Syntheses in enantiopure form of four diastereoisomeric naphthopyranquinones derived from aphid insect pigments

Article abstract of DOI:10.1039/b414213f

The first syntheses are described of the four enantiopure naphthopyranquinones (1R,3R,4S)- and (1R,3R,4R)-3,4-dihydro-4,7,9-trihydroxy-1, 3-dimethylnaphtho[2,3-c]pyranquinone (quinone A 1 and quinone A' 2) and their two C-3 epimers, the (1R,3S,4S)- and (1

Full text of DOI:10.1039/b414213f

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A R T I C L E
Syntheses in enantiopure form of four diastereoisomeric
naphthopyranquinones derived from aphid insect pigments†‡
Rachna Aggarwal,a Robin G. F. Giles,*a Ivan R. Green,b Francois J. Oosthuizena and
C. Peter Taylora
a Department of Chemistry, Murdoch University, Murdoch, WA, 6150, Australia.
E-mail: R.Giles@murdoch.edu.au
b Department of Chemistry, University of the Western Cape, Bellville, 7530, South Africa
Received 14th September 2004, Accepted 21st October 2004
First published as an Advance Article on the web 2nd December 2004
The first syntheses are described of the four enantiopure naphthopyranquinones (1R,3R,4S)- and (1R,3R,4R)-3,4-
dihydro-4,7,9-trihydroxy-1,3-dimethylnaphtho[2,3-c]pyranquinone (quinone A 1 and quinone Aꢀ 2) and their two C-3
epimers, the (1R,3S,4S)- and (1R,3S,4R)-diastereoisomers 5 and 6, using enantiopure lactate as the source of
asymmetry. Key factors in these syntheses are the maintenance of stereochemical integrity throughout the sequences
and intramolecular diastereoselective cyclisations of the titanium phenolates of phenolic lactaldehydes. For these
cyclisations the differing degree of diastereoselectivity is explained as are the stereochemistries of the product
2-benzopyran-4,5-diols.
using the method pioneered by Cameron and Craik8 for the
conversion of glucoside B 7 into quinone A 1.
Introduction
Quinone A 1 and glucoside B 7 are the products of reductive
cleavage of the bean aphid insect pigment protoaphin-fb,1 while
the C-4 epimeric quinone Aꢀ 2 and the same glucoside 7 are
obtained similarly from the willow aphid pigment protoaphin-
sl.1 These quinones are of interest, inter alia, since they have
been nominated as potential bioreductive dialkylating agents.2
Cameron et al. have shown3 that each of these protoaphins can
be reconstituted through oxidative coupling of the individual
quinones with glucoside B 7. The assembly of these components
1, 2 and 7 in enantiopure form would be required for syntheses of
the parent protoaphins to avoid diastereomeric mixtures. While
we have previously synthesised4 the racemates of the quinones 1
and 2, this method did not lend itself to the assembly of the in-
dividual enantiomers.5 In a preliminary publication we have
recently reported6 the first syntheses of each of these enantiopure
quinones, as well as those of their C-1 epimers 3 and 4. These
compounds 1–4 comprise all four stereoisomers based on 3R
stereochemistry. After the completion of this work,6 discussions
with Professor Cameron revealed7 preliminary observations
suggesting that the compounds 3 and 4 are the enantiomers
of two further, unreported, derivatives of naturally occurring
aphid pigments. The remainder of this paragraph summarizes
the hitherto unpublished results of Banks and Cameron.7 These
new naturally derived quinones are the C-3 epimers 5 and 6 of
the quinones A 1 and Aꢀ 2. Quinone 5 was isolated7 together with
glucoside B 7 through reductive cleavage1 of a new protoaphin-
pm7 8 that co-occurred with protoaphin-fb in aphid insect species
of the Pemphigidae. The most practical source of protoaphin-
pm, however, was found to be Eriosoma lanigerum Hausmann,
the common woolly apple aphid.7 Furthermore, a new glucoside
9, diastereoisomeric with glucoside B 7 at both C-3 and C-
4, was obtained7 on examination of constituents of Periphyllus
acericola Walker from the aphid insect family Chaitophoridae.
The new glucoside 9 was converted7 into quinone 6 through
Fremy salt oxidation followed by treatment of the glycosidic
Our model experiments had shown9 that the completely
diastereoselective cyclisation of an enantiopure meta-hydroxy-
benzyl ether of lactaldehyde ultimately afforded the target
benzopyranquinone in monochiral form. The extension of these
quinonoid intermediate with enzymic extracts of Aphis fabae
ideas to the present study required, as one option, the assembly
of the naphtholic lactaldehyde 10, but this proved problematic.
As an alternative, the retrosynthetic analysis shown in Scheme 1
was considered based on methyl (R)-lactate 15 as the chiral
† Dedicated to Professor Don Cameron for his outstanding contribution
to research and teaching in organic chemistry.
‡ Electronic supplementary information (ESI) available: additional ex-
perimental details. See http://www.rsc.org/suppdata/ob/b4/b414213f/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3
2 6 3
©

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Scheme 1
pool source of asymmetry for C-3 of the derived naphthopyran-
quinones 1 and 2. The other starting material required would be
the benzyl activated regioselectively brominated hydroquinone
diether 14. The bromine atom in benzopyranquinone 12 was
necessary to direct the Diels–Alder regioselectivity10 in the
forward sense to yield quinone A 1. The use of bromine rather
than chlorine was imperative since recent studies had shown11
that brominated, but not chlorinated, meta-hydroxybenzyl lac-
taldehydes cyclise (with complete diastereoselectivity) to yield
benzopyran-4,5-diols as potential precursors to quinones such
as 12. The Diels–Alder reaction of the diene 11 with the non-
brominated analogue of quinone 12 would be anticipated to
favour the alternative regioisomer of quinone 1 (the 4,6,8-
naphthopyrantriol rather than the required 4,7,9-regioisomer)
through hydrogen bonding between the C-4 alcohol hydrogen
and the C-5 carbonyl oxygen atoms.12 We report here in detail
on the first syntheses of the four naturally derived enantiopure
quinones A 1 and Aꢀ 2 and their C-3 epimers 5 and 6.
deshielded from its value of d 5.03 for the alcohol 20. Imidate
21 was in turn treated with methyl (R)-lactate 15 in the presence
of a catalytic amount of boron trifluoride diethyl etherate16 to
yield an inseparable mixture of the benzyl epimeric lactates 22
in a yield of 91% and in a ratio of 1.3 : 1, as judged by H
NMR spectroscopy. The overall yield of this mixture 22 from
1
2,5-dihydroxyacetophenone was 51% in six steps.
Results and discussion
Syntheses of phenolic lactaldehydes 25 and 28
Attempted oxidative dealkylation of the benzopyran-4,5-diol
1611 with either ceric ammonium nitrate13 or argentic oxide14 did
not afford the target quinone 12. Other oxidants investigated
either failed to react or led to decomposition of starting material.
A comparison of the failure of this diol 16 to undergo oxidation
using argentic oxide with the smooth oxidation of its non-
brominated enantiomer9 suggested that the environment of the
C-8 methoxy substituent between the C-7 bromine and the C-1
methyl was too crowded to permit this oxidative dealkylation.
Alternative protection of the hydroquinone diether 14 was
therefore established.
Just sufficient lithium aluminium hydride (monitored by thin
layer chromatography) was added to the ester mixture22 to effect
complete conversion into the chromatographically separable
benzyl-epimeric alcohols 23 and 30, obtained in a combined
yield of 91% and individual yields of 52% and 39% respectively.
An excess of the reducing agent also removed the bromine
atom from the aromatic ring. Individual assignments were not
possible to make at this stage, but followed from the 1H NMR
spectra of the derived benzopyrans (see below). In order to
establish that no epimerisation of the lactate asymmetric centre
had occurred during either its benzylation or the subsequent
reduction, the enantiomeric excess for each of these alcohols
23 and 30 was investigated. This was achieved by preparing
their enantiomers 31 and 26 respectively as above from the
trichloroacetimidate 21 and ethyl (S)-lactate via the inseparable
mixture of esters 29. These were obtained in a ratio of 1 : 1. The
values for the specific rotations of these alcohols corresponded
closely to those expected for their enantiomers 23 and 30 (see
Experimental). Mixtures of the enantiomeric pairs 23/31 and
26/30 were assembled, each in a 60 : 40 ratio, and examined
both by 1H NMR spectroscopy using the lanthanide shift
reagent europium tris[3-(heptafluoropropylhydroxymethylene)-
(+)-camphorate] (Eu(hfc)3)9,17 and by chiral high pressure
liquid chromatography. In each procedure good separation was
achieved for signals attributable to each enantiomer within each
mixture, whereas for the enantiopure 23 and 26 required for
the assembly of the natural derivatives virtually none of the
The non-hydrogen bonded, less crowded hydroxy group of
commercially available 2,5-dihydroxyacetophenone was regio-
selectively silylated to give solely the t-butyldimethylsilyl ether 17
in 96% yield, for which, inter alia, the hydrogen bonded hydroxyl
hydrogen was observed in the 1H NMR spectrum at d 11.85. This
was in turn regioselectively monobrominated, using bromine in
dichloromethane containing pyridine, ortho to the phenolic and
meta to the acetyl substituents to afford the bromobenzene 18
1
in 96% yield, for which the H NMR spectrum showed two
meta-coupled aromatic protons. Benzylation of the remaining
phenolic oxygen using benzyl bromide in the presence of
anhydrous potassium carbonate yielded the differently protected
hydroquinone diether 19 in 95% yield. Reduction of the ketone
function gave the benzylic alcohol 20 in 94% yield. This was
converted into its trichloroacetimidate 21 in a yield of 88%
using trichloroacetonitrile and a catalytic quantity of sodium
hydride.15 The infrared spectrum of the product showed an
imine absorption at 1661 cm−1 and, in the 1H NMR spectrum,
the characteristic resonances of the NH and benzylic methine
protons at d 8.35 and d 6.25 respectively, the latter strongly
2 6 4
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alternative enantiomers were observed (and likewise for the
enantiopure 30 and 31).
be significantly deshielded from these, and, therefore, that the
product 32 possessed a trans arrangement21 of the two methyl
substituents at C-1 and C-3. It followed that the C-1 methyl was
pseudoaxial.
