,2,3,4-tetrahydro-5,8-
naphthoquinone (9)
A solution of ammonium cerium(IV) nitrate (341 mg, 0.622 mmol)
in water (6 ml) was added over 5 min to a stirred solution of the quinol
dimethyl ether (23) (74 mg, 0.31 mmol) in acetonitrile (6 ml). The
mixture was stirred at room temperature for 5 min and then diluted with
water (30 ml). The products were extracted into dichloromethane (5×20
ml), dried and evaporated to give the (1S,3S)-naphthoquinone (9) (65
mg, 100%) as a yellow gum (Found: M+, 208.0737. C11H12O4 requires
M+, 208.0736). [␣]D –63 (c, 0.81 in EtOH) {(1R,3R) ent-(9) [␣]D +62 (c,
0.80 in EtOH)}. ␦H (400 MHz) 1.41 (3H, s, 3-Me), 1.77 (1H, dd, J 14.7,
5.1 Hz, H2), 2.24 (1H, ddd, J 14.7, 2.2, 2.2 Hz, H 2), 2.30 (1H, dd, J
19.8, 1.5 Hz, H 4), 2.86 (1H, dd, J 19.8, 2.2 Hz, H 4), 3.07 (1H, m, OH),
4.91 (1H, m, H1), 6.79 (2H, m, ArH). ␦C (100 MHz) 29.9, 37.0, 40.0,
62.2, 68.2, 136.3, 136.6, 139.5, 140.3, 187.2, 187.6. m/z 208 (M+,
27%), 205 (24), 190 (70), 189 (45), 180 (30), 177 (90), 165 (33), 151
(1S,3S)-Austrocortirubin (2)
A solution of boron trichloride in dichloromethane (1 M, 280 ␮l,
0.28 mmol) was added dropwise to a solution of the methyl ether (34)
(9.4 mg, 0.028 mmol) in dichloromethane (25 ml) at –78°C. The
mixture was stirred at –78°C for 4 h and methanol (8 ml) was added.
The mixture was diluted with dichloromethane (50 ml) and the solution
was washed with water (3×25 ml), dried and evaporated to dryness.
Flash pad chromatography with toluene/ethyl formate/formic acid
(50: 49: 1) gave a red zone (6.8 mg, 80%) that was crystallized from
benzene to give (1S,3S)-austrocortirubin (2) as bright red needles, m.p.
193–195°C (lit.1 m.p. 193–195°C) [␣]D +34 (c, 0.54) {lit.1 [␣]D +34 (c,
0.543)} (Found: M+,320.0886. Calc. for C17H18O7: M+, 320.0895). ␭
229 (log⑀ 4.56), 304 (3.96), 475 (3.83), 506 (3.89), 542 nm (3.71). ␯
max
max

256
M. Gill, M. F. Harte and A. Ten
13
14
3445, 1602, 1409, 1256 cm–1. ␦H see Table 2. m/z 320 (M+, 92%), 303
(16), 302 (72), 287 (38), 284 (42), 278 (21), 260 (49), 259 (50), 245
(30), 244 (100), 242 (22).
Frye, S. V., and Eliel, E. L., Tetrahedron Lett., 1985, 26, 3907.
Staring, E. G. J., Moorlag, H., and Wynberg, H., Recl Trav. Chim.
Pays-Bas, 1986, 105, 374.
Silverstein, R. M., Bassler, G. C., and Morrill, T. C., ‘Spectroscopic
Identification of Organic Compounds’ 5th Edn (John Wiley: New
York 1991).
15
Acknowledgments
16
17
Jurd, L., Aust. J. Sci. Res., Ser. A, 1949, 2, 595.
A.T. is grateful for financial support from a Common-
wealth Postgraduate Research Award while M.G. is thankful
for Australian Research Council Large and Small Grant
support of this and other aspects of research.
Dess, D. B., and Martin, J. C., J. Am. Chem. Soc., 1991, 113, 7277;
Ireland, R. E., and Liu, L., J. Org. Chem., 1993, 58, 2899; Meyer, S.
D., and Schreiber, S. L., J. Org. Chem., 1994, 59, 7549.
Mancuso, A. J., Huang, S. L., and Swern, D., J. Org. Chem., 1978,
43, 2480.
Corey, E. J., and Schmidt, G., Tetrahedron Lett., 1979, 20, 399.
Griffith, W. P., and Ley, S. V., Aldrichimica Acta, 1990, 23, 13.
Kelly, T. R., and Montury, M., Tetrahedron Lett., 1978, 19, 4309.
Simoneau, B., and Brassard, P., Tetrahedron, 1986, 42, 3767.
Moore, R. E., and Scheuer, P. J., J. Org. Chem., 1966, 31, 3272;
Kelly, T. R., Saha, J. K., and Whittle, R. R., J. Org. Chem., 1985, 50,
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Carvalho, C. F., Russo, A. V., and Sargent, M. V., Aust. J. Chem.,
1985, 38, 777.
Gill, M., Giménez, A., Jhingran, A. G., and Qureshi, A.,
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Elsworth, C., Gill, M., Raudies, E., and Ten, A., Aust. J. Chem.,
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Casey, M., Leonard, J., Lygo, B., and Procter, G., ‘Advanced
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and references cited therein.
18
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