The benzyl protecting group in compound 32 was removed
through hydrogenolysis, using the catalyst palladium on car-
bon in ethyl acetate, to afford the required hydroquinone
33 together with the analogue 34 arising from unavoidable
debromination. The oily mixture was immediately oxidized with
ceric ammonium nitrate to the chromatographically separable
bromobenzopyranquinone 12 and its debrominated analogue
58, the enantiomer of the latter being known,9 in yields of 41%
and 17% over the two steps. The stereochemistry of each was
confirmed as the same from the chemical shifts of the proton
3-H (d 3.84), the large 3-H/4-H coupling constants (7.7 and
7.8 Hz respectively) and, in addition, the long range homoallylic
couplings between the protons 1-H and 4-H. These values (J 1.4
and 1.6 Hz respectively) are typical for such coupling between a
pseudoequatorial and a pseudoaxial proton and are consistent
with that observed for the natural derivative quinone A.9,22,23 This
hydrogenolytic debromination was useful in that it provided the
parent 2-benzopyranquinone 58 itself, although for the natural
derivative quinone A selective debenzylation to give solely the
brominated quinone 12 was necessary and was achieved by a
change in solvent from ethyl acetate to tetrahydrofuran. Here
the debenzylation afforded solely the rapidly chromatographed
hydroquinone 33 in virtually quantitative yield and this was then
oxidised to the quinone 12 in a yield of 84% over the two steps.
Swern oxidation18 of the alcohol 23 afforded the aldehyde 24 in
88% yield. Pyridinium chlorochromate19 could also be used, but
the yields were lower. Evidence for the aldehyde was observed in
the infrared spectrum, in which the hydroxyl absorption of the
alcohol 23 was replaced by a carbonyl absorption at 1735 cm−1,
1
and in the H NMR spectrum the aldehydic proton appeared
as a doublet at d 9.60 (J 1.7 Hz). Similar oxidation of the
alcohol 26 derived from ethyl (S)-lactate gave, in 85% yield, the
aldehyde 27 for which the corresponding aldehydic proton was
observed at d 9.49 (J 1.2 Hz). Two observations confirmed that
no epimerisation of the carbon a to the aldehydic carbonyl had
occurred during the oxidation step. First, such epimerisation
of the aldehyde 24 would yield the epimeric aldehyde 27, but
The brominated quinone 59, the C-4 pseudoaxial epimer
of 12 required for the synthesis of quinone Aꢀ, could not be
obtained readily by the cyclisation of the magnesium phenolate20
of phenolic lactaldehyde 25, presumably owing to the inability of
the magnesium to coordinate effectively to both the carbonyl and
lactaldehyde oxygen atoms. The benzopyranquinone 59 was ob-
tained through phenolic methylation of the benzopyran 32 to af-
ford the methyl ether 35 in 96% yield. The C-4 pseudoequatorial
stereochemistry of this alcohol was reversed through treatment
of 35 with phosphorus pentachloride followed by silver nitrate
in aqueous acetonitrile4 to afford the epimeric C-4 pseudoaxial
alcohol 36 in 72% yield, together with a 21% recovery of the
starting material 35. This represented an overall yield of 87%
over the two steps from the alcohol 35 based on unrecovered
alcohol 35. Debenzylation of this hydroquinone dialkyl ether
in ethyl acetate (see above) afforded the monomethyl ether 37,
together with the corresponding product of debromination 38.
This 5-methoxybenzopyran-4,8-diol 37 was a structurally iso-
meric analogue of the 8-methoxybenzopyran-4,5-diol 16 above
which could not be oxidized. In contrast, the mixture containing
this new isomer underwent smooth oxidative demethylation to
afford the separable mixture of benzopyranquinones 59 and 60
in yields of 51% and 22% for the two steps from alcohol 36. The
ready oxidation of the 5-methoxy compound 37 confirmed the
earlier assumption that steric crowding prevented the oxidation
of its isomer 16. The new benzopyranquinones 59 and 60
possessed the same stereochemistry for the pyran ring. This was
evident from chemical shifts of the proton 3-H in each case
(d 3.96 and d 3.97 respectively), the identical 3-H/4-H coupling
constant (J 2.2 Hz) and the lack of long range homoallylic
coupling between the two pseudoequatorial protons 1-H and
4-H.9,22,23 Selective debenzylation without debromination was
1
this was not observed in its H NMR spectrum. Secondly, the
aldehyde 24 was reduced back to its precursor alcohol 23 for
which the specific rotation agreed with the value for material
obtained directly through reduction of the ester 22. The same
two observations were made for the epimeric aldehyde 27.
Removal of the silyl protecting group in aldehyde 24 was
achieved using a mixture (1 : 1) of saturated solutions of
sodium fluoride and ammonium chloride, whereupon the crude
phenolic aldehyde 25 was obtained in 73% yield after rapid
chromatography. Deprotection of the epimeric aldehyde 27 was
similarly accomplished in 76% yield to afford the crude benzyl
epimeric lactaldehyde 28.
Syntheses of benzopyranquinones 12 and 58–64
The phenolic lactaldehyde 25 was immediately cyclised with
titanium tetraisopropoxide9,20 using ultrasound. This afforded
solely the benzopyran-4,5-diol 32 in a completely diastereo-
selective reaction in 55% yield for the two steps from the
silyloxyphenyl lactaldehyde 24. The stereochemistry of pyran
32 was determined from its 1H NMR spectrum, which showed,
first, that the coupling constant between the protons 3-H and 4-
H was 8.7 Hz. This required an almost trans-diaxial arrangement
for the two protons and therefore the C-3 methyl to be equatorial
and the C-4 hydroxyl to be pseudoequatorial. Secondly, the
chemical shift of the proton 3-H was d 3.86. A comparison
of this with the related values for the two benzopyran-4,5-diols
from the alternative lactaldehyde 28 (see below) showed it to
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3
2 6 5

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achieved again using the alternative solvent tetrahydrofuran,
giving solely the bromoquinone 59, after oxidation, in a yield of
73% for the two steps from benzopyran 36.
Immediate cyclisation of the diastereomeric lactaldehyde
28 with titanium tetraisopropoxide and ultrasound was only
partially diastereoselective, with the formation of the two
chromatographically separable C-4 epimeric benzopyran-4,5-
diols 39 and 44 being obtained in a combined yield of 62% over
the two steps from the silyl-protected aldehyde 27 and respective
yields of 51% and 30% for the cyclisation step. Individual
stereochemistries were established, first, from the coupling
constants between 3-H and 4-H for the two stereoisomers, these
being 8.8 Hz and 1.6 Hz respectively. For the major isomer 39 this
required that the C-3 methyl was equatorial and the C-4 hydroxy
group pseudoequatorial. For the minor diastereoisomer, the
smaller coupling constant indicated a smaller dihedral angle
between the two protons and therefore, with the C-3 methyl still
equatorial, the C-4 hydroxy group was pseudoaxial. Secondly,
the chemical shifts for 3-H for the two diastereoisomers 39 and
44 were d 3.39 and d 3.59, both at significantly lower chemical
shift than that (d 3.86) for the 1,3-trans-dimethyl stereoisomer 32
above. Both these values were consistent with the alternative 1,3-
cis-dimethyl stereochemistry,21 which required the C-1 methyl in
each case to be pseudoequatorial.
For that leading from lactaldehyde 49 to pyran 42, the C-1
methyl is pseudoequatorial, which is preferred since there are no
significant 1,8-peri-interactions with the neighbouring hydrogen
and a single diastereomer is therefore formed. For those tran-
sition states 56 involved in the conversions of the lactaldehydes
28 and 50 into the remaining cis-1,3-dimethylbenzopyrans 39
and 43, however, the pseudoequatorial C-1 methyl orientation
leads to significant 1,8-peri-interactions with the neighbouring
alkoxy substituents. Here, intramolecular arylation occurs at
the Re face of the aldehyde.9 The alternative conformation
57 of the transition state is therefore adopted by ∼38% and
∼25%, respectively, of the molecules in the cyclisations to the
minor C-4 epimers 44 and 48, in which the incipient C-4
alcohol retains the pseudoequatorial orientation to minimize
the inter-oxygen distance through coordination. The C-1 methyl
becomes pseudoaxial to reduce these 1,8-peri-interactions with
the neighbouring C-8 alkoxy group at the expense of the C-
3 methyl becoming axial,24 and intramolecular arylation in 57
occurs at the Si face of the aldehyde. Upon hydrolysis of the
titanium complex the conformation of the derived dihydropyran
rings in 44 and 48 invert so that the C-1 and C-3 methyl groups
become pseudoequatorial and equatorial respectively, and the
C-4 alcohol becomes pseudoaxial. The dihydropyrans 44 and 48
obtained from this alternative transition state are therefore the
C-4 epimers of dihydropyrans 39 and 43. The greater the steric
demand of the C-8 substituent in the developing benzopyran the
greater the proportion of molecules adopting this alternative
conformation leading to the pseudoaxial C-4 alcohols. In the
case of 44 this steric compression may be increased by the but-
tressing effect of the additional bromine atom.
In a recent study24,25 we showed that the phenolic lactalde-
hyde 49 unsubstituted para to the phenolic hydroxyl group
cyclised with complete diastereoselectivity to give the cis-1,3-
dimethylbenzopyran-4,5-diol 42 in good yield, none of the
epimeric C-4 diol 47 being formed, whereas an earlier study9
showed that the corresponding methoxy lactaldehyde 50 cyclised
with lower diastereoselectivity to afford the pair of C-4 epimeric
cis-1,3-dimethylbenzopyran-4,5-diols 43 and 48 in a ratio of 75 :
25, with the pseudoequatorial alcohol still predominating. In the
present study the diastereoselectivity is even less, with cyclisation
of the corresponding brominated benzyloxy derivative yielding
the two C-4 epimeric cis-1,3-dimethylbenzopyrans 39 and 44 in
a ratio of 62 : 38. For the corresponding three benzyl-epimeric
lactaldehydes 25, 51 and 52, (the first with the enantiomeric
stereochemistry of the latter two) the cyclisations to the trans-
1,3-dimethyl compounds were all completely diastereoselective.
We propose that in the conformation for the transition state 55§
(numbering for the developing benzopyran ring-system) leading
to all the trans-1,3-dimethylbenzopyrans 32, 53 and 54 the
developing C-4 alcohol oxygen assumes the pseudoequatorial
orientation to minimize the inter-oxygen distance for titanium
coordination, the C-3 methyl is equatorial to avoid 1,3-diaxial
interactions and the C-1 methyl is pseudoaxial, which minimizes
the 1,8-peri-interactions with the neighbouring alkoxy group in
the first and third cases. The exclusive products in these two cases
are therefore 32 and 54. The transition state for the conversion of
the lactaldehyde 51 into the pyranol 53 and the possible inversion
of the dihydropyran ring of the latter has recently been published
elsewhere.24,25
The benzopyran 39 was debenzylated over palladium on
charcoal in ethyl acetate to afford the hydroquinone 40 mixed
with its debrominated analogue 41. This mixture was oxidized
immediately with ceric ammonium nitrate to give the chromato-
graphically separable benzopyranquinones 63 and 64 in yields
of 43% and 40%. Once again, the stereochemistry was shown
to be the same for both products. The chemical shifts for the
protons 3-H were at d 3.57 and d 3.69 respectively, the 3-H/4-H
coupling constants identical (J 8.3 Hz), and the large long range
homoallylic coupling between 1-H and 4-H (J 2.9 Hz) further
confirmation that both these protons were pseudoaxial in each
of the product 2-benzopyranquinones.9,23
§ The transition state 55 is drawn for the conversion of the lactaldehyde
25 into the benzopyran 16. For the conversions of the lactaldehydes 51
and 52 into the benzopyrans 53 and 54 the transition states would have
the enantiomeric stereochemistry.
2 6 6
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each of the brominated 2-benzopyranquinones 61 and 63 to
form the hitherto unreported quinones 5 and 6 in yields of 24%
and 23% respectively.
The NMR data for the four naturally derived quinones 1,
2, 5 and 6 have not been reported and we determined these
in acetone-d6 and methanol-d4. In subsequent discussions with
1
Professor Cameron it transpired that he had obtained the H
NMR spectra for these four compounds in dimethyl sulfoxide-
d6.7 In comparing the combined data, provided in Table 1,
three factors in particular confirm the stereochemistries of the
dihydropyran rings in each case; the chemical shifts of the
protons 3-H, the coupling constants between the protons 3-
H and 4-H and the long-range homoallylic coupling between
the protons 1-H and 4-H. This long-range coupling is largest
for two pseudoaxial protons (∼3 Hz), less for one pseudoaxial
and one pseudoequatorial proton (∼1.5–2 Hz) and negligible
for two pseudoequatorial protons. The proton chemical shifts
for the corresponding brominated and parent non-brominated
2-benzopyranquinones are given in Table 2.
Similar debenzylation of the all cis benzopyran 44 followed
by oxidation afforded the separable mixture of benzopyran-
quinones 61 and 62 (the latter known as the racemate26) in yields
of 42% and 33%. The identical values for the chemical shifts of
the protons 3-H (d 3.59), the 3-H/4-H coupling constants (J
1.6 Hz), and the long range homoallylic coupling constants (J
1.4 Hz) between the pseudoaxial 1-H and pseudoequatorial 4-H
confirmed the same stereochemistry for each product. This latter
value is very close to that (J 1.6 Hz) for compounds 12 and 58
above, where 1-H is pseudoequatorial and 4-H pseudoaxial.
The specific rotations of each of the synthetic materials
compared very well with the hitherto unreported7 values for
the natural derivatives, as shown in Table 3. The signs of our
rotations support the assignment of absolute stereochemistries
for quinones A and Aꢀ 1 and 2 already made1 and also the
absolute stereochemistries for quinones 5 and 6 assumed by
Banks and Cameron7 through a comparison with both the values
for 1 and 27 and also the literature values for eleutherin and
isoeleutherin30 and related materials.
Conclusions
The first routes have been developed for the syntheses,
in principle, of all eight possible enantiopure diastereoiso-
mers of 3,4-dihydro-4,7,9-trihydroxy-1,3-dimethylnaphtho[2,3-
c]pyran-5,10-quinones. This paper describes the assembly of
four of these, quinones A 11 and Aꢀ 21 and their hitherto
unreported C-3 epimers, the quinones 57 and 6,7 all of which
have been isolated from natural sources as derivatives of a variety
of different aphid insect pigments. The quinones 1, 5 and 6
were obtained in thirteen, and quinone 2 in sixteen, consecutive
steps from the commercially available starting materials 2,5-
dihydroxyacetophenone and lactate, the latter as the source of
asymmetry from the chiral pool. Although the yield of the
last step in each sequence, a Diels–Alder reaction between
the diene 11 and diastereoisomers of the 2-benzopyranquinone
12, was only moderate, all other yields were gratifyingly high.
Key factors that enabled these achievements were, first, the
successful maintenance of stereochemical integrity throughout
each sequence even when the asymmetric centres were a to
ester and aldehydic carbonyl groups. Secondly, cyclisation of
the phenolic lactaldehyde 25 to the benzopyran-4,5-diol 32
was completely diastereoselective while the related process
for the benzyl-epimeric lactaldehyde 28 into the pair of C-
4 epimeric benzopyrans 39 and 44 was almost completely
non-stereoselective. These stereochemical differences for these
two related reactions have been rationalised in terms of the
differences in peri-interactions in the transition states involved.
Once again, selective debenzylation with retention of the
aromatic bromine atom could be achieved using tetrahydrofuran
as the solvent for each of the O-benzyl-protected 2-benzopyrans
39 and 44, giving, respectively, the hydroquinones 40 and
45. Ceric ammonium nitrate oxidation of these individual
hydroquinones afforded the brominated 2-benzopyranquinones
63 and 61, which were obtained in yields of 70% and 77%
respectively.
Syntheses of quinone A 1, quinone Aꢀ 2, and their two C-3
epimers 5 and 6
2-Bromo-6-methyl-1,4-benzoquinone 6527 was used as a readily
available model to optimize conditions for the reaction of
bromobenzopyranquinones such as 12 with the diene 11.28
After considerable experimentation, modification of a literature
method29 was used with this model to afford 6,8-dihydroxy-
2-methyl-1,4-naphthoquinone 66 in 73% yield. When these
conditions were used for the Diels–Alder reaction of diene 11
with the benzopyranquinone 12, quinone A 1 was crystallized
directly from the solution (as were the quinones 2, 5 and 6 below)
in a 30% yield. Combustion data and a high-resolution mass
spectrum confirmed the molecular formula. Similar reaction
of the diene 11 with the C-4 epimeric benzopyranquinone 59
afforded quinone Aꢀ 2 in a yield of 20%. The chromatographic
behaviour of each of these quinones 1 and 2 was identical with
that of each natural derivative. Likewise diene 11 reacted with
Experimental
General
Melting points were determined on a Reichert hot stage appara-
tus and are uncorrected. Optical rotations were measured using
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an Optical Activity PolAAr 2001 polarimeter for chloroform
solutions of c 1.0 at 20 ◦C, unless otherwise stated, and are given
in 10−1 deg cm2 g−1. Infrared (IR) spectra were recorded as a nujol
mull for solids and as thin films between NaCl plates for oils,
using a Perkin Elmer 1720-X Fourier Transform Spectrometer.
The sonication bath used was a Branson B3200-E4, operating
at a frequency of 44 kHz. Mass spectra were obtained on a
VG Autospec spectrometer operating in the electron impact
mode at 70 eV. Elemental analyses were determined by the
Canadian Microanalytical Service Ltd. Unless otherwise stated,
nuclear magnetic resonance (NMR) spectra were recorded using
a Bruker AM-300 spectrometer (1H, 300 MHz; 13C, 75.5 MHz).
These were run at ambient temperature in deuterochloroform
(CDCl3) solution, with tetramethylsilane (TMS) (d 0.00) for 1H
NMR spectra and TMS (d 0.00) and chloroform (d 77.00) for
13C NMR spectra as internal standards. Assignments of signals
with the same superscripts are interchangeable. All solvents were
purified by distillation and, if necessary, were dried according
to standard methods. The amount of residual water present
in solvents was determined using a Metrohm Karl Fischer
Calorimeter 684. The hydrocarbon solvent referred to as hexane
routinely had a bp range of 65–70 ◦C. Chromatography refers to
dry-packed columns of Merck silica gel 60 (70–230 mesh). Pread-
sorption was carried out on Merck silica gel 60 (35–70 mesh).
The adsorbent for radial chromatography was Merck silica gel
60 PF254. Merck silica gel 60 F254 aluminium backed sheets were
used for thin layer chromatography (TLC). The phrase “residue
obtained upon work-up” refers to the residue when the organic
layer was separated, dried with anhydrous magnesium sulfate
(MgSO4) and concentrated under reduced pressure.
5ꢀ-t-Butyldimethylsilyloxy-2ꢀ-hydroxyacetophenone 17
t-Butyldimethylsilyl chloride (5.94 g, 39 mmol) and imida-
zole (2.68 g, 39 mmol) were added to a solution of 2,5-
dihydroxyacetophenone (5 g, 33 mmol) in dry dimethylform-
amide (80 cm3). The mixture was stirred under argon for
12 h at room temperature after which water was added and
the mixture exhaustively extracted with ethyl acetate. The
residue obtained upon work-up was chromatographed (10%
ethyl acetate–hexane) to give product 17 as a yellow oil (8.5 g,
97%) (Found: C, 62.9; H, 8.4; M+, 266.1336. C14H22O3Si requires
C, 63.1; H, 8.3%; M, 266.1338); tmax(film)/cm−1 1648 (C O) and
=
=
1616, 1588 and 1481 (C C); dH 0.21 (6H, s, OSi(CH3)2C(CH3)3),
0.99 (9H, s, OSi(CH3)2C(CH3)3), 2.59 (3H, s, COCH3), 6.86
(1H, d, J 8.9 Hz, 3ꢀ-H), 7.02 (1H, dd, J 2.9 and 8.9 Hz,
4ꢀ-H), 7.16 (1H, d, J 2.9 Hz, 6ꢀ-H) and 11.85 (1H, s, OH);
dC −4.6 (OSi(CH3)2C(CH3)3), 17.1 (OSi(CH3)2C(CH3)3), 24.7
(OSi(CH3)2C(CH3)3), 25.6 (COCH3), 118.0 (C-1ꢀ), 118.4 (C-6ꢀ),
119.1 (C-3ꢀ), 128.3 (C-4ꢀ), 146.2 (C-2ꢀ), 155.7 (C-5ꢀ) and 202.9
(COCH3); m/z 266 (M+, 60%), 209 (100), 181 (20), 167 (10), 86
(11) and 84 (17).
3ꢀ-Bromo-5ꢀ-t-butyldimethylsilyloxy-2ꢀ-hydroxyacetophenone 18
Bromine (2.40 g, 15 mmol) was added to
a solution
of 5ꢀ-t-butyldimethylsilyloxy-2ꢀ-hydroxyacetophenone 17 (4 g,
15 mmol) and pyridine (4.75 g, 60 mmol) in dry dichloromethane
(150 cm3) at 0 ◦C. The solution was stirred at this temperature
for 5 min and then at room temperature for 3 h. The reaction was
then quenched with hydrochloric acid (1 M) and the mixture was
exhaustively extracted with dichloromethane. The organic ex-
tracts were washed further with hydrochloric acid (1 M) and sat-
urated sodium chloride, after which the residue obtained upon
work-up was chromatographed (10% ethyl acetate–hexane) to
give product 18 (5 g, 96%) as light yellow prisms mp 66–67 ◦C
(hexane) (Found: C, 49.0; H, 6.2; M+, 344.0443. C14H21BrO3Si
requires C, 48.7; H, 6.15%; M(79Br), 344.0443); tmax/cm−1 1654
=
=
(C O) and 1447 (C C); dH 0.21 (6H, s, OSi(CH3)2C(CH3)3),
0.99 (9H, s, OSi(CH3)2C(CH3)3), 2.61 (3H, s, COCH3). 7.15 (1H,
d, J 2.8 Hz, 4ꢀ-H), 7.30 (1H, d, J 2.8 Hz, 6ꢀ-H) and 12.49 (1H, s,
2 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3

View Article Online
Table 2 Chemical shifts (d) and coupling constants (J) for the 2-benzopyrans 12, 58–64 in deuterochloroform
Compound
12
58
59
60
61
62
63
64
3-CH3
1-CH3
4-OH
3-H
4-H
1-H
6-H
7-H
J 3-H/4-H
J 1-H/4-H
1.37
1.54
3.43
3.84
4.35
4.80
7.27
—
1.37
1.52
3.52
3.84
4.35
4.75
6.73
6.73
7.8
1.37
1.47
2.25
3.96
4.35
4.89
7.32
—
1.37
1.45
2.22
3.97
4.36
4.85
6.75a
6.80a
2.2
1.37
1.54
2.13
3.59
4.37
4.67
7.32
—
1.37
1.53
2.08
3.59
4.37
4.64
6.73b
6.80b
1.6
1.41
1.46
3.57
3.41
4.38
4.70
7.25
—
1.41
1.45
3.69
3.42
4.38
4.67
6.72
6.72
8.3
7.7
1.4
2.2
0
1.6
1.4
8.3
2.9
1.6
0
1.4
2.9
a,bAssignments with identical superscripts may be interchanged.
Table 3 A comparison of the specific rotations of the naturally derived
quinones 1, 2, 5 and 6 with those of the synthesised compounds [a]D20
(c 1.0, 1% AcOH in MeOH)
(6H, s, OSi(CH3)2C(CH3)3), 0.98 (9H, s, OSi(CH3)2C(CH3)3),
1.38 (3H, d, J 6.4 Hz, 1-CH3), 1.94 (1H, d, J 2.9 Hz, OH), 4.99
(2H, s, OCH2), 5.03 (1H, dq, J 2.9 and 6.4 Hz, 1-H), 6.88 (1H, d, J
2.9 Hz, 6ꢀ-H), 7.00 (1H, d, J 2.9 Hz, 4ꢀ-H) and 7.34–7.48 (5H, m,
C6H5); dC −4.5 (OSi(CH3)2C(CH3)3), 18.2 (OSi(CH3)2C(CH3)3),
23.9 (C-2), 25.6, (OSi(CH3)2C(CH3)3), 65.1 (C-1), 75.6 (OCH2),
117.0 (C-6ꢀ), 117.1 (C-3ꢀ), 123.8 (C-2ꢀꢀ and C-6ꢀꢀ), 125.9 (C-4ꢀꢀ),
128.4 (C-4ꢀ), 128.6 (C-3ꢀꢀ and C-5ꢀꢀ), 136.5 (C-1ꢀꢀ), 141.1 (C-1ꢀ),
146.6 (C-2ꢀ) and 152.7 (C-5ꢀ); m/z 438 [M+ (81Br), 6%], 436 [M+
(79Br), 6%], 347 (10), 345 (10), 330 (57), 328 (55), 273 (30), 271
(26), 115 (28), 91 (84) and 73 (100).
Quinone
1
2
5
6
Natural derivative
Synthetic product
+41
+40
+258
+262
+278
+260
+568
+550
OH); dC −4.5 (OSi(CH3)2C(CH3)3), 18.2 (OSi(CH3)2C(CH3)3),
25.6 (OSi(CH3)2C(CH3)3), 26.7 (COCH3), 111.8 (C-1ꢀ), 119.7
(C-3ꢀ), 119.9 (C-4ꢀ), 132.2 (C-6ꢀ), 147.3 (C-2ꢀ), 153.7 (C-5ꢀ) and
203.7 (COCH3); m/z 346 [M+ (81Br), 24%], 344 [M+ (79Br), 22%],
289 (39), 287 (37), 97 (15), 95 (11), 84 (100), 83 (18), 81 (12) and
71 (18).
2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxy-aꢀ-methyl-
benzyl-2,2,2-trichloroethanimidate 21
The benzyl alcohol 20 (3 g, 6.9 mmol) in dry diethyl ether
(10 cm3) was added drop-wise to a stirred suspension of sodium
hydride (60% dispersion in mineral oil) (110 mg, 4.6 mmol) in
diethyl ether (15 cm3). The mixture was stirred for 10 min under
argon at −10 ◦C. Trichloroacetonitrile (1.94 g, 13.7 mmol) was
added drop-wise over 10 min and the reaction mixture stirred for
a further 30 min at that temperature, after which it was allowed
to reach room temperature. The solution was concentrated and
chromatographed (radial, 5% ethyl acetate–hexane) to afford the
imidate 21 (3.5 g, 88%) as a light yellow oil. (Found: C, 47.9; H,
5.1; N, 2.3; M+, 579.0165. C23H29BrCl3NO3Si requires C, 47.5; H,
5.05; N, 2.4%; M(79Br and 35Cl), 579.0165); tmax(film)/cm−1 3337
2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxyacetophenone
19
Anhydrous potassium carbonate was added to a solution of
compound 18 (1.00 g, 2.9 mmol) in dry acetone at 45 ◦C
under nitrogen. Benzyl bromide (0.497 g, 2.9 mmol) was added
dropwise to the reaction mixture over a period of 10 min.
The mixture was stirred at that temperature until completion
of the reaction as monitored by TLC (30–60 min) and then
filtered through Celite, whereupon the filtrate was concentrated
under reduced pressure. The residue was chromatographed
(5% ethyl acetate–hexane) to give the benzyl ether 19 (1.23 g,
=
=
(N–H), 1661 (C N) and 1600, 1562 and 1464 (C C); dH 0.18
(6H, s, OSi(CH3)2C(CH3)3), 0.96 (9H, s, OSi(CH3)2C(CH3)3),
◦
97%) as pale yellow needles, mp 89–90 C (dichloromethane).
Found: M+, 434.0923. C21H27BrO3Si requires M(79Br), 434.0912;
ꢀ
1.54 (3H, d, J 6.5 Hz, a -CH3), 5.10 and 5.14 (each 1H, d, J
tmax(film)/cm−1 1677 (C O) and 1591 and 1495 (C C); dH 0.24
(6H, s, OSi(CH3)2C(CH3)3), 1.01 (9H, s, OSi(CH3)2C(CH3)3),
2.55 (3H, s, COCH3), 4.95 (2H, s, OCH2), 7.01 (1H, d, J 3.0 Hz,
4ꢀ-H), 7.24 (1H, d, J 3.0 Hz, 6ꢀ-H) and 7.38–7.51 (5H, m, C6H5);
dC −4.1 (OSi(CH3)2C(CH3)3), 18.5 (OSi(CH3)2C(CH3)3), 26.0
(OSi(CH3)2C(CH3)3), 31.0 (COCH3), 70.1 (OCH2), 119.1 (C-1ꢀ),
120.0 (C-3ꢀ), 128.6 (C-6ꢀ), 128.7 (C-4ꢀꢀ), 128.9 (C-2ꢀꢀ and C-6ꢀꢀ),
129.0 (C-3ꢀꢀ and C-5ꢀꢀ), 136.3 (C-4ꢀ), 136.5 (C-1ꢀꢀ), 148.9 (C-5ꢀ),
152.8 (C-2ꢀ) and 199.9 (COCH3); m/z 436 [M+ (81Br), 5%], 434
[M+ (79Br), 5%], 394 (9), 392 (9), 345 (6), 343 (5), 289 (8), 287
(8), 115 (11), 91 (100) and 73 (52).
ꢀ
=
=
10.6 Hz, OCH2), 6.25 (1H, q, J 6.5 Hz, a -H), 6.94 (1H, d, J
2.9 Hz, 6ꢀ-H), 7.02 (1H, d, J 2.9 Hz, 4ꢀ-H), 7.32–7.44 (5H, m,
C6H5) and 8.35 (1H, br s, NH); dC −4.5 (OSi(CH3)2C(CH3)3),
ꢀ
18.1 (OSi(CH3)2C(CH3)3), 22.1 (OSi(CH3)2C(CH3)3), 25.6 (a -
ꢀ
CH3), 72.7 (C-a ), 74.8 (OCH2), 91.6 (CCl3), 116.4 (C-6ꢀ), 117.3
(C-3ꢀ), 124.1 (C-4ꢀ), 127.8 (C-4ꢀꢀ), 128.2 (C-2ꢀꢀ and C-6ꢀꢀ), 128.5
(C-3ꢀꢀ and C-5ꢀꢀ), 137.1 (C-1ꢀꢀ), 137.6 (C-1ꢀ), 146.5 (C-2ꢀ), 152.7
(C-5ꢀ) and 161.2 (C-1); m/z 581 [M+ (81Br35Cl), 4%], 579 [M+
(79Br35Cl), 2%], 420 (34), 418 (31), 363 (17), 361 (16), 329 (38),
327 (34), 272 (11), 270 (13), 248 (18), 191 (100) and 91 (77).
Methyl (aꢀS and R,2R)-2-(2ꢀ-benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldi-
methylsilyloxy-aꢀ-methylbenzyloxy)propanoate 22
1-(2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxyphenyl)-
ethanol 20
Boron trifluoride diethyl etherate (79 mg, 0.56 mmol) was
added dropwise to a solution of imidate 21 (1.61 g, 2.8 mmol)
and methyl (R)-lactate 15 (577 mg, 5.5 mmol) in dry hexane–
dichloromethane (20 cm3, 2 : 1). The reaction was stirred
under nitrogen for 40 min. Solid sodium hydrogencarbonate
was added to the reaction and the resulting suspension was
filtered through Celite. The clear solution was then concentrated
and chromatographed (radial, 10% ethyl acetate–hexane) to
afford the yellow, oily inseparable mixture of diastereoisomeric
esters 22 (1.33 g, 91%) (Found: M+, 522.1426. C25H35BrO5Si
To a stirred slurry of sodium borohydride (570 mg, 1.5 mmol)
in dry ethanol (30 cm3) was added drop-wise a solution of
the compound 19 in dry ethanol (10 cm3). The mixture was
stirred at room temperature for 1 h, after which a saturated
ammonium chloride solution was added drop-wise, followed
by anhydrous magnesium sulfate. Filtration through Celite and
concentration of the filtrate followed by chromatography (radial,
10–20% ethyl acetate–hexane) yielded alcohol 20 (525 mg, 91%)
as a light yellow oil. (Found: C, 57.8; H, 6.6; M+, 436.1082.
C21H29BrO3Si requires C, 57.65; H, 6.7%; M(79Br), 436.1069);
requires M(79Br), 522.1437); tmax(film)/cm−1 1754 (C O) and
=
tmax(film)/cm−1 3409 (OH), and 1599 and 1496 (C C); dH 0.21
1598 and 1498 (C C); dH (mixture of two diastereoisomers)
=
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3
2 6 9

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0.21 (12H, s, OSi(CH3)2C(CH3)3), 0.98 and 0.99 (each 9H, s,
OSi(CH3)2C(CH3)3), 1.33 and 1.35 (each 3H, d, J 6.8 Hz, 2-
CH3), 1.36 and 1.40 (each 3H, d, J 6.5 Hz, a -CH3), 3.61 and
argon was added dropwise a solution of dimethyl sulfoxide
(558 mg, 7.14 mmol) in dry dichloromethane (2 cm3) keeping
the temperature below −65 ◦C. After stirring for 15 min, a
ꢀ
ꢀ
3.65 (each 3H, s, CO2CH3), 3.80 and 3.88 (each 1H, q, J 6.8 Hz,
solution of the (a R,2R)-alcohol 23 (354 mg, 0.71 mmol) in
ꢀ
2-H), 4.70–5.11 (6H, m, a -H and OCH2), 6.88, 6.93, 6.99 and
dry dichloromethane (2 cm3) was added drop-wise keeping
the temperature below −65 ◦C and the stirring continued for
a further 15 min at that temperature. Dry diisopropylamine
(1.11 g, 8.59 mmol) was added slowly and the reaction stirred
for a further 10 min at −70 ◦C before being allowed to
warm to room temperature over 1 h. The reaction mixture
was quenched with water and exhaustively extracted with
dichloromethane. The residue obtained upon work-up was
chromatographed (radial, 10–20% ethyl acetate–hexane) to give
aldehyde 24 (312 mg, 88%) as a colourless oil. [a]D +46.6 (c 1.0 in
CHCl3); (Found: M,+ 492.1333. C24H33BrO4Si requires M(79Br),
7.02 (each 1H, d, J 2.9 Hz, 4ꢀ and 6ꢀ-H) and 7.33–7.51 (10H,
m, 2 × C6H5); dC (mixture of two diastereoisomers) −4.57 and
−4.56 (OSi(CH3)2C(CH3)3), −4.48 (2 × (OSi(CH3)2C(CH3)3),
18.06 and 19.0 (C-3), 18.14 and 18.2 (OSi(CH3)2C(CH3)3), 23.2
ꢀ
and 23.6 (a -CH3), 25.6 (OSi(CH3)2C(CH3)3), 51.8 and 51.9
ꢀ
(OCH3), 70.9 and 71.4 (C-a ), 72.2 and 72.5 (C-2), 75.4 and 75.6
(OCH2Ph), 116.9 and 117.3 (C-3ꢀ), 117.1 and 117.9 (C-6ꢀ),a 124.0
and 124.2 (C-4ꢀ),a 128.0 (C-2ꢀꢀ and C-6ꢀꢀ), 128.2 (C-4ꢀꢀ), 128.5 and
128.6 (C-3ꢀꢀ and C-5ꢀꢀ), 136.7 and 136.9 (C-1ꢀ),b 138.9 and 139.0
(C-1ꢀꢀ),b 147.0 and 147.6 (C-2ꢀ),c 152.8 and 152.9 (C-5ꢀ),c 173.0
+
81
+
79
and 173.9 (C O); m/z 524 [M ( Br), 5%], 522 [M ( Br), 5%],
433 (46), 431 (43), 330 (41), 328 (38), 272 (16), 270 (16), 191 (29)
and 91 (100).
492.1331); tmax(film)/cm−1 1735 (C O) and 1596 and 1496
=
=
=
(C C); dH 0.21 (6H, s, OSi(CH3)2C(CH3)3), 0.99 (9H, s,
OSi(CH3)2ꢀC(CH3)3), 1.18 (3H, d, J 7.0 Hz, 2-CH3), 1.39 (3H, d,
J 6.4 Hz, a -CH3), 3.59 (1H, dq, J 1.7 and 7.0 Hz, 2-H), 4.80 (1H,
(aꢀR,2R)-2-(2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxy-
aꢀ-methyl-benzyloxy)propanol 23 and (aꢀS,2R)-2-(2ꢀ-
benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxy-aꢀ-
methylbenzyloxy)propanol 30
q, J 6.4 Hz, a -H), 4.84 and 4.95 (each 1H, d, J 10.9 Hz, OCH2),
ꢀ
6.88 (1H, d, J 2.9 Hz, 6ꢀ-H), 7.03 (1H, d, J 2.9 Hz, 4ꢀ-H), 7.32–
7.48 (5H, m, C6H5) and 9.60 (1H, d, J 1.7 Hz, CHO); dC −4.5,
(OSi(CH3)2C(CH3)3), 15.8 (C-3), 18.2 (OSi(CH3)2C(CH3)3, 23.6
ꢀ
(a -CH3), 25.6 (OSi(CH3)2C(CH3)3), 71.8 (C-2), 75.6 (OCH2),
Lithium aluminium hydride was added portion-wise to a
solution of the methyl esters 22 (600 mg, 1.15 mmol) in dry
diethyl ether (25 cm3) until TLC indicated no starting material
remained. A saturated ammonium chloride solution was added
drop-wise to the reaction mixture followed by anhydrous magne-
sium sulfate. Filtration through Celite and concentration of the
filtrate gave crude product, which was chromatographed (radial,
5–50%ethyl acetate–hexane)to afford two products as colourless
oils. The product of higher Rf was identified as compound
30 (224 mg, 39%); [a]D −58.0 (c 1.0 in CHCl3) (Found: C,
58.55; H, 7.0; M+, 494.1474. C24H35BrO4Si requires C, 58.3;
H, 7.15%; M(79Br), 494.1487); tmax(film)/cm−1 3466 (OH), 1598
ꢀ
77.9 (C-a ), 117.0 (C-6ꢀ), 117.2 (C-3ꢀ), 124.3 (C-4ꢀ), 128.2 (C-2ꢀꢀ
and C-6ꢀꢀ), 128.4 (C-4ꢀꢀ), 128.6 (C-3ꢀꢀ and C-5ꢀꢀ), 136.6 (C-1ꢀꢀ),
138.7 (C-1ꢀ), 147.3 (C-2ꢀ), 152.8 (C-5ꢀ) and 203.3 (C-1); m/z 494
[M+ (81Br), 1%], 492 [M+ (79Br), 1%], 420 (15), 418 (14), 359 (13),
357 (13), 329 (32), 248 (11), 191 (66), 149 (21), 91 (88) and 73
(100).
(aꢀR,2R)-2-(2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-hydroxy-aꢀ-methylbenzyl-
oxy)propanal 25
A mixture of the aldehyde 24 (300 mg, 0.61 mmol), tetrahy-
drofuran (20 cm3) and saturated solutions of aqueous am-
monium chloride and sodium fluoride (40 cm3, 1 : 1) was
stirred for 16 h at room temperature. The reaction mixture
was exhaustively extracted with diethyl ether and the residue
obtained upon work-up was rapidly chromatographed (radial,
35% ethyl acetate–hexane) to afford the potentially unstable
phenolic aldehyde 25 (168 mg, 73%) as a colourless oil. (Found:
(M − H2O)+, 360.0353. C18H17BrO3 requires M(79Br), 360.0361);
=
and 1495 (C C); dH 0.21 (6H, s, OSi(CH3)2C(CH3)3), 0.98 (9H, s,
OSi(CH3)2C(CH3)3), 1.08 (3H, d, J 5.7 Hz, 2-CH3), 1.33 (3H,
ꢀ
d, J 6.4 Hz, a -CH3), 1.85 (1H, br s, OH), 3.34–3.48 (3H, m,
ꢀ
CH2OH and 2-H), 4.90 (1H, q, J 6.4 Hz, a -H), 4.93 and 4.96
(each 1H, d, J 11.0 Hz, OCH2), 6.86 (1H, d, J 2.9 Hz, 6ꢀ-H), 7.01
(1H, d, J 2.9 Hz, 4ꢀ-H) and 7.35–7.51 (5H, m, C6H5); dC −4.5,
(OSi(CH3)2C(CH3)3), 15.8 (C-3), 18.2 (OSi(CH3)2C(CH3)3), 23.8
ꢀ
tmax(film)/cm−1 3383 (OH), 1730 (C O) and 1603 and 1497
=
(a -CH3), 25.6 (OSi(CH3)2C(CH3)3), 66.7 (C-1), 68.7 (C-2), 73.1
ꢀ
(C-a ), 75.9 (OCH2), 117.2 (C-6ꢀ), 124.0 (C-4ꢀ), 125.9 (C-3ꢀ), 128.0
(C C); dH 1.19 (3H, d, J 7.0 Hz, 2-CH3), 1.39 (3H, d, J 6.4 Hz,
=
(C-2ꢀꢀ and C-6ꢀꢀ), 128.3 (C-4ꢀꢀ), 128.6 (C-3ꢀꢀ and C-5ꢀꢀ), 136.8 (C-
1ꢀꢀ), 139.6 (C-1ꢀ), 147.3 (C-2ꢀ) and 152.9 (C-5ꢀ); m/z [M+ 496
(81Br), 5%], 494 [M+ (79Br), 5%], 421 (7), 419 (7), 330 (87), 328
(84), 273 (41), 271 (36), 192 (18) and 91 (100). The product
of lower Rf was identified as compound 23 (298 mg, 52%); [a]D
+23.5 (c 1.0 in CHCl3); (Found: C, 58.35; H, 7.15; M+, 494.1475.
C24H35BrO4Si requires C, 58.3; H, 7.15%; M(79Br), 494.1487);
a -CH3), 3.64 (1H, dq, J 1.5 and 7.0 Hz, 2-H), 4.80 (1H, J 6.4 Hz,
ꢀ
ꢀ
a -H), 4.85 and 4.93 (each 1H, d, J 10.8 Hz, OCH2), 6.40 (1H,
br s, OH), 6.90 (1H, d, J 2.9 Hz, 6ꢀ-H), 7.03 (1H, d, J 2.9 Hz,
4ꢀ-H), 7.35–7.48 (5H, m, C6H5) and 9.58 (1H, d, J 1.5 Hz, CHO);
ꢀ
ꢀ
dC 16.1 (C-3), 23.8 (a -CH3), 74.4 (C-2), 76.2 (OCH2), 78.4 (C-a ),
113.0 (C-6ꢀ), 118.0 (C-3ꢀ), 120.2 (C-4ꢀ), 128.7 (C-2ꢀꢀ and C-6ꢀꢀ),
128.8 (C-4ꢀꢀ), 129.0 (C-3ꢀꢀ and C-5ꢀꢀ), 136.9 (C-1ꢀꢀ), 139.4 (C-1ꢀ),
146.9 (C-2ꢀ), 153.7 (C-5ꢀ) and 203.8 (C-1); m/z 362 [(M − H2O)+
(81Br), 4%], 360 [(M − H2O)+ (79Br), 4%], 167 (8) 149 (27) and
91 (100).
tmax(film)/cm−1 3447 (OH) and 1598 and 1496 (C C); dH 0.21
=
(6H, s, OSi(CH3)2C(CH3)3), 0.98 (3H, d, J 6.3 Hz, 2-CH3), 0.99
ꢀ
(9H, s, OSi(CH3)2C(CH3)3), 1.33 (3H, d, J 6.4 Hz, a -CH3), 1.90
(1H, br s, OH), 3.36–3.62 (3H, m, CH2OH and 2-H), 4.87 (1H,
ꢀ
q, J 6.4 Hz, a -H), 4.95 (2H, s, OCH2), 6.90 (1H, d, J 2.9 Hz,
(1R,3R,4S)-8-Benzyloxy-7-bromo-3,4-dihydro-4,5-dihydroxy-
1,3-dimethylbenzo[c]pyran 32
6ꢀ-H), 7.00 (1H, d, J 2.9 Hz, 4ꢀ-H) and 7.34–7.51 (5H, m, C6H5);
dC −4.5, (OSi(CH3)2C(CH3)3), 17.4 (OSi(CH3)2C(CH3)3), 18.2
Fresh neat titanium tetraisopropoxide (253 mg, 0.89 mmol) was
added to a solution of the crude (prior to chromatography)
ꢀ
(C-3), 23.7 (a -CH3), 25.6 (OSi(CH3)2C(CH3)3), 65.7 (C-1), 70.6
(C-2), 74.4 (C-a ), 75.6 (OCH2), 117.0 (C-3ꢀ), 117.5 (C-6ꢀ), 123.9
ꢀ
ꢀ
(a R,2R) phenolic aldehyde 25 (240 mg, 0.63 mmol) in dry di-
(C-4ꢀ), 128.5 (C-2ꢀꢀ and C-6ꢀꢀ), 128.7 (C-4ꢀꢀ), 129.0 (C-3ꢀꢀ and C-
5ꢀꢀ), 136.8 (C-1ꢀꢀ), 140.4 (C-1ꢀ), 146.9 (C-2ꢀ) and 152.7 (C-5ꢀ); m/z
496 [M+ (81Br), 4%], 494 [M+ (79Br), 4%], 421 (7), 419 (6), 330
(80), 328 (76%), 274 (15), 272 (15), 191 (18) and 91 (100).
chloromethane (15 cm3) at 0 ◦C, under an atmosphere of argon.
After standing for 10 min at 0 ◦C, the reaction mixture was son-
ically irradiated at 8–35 ◦C for 5 h, after which dichloromethane
(30 cm3) and saturated solutions of aqueous sodium fluoride
and ammonium chloride (60 cm3, 1 : 1) were added. The
mixture was stirred until the yellow colour had discharged.
The aqueous layer was extracted with dichloromethane and the
residue obtained upon work-up was rapidly chromatographed
(radial, 30–50% ethyl acetate–hexane) to give the potentially
(aꢀR,2R)-2-(2ꢀ-Benzyloxy-3ꢀ-bromo-5ꢀ-t-butyldimethylsilyloxy-
aꢀ-methybenzyloxy)propanal 24
To a solution of oxalyl chloride (453 mg, 3.57 mmol) in dry
dichloromethane (10 cm3) at 70 ◦C under an atmosphere of
2 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3

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unstable cyclised product 32 (180 mg, 75%) as white prisms
mp 149–150 ◦C (dichloromethane–hexane) [a]D −46.5 (c 1.0 in
CHCl3); (Found: M+, 378.0472. C18H19BrO4 requires M(79Br),
378.0466); tmax/cm−1 3450 and 3292 (OH) and 1581 and 1496
35% ethyl acetate–hexane) to afford the hydroquinone (115 mg)
as an oil. This was immediately dissolved in acetonitrile (10 cm3)
and cerium(IV) ammonium nitrate (420 mg, 0.762 mmol) in
water (4 cm3) was added drop-wise to the solution. After
stirring for 20 min the reaction was exhaustively extracted
with dichloromethane. The residue obtained upon work-up was
chromatographed (15–25% ethyl acetate–hexane) to give the
product 12 (95 mg, 84%), identical to that reported above.
=
(C C); dH 1.36 (3H, d, J 6.1 Hz, 3-CH3), 1.54 (3H, d, J 6.7 Hz,
1-CH3), 3.86 (1H, dq, J 6.1 and 8.7 Hz, 3-H), 4.20–5.20 (2H,
br s, 4- and 5-OH), 4.51 (1H, d, J 8.7 Hz, 4-H), 4.71 and 5.12
(each 1H, d, J 10.7 Hz, OCH2), 4.96 (1H, q, J 6.7 Hz, 1-H),
6.99 (1H, s, 6-H) and 7.34–7.48 (5H, m, C6H5); dC 18.3 (3-CH3),
19.8 (1-CH3), 67.3 (C-3), 69.0 (C-4), 70.7 (C-1), 75.0 (OCH2),
117.0 (C-8), 119.4 (C-6), 120.6 (C-7), 128.4 (C-2ꢀꢀ and C-6ꢀꢀ),
128.7 (C-4ꢀꢀ), 129.0 (C-3ꢀꢀ and C-5ꢀꢀ), 135.5 (C-1ꢀꢀ), 136.7 (C-8a),
144.4 (C-4a) and 152.9 (C-5); m/z 380 [M+ (81Br), 22%], 378 [M+
(79Br), 22%], 363 (17), 361 (20), 299 (42), 287 (17), 282 (14), 270
(77), 253 (30), 227 (96) and 148 (100).
(1R,3R,4S)-8-Benzyloxy-7-bromo-4-hydroxy-3,4-dihydro-1,3-
dimethyl-5-methoxybenzo[c]pyran 35
Diol 32 (450 mg, 1.19 mmol) in dry dimethylformamide (15 cm3)
was treated with an excess of potassium carbonate (819 mg,
5.93 mmol) and iodomethane (843 mg, 5.93 mmol) and the
mixture refluxed under an atmosphere of argon for 1 h. The
reaction mixture was then cooled, filtered, concentrated and
chromatographed (radial, 15% ethyl acetate—hexane) to give
the methylated product 35 as a light yellow oil (450 mg, 96%) [a]D
−47.7 (c 1.0 in CHCl3); (Found: C, 58.6; H, 5.45; M+, 392.0636.
C19H21BrO4 requires C, 58.15; H, 5.4%; M (79Br), 392.0623);
(1R,3R,4S)-7-Bromo-3,4-dihydro-4-hydroxy-1,3-dimethyl-
benzo[c]pyran-5,8-quinone 12 and (1R,3R,4S)-3,4-dihydro-4-
hydroxy-1,3-dimethylbenzo[c]pyran-5,8-quinone 58
A solution of the diol 32 (165 mg, 0.44 mmol) in dry ethyl
acetate (15 cm3) was stirred with 10% palladium on carbon
catalyst (165 mg) under a hydrogen atmosphere until one
molar equivalent had been consumed (1.5 h). The mixture was
filtered through Celite, concentrated and purified through rapid
chromatography (radial, 35% ethyl acetate–hexane) to afford
unstable hydroquinones 33 and 34 as an oily mixture (126 mg).
This was immediately dissolved in acetonitrile (15 cm3) and
cerium(IV) ammonium nitrate (342 mg, 0.62 mmol) in water
(3 cm3) was added drop-wise to the solution. After stirring for
20 min the reaction was quenched with water and exhaustively
extracted with dichloromethane. The residue obtained upon
work-up was chromatographed (radial, 15–25% ethyl acetate–
hexane) to give a mixture of the brominated quinone 12 and the
debrominated quinone 58, each as bright yellow crystals. The
product of higher Rf was identified as 12 (51 mg, 41%) mp 140–
tmax(film)/cm−1 3569 (OH) and 1580 and 1498 (C C); dH 1.35
=
(3H, d, J 6.2 Hz, 3-CH3), 1.59 (3H, d, J 6.6 Hz, 1-CH3), 3.64
(1H, d, J 2.5 Hz, OH), 3.86 (3H, s, OCH3), 3.96 (1H, dq, J 7.5
and 6.2 Hz, 3-H), 4.50 (1H, dd, J 2.5 and 7.5 Hz, 4-H), 4.75 and
5.12 (each 1H, d, J 10.8 Hz, OCH2), 4.96 (1H, q, J 6.6 Hz, 1-H),
7.01 (1H, s, 6-H) and 7.32–7.49 (5H, m, C6H5); dC 19.6 (3-CH3),
20.6 (1-CH3), 56.9 (OCH3), 68.4 (C-3), 68.7 (C-4), 69.1 (C-1),
75.7 (OCH2), 114.6 (C-6), 116.9 (C-8), 125.8 (C-7), 128.8 (C-4ꢀꢀ),
129.1 (C-2ꢀꢀ and C-6ꢀꢀ), 129.4 (C-3ꢀꢀ and C-5ꢀꢀ), 137.2 (C-1ꢀꢀ), 137.6
(C-8a), 146.3 (C-4a) and 155.4 (C-5); m/z 394 [M+ (81Br), 2%],
392 [M+ (79Br), 2%], 302 (10), 300 (10), 286 (8), 284 (8), 149 (19)
and 91 (100).
(1R,3R,4R)-8-Benzyloxy-7-bromo-3,4-dihydro-4-hydroxy-1,3-
dimethyl-5-methoxybenzo[c]pyran 36
◦
142 C (dichloromethane–hexane) [a]D −156 (c in 1.0 CHCl3);
(Found: C, 46.4; H, 3.95; M+, 285.9843. C11H11BrO4 requires C,
Phosphorus pentachloride (100 mg, 0.48 mmol) was added to a
stirred solution of compound 35 (94 mg, 0.24 mg), in dry diethyl
ether (10 cm3). The mixture was stirred for 10 min at room
temperature under an atmosphere of argon, then quenched with
water (20 cm3), extracted with diethyl ether and concentrated.
The residue obtained was immediately redissolved in acetonitrile
(10 cm3) and then deionised water (1 cm3) containing silver
nitrate (222 mg, 1.31 mmol) was added. The mixture was stirred
for a further 3.5 h at room temperature during which time a white
precipitate formed. The reaction mixture was extracted with
diethyl ether, dried, concentrated and chromatographed (radial,
15% ethyl acetate–hexane) to afford, first, starting material 35
(20 mg, 22%) followed by its C-4 epimeric alcohol 36 (67 mg,
72%) as white plates mp 81.5–82 ◦C (hexane–dichloromethane)
[a]D −50 (c 1.0 in CHCl3); (Found: C, 58.4; H, 5.1; M+, 392.0637.
C19H21BrO4 requires C, 58.15; H, 5.4%; M(79Br), 392.0623);
46.15; H, 3.9%; M(79Br), 285.9843); tmax/cm−1 3505 (OH), 1677
=
=
and 1652 (C O) and 1590 (C C); dH 1.37 (3H, d, J 6.2 Hz,
3-CH3), 1.54 (3H, d, J 6.8 Hz, 1-CH3), 3.43 (1H, d, J 2.6 Hz,
OH), 3.84 (1H, dq, J 6.2 and 7.7 Hz, 3-H), 4.35 (1H, ddd, J
1.4, 2.6 and 7.7 Hz, 4-H), 4.80 (1H, dq, J 1.4 and 6.8 Hz, 1-H)
and 7.27 (1H, s, 6-H); dC 18.8 (3-CH3), 19.2 (1-CH3), 67.5 (C-3),
67.6 (C-4), 67.8 (C-1), 138.1 (C-7), 138.3 (C-6), 139.7 (C-8a),
145.7 (C-4a), 178.7 (C-8) and 186.0 (C-5); m/z 270 [M+ − H2O
(81Br), 20%], 268 [M+ − H2O (79Br), 13%], 244 (100), 242 (98),
216 (40), 214 (41), 163 (12), 134 (23) and 107 (34). The product
of lower Rf was identified as 58 (15 mg, 17%) mp 95–97◦◦C
(dichloromethane–hexane) (Lit.9 for enantiomer 96.5–99.5 C)
[a]D −307.7 (c in 1.0 CHCl3) (Lit.9 for enantiomer +313.1 ◦);
(Found: C, 63.7; H, 6.2; (M + 2)+, 210.0879. C11H12O4 requires
C, 63.45; H, 5.8%; M, 210.0892); tmax/cm−1 3492 (OH) and 1650
tmax(film)/cm−1 3466 (OH) and 1577 and 1498 (C C); dH 1.38
=
(C O); dH 1.37 (3H, d, J 6.2 Hz, 3-CH3), 1.52 (3H, d, J 6.8 Hz,
=
1-CH3), 3.52 (1H, d, J 2.5 Hz, OH), 3.84 (1H, dq, J 7.8 and
6.2 Hz, 3-H), 4.35 (1H, ddd, J 1.6, 2.5 and 7.8 Hz, 4-H), 4.75
(1H, dq, J 1.6 and 6.8 Hz, 1-H) and 6.73 (2H, s, 6- and 7-H);
dC 18.8 (3-CH3), 19.3 (1-CH3), 67.2 (C-3), 67.3 (C-4), 67.6 (C-1),
136.8 (C-6), 137.3 (C-7), 138.3 (C-8a), 146.5 (C-4a), 186.3 (C-8)
and 188.8 (C-5); m/z 210 [(M + 2)+, 100%], 208 (12), 193 (74),
191 (20), 175 (32), 165 (11) and 147 (11).
(3H, d, J 6.4 Hz, 3-CH3), 1.51 (3H, d, J 6.7 Hz, 1-CH3), 2.13
(1H, br s, OH), 3.85 (3H, s, OCH3), 4.03 (1H, q, J 1.9 and 6.4 Hz,
3-H), 4.49 (1H, d, J 1.9 Hz, 4-H), 4.71 and 5.13 (each 1H, d, J
10.7 Hz, OCH2), 5.06 (1H, q, J 6.7 Hz, 1-H), 7.01 (1H, s, 6-H)
and 7.32–7.49 (5H, m, C6H5); dC 18.7 (3-CH3), 20.8 (1-CH3),
58.0 (OCH3), 64.1 (C-3), 68.0 (C-4), 71.1 (C-1), 76.9 (OCH2),
115.6 (C-6), 118.9 (C-7), 127.1 (C-8), 129. 9 (C-4ꢀꢀ), 130.2 (C-2ꢀꢀ
and C-6ꢀꢀ), 130.5 (C-3ꢀꢀ and C-5ꢀꢀ), 137.2 (C-1ꢀꢀ), 138.7 (C-8a),
147.3 (C-4a) and 156.3 (C-5); m/z 394 [M+ (81Br), 1%), 392 [M+
(79Br), 1%], 376 (3), 374 (3), 302 (8), 300 (8), 286 (17), 284 (17),
149 (36), 91 (100) and 65 (11).
(1R,3R,4S)-7-Bromo-3,4-dihydro-4-hydroxy-1,3-dimethyl-
benzo[c]pyran-5,8-quinone 12
A solution of the diol 32 (150 mg, 0.4 mmol) in dry tetrahy-
drofuran (8 cm3) was stirred with 10% palladium on carbon
catalyst (200 mg) at room temperature for 3 h and the mixture
was then hydrogenated until one mole equivalent of the gas had
been consumed (30–60 min). The mixture was filtered through
Celite, concentrated and then chromatographed rapidly (radial,
6,8-Dihydroxy-2-methyl-1,4-naphthoquinone 66
To a stirred solution of 2-bromo-6-methyl-1,4-benzoquinone
6527 (150 mg, 0.75 mmol) in dry tetrahydrofuran (10 cm3) at
0
◦C was added drop-wise a solution of the diene 11 (1.29 g,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3
2 7 1

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4.96 mmol) in tetrahydrofuran (5 cm3). The green coloured
mixture was stirred for 24 h during which time a bright yellow
solution was obtained. The reaction mixture was diluted with
dichloromethane (100 cm3) and the mixture poured into water
(150 cm3) and exhaustively extracted with dichloromethane. The
residue obtained upon work-up was chromatographed (radial,
30% ethyl acetate–hexane) and recrystallised (dichloromethane–
hexane) to give 66 (110 mg, 73%) as bright orange plates, mp 190◦
C (decomp.) (hexane). (Found: C, 64.15; H, 3.9; M,+ 204.0415.
C11H8O4 requires C, 64.7; H, 3.9%; M, 204.0422); tmax/cm−1 3405
the benzoquinone 12 into the naphthopyranquinone 1, to give
the product 5 (14 mg, 23%) as bright orange plates, mp 102–
103 ◦C (decomp.) (benzene) [a]D +260 (c 1.0 in 1% CH3CO2H–
CH3OH) (Lit.7 +278) (Found: (M − H)+, 289.0711. C15H14O6
requires (M − H), 289.0712); tmax/cm−1 3444 (OH), 1639 (C O)
=
=
and 1463 (C C); dH (acetone-d6) 1.31 (3H, d, J 6.3 Hz, 3-CH3),
1.56 (3H, d, J 6.5 Hz, 1-CH3), 3.20–3.60 (2H, br s, 4- and 7-OH),
3.64 (1H, dq, J 1.2 and 6.3 Hz, 3-H), 4.44 (1H, t, J 1.2 Hz, 4-H),
4.76 (1H, dq, J 1.2 and 6.5 Hz, 1-H), 6.62 (1H, d, J 2.3 Hz,
8-H), 7.10 (1H, d, J 2.3 Hz, 6-H) and 12.16 (1H, br s, 9-OH);
dC 17.0 (3-CH3), 21.8 (1-CH3), 62.4 (C-3), 70.6 (C-1), 73.1 (C-
4), 108.7 (C-8), 109.2 (C-6), 110.1 (C-4a), 135.3 (C-10a), 143.9
(C-5a), 148.6 (C-9a), 165.7 (C-7), 166.3 (C-9), 183.5 (C-5) and
189.5 (C-10).
=
=
(OH), 1637 and 1616 (C O) and 1490 (C C); dH (acetone-d6)
2.09 (3H, d, J 1.5 Hz, 2-CH3), 6.54 (1H, d, J 2.4 Hz, 7-H), 6.74
(1H, q, J 1.5 Hz, 3-H), 6.96 (1H, d, J 2.4 Hz, 5-H), 9.86 (1H,
br s, 6-OH) and 12.21 (1H, br s, 8-OH); dC 18.1 (2-CH3), 107.8
(C-8), 110.3 (C-5), 110.6 (C-3), 112.3 (C-8a), 138.6 (C-4a), 137.6
(C-7), 151.7 (C-2), 167.6 (C-6), 186.8 (C-1) and 192.0 (C-4); m/z
204 (M+, 64%), 149 (40), 91 (16) and 57 (100).
(1R,3S,4R)-3,4-Dihydro-4,7,9-trihydroxy-1,3-dimethyl-
naphtho[2,3-c]pyran-5,10-quinone 6
Bromoquinone 63 (84 mg, 0.29 mmol) was treated with the diene
11 (152 mg, 0.58 mmol), as described above for the conversion of
quinone 12 into quinone A 1, to give the naphthopyranquinone 6
(20 mg, 23%) as bright orange plates, mp 196–198 ◦C (decomp.)
(benzene) [a]D +550 (c 1.0 in 1% CH3CO2H–CH3OH) (Lit.,7
+568) Found: M+, 290.0815. C15H14O6 requires M, 290.0790;
(1R,3R,4S)-3,4-Dihydro-4,7,9-trihydroxy-1,3-dimethyl-
naphtho[2,3-c]pyran-5,10-quinone [Quinone A] 1
To a stirred solution of bromoquinone 12 (100 mg, 0.35 mmol)
in dry tetrahydrofuran (10 cm3) at 0 ◦C was added drop-wise a
solution of the diene 11 (181 mg, 0.70 mmol) in tetrahydrofuran
(5 cm3). The green coloured mixture was stirred for 24 h during
which time a bright yellow solution was obtained. The reaction
mixture was diluted with dichloromethane (100 cm3) and the
mixture poured into water (150 cm3) and exhaustively extracted
with dichloromethane. The residue obtained upon work-up
was chromatographed (radial, 30% ethyl acetate–hexane) and
recrystallised to give quinone A 1 (30 mg, 30%) as bright orange
plates, mp 200 ◦C (decomp.) (benzene) (Lit.,1 200 ◦C) [a]D +40
(c 1.0 in 1% CH3CO2H–CH3OH) (Lit.7 +41) (Found: C, 61.75;
H, 4.4; (M − H)+, 289.0702. C15H14O6 requires C, 62.05; H,
tmax/cm−1 3492 and 3222 (OH), 1631 (C O) and 1497 (C C);
dH (acetone-d6) 1.15 (3H, d, J 6.2 Hz, 3-CH3), 1.31 (3H, d, J
6.6 Hz, 1-CH3), 2.60–2.80 (1H, br s, 4-OH), 3.23 (1H, dq, J 6.2
and 8.2 Hz, 3-H), 4.15–4.30 (1H, br s, 7-OH), 4.18 (1H, dd, J
2.5 and 8.2 Hz, 4-H), 4.60 (1H, dq, J 2.5 and 6.6 Hz, 1-H), 6.42
(1H, d, J 2.3 Hz, 8-H), 6.87 (1H, d, J 2.3 Hz, 6-H) and 11.92
(1H, br s, 9-OH); dC 21.1 (3-CH3), 23.8 (1-CH3), 68.6 (C-3), 71.1
(C-1), 74.3 (C-4), 111.0 (C-8), 111.3 (C-6), 127.3 (C-4a), 137.4
(C-10a), 147.5 (C-5a), 150.7 (C-9a), 167.7 (C-7), 168.1 (C-9),
187.6 (C-5) and 191.1 (C-10).
=
=
4.85%; (M − H), 289.0712); tmax/cm−1 3402 (OH), 1641 (C O)
=
=
and 1552 (C C); dH (acetone-d6) 1.09 (3H, d, J 6.3 Hz, 3-CH3),
Acknowledgements
1.36 (3H, d, J 6.8 Hz, 1-CH3), 2.60–2.70 (1H, br s, 4-OH), 3.66
(1H, dq, J 6.3 and 7.2 Hz, 3-H), 4.00–4.10 (1H, br s, 7-OH),
4.15 (1H, dd, J 1.2 and 7.2 Hz, 4-H), 4.61 (1H, dq, J 1.2 and
6.8 Hz, 1-H), 6.40 (1H, d, J 2.4 Hz, 8-H), 6.85 (1H, d, J 2.4 Hz,
6-H) and 11.89 (1H, s, 9-OH); dC 18.5 (3-CH3), 19.5 (1-CH3),
66.9 (C-3), 67.2 (C-1), 69.0 (C-4), 108.4 (C-8), 108.9 (C-6), 126.8
(C-4a), 135.0 (C-10a), 142.5 (C-5a), 148.5 (C-9a), 165.3 (C-7),
165.7 (C-9), 185.0 (C-5) and 188.0 (C-10).
The authors wish to thank Professor D. W. Cameron both
for the very generous provision of his hitherto unpublished
research results that have been referred to and acknowledged
in this text and also for samples of naturally derived quinone A
and quinone Aꢀ. Financial support is gratefully acknowledged
from the Australian Research Council, the Senate of Murdoch
University and (for I. R. G.) the Council of the University of
the Western Cape. Murdoch University Research Scholarships
were provided (to R. A., F. J. O. and C. P. T.).
(1R,3R,4R)-3,4-Dihydro-4,7,9-trihydroxy-1,3-dimethyl-
naphtho[2,3-c]pyran-5,10-quinone [Quinone Aꢀ] 2
Bromoquinone 59 (100 mg, 0.35 mmol) was treated with the
diene 11 (181 mg, 0.70 mmol), as described above for the
conversion of 12 to the naphthoquinone 1, to give quinone Aꢀ
References
1 D. W. Cameron, R. I. T. Cromartie, D. G. I. Kingston and A. R.
Todd, J. Chem. Soc., 1964, 51.
2 H. W. Moore, Science, 1977, 197, 527.
3 D. W. Cameron and H. W.-S. Chan, J. Chem. Soc. (C), 1966, 1825.
4 J. F. Elsworth, R. G. F. Giles, I. R. Green, J. E. Ramdohr and S. C.
Yorke, J. Chem. Soc., Perkin Trans. 1, 1988, 2469.
5 R. G. F. Giles and I. R. Green, Synth. Commun., 1996, 26, 3161.
6 R. G. F. Giles, I. R. Green, F. J. Oosthuizen and C. P. Taylor,
Tetrahedron Lett., 2001, 42, 5753.
7 (a) H. J. Banks and D. W. Cameron, unpublished results; (b) D. W.
Cameron, personal communication.
8 D. W. Cameron and J. C. A. Craik, J. Chem. Soc. (C), 1968, 3068.
9 R. G. F. Giles and C. A. Joll, J. Chem. Soc., Perkin Trans. 1, 1999,
3039.
10 (a) J. Banville and P. Brassard, J. Chem. Soc., Perkin Trans. 1, 1976,
1852; (b) D. W. Cameron, G. I. Feutrill and D. J. Hodder, J. Chem.
Soc., Chem. Commun., 1978, 688; (c) J. Savard and P. Brassard,
Tetrahedron Lett., 1979, 4911; (d) D. W. Cameron, C. Conn and
G. I. Feutrill, Aust. J. Chem., 1981, 34, 1945.
11 R. G. F. Giles, I. R. Green, F. J. Oosthuizen and C. P. Taylor,
ARKIVOC, 2002, (ix), 99.
12 J. Birch and V. H. Powell, Tetrahedron Lett., 1970, 3467.
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◦
2 (20 mg, 20%) as bright orange plates, mp 234 C (decomp.)
(benzene) (Lit.,1 236 ◦C) [a]D +262 (c 1.0 in 1% CH3CO2H–
CH3OH) (Lit.,7 +258) (Found: C, 62.4; H, 5.05; (M − H)+,
289.0724. C15H14O6 requires C, 62.05; H, 4.85%; (M − H),
289.0712); tmax/cm−1 3438 (OH) and 1643 (C O); dH (acetone-
=
d6) 1.11 (3H, d, J 6.3 Hz, 3-CH3), 1.35 (3H, d, J 6.8 Hz, 1-CH3),
2.64–2.80 (2H, br s, 4- and 7-OH), 3.84 (1H, dq, J 1.9 and 6.3 Hz,
3-H), 4.41 (1H, d, J 1.9 Hz, 4-H), 4.75 (1H, q, J 6.8 Hz, 1-H),
6.48 (1H, d, J 2.4 Hz, 8-H), 6.98 (1H, d, J 2.4 Hz, 6-H) and 12.05
(1H, br s, 9-OH); dC 16.7 (3-CH3), 18.5 (1-CH3), 61.6 (C-3), 68.0
(C-1), 68.3 (C-4), 108.4 (C-8), 109.5 (C-6), 110.1 (C-4a), 135.2
(C-10a), 142.53 (C-5a), 148.2 (C-9a), 165.8 (C-7), 166.7 (C-9),
183.8 (C-5) and 188.6 (C-10); m/z 290 (M,+ 20%), 275 (13), 183
(100) and 90 (22).
(1R,3S,4S)-3,4-Dihydro-4,7,9-trihydroxy-1,3-dimethyl-
naphtho[2,3-c]pyran-5,10-quinone 5
Bromoquinone 61 (60 mg, 0.21 mmol) was treated with the diene
11 (108 mg, 0.42 mmol), as described above for the conversion of
2 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3

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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 6 3 – 2 7 3
2 7 3